Delivery of high-quality survivorship care to the growing population of cancer survivors in the United States is often predicated on a mixture of individual provider and survivor factors such as awareness of guidelines and health knowledge risk perception.1–3 Therefore, it is critical to regularly consider commonly held beliefs to assess whether these principles support the best possible outcomes for cancer survivors, with outcomes defined as the results or effects of survivorship care that are most meaningful to each survivor. Commonly held beliefs may create barriers to the advancement of cancer survivorship research by discouraging researchers from proposing hypotheses, developing studies, or receiving grant funding for ideas that contradict assumptions.
With that in mind, examining myths (beliefs held to be true despite refuting evidence) and presumptions (beliefs held to be true for which convincing evidence does not yet confirm or disprove their truth) to establish an evidence base is necessary. Casazza et al previously published on myths and presumptions about obesity, examining the lack of evidence underlying beliefs in this field such as setting realistic goals in obesity treatment is important because otherwise patients will become frustrated and lose less weight (a myth) and regularly eating (versus skipping) breakfast is protective against obesity (a presumption). Drawing on the framework of Casazza et al,4 we have identified several cancer survivorship myths and presumptions which may be perpetuated in survivorship circles and thereby limit efforts to improve cancer survivorship research and care.
Myth: Shared Care Results in the Best Outcomes for Cancer Survivors
Shared care is a term that describes deliberate efforts to coordinate components of survivorship care between specialty and primary care providers (PCPs), practice settings, or electronic health records (EHRs). Multiple reports and manuscripts recommend shared care as the preferred model for survivorship care,5–7 starting with the Lost in Transition report calling for coordination between specialists and PCPs.8 However, available data challenge the belief that shared care is superior to PCP or oncology-led care in several ways.
First, the terminology for and definitions of shared care in published studies vary widely. In noncancer settings, shared care is defined as a treatment approach integrating primary- and tertiary-level care. None of the identified survivorship studies in a recent systematic review, however, adhered to the definition of shared care, and few studies had documented interprofessional collaboration.9–11 Other survivorship research used the label shared care despite a focus on one clinical specialty. For example, in a Dutch study of a shared care intervention for survivors age 70 years and older after colorectal cancer surgery, general practitioners (GPs) scored patients’ frailty and health status at multiple time points postdischarge and decided whether interventions were needed; oncology team members were available to answer questions but are not described as otherwise regularly participating in survivors’ care.12 Similarly, a retrospective analysis classified survivors as having received shared care on the basis of receiving at least one visit with an oncologist and at least one visit with a generalist within the study time period.13 Yet, it is unlikely that care provided by an oncologist including a single generalist visit or care by a generalist with a single oncologist visit truly represents shared care.
Notwithstanding the differences in definition and measurement, studies of shared care for cancer survivors have reported mixed results. In a study comparing shared care to usual care among 88 Australian men with low- to moderate-risk prostate cancer, shared care was associated with significantly lower costs; these cost differences were largely driven by replacing hospital-based outpatient visits with GP visits. However, there were no differences in distress score, prostate-specific quality of life, patient satisfaction, or unmet needs.14 In a recent scoping review, Mobley et al15 identified four studies reporting on the use of shared care models for childhood cancer survivors. Of these four studies, one reported that shared care resulted in increased adherence to follow-up care, another resulted in lower adherence to guideline-recommended care, and the remaining two produced improvements in different outcomes. A systematic review of the effectiveness of shared care, including eight randomized controlled trials and three descriptive studies, found few or no significant differences between shared care and usual care in survivor quality of life, mental health, performance status, unmet needs, or serious clinical events.16 An overview of systematic reviews by Chan et al17 found few differences in multiple survivorship care outcomes for shared care versus other models, including no reduction in patient or health care system costs.
Two recent publications reported no relationship between physician specialty or the number of follow-up providers and survivor satisfaction or quality of life.18,19 Weaver et al20 found that long-term survivors in shared care reported similar levels of high-quality cancer-related follow-up as did those receiving care from oncologists or PCPs. Doose et al21 found that shared care was not associated with differences in patient-reported quality of cancer care, defined as receipt of necessary medical care, instructions for routine care, and a written cancer treatment summary. A recent study that classified shared care using Medicare claims data to estimate the proportion of oncologist or PCP outpatient visits found no differences in patient-reported experiences for shared care and oncologist-led or PCP-led survivorship care patterns.22
Previous studies suggest that cancer survivors prefer oncology-led survivorship care to PCP-led care.11,23–29 A study of survivors with early-stage breast cancer recruited from an academic center in Toronto found that 93% were satisfied with specialist follow-up care versus 54% with shared care.30 An earlier study of thyroid cancer survivors from a Toronto academic center reported similar results: 90.6% were satisfied with specialist care versus 67.5% with shared care.31 However, one study of survivors with advanced cancer receiving care at teaching hospital-based cancer clinics found that greater PCP involvement was associated with significantly greater patient satisfaction.32 It is possible that shared care will be shown to improve outcomes for specific groups of cancer survivors. However, currently available evidence suggests that the superiority of shared care is a myth.
Presumption: Primary Care Physicians Feel Unable to Provide Survivorship Care
One potential barrier for transition of cancer survivors to primary care settings is the belief that PCPs feel unable to provide high-quality survivorship care.33 This presumption has persisted despite a randomized control trial, published more than 15 years ago, indicating that PCPs perform as well or better than oncology clinicians in caring for early-stage breast cancer survivors.34
Available evidence suggests that PCPs experience challenges in this area, particularly in addressing certain cancer-related care needs.35,36 In a survey of 227 PCPs, most believed that guidelines for cancer survivors are not well defined and about half felt inadequately prepared to deliver high-quality care.37 McDonough et al surveyed 117 PCPs associated with an academic medical center. Although most PCPs were engaged in survivorship care, including 94% managing psychological sequelae of cancer and 84% managing chronic physical complications, 65% felt unprepared to screen for late complications and 36% felt unprepared to screen for recurrence.38 In another survey of PCPs focused on care for head and neck cancer survivors, fewer than one-third indicated they were confident that they could manage late/long-term symptoms or provide appropriate cancer screening.39 A 2016 systematic review reported that approximately half of surveyed PCPs felt unprepared to manage long-term side effects or conduct surveillance for recurrence.36 Based on survey responses, PCPs were less aware of the side effects of several frequently used chemotherapy agents than oncologists.40
At the same time, a number of studies also suggest that PCPs are both willing and able providers of survivorship care.41 In a recent survey of a larger number of PCPs, most believed that they were better able to perform breast and colorectal cancer follow-up, detect recurrent cancers, and offer psychosocial support than their oncology peers.42 Stephens et al43 reported that only 28% were not confident in managing late effects of treatment and only 4% were not confident in addressing chronic comorbidities. In a larger survey of PCPs at a safety net health network being somewhat or very confident in knowledge regarding surveillance testing for breast and colorectal cancer survivors was very common (64% and 72%, respectively), as was being somewhat or very confident in managing late/long-term effects or adverse psychosocial outcomes.44 Other studies have reported similarly levels of confidence among PCPs in providing care for cancer survivors.33,45
Recent data from a national survey indicate that approximately two thirds of cancer survivors received most of their health care from PCPs, either family medicine physicians or general internists.46
Thus, the available evidence related to delivery of survivorship care by PCPs is mixed. PCPs express confidence in their skills to care for cancer survivors, particularly for survivors of more common cancers, and most survivors receive their care from PCPs. However, PCPs may also lack survivorship-specific knowledge regarding management of long-term symptoms and appropriate surveillance.
Myth: Oncology Providers Are Hesitant to Transition Survivors to Primary Care
Some studies suggest that oncologists enjoy taking care of survivors who have completed treatment.35,47 A recently published evaluation of survivorship care stakeholders reported that oncologists were concerned that transitioning patients to PCP survivorship specialists would take away their patient population that brings joy to medicine.47 In that study, one stakeholder noted that substituting diagnostic and treatment visits for survivorship visits in the clinic schedule could cause “burnout… seeing those survivorship types (is) easier. I mean… it’s just an easier 20-minute visit than a complicated metastatic disease conversation.” Other research indicates that oncologists have a high level of confidence in their knowledge about survivorship follow-up care components.33
Yet, evidence suggests that oncology providers have less positive attitudes toward survivorship care. In one study of Australian medical and radiation oncologists providing breast cancer survivorship care, most felt that the clinical time they spent on breast cancer survivorship was about right; only 3% and 7%,respectively, wanted to spend more time while 15% and 27%, respectively, wanted to spend less time.48
Oncologists’ concerns about transitioning survivors to primary care may be more patient-focused than provider-focused. In a survey of 39 medical oncologists, concern about survivor anxiety was cited as key to decisions about care transition while reimbursement and the longitudinal nature of the provider-patient relationship were reportedly not relevant.49 The perception of survivor anxiety about transition away from oncology has been documented.35,50
At the same time, the large number of cancer survivors followed in primary care settings suggests that oncologists may already care for survivors who are seen by primary care. Using SEER-Medicare data, Snyder et al51 found that in the first year after the end of active treatment, 81.0% of colorectal cancer survivors had a visit with a PCP and 51.6% had a visit with an oncologist. During the fifth year after the end of active treatment, 82.5% had a visit with a PCP while only 24.9% had a visit with an oncologist. The mean number of PCP visits increased from 4.2 in year 1 to 4.7 in year 5 while the mean number of oncologist visits decreased from 1.3 in year 1 to 0.5 in year 5.52 In the Australian survey cited earlier, 68% of medical oncologists and 70% of radiation oncologists had discharged their breast cancer survivors by 10 years after diagnosis.48 Similarly, a survey of Canadian radiation oncologists reported that 55% followed cancer survivors for ≤5 years while 36% followed survivors for 5-10 years, with decreasing visit frequency over time.53
Therefore, the available evidence suggests that the belief that oncologists are hesitant to transition survivors to primary care is a myth. Although many oncologists report enjoying survivorship care, most are not creating barriers to transition but are seeing survivors less often as time from diagnosis increases.
Presumption: Survivorship Clinics Lose Money
In oncology clinical settings, survivorship care may be perceived as insolvent or unprofitable. One recent article called survivorship care a non–revenue-generating service.6 In fact, few studies provide details of reimbursement for survivorship visits, although a growing literature describes barriers to adequate reimbursement for managing physical, social, and emotional side effects or care coordination.6,54–57 A recent publication included a quote from a cancer center key informant that, “we’re not able to get insurers to pay for survivorship visits”; this comment was later clarified as focusing on the lack of reimbursement for preparing treatment summaries and care plans.55 Similarly, a study describing survivorship clinics in Wisconsin suggested that mental health services, exercise/lifestyle services, sexual health, and fertility counseling were underrepresented at survivorship clinics because of lack of adequate insurance coverage of these services.57 Yet, profit or reimbursement was not directly evaluated.
Few economic analyses of cancer survivorship program have been performed58; those available suggest that revenues generated by survivorship care programs likely cover or exceed the costs of the programs.59–61 For example, Rosales et al reported that the staff expense per survivorship care visit was $141.73 US dollars (USD), and the average reimbursement per visit was $150.69 USD.59 One recent study of a childhood cancer survivor program emphasized lost profit opportunity, that is, the lost opportunity for reimbursement when survivors are not adherent to screening recommendations.62 Finally, a study suggesting that operating expenses of a clinic for childhood cancer survivors may exceed revenue also acknowledged that full revenues such as those from subspecialty referrals were not included.63 While not economic analyses, other reports have described cancer survivorship services that are reimbursable. These include group wellness program64 and rehabilitation services.65
At the same time, revenue may be lower for survivorship than cancer treatment-related care. Survivorship clinical services may be reimbursed on the basis of evaluation and management codes, whereas reimbursement for those in treatment may include technical codes as well.66 Overall, given the limited evidence on the economics of survivorship care, the belief that survivorship clinics lose money is a presumption.
Presumption: Shared Electronic Health Records Can Address Survivorship Care Coordination Challenges
In the 2018 National Academies of Sciences, Engineering, and Medicine publication Long-term survivorship care after cancer treatment: Proceedings of a workshop, an introductory lecture by Dr Patricia Ganz describes her optimism that advances in the EHR will improve communication and facilitate high-quality survivorship care.67
Although this presumption has been inadequately tested, current evidence regarding whether a shared EHR improves survivorship care coordination is mixed. Importantly, most studies of the EHR for cancer survivors focus on the capacity of an EHR to facilitate creation of a survivorship care plan (SCP).68 Although consolidation and transfer of diagnostic and treatment information may increase PCP or survivor knowledge,69 it is not clear that this results in improved care.70 For example, a study of PCPs found that they thought an EHR-generated SCP was useful for care coordination and appreciated receiving SCP information via the EHR.71 Recently, efforts to create online tools for survivors to generate SCPs have been described.72,73 Potentially, survivors could use a personal health record to share health history, test results, and recommendations between providers. Whether this strategy will improve care or survivor outcomes is still being tested. Furthermore, access to these tools and capacity to use them are likely barriers to their widespread success in fostering care coordination.
The potential benefits of EHRs extend beyond creating SCPs to increasing care coordination or reducing service duplication. However, Klabunde et al74 found that less than one quarter of oncologists reported using EHRs or email to communicate with PCPs, and use of an integrated EHR by oncologists was not associated with greater engagement with PCPs. These researchers suggested that lack of interoperability of EHR systems may impede communication. Interviews with oncologists also suggest that EHRs do not adequately support teamwork of oncology providers, with particular concerns regarding information overload, missing information, and lack of feedback or acknowledgment to close the loop.75 The modular design of EHRs may also create barriers for PCPs to access information from oncologists.76 Overall, there has been little research on whether use of shared or integrated EHRs improves survivorship care.
Given the limited evidence regarding the effectiveness of shared electronic medical records to improve survivorship care or outcomes, the belief that these record systems can address care coordination challenges is a presumption.
Discussion
The purpose of this work was to identify a set of commonly held beliefs regarding survivorship care and examine available evidence to support or refute these beliefs, that is, to assess whether these beliefs are well-founded claims on the basis of available data, presumptions without evidence to confirm or disprove their truth, or myths contradicted by available evidence. We believe that myths and presumptions in survivorship may cause harm. Widely held beliefs may create barriers that discourage survivorship research, ranging from limits on proposing hypotheses to developing research collaboration or studies as well as preparing grant applications or receiving less favorable review scores on applications. Health care administrators and clinical leadership may propagate these beliefs to the detriment of survivors, clinical programs, and providers. Notably, this work focuses on adult cancer survivors but includes a small number of childhood cancer survivorship studies. As the literature base grows, future investigations may be able to examine these populations separately.
This study identified two myths: shared care is preferred, and oncology providers are hesitant to transition survivors to PCP-led care and three presumptions: PCPs feel unable to care for survivors, survivorship clinics lose money, and shared EHRs will eliminate care coordination barriers. These myths and presumptions represent opportunities to research new ways to improve survivorship care. For example, acknowledging that the belief that survivorship clinics lose money is a presumption (and not supported by available evidence) can prompt further studies of the cost of survivorship care and the organizational policies or procedures that may create barriers to its provision. As survivorship science evolves with the growth in the number of survivors, new and novel treatments, and increased length of survival, it is even more essential for survivorship researchers and clinicians to question and challenge such beliefs about survivorship care. Doing so will promote the development of credible evidence on the most effective ways to deliver timely and high-quality care that is affordable, accessible, and patient-centered.77
Furthermore, it is likely that there is not a single optimal approach or best venue for survivorship care. Rather, survivorship care needs to be tailored to cancer diagnosis, treatment, and risk for late effects, as well as local resources and individual survivor preferences. A critical research problem is, therefore, to determine which care delivery models (or model components) result in the best outcomes for specific groups of survivors, in specific care settings with real-world constraints on financial and other resources. This problem raises an even greater need to identify the myths and presumptions that limit the range of research questions and need to be challenged to advance research to improve the lives of cancer survivors.
Pancreatic cancer remains among the malignancies with the worst outcomes. Survival has been improving, but at a slower rate than other cancers. Multimodal treatment, including chemotherapy, surgical resection, and radiotherapy, has been under investigation for many years. Because of the anatomical characteristics of the pancreas, more emphasis on treatment selection has been placed on local extension into major vessels. Recently, the development of more effective treatment regimens has opened up new treatment strategies, but urgent research questions have also become apparent. This review outlines the current management of pancreatic cancer, and the recent advances in its treatment. The review discusses future treatment pathways aimed at integrating novel findings of translational and clinical research.
Introduction
Pancreatic cancer has been considered a deadly disease with a very small probability of long term survival.1 Despite slow progress, long term survival rates have greatly improved, especially for resected patients. From 1975 to 2011, the five year survival for resected pancreatic cancer improved from 1.5% to 17.4%.2 However, more recent data show that five year survival for all pancreatic cancers between 2012-18 reached only 11.5% in the United States.3
As a systemic disease, the changes in the survival of patients with pancreatic cancer have been affected most by the improvements in systemic treatments.45 Consequently, the anatomical factors influencing the resectability of pancreatic cancer, which are defined in the National Comprehensive Cancer Network (NCCN) clinical practice guidelines,6 have diminished in importance owing to better local and systemic control with higher response rates.
This review summarizes and contextualizes recent studies on the management of pancreatic cancer, and discusses potential treatments that are on the horizon. A detailed discussion of the preclinical or translational studies of diagnosis tools, drugs, and procedures is outside the scope of this review.
Sources and selection criteria
We searched Pubmed, the Cochrane database, and the Central Register of Controlled Trials (clinicaltrials.gov) between January 2000 and December 2022 for English language literature. We used the following keywords and keywords combinations: “pancreatic cancer”, “molecular characteristics”, “biology”, “resectability”, “metastatic”, “treatment”, “surgery”, “chemotherapy”, “radiation therapy”, “immunotherapy”, “prevention”, “precursor”, and “risk factor”. We also included the NCCN clinical practice guidelines,6 the European Society for Medical Oncology (ESMO) clinical practice guidelines,7 and the clinical practice guidelines from the Japan Pancreas Society.8 We included studies based on the level of evidence; randomized controlled trials, meta-analyses, systematic reviews, and large retrospective cohort studies were prioritized. Meta-analyses included retrospective and prospective studies unless otherwise specified. We prioritized the most recent studies and excluded narrative reviews, case series, and case reports. We included additional landmark studies published before January 2000, as well as after December 2022.
Epidemiology
Pancreatic cancer is reported to account for 495 773 new cases and 466 003 deaths worldwide as of 2020, with the incidence and mortality rates stable or slightly increased in many countries.9 In the US, the estimated incidence of pancreatic cancer is increasing, with more than 50 000 new cases in 2020. Mortality rates have also increased moderately in men, to 12.7 per 100 000 men in 2020; but have remained stable in women, ranging from 9.3 to 9.6 per 100 000 women. Accordingly, pancreatic cancer is the third most common cause of cancer related death in 2023, and is predicted to become the second leading cause of cancer mortality by 2040.310
Clinical presentation/features
Symptoms of pancreatic cancer are mostly non-specific, and generally manifest after the tumor has grown and metastasized. In a multicenter prospective study of 391 patients who were referred for suspicion of pancreatic cancer (119 had pancreatic cancer), the most common initial symptoms were decreased appetite (28%), indigestion (27%), and change in bowel habits (27%).11 The initial symptoms were similar between the pancreatic cancer group and the non-cancer group, though several subsequent symptoms were associated with pancreatic cancer: jaundice (49% v 12%), fatigue (51% v 26%), decreased appetite (48% v 26%), weight loss (55% v 22%), and change in bowel habits (41% v 16%).
Risk factors
Box 1 summarizes the risk factors for pancreatic cancer. Research is continuing into subtypes and modifiers of familial syndromes.
Box 1
Factors that increase the risk of pancreatic cancer
Family history
Up to 10% of all pancreatic cancers are estimated to be familial (meaning that at least two first degree relatives have pancreatic cancer)
Patients who have two first degree relatives with pancreatic cancer have a standardized incidence ratio of 6.4 (lifetime risk 8-12%)12
Patients who have three first degree relatives with pancreatic cancer have a standardized incidence ratio of 32.0 (lifetime risk 40%)12
Approximately 20% of these families have a germline mutation that is already reported and known
*Diabetes mellitus is also a symptom of pancreatic cancer; new onset diabetes in older people could be an early sign of pancreatic cancer and can lead to early diagnosis.22 The association between diabetes and pancreatic cancer is currently undergoing further research.23
Molecular research has proposed two evolutionary models of pancreatic cancer: the classic “stepwise” model, with gradual accumulation of driver gene mutations, and the novel “punctuated” model,24 in which driver gene mutation occurs simultaneously by chromosomal rearrangements. The stepwise model is characterized by tumor evolution from a precancerous lesion (low grade or high grade dysplasia) to invasive cancer, and is believed to be the main evolutionary pattern. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs) are well known precancerous lesions. By contrast to PanIN, which is a microscopic neoplastic lesion, IPMNs can be detected and followed by imaging studies. Consequently, extensive studies have been conducted to evaluate the association between imaging findings and pathological findings of IPMNs. Branch duct IPMNs have been reported to have a low malignant nature (1.0% patient years),25 but harbor a risk of concomitant pancreatic cancer (0.8%).26 Main duct IPMNs have been reported to be a high risk factor for pancreatic cancer (odds ratio 5.66).27
Screening and early detection
Because early stage (ie, stage I, T1N0M0) disease or precancerous lesions are more likely to be curable, the goal of screening or surveillance for pancreatic cancer is to detect lesions of 2 cm or smaller, or patients with high grade dysplasia.28 Several studies have estimated an interval of several years between a high grade dysplasia lesion (high grade PanIN and IPMN) and invasive cancer, which can give opportunities for early detection and intervention: 2.3-11 years for high grade PanIN,2930 and more than three years for high grade IPMN.31 The International Cancer of the Pancreas Screening (CAPS) consortium has published consensus guidelines about screening for high risk patients who have high risk germline mutations or relatives with pancreatic cancer, or both.28 A recent prospective cohort study (CAPS5) from the CAPS group including 1461 high risk patients showed positive results of surveillance25; seven of nine patients (77.8%) who developed pancreatic cancer had stage I cancer. However, only three of the eight patients (37.5%) who had IPMNs with worrisome features had high grade dysplasia (five had low grade dysplasia). A multicenter retrospective study (n=2552) of the CAPS consortium showed that 13 of the 28 patients (46.4%) who developed high grade dysplasia or cancer developed the new lesion during the scheduled examination interval.32 Regarding IPMNs in the general population, a recent retrospective study showed that only 177 of 1439 patients with resected IPMN (12.3%) had high grade dysplasia, and 497 (34.5%) had a diagnosis of invasive cancer.33 These results suggest that a novel strategy distinct from current guidelines3435 is needed for IPMN lesions, and new diagnostic tests are needed to detect tiny tumors.
The United States Preventive Services Task Force (USPSTF)36 recommends avoiding pancreatic cancer screening in asymptomatic adults with average risk, considering the relatively low prevalence (estimated 64 050 new cases in 2023).36 However, the USPSTF does not discuss screening in patients with risk factors of age and lifestyle, and neither do the consensus guidelines of the CAPS consortium. A risk assessment model including all known risk factors (box 1) could help to identify good candidates for pancreatic cancer screening.
Carbohydrate antigen 19-9 (CA19-9) is a cell surface tetrasaccharide often elevated in pancreatic cancer, as well as in other cancers and some benign diseases. Historically, CA19-9 has not been used for early detection, owing to its insufficient sensitivity for early stage pancreatic cancer.37 We also know that 5-10% of the population does not synthesize CA19-9, owing to a deficiency of a fucosyltransferase enzyme. However, a recent large retrospective cohort study showed that CA19-9 levels increase from two years before diagnosis of pancreatic cancer, with a sensitivity of 50% and specificity of 99% within 0-6 months before diagnosis in early stage disease. In addition, in cases with CA19-9 levels below the cut-off value, the combination of LRG1 and TIMP1 could complement CA19-9, leading to the identification of cases missed by CA19-9 alone.38 Novel tests (ie, cytology39 and DNA alterations40) using pancreatic juice and cystic fluid have been reported to play a promising role in identifying high grade dysplasia and invasive cancer with high specificity. However, the sensitivity of these tests is low (˂50%). Extensive studies have investigated the role of liquid biopsy in pancreatic cancer: circulating tumor cells,41 circulating tumor DNA,4243 microRNA,44 exosomes,45 and methylation signatures of cell free DNA.46 Although these new biomarkers show promise, many problems remain unsolved with regard to standardization of testing techniques and cut-off values (table 1). However, advances in this field could increase survival drastically.
Table 1
Summary of novel techniques for diagnosis and early detection of pancreatic cancer
CT (computed tomography) is the standard tool to evaluate the extent of the primary tumor and determine its anatomical resectability. Two meta-analyses showed similar performance of CT (sensitivity 70%, specificity 95%) and MRI (magnetic resonance imaging) (sensitivity 65%, specificity 95%) in the diagnosis of vascular involvement.5051 A meta-analysis showed that endoscopic ultrasound performed similarly to CT in evaluating vascular invasion.52 A multimodal approach (ie, CT plus MRI plus endoscopic ultrasound) provides a better assessment of resectability. Several studies have attempted to evaluate the response to chemotherapy with imaging studies to determine the course of treatment (ie, proceeding to surgery or continuing chemotherapy). However, the currently used response evaluation criteria in solid tumors (RECIST) are not sufficient to reassess local response after chemotherapy in pancreatic cancer, especially regarding the involvement of vessels. Distinguishing scar areas with fibrosis that occur with treatment from cancer cell death from viable tumor associated desmoplasia is challenging; both are common in pancreatic cancer. A meta-analysis including six studies with 217 patients showed the difficulty of using CT scans to predict margin negative resection after preoperative treatment; the sensitivity was 81% and specificity was as low as 42%.53 MRI5455 and fluorodeoxyglucose PET (positron emission tomography)/CT or PET/MRI56 have been reported to be associated with the pathological response to preoperative treatment, though the ability to evaluate the vessel involvement and resectability is unclear. However, it should also be noted that even in the setting of histological response assessment, moderate inter-rater reliability differences have been reported between pathologists.57
Biomarker for evaluation
CA19-9 has been used to assess response to treatment and predict prognosis. A meta-analysis showed that CA19-9 was associated with the effect of preoperative treatment, and suggested that either normalization of CA19-9 or a decrease of more than 50% from the baseline level are positive predictors of survival.58 A recent retrospective study analyzing the combination of CT and CA19-9 showed a good predictive performance of survival after chemoradiotherapy.59 However, the optimal evaluation of response to treatment remains unclear. The ability of liquid biopsy (table 1) to detect minimal residual disease following all planned treatment could identify a new subset of patients who require further treatment, and would lead to a true precision medicine approach, as has been achieved with other cancer types.60
Cancer cell intrinsic and tumor microenvironment factor
Transcriptional studies have proposed several classifications of pancreatic cancer. A recent bioinformatic study61 from The Cancer Genome Atlas research network supported the two subgroup model62: the basal-like subtype, which has low levels of GATA6 expression, and the classic subtype. In a prospective translational trial, the basal-like subtype was reported to be associated with a poor response to chemotherapy with FOLFIRINOX (combined leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin) for patients with advanced cancer.63 However, a more recent study using single cell analysis suggested that pancreatic cancer consists of a mixture of tumor cells with both molecular subtypes, and the composition is plastic and unstable.64
In addition to the cancer cells themselves, the tumor microenvironment has been identified as being an essential factor associated with tumor progressions and tumor immunity. Pancreatic cancer is notorious for poor tumor cellularity and an abundant, fibrotic extracellular matrix. Although the dense extracellular matrix has been known to impair drug delivery and immune cell migration, it appears to have an essential role in maintaining the tumor microenvironment and supporting the progression of tumor cells.65 Therefore, the efficacy of controlling the extracellular matrix by targeting its components (ie, collagen, cancer associated fibroblasts, and hyaluronan) and cytokines (ie, transforming growth factor β and sonic hedgehog) has been evaluated.
Treatment
Figure 1 outlines the current management for pancreatic cancer based on the anatomic resectability of the tumor, with the first consensus statement defined in 2009,66 before the advent of more effective systemic treatments. In primary resectable disease, upfront surgery followed by adjuvant chemotherapy has been considered the standard of care. By contrast, for borderline resectable and locally advanced diseases, preoperative treatment is generally proposed, because of the high likelihood of micrometastasis and the low likelihood of margin negative resection in these tumors.67 However, the improvement of medical treatment is challenging this concept; neoadjuvant treatment for resectable diseases is under investigation. At present, the recommendation is that the decision for treatment should be made at a multidisciplinary conference at a high volume center.
Fig 1
Current management for pancreatic cancer. CA19-9=carbohydrate antigen 19-9
The standard drug treatment for systemic treatment is still cytotoxic chemotherapy, and the efficacy of targeted treatment or immunotherapy remains unproven. Table 2 summarizes the clinical trials of medical treatment.
Table 2
Summary of key studies of medical treatment of pancreatic cancer
Gemcitabine became the standard chemotherapy drug for pancreatic cancer more than 20 years ago. In 1997, gemcitabine showed clinical benefit and marginally improved overall survival compared with fluorouracil (median survival 5.65 v 4.41 months) in a small randomized controlled trial that included 63 patients in each arm.68 Consequently, several trials were performed investigating combinations with gemcitabine.697071 However, most studies did not show a significant improvement in overall survival; the combinations tested included fluorouracil,72 irinotecan,73 oxaliplatin,7475 cisplatin,7677 and capecitabine.787980 Unfortunately, the addition of targeted treatment to gemcitabine based chemotherapy also did not show a survival benefit, with any of tipifarnib,81 cetuximab,82 bevacizumab,8384 axitinib,85 and vandetanib.86 In 2011, a landmark randomized phase 2/3 trial (PRODIGE 4/ACCORD 11) defined a new standard chemotherapy for metastatic pancreatic cancer.71 This multicenter trial enrolled 171 patients in each arm and showed a significant improvement in survival, with a median overall survival of 11.1 months in the FOLFIRINOX group, compared with 6.8 months in the gemcitabine group (hazard ratio 0.57; 95% confidence interval 0.45 to 0.73). FOLFIRINOX also had a higher response rate (31.6%) than gemcitabine (9.4%). Subsequently, the MPACT trial, a large randomized phase 3 study, showed another cytotoxic combination option (gemcitabine/nab-paclitaxel) for metastatic pancreatic cancer.87 This study included 861 patients, and showed that gemcitabine/nab-paclitaxel improved survival compared with gemcitabine alone (median survival 8.5 v 6.7 months; hazard ratio 0.72; 95% confidence interval 0.62 to 0.83). FOLFIRINOX and gemcitabine/nab-paclitaxel have formed the cytotoxic “backbones” for multiple clinical trials.
Nanoliposomal irinotecan is a drug encapsulating irinotecan sucrosofate salt payload in tiny pegylated liposomal particles, which theoretically can enhance the exposure of irinotecan to tumor cells. A recent randomized phase 3 trial (NAPOLI-3) enrolled 770 patients with metastatic pancreatic cancer and compared NALIRIFOX (combined liposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin) (n=383) to gemcitabine/nab-paclitaxel (n=387) as the first line treatment.88 Preliminary results showed an improved overall survival (median 11.1 v 9.2 months; hazard ratio 0.84; 95% confidence interval 0.71 to 0.99), which was the primary endpoint, and an improved progression free survival (7.4 v 5.6 months; 0.70; 0.59 to 0.84). For Asian populations, S-1 (an oral fluoropyrimidine derivative) is another treatment option, after it showed non-inferiority to gemcitabine for advanced pancreatic cancer in a randomized phase 3 study (GEST).89
Second line systemic treatment for advanced disease
Second line regimens after gemcitabine based chemotherapy for advanced pancreatic cancer have been studied in several trials. The CONKO-003 randomized phase 3 trial showed that the addition of oxaliplatin to folinic acid and fluorouracil (5FU/LV) significantly improved overall survival (median 5.9 v 3.3 months, hazard ratio 0.66; 95% confidence interval 0.48 to 0.91).90 By contrast, another randomized phase 3 trial (PANCREOX) found a deleterious effect on survival of oxaliplatin (mFOLFOX6) over infusional fluorouracil/leucovorin (hazard ratio 1.78; 95% confidence interval 1.08 to 2.93) in the second line setting.91
A large randomized phase 3 trial (NAPOLI-1) investigated the efficacy of nanoliposomal irinotecan to 5FU/LV for metastatic disease after gemcitabine based treatment.92 The results showed that nanoliposomal irinotecan plus 5FU/LV incrementally improved survival compared with 5FU/LV (6.1 v 4.2 months, hazard ratio 0.67; 95% confidence interval 0.49 to 0.92). Patients who received nanoliposomal irinotecan monotherapy, however, had similar survival to those who received 5FU/LV (4.9 v 4.2 months, 0.99; 0.77 to 1.28). Further studies on second line regimens after FOLFIRINOX or gemcitabine/nab-paclitaxel are warranted.
Maintenance systemic treatment for advanced disease
A poly adenosine diphosphate ribose polymerase (PARP) inhibitor was investigated as the maintenance treatment in patients who had germline loss-of-function mutations in BRCA1 or BRCA2, and platinum sensitive advanced disease. A randomized double blind phase 3 trial (POLO) showed no survival benefit of olaparib (n=62) compared with placebo (n=92) (median overall survival 19.0 v 19.2 months; hazard ratio 0.83; 95% confidence interval 0.56 to 1.22), but did show an improvement in progression free survival, which resulted in US Food and Drug Administration approval.9394 Another PARP inhibitor, niraparib, combined with an anti-CTLA-4 (ipilimumab) drug, showed a median overall survival of 17.3 months (95% confidence interval 12.8 to 21.9 months) in a phase 1b/2 trial.95 Maintenance treatment for non-BRCA mutated patients with metastatic diseases following FOLFIRINOX was evaluated in the PANOPTIMOX-PRODIGE 35 phase 2 trial.96 This study randomly assigned 273 patients to six month FOLFIRINOX (n=91), four month FOLFIRINOX followed by leucovorin/5-FU maintenance (n=92), or a sequential treatment alternating gemcitabine and FOLFIRI.3 every two months (n=90). The results showed a comparable six month progression free survival rate and median progression free survival in the maintenance arm eliminating oxaliplatin (44%, 5.7 months), and the worst survival in the gemcitabine/FOLFIRI approach (34%, 4.5 months) compared with the six month FOLFIRINOX arm (47%, 6.3 months).
Adjuvant systemic treatment
Adjuvant systemic treatment is recommended for all eligible resected patients. The first large randomized phase 3 trial that showed the survival benefit of adjuvant chemotherapy was the ESPAC-1 trial, which assigned resected patients (n=289) to 5-FU/LV versus control.497 Adjuvant chemotherapy prolonged the median overall survival by 4.6 months (hazard ratio 0.71; 95% confidence interval 0.55 to 0.92).4 The CONKO-001 randomized phase 3 trial showed that adjuvant gemcitabine (n=179) improved overall survival compared with observation (n=172) (median 22.8 v 20.2 months; hazard ratio 0.76; 95% confidence interval 0.61 to 0.95).98 When 5FU/LV and gemcitabine were compared head-to-head, no difference in overall survival was found, but gemcitabine had less toxicity in the ESPAC-3 randomized phase 3 trial.99 Subsequently, multiple trials tried to find a new effective combination treatment with gemcitabine. A randomized phase 3 trial combining erlotinib with gemcitabine was negative,100 but the addition of capecitabine had a survival benefit over gemcitabine alone (28.0 v 25.5 months; 0.82; 0.68 to 0.98) in the ESPAC-4 phase 3 trial.101 However, this combination treatment was short lived; FOLFIRINOX drastically changed the survival of patients and became the new standard regimen for adjuvant treatment. The PRODIGE 24/CCTG PA6 phase 3 trial randomly assigned 493 resected patients to receive adjuvant modified (dose reduced) FOLFIRINOX (mFOLFIRINOX) or gemcitabine for 24 weeks. The mFOLFIRINOX group (n=247) showed a significantly improved median overall survival (53.5 v 35.5 months; 0.68; 0.54 to 0.85).5102 By contrast, gemcitabine/nab-paclitaxel failed to show a survival benefit over gemcitabine alone in a randomized phase 3 trial (APACT).103 It did not meet the primary endpoint of disease free survival by central review,103 although overall survival improved marginally in the gemcitabine/nab-paclitaxel group (40.5 v 36.2 months; 0.82; 0.680 to 0.996). In Asia, S-1 is the standard regimen, based on the results of a randomized phase 3 trial.104 The role of adjuvant treatment after neoadjuvant chemotherapy and surgical resection is still debatable. A recent large retrospective study showed a potential benefit in survival for patients able to receive adjuvant chemotherapy after neoadjuvant and surgery.105
Neoadjuvant systemic treatment
One of the underpinnings of neoadjuvant treatment is that 36% of patients with pancreatic cancer are unable to receive adjuvant chemotherapy after resection,106 and surgical resection alone does not achieve long term survival for most patients. The rationale for neoadjuvant treatment is to increase the dose intensity and tolerance of planned systemic treatment before patients are weakened by surgery, and to avoid delayed treatment of micrometastatic disease, which is the main cause of mortality.107 Two prospective single arm phase 2 studies showed the safety of neoadjuvant gemcitabine plus a platinum based drug.108109
The only published phase 3 trial of neoadjuvant systemic treatment (PREOPANC-1) randomly assigned 246 patients with resectable (54.1%) or borderline resectable disease (45.9%) to neoadjuvant chemoradiotherapy (n=119) or upfront surgery (n=127).110111 The neoadjuvant chemoradiotherapy arm received three cycles of neoadjuvant gemcitabine with 36 Gy radiotherapy in 15 fractions and four cycles of adjuvant gemcitabine, whereas the upfront surgery arm received six cycles of adjuvant gemcitabine. Long term results showed a consistent survival benefit of neoadjuvant treatment regardless of the resectability of the primary tumors, for borderline resectable diseases (hazard ratio 0.67; 95% confidence interval 0.45 to 0.99) and resectable diseases (0.79; 0.54 to 1.16). However, the chemotherapy regimen (gemcitabine alone) was outdated. The recent ESPAC-5 phase 2 trial112 randomly assigned 90 patients with borderline resectable diseases to neoadjuvant treatment (n=56), which included multiagent neoadjuvant chemotherapy and single agent chemoradiotherapy, or upfront surgery (n=33). It showed a better one year overall survival in the neoadjuvant treatment groups compared with the upfront surgery group (76% v 39%; hazard ratio 0.29; 95% confidence interval 0.14 to 0.60), although it did not provide evidence of the optimal regimen owing to the small sample size.
Regarding resectable diseases, one concern of neoadjuvant treatment is the possibility of disease progression during neoadjuvant treatment, which could cause patients to miss the opportunity for surgical resection. Indeed, the role of neoadjuvant treatment for resectable disease is still under investigation. A randomized phase 2 trial (PACT-15) showed that neoadjuvant chemotherapy with the PEFG regimen (cisplatin, epirubicin, fluorouracil, and gemcitabine) improved overall survival compared with adjuvant gemcitabine and adjuvant PEFG regimen for resectable disease.113 The Prep-02/JSAP-05 phase 2/3 trial randomly assigned patients with resectable (about 80%) or borderline resectable diseases to one month neoadjuvant gemcitabine plus S-1 (n=182), or upfront surgery (n=180). Both arms received six month S-1 as the adjuvant treatment.114 The results showed improved overall survival in the neoadjuvant chemotherapy arm (36.7 v 26.6 months; hazard ratio 0.72; 95% confidence interval 0.55 to 0.94). Conversely, studies of FOLFIRINOX have not shown positive results.115116 The SWOG S1505 phase 2 study showed equivalent efficacy of neoadjuvant mFOLFIRINOX versus nab-paclitaxel/gemcitabine for three months for resectable disease.115 The median overall survival in both arms (23.2 and 23.6 months) did not show improvement compared with previous trials of adjuvant treatment.
A recent phase 2 trial (NORPACT-1) randomly assigned 140 patients with resectable diseases to the neoadjuvant FOLFIRINOX arm (n=77) or the upfront surgery arm (n=63), and found no survival benefit of neoadjuvant FOLFIRINOX. However, the results have several problems. While not significant, the median survival was 13.4 months shorter (25.1 v 38.5 months) in the neoadjuvant FOLFIRINOX arm, despite the higher rates of node negative (N0) and margin negative (R0) resection in that arm. Given the high resection rate (n=63, 82%) despite the low completion rate of neoadjuvant chemotherapy (n=40, 52%), and the high rate of adjuvant chemotherapy other than FOLFIRINOX (75%) in the neoadjuvant group, it seems that the neoadjuvant group did not receive sufficient FOLFIRINOX chemotherapy. In addition, whether two months is sufficient for neoadjuvant FOLFIRINOX is unclear. Three ongoing large randomized phase 3 trials might provide some insight into the optimal sequence and the number of cycles of FOLFIRINOX; two are recruiting patients (ALLIANCE-A021806 and PREOPANC-3), and one recently opened (NCT05529940). The first two trials plan to enrol more than 300 patients with resectable disease to assess the overall survival of perioperative FOLFIRINOX (eight cycles of neoadjuvant and four cycles of adjuvant) compared with adjuvant FOLFIRINOX (12 cycles). The NCT05529940 trial plans to enrol more than 600 patients and evaluate the two year survival of perioperative FOLFIRINOX (six cycles of neoadjuvant and six cycles of adjuvant) compared with adjuvant FOLFIRINOX (12 cycles).
Systemic treatment for locally advanced disease
After the positive results of FOLFIRINOX and gemcitabine/nab-paclitaxel for metastatic disease, several studies have investigated its efficacy in locally advanced diseases. A systematic review that analyzed 315 patients with locally advanced diseases from 11 studies between 1994 and 2015 showed that FOLFIRINOX was associated with a longer median overall survival of 24.2 months (95% confidence interval 21.7 to 26.8 months).117 The proportion of patients who underwent surgical resection after FOLFIRINOX ranged from 0-43%. A phase 2 study (LAPACT) investigated gemcitabine/nab-paclitaxel for 106 patients118; the median overall survival was 18.8 months (90% confidence interval 15.0 to 24.0 months). In total, 62 patients (58%) completed induction gemcitabine/nab-paclitaxel, and 17 patients (16%) underwent surgical resection. Another randomized phase 2 study (NEOLAP-AIO-PAK-0113) showed high surgical conversion rates of gemcitabine/nab-paclitaxel (23/64, 35.9%) and gemcitabine/nab-paclitaxel followed by FOLFIRINOX (29/66, 43.9%).119 No survival differences were observed between the two arms (hazard ratio 0.86; 95% confidence interval 0.55 to 1.36). These results suggest a new potential treatment strategy for surgical conversion of locally advanced disease, which could achieve longer survival in selected patients.
Surgical treatment
Pancreatectomy, especially pancreaticoduodenectomy, has been considered a high risk surgery. The centralization of pancreatectomy has played an essential role in the improvement of perioperative outcomes. The 90 day mortality is reported to be under 5-10% in experienced high volume centers.120121 A recent meta-analysis including 46 retrospective studies (2015-2021) showed a significantly lower postoperative morbidity rate in high volume centers compared with low volume centers (47.1% v 56.2%; odds ratio 0.75; 95% confidence interval 0.65 to 0.88).121
Surgery for locally advanced and borderline disease
Some experts have pushed for more aggressive operations for patients with borderline resectable and locally advanced diseases with the advent of more effective systemic drugs. Resection after neoadjuvant treatment was reported to have similar short term outcomes compared with upfront resection in a meta-analysis122 including randomized controlled trials and a subgroup report of a randomized phase 3 trial.123 However, data on arterial resection and reconstruction are more controversial, and depend on the resected artery and the technical approach; the mortality rates were reported as 5.7% for resection of the superior mesenteric artery,124 and 1.7% for resection of the celiac axis.125 More recently, arterial divestment has been proposed as an alternative to arterial resection in selected patients. A retrospective study of a high volume center reported a mortality rate of 7.0% for arterial resections and 2.3% for arterial divestment from 2015 to 2019, although the breakdown of resected arteries was not shown by periods.126 To be clear, these aggressive procedures should be performed only when long term survival is expected. A previous meta-analysis including 13 studies (2005-2015) with 355 locally advanced tumors showed no significant association between the resection rate after chemotherapy and overall survival.117 However, large, retrospective studies recently showed that conversion surgery for locally advanced diseases after FOLFIRINOX was associated with improved survival in a selected subgroup.127128 Further studies are expected.
Surgery for patients with metastatic disease
Macroscopic distant metastasis is a contraindication to surgical resection in general. However, several studies have reported a potential role of resection in highly selected patients with limited metastatic diseases. A meta-analysis including three retrospective studies (2016-2019) showed a longer overall survival (23-56 months v 11-16 months) in patients with synchronous liver metastasis who underwent resection after chemotherapy (n=44) compared with those who did not (n=166).129 In another review, lung metastasectomy was associated with a longer survival with a median overall survival after resection ranging from 18.6 to 38.3 months.130 A large retrospective study suggested that only patients who achieved a complete pathological response of metastasis could derive a survival benefit from resection.131 Further studies are expected to provide data on patient selection criteria and metastatic sites. A single arm phase 2 study (NCT04617457) and a randomized phase 3 trial (NCT03398291) are recruiting patients with oligometastasis in liver from pancreatic cancer to evaluate the efficacy of resection after chemotherapy.
Minimally invasive surgery
Minimally invasive surgery for pancreatic cancer had until recently been lagging behind that for other cancers. Results of a recent randomized trial132 (n=656) and a meta-analysis of three randomized controlled trials133 (n=224) showed that laparoscopic pancreatoduodenectomy was associated with a shorter hospital stay, but a similar postoperative morbidity rate. Box 3 summarizes the studies comparing robotic pancreatoduodenectomy with open or laparoscopic pancreatoduodenectomy. Notably, all studies on pancreatoduodenectomy to date have included patients with diseases other than pancreatic cancer. Another meta-analysis including 12 randomized or matched studies (n=4346) showed a similar morbidity rate, but a higher margin negative resection rate (odds ratio 1.46) and shorter time to adjuvant treatment, in the laparoscopic distal pancreatectomy group.139 Most recently, an international randomized trial (DIPLOMA)140 including 117 patients with resectable pancreatic cancer in the minimally invasive distal pancreatectomy group and 114 patients in the open distal pancreatectomy group showed the non-inferiority of the oncological safety of minimally invasive distal pancreatectomy: a higher margin negative resection rate (73% v 69%) and comparable lymph node yield and intraperitoneal recurrence.
Box 3
Comparison between robotic pancreaticoduodenectomy and open pancreatoduodenectomy or laparoscopic pancreatoduodenectomy
Robotic pancreatoduodenectomy (v open pancreatoduodenectomy )134135136 | Robotic pancreatoduodenectomy (v laparoscopic pancreatoduodenectomy )135137138
R0 resection: Comparable135136 or higher134 | Comparable135
Lymph nodes harvested: Comparable135136 or more134 | Comparable135 or more137138
Radiotherapy is used as a part of local treatment for pancreatic cancer, generally combined with chemotherapy. Since the gold standard for this disease remains surgical resection,67 the role of radiotherapy has been logically examined in both the adjuvant setting and in locally advanced inoperable patients. The neoadjuvant application of radiotherapy has also been investigated in several studies. In this setting, however, high level evidence comparing the role of radiotherapy in a head-to-head design to neoadjuvant chemotherapy is lacking. The true efficacy of radiotherapy on long term survival remains unclear, especially when combined with modern multiagent systemic treatments and surgical resection. Another concern in many radiotherapy studies is the heterogeneity of the treatment technique and dose used. For example, the techniques have evolved from conventional treatments to intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), more ablative approaches with adaptive planning platforms. Box 4 summarizes the characteristics of radiotherapy by types and doses. Table 3 summarizes the clinical studies of radiotherapy.
Box 4
Characteristics of radiotherapy for pancreatic cancer by types and doses
Using multiple beams shaped to conform to a tumor that is identified its size, shape, and location by 3D imaging (ie, CT, MRI)
Generally used dose:* 45.0-56.0 Gy in 1.75-2.20 Gy fractions
Image guided radiation therapy (IGRT)
An adjunctive technique to adjust the tumor location difference by using 3D imaging (ie, CT, MRI) performed immediately before each radiation treatment
Intensity modulated radiation therapy (IMRT)
Possible to adjust the irradiation intensity within a target volume
Possible to deliver a concentrated dose to a tumor and better spare the normal tissue
Generally used dose:* 45.0-56.0 Gy in 1.75-2.20 Gy fractions
Stereotactic body radiotherapy (SBRT)
Accurately irradiate a tumor with high dose radiation in three dimensions from multiple directions
In theory, the purpose of adjuvant radiotherapy is to reduce the risk of local recurrence. NCCN guidelines recommend considering adjuvant chemoradiation treatment for patients with positive surgical margins.67 However, prospective studies that support adjuvant radiotherapy are lacking, regardless of the surgical margin status. The aforementioned large randomized phase 3 trial (ESPAC-1) included 289 resected patients: 51 (17.6%) had positive resection margins. The results showed worse survival in the chemoradiotherapy arm (n=145) than in the non-radiotherapy arm (n=144) (median overall survival 15.9 v 17.9 months; hazard ratio 1.28; 95% confidence interval 0.99 to 1.66).4 This study has discouraged further studies of adjuvant radiotherapy in Europe. However, the study had two major drawbacks. Firstly, the chemotherapy regimen was different in the chemotherapy arm (fluorouracil/leucovorin) and the chemoradiotherapy arm (fluorouracil). Secondly, the total dose of radiotherapy (20 Gy) did not reach 45 Gy, which represents the treatment dose of conventional, fractionated external beam radiotherapy.67 Two randomized phase 2 studies investigated adjuvant gemcitabine plus radiotherapy for patients with negative resection margins. The first study administered 50.4 Gy in 28 fractions of radiotherapy, and found a lower local alone recurrence rate (11% v 24%), but did not show a difference in overall survival or disease free survival between the two arms (45 patients each).143 The other small study (n=38) used a modern SBRT technique (25 Gy in five fractions), but showed no difference in any of the survival endpoints (recurrence free survival, locoregional recurrence free survival, or overall survival), even in the node positive subgroup.144 An older systematic review included five randomized controlled trials (1985-2005) of adjuvant chemoradiotherapy consisting of fluorouracil based chemotherapy plus conventional radiotherapy, and showed no survival benefit of chemoradiation (pooled hazard ratio 1.09; 95% confidence interval 0.89 to 1.32).145 The subgroup analysis in this study showed a possible efficacy of adjuvant chemoradiotherapy in patients with positive resection margins.
The RTOG0848 trial is a randomized phase 2/3 study that enrolled 322 resected patients. The ongoing phase 3 of this trial assesses the survival benefit of added radiotherapy (50.4 Gy) after six cycles of adjuvant gemcitabine based chemotherapy. However, because the standard of care regimen of adjuvant chemotherapy has changed to FOLFIRINOX, the results of this study might have a limited impact on clinical practice. Ultimately, the role of adjuvant radiotherapy is still ambiguous.
Neoadjuvant radiotherapy
One of the primary goals of neoadjuvant radiotherapy is to reduce the rate of positive margin resection, which is a risk factor for local recurrence. Two single arm phase 2 studies showed the tolerability and feasibility of concurrent radiotherapy combined with fluorouracil plus cisplatin146 (n=41) and gemcitabine (n=41).147 However, the evidence on the efficacy of neoadjuvant radiotherapy is inconsistent. A meta-analysis of three randomized controlled trials (n=189) that investigated chemoradiotherapy (fluorouracil based chemotherapy with a radiotherapy dose of 45-50.4 Gy) did not show any difference in overall survival between neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy (hazard ratio 0.93; 95% confidence interval 0.69 to 1.25).148 The aforementioned PREOPANC-1 phase 3 trial, which showed a survival benefit of neoadjuvant chemoradiation for borderline resectable disease, did not evaluate effects with and without radiation.110 Regarding neoadjuvant chemoradiotherapy with FOLFIRINOX, a phase 2 trial (n=48) showed that neoadjuvant FOLFIRINOX plus chemoradiotherapy in borderline resectable disease showed a high rate of margin negative resection, and prolonged median progression free survival and even median overall survival.149 By contrast, a randomized phase 2 trial (ALLIANCE-A021501) showed worse survival in the patients with borderline resectable disease who were allocated to the neoadjuvant mFOLFIRINOX plus radiotherapy (SBRT or hypofractionated image guided radiotherapy) arm (n=56) compared with those who allocated to the neoadjuvant mFOLFIRINOX alone arm (n=70) (median overall survival 17.1 v 29.8 months; median event free survival 10.2 v 15.0 months).150 However, the number of patients was modest, and the dropout rates were high in both the chemotherapy arm (71.4%) and the chemoradiation arm (82.1%). A meta-analysis comprising 15 studies (512 patients) of neoadjuvant FOLFIRINOX with or without radiotherapy for resectable and borderline resectable disease showed a better rate of margin negative resection in the chemoradiotherapy group (97.6% v 88.0%).151 No differences were observed in resection rate, overall survival, or pathological outcomes. The PANDAS-PRODIGE 44 study, a randomized phase 2 study, assigned 130 patients with borderline resectable diseases to mFOLFIRINOX or mFOLFIRINOX plus conformal external radiation (50.4 Gy). This ongoing study aims to evaluate the histological negative margin resection rate as the primary endpoint.
Radiation for locally advanced disease
For locally advanced pancreatic cancer, radiation is used as the primary modality for local control and, on rare occasions, to facilitate margin negative resection in select patients who achieve good responses to treatment.67 Trials for locally advanced diseases have reported various levels of efficacy. A randomized trial assigned 37 patients to receive chemoradiotherapy (gemcitabine, 50.4 Gy) and 34 patients to receive gemcitabine alone. The trial showed improved overall survival in the chemoradiotherapy group (11.1 v 9.2 months).152 Progression free survival was not different, but the sample size was notably small. The LAP07 trial was a large randomized phase 3 trial that aimed to investigate the survival benefit of adding radiotherapy to chemotherapy (54 Gy plus capecitabine) compared with chemotherapy (gemcitabine or gemcitabine plus erlotinib) after four months of gemcitabine based induction chemotherapy.153 The results showed no differences in overall (median 15.2 v 16.5 months; hazard ratio 1.03; 95% confidence interval 0.79 to 1.34) or progression free survival (9.9 v 8.4 months; 0.78; 0.61 to 1.01) between the chemoradiotherapy group (n=133) and the chemotherapy group (n=136). An older randomized phase 3 trial (2000-01 FFCD/SFRO) also compared gemcitabine chemotherapy (n=60) to chemoradiotherapy with fluorouracil and cisplatin (60 Gy) (n=59),154 and showed worse overall survival (median 8.6 v 13.0 months) and progression free survival in the chemoradiotherapy group.154 The study, however, suffered from major inconsistencies in the proportion of patients who received at least 75% of the planned dose of induction chemotherapy, being only 42.4% in the chemoradiotherapy group compared with 73.3% in the chemotherapy group.
Given that conventional fractionated radiotherapy techniques combined with gemcitabine based chemotherapy have failed to show a significant survival advantage, the focus of research has moved to SBRT and FOLFIRINOX. A meta-analysis of 1147 patients from 21 studies including randomized controlled trials (2002-2014) compared conventional external beam techniques to SBRT.141 The estimated two year overall survival was higher in the SBRT group (26.9% v 13.7%), with less acute grade 3/4 toxicity (5.6% v 37.7%) and similar late grade 3/4 toxicity (9.0% v 10.1%). A phase 2 trial (LAPC-1) enrolled 50 patients to receive eight cycles of FOLFIRINOX followed by SBRT (40 Gy in five fractions).155 In total, 39 patients underwent SBRT (78.0%) and seven (14.0%) patients underwent surgical resection; all had negative margins and pathological N0 stage. The overall survival in the resected patients was longer than in the unresected patients (median 24 v 15 months; three year survival rate 43% v 6.5%). A systematic review including 2446 patients from 28 phase 2/3 studies also showed a similar resection rate of 12.1% (95% confidence interval 10.0% to 14.5%). Therefore, this newest chemoradiotherapy approach could give the best chance of curative intent surgery, and achieve long term survival in a highly selected subgroup of patients.
Four phase 2/3 trials are ongoing. The CONKO-007 trial is a large randomized phase 3 trial enrolling 525 patients to evaluate chemoradiotherapy (50.4 Gy with gemcitabine) after induction chemotherapy with FOLFIRINOX (n=402) or gemcitabine (n=93) for three months; the primary endpoint was margin negative resection rate. The first results came out in 2022, and showed a higher rate of margin negative resection (resection and circumferential resection margin) (9.0% v 19.6%) in the chemoradiation arm (n=168, 61 underwent surgery) compared with the chemotherapy arm, which was continuing FOLFIRINOX or gemcitabine (n=167, 60 underwent surgery).156 However, the total surgical resection margin negativity rate and survival did not reach statistical significance. The publication is pending. The other three trials are phase 2 trials and are still recruiting patients (SCALOP-2,157 MASTERPLAN,158 and GABRINOX-ART159). These studies could provide more data about gemcitabine/nab-paclitaxel and SBRT for locally advanced pancreatic cancer. However, we are unable to draw a conclusion without well designed phase 3 trials using the latest technology and chemotherapy regimen.
Supportive care and palliative care
Weight loss is seen in more than half of patients at diagnosis of pancreatic cancer11; as a result, the rates of malnutrition160161 (33.7-70.6%) and sarcopenia162 (up to 74%) are high. Malnutrition and sarcopenia have been reported to be associated with poor outcomes of surgical resection and chemotherapy.163 Given that the majority of patients suffer from metastatic diseases, palliative care, including pain management and nutrition support, is essential to their quality of life, and even prognosis. Table 4 highlights major studies on these topics.
Table 4
Summary of studies on supportive/palliative care for pancreatic cancer
Fibrosis, both chemoradiotherapy induced and cancer associated, has been reported to be associated with overall survival. An MRI probe targeting chemoradiotherapy induced collagen (type I collagen) can detect this change in fibrosis.170 Radiolabeled fibroblast activation protein inhibitors (FAPI) can target the expression of fibroblast activation protein in cancer associated fibroblasts, which is abundant in pancreatic cancer.171 A meta-analysis showed superior performance of FAPI PET over FDG PET/CT/MRI for the determination of tumor, node, metastases (TNM) classification and peritoneal carcinomatosis.172 A phase 2 trial is recruiting patients to evaluate the efficacy of FAPI PET/CT in patients with locally advanced disease (NCT05518903).
Radiomics using machine learning or deep learning (artificial intelligence) is a new field of research, driven by advances in computer systems. Theoretically, a computer can learn and identify features and differences that a human cannot. A systematic review showed that radiomics models of the primary tumors had good performance in predicting patient prognosis.173 Further studies with larger sample sizes for training and validating models with risk factors, images, and biomarkers will yield more conclusive results in this regard.
Systemic treatment
In the era of neoadjuvant chemotherapy, a new question has emerged of how to manage patients who have tumor progression during neoadjuvant treatment. A phase 2 trial (NCT03322995) is recruiting patients (n=125) with resectable and borderline resectable disease to evaluate the efficacy of adaptive modification of neoadjuvant treatment (four months). Based on the results of restaging after four cycles of FOLFIRINOX, a decision will be made to either continue the same regimen, or switch to a gemcitabine based regimen and chemoradiotherapy. For locally advanced pancreatic cancer, the NEOPAN phase 3 trial successfully enrolled 171 patients with locally advanced pancreatic cancer to compare the progression free survival of FOLFIRINOX (12 cycles) with gemcitabine (four cycles), with preliminary results expected soon. Few data exist on the comparison of FOLFIRINOX with gemcitabine/nab-paclitaxel for both localized and advanced cancer. A randomized phase 2 study (PASS-01) is recruiting patients (planned n=150) with metastatic disease to investigate the difference in progression free survival between the two regimens. Moreover, genomic factors and putative biomarkers will be explored using whole genome sequencing and RNA sequencing, and patient derived organoids.
Immunotherapy has been largely ineffective in pancreatic cancer, potentially owing to both tumor cell intrinsic and tumor microenvironment factors. Recent trials have taken a combined approach. CISPD3, a randomized phase 3 trial (n=110), showed an improved objective response rate (50.0% v 23.9%; P=0.010) by adding sintilimab (a monoclonal antibody against programmed cell death protein 1) to FOLFIRINOX for metastatic patients,174 albeit without superior overall survival and progression free survival. The same group is conducting a phase 3 trial to evaluate the same regimen in patients with borderline resectable and locally advanced diseases (NCT03983057). Given the results of basic research in pancreatic cancer showing that the extracellular matrix plays an essential role in the tumor microenvironment and progression, several new agents have been introduced. A phase 2 trial (NCT03336216) combining an immune checkpoint inhibitor with chemotherapy (FOLFIRINOX or gemcitabine based regimen) and cabiralizumab (a colony stimulating factor 1 receptor inhibitor that suppresses the activities of tumor associated macrophages) has been conducted. However, a 2020 press release175176 announced that this study missed the primary endpoint of progression free survival.
Pamrevlumab, a recombinant human monoclonal antibody against connective tissue growth factor, has been investigated in a randomized phase 3 trial (LAPIS) combined with FOLFIRINOX or gemcitabine/nab-paclitaxel (up to six cycles) for locally advanced tumors. The study has completed recruitment (n=284) and is continuing to evaluate the primary endpoint of overall survival. Most recently, a phase 1 trial proposed a notable approach to stimulating cancer immunity in pancreatic cancer, with promising results.177 The study adopted the messenger RNA (mRNA) vaccine technique to make a personalized mRNA vaccine encoding five or more neoantigens, which were bioinformatically predicted from the resected primary tumor. This adjuvant treatment consisted of one dose of atezolizumab (anti-PDL1 (programmed death ligand 1) antibody) and eight doses (one week) of mRNA neoantigen vaccines, followed by 12 cycles of mFOLFIRINOX. In total, 16 of 28 resected patients received personalized vaccines, and eight patients responded to the vaccines, with no recurrence among responders after a median follow-up of 18.0 months. Larger studies will help establish whether this is a breakthrough in immunotherapy for pancreatic cancer.
Treatment strategies targeting specific genomic alterations have been explored in various molecularly defined patient subsets. Given the positive results for metastatic cancer in the POLO trial,93 olaparib is being studied in a randomized phase 2 trial (APOLLO) to evaluate the additional benefit of one year of treatment on recurrence free survival in patients with a pathogenic BRCA1, BRCA2, or PALB2 mutation, who have received at least three months of multi-agent chemotherapy after curative resection. KRAS is an attractive target owing to its high rate of mutation (90%) in pancreatic cancer.178 Although KRAS G12C mutations are rare (1.6% of pancreatic ductal adenocarcinoma (PDAC) cases), the ability to create covalent G12C inhibitors led to FDA approval in non-small cell lung cancer, and promising initial results in PDAC. Sotorasib, a KRAS G12C inhibitor, showed a median progression free survival of four months, and an objective response rate of 21% in metastatic patients with KRAS G12C mutations who received at least two lines of chemotherapy in a phase 1/2 trial.179 Another KRAS G12C inhibitor, adagrasib, showed a median progression free survival of 6.6 months, and an objective response rate of 50% (5/10 patients), in patients with advanced pancreatic cancer in a phase 1/2 trial (KRYSTAL).180
By contrast to the low mutation rate in BRCA1 (1.08%), BRCA2 (1.48%), PALB2 (0.54%), and KRAS G12C (1-2%), other KRAS mutations are quite common, and pan-KRAS inhibitors are under investigation. Two phase 1 studies of pan-RAS inhibitors are recruiting patients (NCT04678648 and NCT05379985). Further studies on other KRAS targeting approaches are expected.
Radiotherapy
Radiotherapy has been suggested to have synergistic effects on local and even distant tumors when combined with immunotherapy.181182 A large randomized phase 3 trial showed that chemoradiotherapy followed by durvalumab (PDL1 inhibitor) had significantly longer overall survival than placebo in locally advanced, non-small cell lung cancer.183 Recently, a phase 2 trial (CheckPAC) assigned 84 patients with refractory metastatic pancreatic cancer to receive SBRT/nivolumab (n=41) or SBRT/nivolumab/ipilimumab (n=43).184 The SBRT/nivolumab/ipilimumab arm had a higher disease control rate (37.2% v 17.1%). Further studies with an immunotherapy–SBRT backbone are anticipated in locally advanced and metastatic disease settings.
Figure 2 summarizes all the data discussed above, and gives perspective on the future of the management of pancreatic cancer.
Fig 2
Precision medicine for pancreatic cancer. PanIN=pancreatic intraepithelial neoplasm
Several national and international guidelines for the management of pancreatic cancer have been published. Recommendations of those guidelines are proposed considering the evidence and the healthcare system of each country. We reviewed two major guidelines of the US and Europe, and also included the recent 2022 updated Japanese guideline.678 All recommendations of these guidelines are made based on the metastatic status and the anatomical resectability of the primary tumors. Regarding treatments for resectable diseases, the NCCN guidelines list neoadjuvant chemotherapy as an option for high risk patients, and the Japan Pancreas Society guidelines recommend neoadjuvant for all patients. The ESMO guidelines recommend only upfront surgery. The NCCN and ESMO guidelines recommend mFOLFIRINOX as the first option of adjuvant chemotherapy, although S-1 monotherapy is recommended by the Japan Pancreas Society guidelines. Conversion surgery for locally advanced disease is an option in the NCCN and Japan Pancreas Society guidelines. No recommendation is made for conversion surgery for metastatic disease in any of the three sets of guidelines. Radiotherapy is listed as an option for non-metastatic diseases in the NCCN guidelines, while the other guidelines do not recommend it for resectable diseases. The NCCN guidelines recommend genetic testing of inherited mutations for all patients with pancreatic cancer, but no clear recommendations are made in the other sets of guidelines.
Conclusions
In the US and Europe, the incidence of pancreatic cancer has been increasing consistently, and this trend is estimated to continue for several decades. Advances in the combination of cytotoxic drugs have resulted in improvements in survival for all stages of the disease, and are changing treatment algorithms. Further investigation into the role of immuno-oncology agents and radiation could help a subset of patients. In addition, extensive efforts need to focus on risk assessment, screening, and early detection.
Research questions
・In patients treated with upfront systemic treatment, what is the optimal duration of systemic treatment and patient selection for surgical resection?
・How can immuno-oncology and targeted treatment be made effective?
・What is the optimal combination and sequence of radiotherapy, and who are the ideal targets?
・What is the specific population that needs routine screening and what is an effective combination of tests to detect precancerous lesions?
Glossary of abbreviations
NCCN: National Comprehensive Cancer Network
ESMO: European Society for Medical Oncology
PanIN: pancreatic intraepithelial neoplasia
IPMN: intraductal papillary mucinous neoplasm
CAPS: International Cancer of the Pancreas Screening
USPSTF: United States Preventive Services Task Force
CA19-9: carbohydrate antigen 19-9
RECIST: response evaluation criteria in solid tumors
FOLFIRINOX: combined leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin
NALIRIFOX: combined liposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin
mFOLFIRINOX: modified FOLFIRINOX
PEFG regimen: cisplatin, epirubicin, fluorouracil, and gemcitabine
High-functioning doctor-patient relationships can be mutually rewarding
I was reading about the relationship between the pioneering psychologist Erik Erikson and the iconic painter Norman Rockwell. Erikson, who gained fame for explicating eight crucial stagesopens in a new tab or window of psychosocial development across the lifespan, was Rockwell’s psychotherapist.
Both men lived in the idyllic Massachusetts town of Stockbridge, where Rockwell painted one of his most recognized pieces — “Stockbridge Main Street at Christmas” — depicting picturesque Main Street during the holiday season. Stockbridge Main Street was also home to the famous Austen Riggs Center, a bastion of psychoanalytic practice and long inpatient stays. Rockwell’s wife was hospitalized at Austen Riggs for treatment of depression and alcohol use disorder. Rockwell, himself, fell into a deep depression, which led to a serendipitous encounter with Erikson and subsequent outpatient treatment with him.
Rockwell was fussy about his paintings — a perfectionist at heart. In a depressed state, his obsessiveness was insufferable, overthinking his technique and questioning the quality of his artwork. Erikson pulled Rockwell out of depression and helped impart the social milieu of the 1950s into Rockwell’s paintings. In audio recordings, one can hear Rockwell tell his son Tom how Erikson helped him revitalize his painting, even dispensing advice to Rockwell about how he should begin the lineage of Rockwell’s celebrated “Family Tree.opens in a new tab or window“
One wonders whether the relationship between the two men held any meaning for Erikson. Erikson was born in Germany and emigrated to the U.S. at age 31. He never knew his biological father — in fact, he was initially deceived about his paternity. As Erikson wrestled with his identity, he changed his name several times, finally arriving at “Erik Erikson” and subsequently coining the term “identity crisis.” According to Jane Tillman, PhD,opens in a new tab or window director of the Erikson Institute, Rockwell’s paintings helped suffuse Erikson’s identity by enabling him to reflect on art that was quintessentially American.
Tillman’s account leads me to believe that the doctor-patient relationship is, at its best, a bidirectional affair — a two-way street. Although high-functioning doctor-patient relationships are not the same in magnitude as the one between Erikson and Rockwell, who ended up good friends, they have a special give-and-take quality. My premise is that while the physician is the ostensible healer, the patient helps heal the physician, usually through subtle means uncovered after the physician reflects on a patient’s visit or upon termination of the relationship.
The idea first dawned on me as a psychiatry resident. I evaluated a young woman for a relationship problem. I thought the initial session went quite well. I asked her if she would return to discuss some issues in more depth. “I’m not seeing you again,” she replied. Puzzled, I asked why. “Look at your plants,” she said angrily. “They’re half-dead. If you can’t give your plants a little TLC, how do you expect to take care of me?”
I was shocked. I had no answer. Admittedly, I never had much of a green thumb, but the patient rightly pointed out that my inaction — not watering my plants — was inexcusable. It had a profound effect on me and led to my subsequent interest in horticulture, perhaps over-compensating for a perceived failure.
As a physician, I find it much easier to give advice than receive it, which is not a surprise. If I have to see a doctor for personal reasons, the conversation starts off stilted until I tell them I am also a physician. Upon informing the doctor I am a psychiatrist, there is often an enthusiastic exchange of stories about difficult or unusual patients. Bruce Springsteen would say that physicians’ collective stories are “The Ties That Bind.”
I recently moved to Charlotte, North Carolina, and I had my initial visit with a primary care physician (PCP) who went to medical school and trained in my hometown of Philadelphia. He told me his wife trained in emergency medicine at the same institution where I attended medical school and did my residency. We shared a good laugh when discussing the sundry characters known to visit emergency departments who are not really in crisis, and how difficult it was to decide whether to prioritize their medical needs or mental health needs.
The conversation quickly turned serious. The PCP informed me that at least half his patients had concomitant mental health problems that went unaddressed mainly due to time constraints (he was allotted only 15 minutes per visit). He also confessed that he didn’t feel comfortable playing the role of quasi-therapist. I told him that back in the day, I was a consultation-liaison psychiatrist, and I was routinely called to assess med-surg patients. I informed the PCP he could easily brush up on psychiatry, and I recommended a couple of primers he could read, including The Fifteen Minute Hour: Applied Psychotherapy for the Primary Care Physician, considered a classic.
Research confirmsopens in a new tab or window that physicians who can emotionally engage with patients have better outcomes and higher patient satisfaction scores. When a patient perceives that their physician cares and listens to their concerns, they are more likely to complyopens in a new tab or window with medical recommendations and return for follow-up visits. But there is very little research indicating that paying credence to our patients’ advice and musings makes us better doctors. Can patients stimulate our personal growth, as Rockwell did for Erikson in his search for identity?
The short answer is that physicians can become better doctorsopens in a new tab or window by being patients. When doctors exchange the white coat for a hospital gown, they learn the importance of empathy and language and gain an appreciation for the trauma of illness and trauma of treatmentopens in a new tab or window. The well-known author and speaker Danielle Ofri, MD, PhD, echoed the same sentiment; she devoted an entire bookopens in a new tab or window to lessons she learned from her patients. One of the most important, she believes, is learning what it feels like to actually be a patient — in her case, the humiliation and helplessness she felt both during and after giving birth.
In addition to assuming the patient role, listening carefully to our patients, especially the pooropens in a new tab or window and others who are disadvantaged, helps physicians grow, because learning how to overcome barriers to high-quality treatment — barriers such as poverty, poor access to care, time limits on interactions, bureaucratic red tape, and general mistrust of healthcare systems — enables physicians to adopt more personalized approaches to healthcare. Clearly, if we accept our patients as teachers, they will infuse elements of humanismopens in a new tab or window in our training and practice. Patients have been known to “define our work, instantiate our values, and shape our identitiesopens in a new tab or window,” much like Rockwell aided Erikson. It is not unreasonable to expect that doctors who are exposed to diverse communities will develop strong clinical skills, become patient advocates, and contribute to a vibrant physician workforce.
It’s been saidopens in a new tab or window that medicine is an art whose magic and creative ability reside in the interpersonal aspects of physician-patient relationships. Too often, however, medical practice has become stymied by tasks that need completing and patients that need complex services. Grinding through our day, we lose sight of what a special role we can play in patients’ lives. It is only when we rediscover our passion for the practice of medicine and embrace our mission — to serve the sufferingopens in a new tab or window — that we realize we have the power to transform patients, and in doing so, transform ourselves.
Arthur Lazarus, MD, MBA, is a member of the Physician Leadership Journal editorial board and an adjunct professor of psychiatry at the Lewis Katz School of Medicine at Temple University in Philadelphia.
Clinicians should prepare now for the possibility of having to diagnose and treat cases of monkeypox, according to an opinion paper published in Annals of Internal Medicine.
“Physicians should be communicating [to patients] that if they have high-risk sexual contacts and have known contact with somebody who may have had monkeypox-like lesions, they should seek medical attention,” Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security and an adjunct assistant professor at the Johns Hopkins Bloomberg School of Public Health, told Healio.
Monkeypox rash.
Specifically, physicians in primary care, urgent care, emergency medicine, dermatology and sexually transmitted infection (STI) clinics “may be most likely to identify new patients with monkeypox should they continue to appear,” Adalja and Tom Inglesby, MD, the director of the Johns Hopkins Center for Health Security at the Bloomberg School of Public Health, wrote.
Monkeypox virus is in the same orthopoxvirus family as smallpox. The virus had not been detected outside of Africa before 2003, according to Adalja and Inglesby.
Amesh Adalja
According to the Center for Infectious Disease Research and Policy, at least 226 cases of monkeypox have recently been identified in 21 countries, including the U.S., Canada and countries in Europe. The in the U.S.
“What distinguishes these cases — all of which are outside the endemic region of the virus — is that person-to-person transmission is occurring, with the majority of cases seemingly unlinked to travel from an endemic country and the appearance of multiple, as-yet unlinked clusters,” Adalja and Inglesby wrote. “This suggests that undetected chains of transmission have been occurring.”
Spread
While the CDC noted that there is a “theoretical risk” for airborne transmission of monkeypox, it is mainly spread from close contact with the skin or fluid of an infected person. In the past, the most consistent source of transmission was through contact with animals, according to Adalja and Inglesby. More recent cases seem to be congregated among men who have sex with men (MSM), and many new infections are being diagnosed at STI clinics, the authors reported.
Incubation of the virus ranges from 5 to 21 days, with a contagious risk occurring when symptoms begin. The mortality risk from infection ranges from 1% to 10%, depending on the availability of medical resources.
Diagnosis
Patients with new onset of febrile illness and rash should be evaluated for monkeypox, according to Adalja and Inglesby. The presence of lymphadenopathy is also a warning sign.
The top clues to watch out for with monkeypox are rash, fever and swollen lymph nodes. Attention should be paid to lesions as well as patients’ social histories due to the disproportionate prevalence of monkeypox among MSM, Adalja said.
Rashes usually start in the mouth before moving to the face and body “in a centrifugal pattern,” Adalja and Inglesby wrote. A PCR test of skin lesions or fluid can confirm a diagnosis. A high suspicion of infection warrants testing.
Treatment
Adalja and Inglesby reported that smallpox antivirals with poxvirus activity such as Vistide (cidofovir, Gilead Sciences), Tembexa (brincidofovir, Chimerix) and TPOXX (tecovirimat, SIGA Technologies Inc) may be used against monkeypox. No standard-of-care treatment for the virus currently exists and only anecdotal reports suggest benefit with antivirals.
“Most patients are not going to have severe enough infection to merit antiviral treatment, but it will be important to study the use of antivirals during this outbreak,” Adalja said.
Researchers behind a British retrospective observational study recently published in The Lancet Infectious Diseases evaluated the use of off-label antivirals administered to seven patients with monkeypox that were detected from 2018 to 2021. Three patients were treated with 200 mg of brincidofovir once weekly; all three patients developed elevated liver enzymes and were forced to suspend therapy. Meanwhile, one patient was treated with 200 mg of tecovirimat twice daily for 2 weeks. This patient experienced no adverse effects and had a shorter duration of viral shedding and illness.
The cohort in this study was too small to conclude any benefit or harm from antivirals for “this neglected tropical disease,” Hugh Adler,MB, BCh, BAO, MRCPI, DTM&H, of the Liverpool School of Tropical Medicine, and colleagues reported.
Overall, “the disease course of the patients … were challenging and resource-intensive to manage, even in the high-income setting of the U.K.,” they wrote.
Prevention
The smallpox vaccine Jynneos (Bavarian Nordic) has an FDA indication for the prevention of monkeypox, and an older-generation vaccine (ACAM2000, Sanofi Pasteur Biologics Co.) may be used off-label for monkeypox, according to Adalja and Inglesby. Clinicians who administer either vaccine immediately after a suspected exposure can “abort infection or significantly attenuate it,” they wrote. For patients who cannot receive the smallpox vaccines, vaccinia immune globulin may be administered.
While researchers attempt to uncover what is driving this outbreak of monkeypox, clinicians should apply “enhanced case finding, isolation, contact tracing and postexposure vaccination,” the authors advised. Any new cases of monkeypox should be reported to a state or local health department immediately.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.
The most common surgical treatment for Parkinson’s disease is deep brain stimulation (DBS). Similar to available drug treatments, DBS does not slow down the disease or restore sick and dying nerve cells affected by Parkinson’s disease, but rather offers symptomatic benefits. In DBS, a thin electrode is implanted into the brain, targeting motor circuits that are not functioning properly. Small electrical pulses from a device similar to a cardiac pacemaker are then used to stimulate a small brain region and block the signals that cause some Parkinson’s symptoms.
This past November, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) hosted a Webinarfeaturing Dr. William J. Marks, Jr. discussing DBS. Participants in the Webinar had additional questions which Dr. Marks has answered below:
MJFF: When in the disease course is DBS recommended?
WM: The standard answer is that DBS is intended to be used for “advanced Parkinson’s disease,” but that phrase isn’t all that practically helpful and may be misleading. A better way to think about DBS candidacy is that it should be considered when motor problems produced in PD (slowness, stiffness, shaking, walking problems, wearing off of medication, fluctuations of motor symptoms, dyskinesia) are no longer sufficiently treated by an optimized medication regimen.
MJFF: How does a physician decide whether to recommend DBS?
WM: A physician will assess the extent to which PD motor symptoms are sufficiently controlled (from the patient’s perspective) to determine whether and when to recommend DBS. One effective means for assessing this is to consider what percentage of the day motor symptoms are adequately controlled and what percentage of the day they are not. If motor symptoms present difficulty for a significant extent of the day (perhaps 20 percent or greater) it may be an indicator of insufficient medication control. Another important factor is how severe motor symptoms are when they do emerge, and the extent to which they interfere with a person’s ability to engage in the everyday activities of a patient’s life.
MJFF: Can DBS be performed too early or too late in the course of PD?
WM: Currently, many would consider the use of DBS to be “too early” if all PD motor symptoms for a patient were adequately controlled through the entire day with a medication regimen that produced no unacceptable side effects. “Too late” refers to the concept that in the later stages of PD, for some patients, they may develop symptoms that do not respond to medication or to DBS, such as severe balance problems or significant cognitive difficulties. These resistant symptoms might be responsible for disability and their persistence would overshadow any benefit to motor symptoms that DBS might provide. If a patient has become severely disabled for a long period of time, it may be more difficult to “rescue” individuals than it would have been to use DBS as a preventative measure.
MJFF: Is there an age limit for DBS?
WM: There is no absolute age cut-off for use of DBS although some centers find that older (70 or above) patients may not experience as robust a response as younger patients. Other factors (such as types of symptoms present, responsiveness to levodopa, cognitive function) are probably more important to consider than age per se.
MJFF: What symptoms does DBS treat? Which does it not treat?
WM: Most patients find that DBS is just as effective as a successful levodopa regimen in treating:
Slowness or lack of movement (bradykinesia and akinesia)
Stiffness of muscles (rigidity)
Shaking of the limbs (tremor)
Gait problems that remain responsive to levodopa
Mild balance problems that remain responsive to levodopa
Motor fluctuation (variations in level of motor symptoms and their control by medication)
Dyskinesia (involuntary, excessive movements of the body, usually occurring when medications peak)
Dystonia (painful abnormal muscle activation that causes toe curling or twisting of hand or feet)
Nighttime motor symptoms that emerge due to lack of frequent medication doses
Body pain from PD (sometimes)
As with levodopa, DBS does not typically improve:
Speech problems
Swallowing problems
Cognitive problems
Mood problems (depression, anxiety)
Freezing of gait or other movement that occurs when medications are working at their best
Moderate or greater balance problems
Bladder, bowel, or sexual dysfunction
MJFF: How common are infections associated with DBS?
WM: Clinical experience and formal studies commonly show an infection rate of three to four percent. Such infections most commonly occur in the chest region at the site where the neurostimulator (“pacemaker”) is implanted. Infections most commonly occur weeks or months after the surgical procedure to implant the device. Treatment usually entails removal of the device component in the infected area, treatment with intravenous antibiotics, and then re-implantation of a brand new replacement device. In cases where the infection involves the chest region, usually the brain leads can be left in place (as long as the infection has not spread), so that no additional brain surgery would be required. Rarely, infection can originate in the brain at the level of the electrode which can be more serious, and in some cases require the removal and re-implantation of the electrode.
MJFF: What causes the infections?
WM: Any time the human body is opened during surgery—and particularly when foreign objects like medical devices are inserted inside—bacteria and other organisms can enter, grow, and cause an infection. Other possible sources of infection arise from the bloodstream and can “seed” other parts of the body, though this mechanism is less likely.
A revised and updated drug-free RA protocol based on a pioneering rheumatoid arthritis treatment tends to provide a 60-90 percent improvement rate in most RA sufferers
Important aspects of the treatment protocol include dietary modifications, low-dose Naltrexone, optimizing your vitamin D levels, astaxanthin, probiotics (preferably in the form of fermented foods), and getting regular exercise
Pain control is an important aspect of treating RA. Ideally, you’ll want to use the safest drugs and only when necessary, with the ultimate goal of managing your pain without medications. Some of the safest prescription drugs for pain are the non-acetylated salicylates, such as salsalate, sodium salicylate, and magnesium salicylate (i.e. Salflex, Disalcid, or Trilisate).
Rheumatoid arthritis affects about one percent of our population and at least two million Americans have definite or classical rheumatoid arthritis. This number has increased in recent years, as in 2010 about 2.5 percent of white women developed RA.
It is a much more devastating illness than previously appreciated. Most patients with rheumatoid arthritis have a progressive disability.
The natural course of rheumatoid arthritis is quite remarkable in that less than one percent of people with the disease have a spontaneous remission. Some disability occurs in 50-70 percent of people within five years after onset of the disease, and half will stop working within 10 years. The annual cost of this disease in the U.S. is estimated to be over $1 billion.
This devastating prognosis is what makes this novel form of treatment so exciting, as it has a far higher likelihood of succeeding than the conventional approach.
Over the years I have treated over 3,000 patients with rheumatic illnesses, including SLE, scleroderma, polymyositis and dermatomyositis.
Approximately 15 percent of these patients were lost to follow-up for whatever reason and have not continued with treatment. The remaining patients seem to have a 60-90 percent likelihood of improvement on this treatment regimen.
This level of improvement is quite a stark contrast to the typical numbers quoted above that are experienced with conventional approaches, and certainly a strong motivation to try the protocol I discuss below.
Rheumatoid Arthritis Can Be Deadlier Than Heart Disease
There is also an increased mortality rate with this disease. The five-year survival rate of patients with more than 30 joints involved is approximately 50 percent. This is similar to severe coronary artery disease or stage IV Hodgkin’s disease.
Thirty years ago, one researcher concluded that there was an average loss of 18 years of life in patients who developed rheumatoid arthritis before the age of 50.
Most authorities believe that remissions rarely occur. Some experts feel that the term “remission-inducing” should not be used to describe ANY current rheumatoid arthritis treatment, and a review of contemporary treatment methods shows that medical science has not been able to significantly improve the long-term outcome of this disease.
Dr. Brown Pioneered a Novel Approach to Treat Rheumatoid Arthritis
I first became aware of Doctor Brown’s protocol in 1989 when I saw him on 20/20 on ABC. This was shortly after the introduction of the first edition of his book, The Road Back.
Unfortunately, Dr. Brown died from prostate cancer shortly after the 20/20 program, so I never had a chance to meet him.
My application of Dr. Brown’s protocol has changed significantly since I first started implementing it. Initially, I rigidly followed Dr. Brown’s work with minimal modifications to his protocol.
About the only change I made was changing Tetracycline to Minocin. I believe I was one of the first physicians who recommended the shift to Minocin, and most people who use his protocol now use Minocin.
In 1939, Dr. Sabin, the discoverer of the polio vaccine, first reported chronic arthritis in mice caused by a mycoplasma. He suggested this agent might cause human rheumatoid arthritis. Dr. Brown worked with Dr. Sabin at the Rockefeller Institute.
Dr. Brown was a board certified rheumatologist who graduated from Johns Hopkins medical school. He was a professor of medicine at George Washington University until 1970 where he served as chairman of the Arthritis Institute in Arlington, Virginia. He published over 100 papers in peer reviewed scientific literatureHe was able to help over 10,000 patients when he used this program, from the 1950s until his death in 1989, and clearly far more than that have been helped by other physicians using this protocol.
He found that significant benefits from the treatment require, on average, about one to two years.
I have treated nearly 3000 patients and find that thedietary modificationI advocate, which I started to integrate in the early 1990s, accelerates the response rate to several months. I cannot emphasize strongly enough the importance of this aspect of the program.
Still, the length of therapy can vary widely.
In severe cases, it may take up to 30 months for patients to gain sustained improvement. One requires patience because remissions may take up to three to five years. Dr. Brown’s pioneering approach represents a safer, less toxic alternative to many conventional regimens and results of the NIH trial have finally scientifically validated this treatment.
The dietary changes are absolutely an essential component of my protocol. Dr. Brown’s original protocol was notorious for inducing a Herxheimer, or worsening of symptoms, before improvement was noted. This could last two to six months. Implementing my nutrition plan resulted in a lessening of that reaction in most cases.
When I first started using his protocol for patients in the late ’80s, the common retort from other physicians was that there was “no scientific proof” that this treatment worked. Well, that is certainly not true today. A review of the bibliography will provide over 200 references in the peer-reviewed medical literature that supports the application of Minocin in the use of rheumatic illnesses.
In my experience, nearly 80 percent of people do remarkably better with this program. However, approximately five percent continue to worsen and require conventional agents, like methotrexate, to relieve their symptoms.
Scientific Proof for This Approach
The definitive scientific support for minocycline in the treatment of rheumatoid arthritis came with the MIRA trial in the United States. This was a double blind randomized placebo controlled trial done at six university centers involving 200 patients for nearly one year. The dosage they used (100 mg twice daily) was much higher and likely less effective than what most clinicians currently use.
They also did not employ any additional antibiotics or nutritional regimens, yet 55 percent of patients improved. This study finally provided the “proof” that many traditional clinicians demanded before seriously considering this treatment as an alternative regimen for rheumatoid arthritis.
Dr. Thomas Brown’s effort to treat the chronic mycoplasma infections believed to cause rheumatoid arthritis is the basis for this therapy. Dr. Brown believed that most rheumatic illnesses respond to this treatment. He and others used this therapy for SLE, ankylosing spondylitis, scleroderma, dermatomyositis, and polymyositis.
Dr. Osler was one of the most well respected and prominent physicians of his time (1849- 1919), and many regard him as the consummate physician of modern times. An excerpt from a commentary on Dr. William Osler provides a useful perspective on application of alternative medical paradigms:
Osler would caution us against the arrogance of believing that only our current medical practices can benefit the patient. He would realize that new scientific insights might emerge from as yet unproved beliefs. Although he would fight vigorously to protect the public against frauds and charlatans, he would encourage critical study of whatever therapeutic approaches were reliably reported to be beneficial to patients.
Factors Associated with Your Success on This Program
There are many variables associated with an increased chance of remission or improvement.
The younger you are, the greater your chance for improvement
The more closely you follow thenutrition plan, the more likely you are to improve and the less likely you are to have a severe flare-up. I now offer theNutritional Typing Test for free, so please do not skip this essential step.
Smoking seems to be negatively associated with improvement
The longer you have had the illness and the more severe the illness, the more difficult it seems to treat
Revised Antibiotic-Free Approach
Although I used a revision of his antibiotic approach for nearly 10 years, my particular prejudice is to focus on natural therapies. The program that follows is my revision of this protocol that allows for a completely drug-free treatment of RA,which is based on my experience of treating over 3000 patients with rheumatic illnesses in my Chicago clinic.
If you are interested in reviewing or considering Dr. Brown’s antibiotic approach, I have included a summary of his work and the evidence for it in the appendix.
Crucial Lifestyle Changes
Improving your diet using a combination of my nutritional guidelines, nutritional typing is crucial for your success. In addition, there are some general principles that seem to hold true for all nutritional types and these include:
Eliminating sugar, especiallyfructose, and most grains. For most people it would be best to limit fruit to small quantities
Eating unprocessed, high-quality foods, organic and locally grown if possible
Eating your food as close to raw as possible
Getting plenty high-quality, animal-based omega-3 fats. Krill oil seems to be particularly helpful here as it appears to be a more effective anti inflammatory preparation. It is particularly effective if taken concurrently with 4 mg of Astaxanthin, which is a potent antioxidant bioflavanoid derived from algae
Astaxanthin at 4 mg per day is particularly important for anyone placed on prednisone as Astaxanthin offers potent protection against cataracts and age related macular degeneration
Early Emotional Traumas Are Pervasive in Those with Rheumatoid Arthritis
With the vast majority of the patients I treated, some type of emotional trauma occurred early in their life, before the age their conscious mind was formed, which is typically around the age of 5 or 6. However, a trauma can occur at any age, and has a profoundly negative impact.
If that specific emotional insult is not addressed with an effective treatment modality then the underlying emotional trigger will continue to fester, allowing the destructive process to proceed, which can predispose you to severe autoimmune diseases like RA later in life.
In some cases, RA appears to be caused by an infection, and it is my experience that this infection is usually acquired when you have a stressful event that causes a disruption in your bioelectrical circuits, which then impairs your immune system.
This early emotional trauma predisposes you to developing the initial infection, and also contributes to your relative inability to effectively defeat the infection.
Therefore, it’s very important to have an effective tool to address these underlying emotional traumas. In my practice, the most common form of treatment used is called the Emotional Freedom Technique (EFT).
Although EFT is something that you can learn to do yourself in the comfort of your own home, it is important to consult a well-trained professional to obtain the skills necessary to promote proper healing using this amazing tool.
Vitamin D Deficiency Rampant in Those with Rheumatoid Arthritis
The early part of the 21st century brought enormous attention to the importance and value of vitamin D, particularly in the treatment of autoimmune diseases like RA.
From my perspective, it is now virtually criminal negligent malpractice to treat a person with RA and not aggressively monitor theirvitamin D levelsto confirm that they are in a therapeutic range of 65-80 ng/ml.
This is so important that blood tests need to be done every two weeks, so the dose can be adjusted to get into that range. Most normal-weight adults should start at 10,000 units of vitamin D per day.
If you are in the US, then Lab Corp is the lab of choice.
One new addition to the protocol is low-dose Naltrexone, which I would encourage anyone with RA to try. It is inexpensive and non-toxic and I have a number of physician reports documenting incredible efficacy in getting people off of all their dangerous arthritis meds.
Although this is a drug, and strictly speaking not a natural therapy, it has provided important relief and is FAR safer than the toxic drugs that are typically used by nearly all rheumatologists.
Nutritional Considerations
Limiting sugar is a critical element of the treatment program. Sugar has multiple significant negative influences on your biochemistry. First and foremost, it increases your insulin levels, which is the root cause of nearly all chronic disease. It can also impair your gut bacteria.
In my experience if you are unable to decrease your sugar intake, you are far less likely to improve. Please understand that the number one source of calories in the US is high fructose corn syrup from drinking soda. One of the first steps you can take is to phase out all soda, and replace it with pure, clean water.
Exercise for Rheumatoid Arthritis
It is very important to exercise and increase muscle tone of your non-weight bearing joints. Experts tell us that disuse results in muscle atrophy and weakness. Additionally, immobility may result in joint contractures and loss of range of motion (ROM). Active ROM exercises are preferred to passive.
There is some evidence that passive ROM exercises increase the number of white blood cells (WBCs) in your joints.
If your joints are stiff, you should stretch and apply heat before exercising. If your joints are swollen, application of 10 minutes of ice before exercise would be helpful.
The inflamed joint is very vulnerable to damage from improper exercise, so you must be cautious. People with arthritis must strike a delicate balance between rest and activity, and must avoid activities that aggravate joint pain. You should avoid any exercise that strains a significantly unstable joint.
A good rule of thumb is that if the pain lasts longer than one hour after stopping exercise, you should slow down or choose another form of exercise. Assistive devices are also helpful1 to decrease the pressure on affected joints. Many patients need to be urged to take advantage of these. The Arthritis Foundation has a book, Guide to Independent Living, which instructs patients about how to obtain them.
Of course, it is important to maintain good cardiovascular fitness as well. Walking with appropriate supportive shoes is another important consideration.
If your condition allows, it would be wise to move toward a Peak Fitness program that is designed for reaching optimal health.
It’s Important to Control Your Pain
One of the primary problems with RA is controlling pain. The conventional treatment typically includes using very dangerous drugs like prednisone, methotrexate, and drugs that interfere with tumor necrosis factor, like Enbrel.
The goal is to implement the lifestyle changes discussed above as quickly as possible, so you can start to reduce these toxic and dangerous drugs, which do absolutely nothing to treat the cause of the disease.
However, pain relief is obviously very important, and if this is not achieved, you can go into a depressive cycle that can clearly worsen your immune system and cause the RA to flare.
So the goal is to be as comfortable and pain free as possible with the least amount of drugs. The Mayo Clinic offers several common sense guidelines2 for avoiding pain by paying heed to how you move, so as to not injure your joints.
Safest Anti-Inflammatories to Use for Pain
Clearly the safest prescription drugs to use for pain are the non-acetylated salicylates such as:
Salsalate
Sodium salicylate
Magnesium salicylate (i.e., Salflex, Disalcid, or Trilisate)
They are the drugs of choice if there is renal insufficiency, as they minimally interfere with anticyclooxygenase and other prostaglandins.
Additionally, they will not impair platelet inhibition in those patients who are on an every-other-day aspirin regimen to decrease their risk for stroke or heart disease.
Unlike aspirin, they do not increase the formation of products of lipoxygenase-mediated metabolism of arachidonic acid. For this reason, they may be less likely to cause hypersensitivity reactions. These drugs have been safely used in patients with reversible obstructive airway disease and a history of aspirin sensitivity.
They are also much gentler on your stomach than the other NSAIDs and are the drug of choice if you have problems with peptic ulcer disease. Unfortunately, all these benefits are balanced by the fact that they may not be as effective as the other agents and are less convenient to take. You need to take 1.5-2 grams twice a day, and tinnitus, or ringing in your ear, is a frequent side effect.
You need to be aware of this complication and know that if tinnitus does develop, you need to stop the drugs for a day and restart with a dose that is half a pill per day lower. You can repeat this until you find a dose that relieves your pain and doesn’t cause any ringing in your ears.
If the Safer Anti-Inflammatories Aren’t Helping, Try This Next…
If the non-acetylated salicylates aren’t helping, there are many different NSAIDs to try. Relafen, Daypro, Voltaren, Motrin, Naprosyn. Meclomen, Indocin, Orudis, and Tolectin are among the most toxic or likely to cause complications. You can experiment with them, and see which one works best for you.
If cost is a concern, generic ibuprofen can be used at up to 800 mg per dose. Unfortunately, recent studies suggest this drug is more damaging to your kidneys.
If you use any of the above drugs, though, it is really important to make sure you take them with your largest meal as this will somewhat moderate their GI toxicity and the likelihood of causing an ulcer.
Please beware that they are much more dangerous than the antibiotics or non-acetylated salicylates.
You should have an SMA blood test performed at least once a year if you are on these medications. In addition, you must monitor your serum potassium levels if you are on an ACE inhibitor as these medications can cause high potassium levels. You should also monitor your kidney function. The SMA will show any liver impairment the drugs might be causing.
These medications can also impair prostaglandin metabolism and cause papillary necrosis and chronic interstitial nephritis. Your kidney needs vasodilatory prostaglandins (PGE2 and prostacyclin) to counterbalance the effects of potent vasoconstrictor hormones such as angiotensin II and catecholamines. NSAIDs decrease prostaglandin synthesis by inhibiting cyclooxygenase, leading to unopposed constriction of the renal arterioles supplying your kidney.
Warning: These Drugs Massively Increase Your Risk for Ulcers
The first non-aspirin NSAID, indomethacin, was introduced in 1963. Now more than 30 are available. Relafen is one of the better alternatives as it seems to cause less of an intestinal dysbiosis.
You must be especially careful to monitor renal function periodically. It is important to understand and accept the risks associated with these more toxic drugs.
Every year, they do enough damage to the GI tract to kill 2,000 to 4,000 people with rheumatoid arthritis alone. That is 10 people EVERY DAY. At any given time, 10 to 20 percent of all those receiving NSAID therapy have gastric ulcers.
If you are taking an NSAID, you are at approximately three times greater risk for developing serious gastrointestinal side effects than those who don’t.
Approximately 1.2 percent of patients taking NSAIDs are hospitalized for upper GI problems, per year of exposure. One study of patients taking NSAIDs showed that a life-threatening complication was the first sign of ulcer in more than half of the subjects.
Researchers found that the drugs suppress production of prostacyclin, which is needed to dilate blood vessels and inhibit clotting. Earlier studies had found that mice genetically engineered to be unable to use prostacyclin properly were prone to clotting disorders.
Anyone who is at increased risk of cardiovascular disease should steer clear of these medications. Ulcer complications are certainly potentially life-threatening, but heart attacks are a much more common and likely risk, especially in older individuals.
How You Can Tell if You Are at Risk for NSAID Side Effects
Risk factor analysis can help determine if you will face an increased danger of developing these complications. If you have any of the following, you will likely to have a higher risk of side effects from these drugs:
Old age
Peptic ulcer history
Alcohol dependency
Cigarette smoking
Concurrent prednisone or corticosteroid use
Disability
Taking a high dose of the NSAID
Using an NSAID known to be more toxic
Prednisone
The above drug class are called non steroidal anti inflammatories (NSAIDs). If they are unable to control the pain, then prednisone is nearly universally used. This is a steroid drug that is loaded with side effects.
If you are on large doses of prednisone for extended periods of time, you can be virtually assured that you will develop the following problems:
Osteoporosis
Cataracts
Diabetes
Ulcers
Herpes reactivation
Insomnia
Hypertension
Kidney stones
You can be virtually assured that every time you take a dose of prednisone your bones are becoming weaker. The higher the dose and the longer you are on prednisone, the more likely you are to develop the problems.
However, if you are able to keep your dose to 5 mg or below, this is not typically a major issue.
Typically this is one of the first medicines you should try to stop as soon as your symptoms permit.
Beware that blood levels of cortisol peak between 3 and 9am. It would, therefore, be safest to administer the prednisone in the morning. This will minimize the suppression on your hypothalamic-pituitary-adrenal axis.
You also need to be concerned about the increased risk of peptic ulcer disease when using this medicine with conventional non-steroidal anti-inflammatories. If you are taking both of these medicines, you have a 15 times greater risk of developing an ulcer!
If you are already on prednisone, it is helpful to get a prescription for 1 mg tablets so you can wean yourself off the prednisone as soon as possible. Usually you can lower your dose by about 1 mg per week. If a relapse of your symptoms occurs, then further reduction of the prednisone is not indicated.
How Do You Know When to Stop the Drugs?
Unlike conventional approaches to RA, my protocol is designed to treat the underlying cause of the problem. So eventually the drugs that you are going to use during the program will be weaned off.
The following criteria can help determine when you are in remission and can consider weaning off your medications:
A decrease in duration of morning stiffness to no more than 15 minutes
No pain at rest
Little or no pain or tenderness on motion
Absence of joint swelling
A normal energy level
A decrease in your ESR to no more than 30
A normalization of your CBC. Generally your HGB, HCT, & MCV will increase to normal and your “pseudo”-iron deficiency will disappear
ANA, RF, & ASO titers returning to normal
If you discontinue your medications before all of the above criteria are met, there is a greater risk that the disease will recur.
If you meet the above criteria, you can try to wean off your anti-inflammatory medication and monitor for flare-ups. If no flare-ups occur for six months, then discontinue the clindamycin.
If the improvements are maintained for the next six months, you can then discontinue your Minocin and monitor for recurrences. If symptoms should recur, it would be wise to restart the previous antibiotic regimen.
Evaluation to Determine and Follow Rheumatoid Arthritis
If you have received evaluations and treatment by one or more board certified rheumatologists, you can be very confident that the appropriate evaluation was done. Although conventional treatments fail miserably in the long run, the conventional diagnostic approach is typically excellent, and you can start the treatment program discussed above.
If you have not been evaluated by a specialist then it will be important to be properly evaluated to determine if indeed you have rheumatoid arthritis.
Please be sure and carefully review Appendix Two, as you will want to confirm that fibromyalgia is not present.
Beware that arthritic pain can be an early manifestation of 20-30 different clinical problems.
These include not only rheumatic disease, but also metabolic, infectious and malignant disorders. Rheumatoid arthritis is a clinical diagnosis for which there is not a single test or group of laboratory tests that can be considered confirmatory.
Criteria for Classification of Rheumatoid Arthritis
Morning Stiffness – Morning stiffness in and around joints lasting at least one hour before maximal improvement is noted.
Arthritis of three or more joint areas – At least three joint areas have simultaneously had soft-tissue swelling or fluid (not bony overgrowth) observed by a physician. There are 14 possible joints: right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.
Arthritis of hand joints – At least one joint area swollen as above in a wrist, MCP, or PIP joint.
Symmetric arthritis – Simultaneous involvement of the same joint areas (as in criterion 2) on both sides of your body (bilateral involvement of PIPs, MCPs, or MTPs) is acceptable without absolute symmetry. Lack of symmetry is not sufficient to rule out the diagnosis of rheumatoid arthritis.
Rheumatoid Nodules – Subcutaneous nodules over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician. Only about 25 percent of patients with rheumatoid arthritis develop nodules, and usually as a later manifestation.
Serum Rheumatoid Factor – Demonstration of abnormal amounts of serum rheumatoid factor by any method that has been positive in less than 5 percent of normal control subjects. This test is positive only 30-40 percent of the time in the early months of rheumatoid arthritis.
You must also make certain that the first four symptoms listed in the table above are present for six or more weeks. These criteria have a 91-94 percent sensitivity and 89 percent specificity for the diagnosis of rheumatoid arthritis.
However, these criteria were designed for classification and not for diagnosis. The diagnosis must be made on clinical grounds. It is important to note that many patients with negative serologic tests can have a strong clinical picture for rheumatoid arthritis.
Your Hands Are the KEY to the Diagnosis of Rheumatoid Arthritis
In a way, the hands are the calling card of rheumatoid arthritis. If you completely lack hand and wrist involvement, even by history, the diagnosis of rheumatoid arthritis is doubtful. Rheumatoid arthritis rarely affects your hips and ankles early in its course.
The metacarpophalangeal joints, proximal interphalangeal and wrist joints are the first joints to become symptomatic. Osteoarthritis typically affects the joints that are closest to your fingertips (DIP joints) while RA typically affects the joints closest to your wrist (PIP), like your knuckles.
Fatigue may be present before your joint symptoms begin, and morning stiffness is a sensitive indicator of rheumatoid arthritis. An increase in fluid in and around your joint probably causes the stiffness. Your joints are warm, but your skin is rarely red.
When your joints develop effusions, hold them flexed at 5 to 20 degrees as it is likely going to be too painful to extend them fully.
Radiological Changes
Radiological changes typical of rheumatoid arthritis on PA hand and wrist X-rays, which must include erosions or unequivocal bony decalcification localized to, or most marked, adjacent to the involved joints (osteoarthritic changes alone do not count).
Note: You must satisfy at least four of the seven criteria listed. Any of criteria 1-4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designations as classic, definite, or probable rheumatoid arthritis, are not to be made.
Laboratory Evaluation
The general initial laboratory evaluation should include a baseline ESR, CBC, SMA, U/A, 25 hydroxy D level and an ASO titer. You can also draw RF and ANA titers to further objectively document improvement with the therapy. However, they seldom add much to the assessment.
Follow-up visits can be every two to four months depending on the extent of the disease and ease of testing.
The exception here would be vitamin D testing, which should be done every two weeks until your 25 hydroxy D level is between 65 and 80 ng/ml.
Many patients with rheumatoid arthritis have a hypochromic, microcytic CBC that appears very similar to iron deficiency, but it is not at all related. This is probably due to the inflammation in the rheumatoid arthritis impairing optimal bone marrow utilization of iron.
It is important to note that this type of anemia does NOT respond to iron and if you are put on iron you will get worse, as the iron is a very potent oxidative stress. Ferritin levels are generally the most reliable indicator of total iron body stores. Unfortunately it is also an acute phase reactant protein and will be elevated anytime the ESR is elevated. This makes ferritin an unreliable test in patients with rheumatoid arthritis.
Physicians Who Use This Protocol
Roadback.org is the oldest organization promoting this work and the one Dr. Brown originally worked with. They are an excellent resource to find health care professionals using this approach.
APPENDIX ONE: The Infectious Cause of Rheumatoid Arthritis
It is quite clear that autoimmunity plays a major role in the progression of rheumatoid arthritis. Most rheumatology investigators believe that an infectious agent causes rheumatoid arthritis. There is little agreement as to the involved organism, however.
Investigators have proposed the following infectious agents:
Human T-cell lymphotropic virus Type I
Rubella virus
Cytomegalovirus
Herpesvirus
Mycoplasma
This review will focus on the evidence supporting the hypothesis that mycoplasma is a common etiologic agent of rheumatoid arthritis.
Mycoplasmas are the smallest self-replicating prokaryotes. They differ from classical bacteria by lacking rigid cell wall structures and are the smallest known organisms capable of extracellular existence. They are considered parasites of humans, animals, and plants.
Culturing Mycoplasmas from Joints
Mycoplasmas have limited biosynthetic capabilities and are very difficult to culture and grow from synovial tissues. They require complex growth media or a close parasitic relation with animal cells. This contributed to many investigators’ failure to isolate them from arthritic tissue.
In reactive arthritis, immune complexes rather than viable organisms localize in your joints. The infectious agent is actually present at another site. Some investigators believe that the organism binding in the immune complex contributes to the difficulty in obtaining positive mycoplasma cultures.
Despite this difficulty, some researchers have successfully isolated mycoplasma from synovial tissues of patients with rheumatoid arthritis. A British group used a leucocyte-migration inhibition test and found two-thirds of their rheumatoid arthritis patients to be infected with Mycoplasma fermentens. These results are impressive since they did not include more prevalent Mycoplasma strains like M salivarium, M ovale, M hominis, and M pneumonia.
One Finnish investigator reported a 100 percent incidence of isolation of mycoplasma from 27 rheumatoid synovia using a modified culture technique. None of the non-rheumatoid tissue yielded any mycoplasmas.
The same investigator used an indirect hemagglutination technique and reported mycoplasma antibodies in 53 percent of patients with definite rheumatoid arthritis. Using similar techniques, other investigators have cultured mycoplasma in 80-100 percent of their rheumatoid arthritis test population.
Rheumatoid arthritis can also follow some mycoplasma respiratory infections.
One study of over 1,000 patients was able to identify arthritis in nearly one percent of the patients. These infections can be associated with a positive rheumatoid factor. This provides additional support for mycoplasma as an etiologic agent for rheumatoid arthritis. Human genital mycoplasma infections have also caused septic arthritis.
Harvard investigators were able to culture mycoplasma or a similar organism, ureaplasma urealyticum, from 63 percent of female patients with SLE and only four percent of patients with CFS. The researchers chose CFS, as these patients shared similar symptoms as those with SLE, such as fatigue, arthralgias, and myalgias.
Animal Evidence for the Protocol
The full spectrum of human rheumatoid arthritis immune responses (lymphokine production, altered lymphocyte reactivity, immune complex deposition, cell-mediated immunity, and development of autoimmune reactions) occurs in mycoplasma induced animal arthritis
Investigators have implicated at least 31 different mycoplasma species.
Mycoplasma can produce experimental arthritis in animals from three days to months later. The time seems to depend on the dose given, and the virulence of the organism.
There is a close degree of similarity between these infections and those of human rheumatoid arthritis.
Mycoplasmas cause arthritis in animals by several mechanisms. They either directly multiply within the joint or initiate an intense local immune response.
Arthritogenic mycoplasmas also cause joint inflammation in animals by several mechanisms. They induce nonspecific lymphocyte cytotoxicity and antilymphocyte antibodies as well as rheumatoid factor.
Mycoplasma clearly causes chronic arthritis in mice, rats, fowl, swine, sheep, goats, cattle, and rabbits. The arthritis appears to be the direct result of joint infection with culturable mycoplasma organisms.
Gorillas have tissue reactions closer to man than any other animal, and investigators have shown that mycoplasma can precipitate a rheumatic illness in gorillas. One study demonstrated that mycoplasma antigens do occur in immune complexes in great apes.
The human and gorilla IgG are very similar and express nearly identical rheumatoid factors (IgM anti-IgG antibodies). The study showed that when mycoplasma binds to IgG it can cause a conformational change. This conformational change results in an anti-IgG antibody, which can then stimulate an autoimmune response.
The Science of Why Minocycline Is Used
If mycoplasma were a causative factor in rheumatoid arthritis, one would expect tetracycline type drugs to provide some sort of improvement in the disease. Collagenase activity increases in rheumatoid arthritis and probably has a role in its cause.
Investigators have demonstrated that tetracycline and minocycline inhibit leukocyte, macrophage, and synovial collagenase.
There are several other aspects of tetracyclines that may play a role in rheumatoid arthritis. Investigators have shown minocycline and tetracycline to retard excessive connective tissue breakdown and bone resorption, while doxycycline inhibits digestion of human cartilage.
It is also possible that tetracycline treatment improves rheumatic illness by reducing delayed-type hypersensitivity response. Minocycline and doxycycline both inhibit phosolipases, which are considered proinflammatory and capable of inducing synovitis.
Minocycline is a more potent antibiotic than tetracycline and penetrates tissues better.
These characteristics shifted the treatment of rheumatic illness away from tetracycline to minocycline. Minocycline may benefit rheumatoid arthritis patients through its immunomodulating and immunosuppressive properties. In vitro studies have demonstrated a decreased neutrophil production of reactive oxygen intermediates along with diminished neutrophil chemotaxis and phagocytosis.
Minocycline has also been shown to reduce the incidence and severity of synovitis in animal models of arthritis. The improvement was independent of minocycline’s effect on collagenase.
Minocycline has also been shown to increase intracellular calcium concentrations that inhibit T-cells.
Individuals with the Class II major histocompatibility complex (MHC) DR4 allele seem to be predisposed to developing rheumatoid arthritis.
The infectious agent probably interacts with this specific antigen in some way to precipitate rheumatoid arthritis. There is strong support for the role of T cells in this interaction.
So minocycline may suppress rheumatoid arthritis by altering T cell calcium flux and the expression of T cell derived from collagen binding protein. Minocycline produced a suppression of the delayed hypersensitivity in patients with Reiter’s syndrome, and investigators also successfully used minocycline to treat the arthritis and early morning stiffness of Reiter’s syndrome.
Clinical Studies
In 1970, investigators at Boston University conducted a small, randomized placebo-controlled trial to determine if tetracycline would treat rheumatoid arthritis. They used 250 mg of tetracycline a day.
Their study showed no improvement after one year of tetracycline treatment. Several factors could explain their inability to demonstrate any benefits.
Their study used only 27 patients for a one-year trial, and only 12 received tetracycline, so noncompliance may have been a factor. Additionally, none of the patients had severe arthritis. Patients were excluded from the trial if they were on any anti-remittive therapy.
Finnish investigators used lymecycline to treat the reactive arthritis in Chlamydia trachomatous infections. Their study compared the effect of the medication in patients with two other reactive arthritis infections: Yersinia and Campylobacter.
Lymecyline produced a shorter course of illness in the Chlamydia induced arthritis patients, but did not affect the other enteric infections-associated reactive arthritis. The investigators later published findings that suggested lymecycline achieved its effect through non-antimicrobial actions. They speculated it worked by preventing the oxidative activation of collagenase.
The first trial of minocycline for the treatment of animal and human rheumatoid arthritis was published by Breedveld. In the first published human trial, Breedveld treated 10 patients in an open study for 16 weeks. He used a very high dose of 400 mg per day. Most patients had vestibular side effects resulting from this dose.
However, all patients showed benefit from the treatment, and all variables of efficacy were significantly improved at the end of the trial.
Breedveld expanded on his initial study and later observed similar impressive results. This was a 26-week double-blind placebo-controlled randomized trial with minocycline for 80 patients.
They were given 200 mg twice a day.
The Ritchie articular index and the number of swollen joints significantly improved (p < 0.05) more in the minocyline group than in the placebo group.
Investigators in Israel studied 18 patients with severe rheumatoid arthritis for 48 weeks.
These patients had failed two other DMARD. They were taken off all DMARD agents and given minocycline 100 mg twice a day. Six patients did not complete the study — three withdrew because of lack of improvement, and three had side effects of vertigo or leukopenia.
All patients completing the study improved. Three had complete remission, three had substantial improvement of greater than 50 percent, and six had moderate improvement of 25 percent in the number of active joints and morning stiffness.
APPENDIX TWO: Make Certain You are Assessed for Fibromyalgia
You need to be very sensitive to this condition when you have rheumatoid arthritis as it is frequently a complicating condition. Many times, the pain will be confused with a flare-up of the RA.
You need to aggressively treat this problem. If it is ignored, the likelihood of successfully treating the arthritis is significantly diminished.
Fibromyalgia is a very common problem. Some experts believe that five percent of people are affected with it. Over 12 percent of the patients at the Mayo Clinic’s Department of Physical
Medicine and Rehabilitation have this problem, and it is the third most common diagnosis by rheumatologists in the outpatient setting. Fibromyalgia affects women five times as frequently as men.
Signs and Symptoms of Fibromyalgia
One of the main features offibromyalgiais morning stiffness, fatigue, and multiple areas of tenderness in typical locations. Most people with fibromyalgia complain of pain over many areas of their body, with an average of six to nine locations. Although the pain is frequently described as being “all over,” it is most prominent in the neck, shoulders, elbows, hips, knees, and back.
Tender points are generally symmetrical and on both sides of the body. The areas of tenderness are usually small (less than an inch in diameter) and deep within the muscle. They are often located in sites that are slightly tender in normal people.
People with fibromyalgia, however, differ in having increased tenderness at these sites from the average person. Firm palpation with the thumb (just past the point where the nail turns white) over the outside elbow will typically cause a vague sensation of discomfort. Patients with fibromyalgia will experience much more pain and will often withdraw the arm involuntarily.
More than 70 percent of patients describe their pain as profound aching and stiffness of muscles. Often it is relatively constant from moment to moment, but certain positions or movements may momentarily worsen the pain. Other terms used to describe the pain are “dull” and “numb.”
Sharp or intermittent pain is relatively uncommon.
Patients with fibromyalgia also often complain that sudden loud noises worsen their pain.
The generalized stiffness of fibromyalgia does not diminish with activity, unlike the stiffness of rheumatoid arthritis, which lessens as the day progresses. Despite the lack of abnormal lab tests, patients can suffer considerable discomfort.
The fatigue is often severe enough to impair activities of work and recreation. Patients commonly experience fatigue on arising and complain of being more fatigued when they wake up than when they went to bed.
Over 90 percent of patients believe the pain, stiffness, and fatigue are made worse by cold, damp weather. Overexertion, anxiety, and stress are also factors.
Many find that localized heat, such as hot baths, showers, or heating pads, give them some relief. There is also a tendency for pain to improve in the summer with mild activity, or with rest.
Some patients will date the onset of their symptoms to some initiating event. This is often an injury, such as a fall, a motor vehicle accident, or a vocational or sports injury. Others find that their symptoms began with a stressful or emotional event, such as a death in the family, a divorce, a job loss, or similar occurrence.
Pain Location
Patients with fibromyalgia have pain in at least 11 of the following 18 tender point sites (one on each side of the body):
Base of the skull where the suboccipital muscle inserts
Back of the low neck (anterior intertransverse spaces of C5-C7)
Midpoint of the upper shoulders (trapezius)
On the back in the middle of the scapula
On the chest where the second rib attaches to the breastbone (sternum)
One inch below the outside of each elbow (lateral epicondyle)
Upper outer quadrant of buttocks
Just behind the swelling on the upper leg bone below the hip (trochanteric prominence)
The inside of both knees (medial fat pads proximal to the joint line)
Treatment of Fibromyalgia
There is a persuasive body of emerging evidence that indicates that patients with fibromyalgia are physically unfit in terms of sustained endurance. Some studies show that exercise can decrease fibromyalgia pain by 75 percent.
Sleep is also critical to improvement, and many times, improved fitness will also correct the sleep disturbance.
Normalizing vitamin D levels has also been shown to be helpful to decrease pain as has topical magnesium oil supplementation.
Allergies, especially to mold, seem to be another common cause of fibromyalgia. There are some simple interventions using techniques called Total Body Modification (TBM). Call 800-243-4826.
APPENDIX THREE: Antibiotic Therapy with Minocin
There are three different tetracyclines available: simple tetracycline, doxycycline, or Minocin (minocycline).
Minocin has a distinct and clear advantage over tetracycline and doxycycline in three important areas:
Extended spectrum of activity
Greater tissue penetrability
Higher and more sustained serum levels
Bacterial cell membranes contain a lipid layer. One mechanism of building up a resistance to an antibiotic is to produce a thicker lipid layer. This layer makes it difficult for an antibiotic to penetrate. Minocin’s chemical structure makes it the most lipid soluble of all the tetracyclines.
This difference can clearly be demonstrated when you compare the drugs in the treatment of two common clinical conditions.
Minocin gives consistently superior clinical results in the treatment of chronic prostatitis. In other studies, Minocin was used to improve 75-85 percent of patients whose acne had become resistant to tetracycline. Strep is also believed to be a contributing cause to many patients with rheumatoid arthritis. Minocin has shown significant activity against treatment of this organism.
Important Factors to Consider When Using Minocin
Unlike the other tetracyclines, Minocin tends not to cause yeast infections. Some infectious disease experts even believe that it has a mild anti-yeast activity. Women can be on this medication for several years and not have any vaginal yeast infections. Nevertheless, it would be prudent to take prophylactic oral lactobacillus acidophilus and bifidus preparations.
This will help to replace the normal intestinal flora that is killed with the Minocin.
Another advantage of Minocin is that it tends not to sensitize you to the sun. This minimizes your risk of sunburn and increased risk of skin cancer.
However, you must incorporate several precautions with the use of Minocin.
Like other tetracyclines, food impairs its absorption. However, the absorption is much less impaired than with other tetracyclines. This is fortunate because some people cannot tolerate Minocin on an empty stomach and have to take it with a meal to avoid GI side effects.
If you need to take it with a meal, you will still absorb 85 percent of the medication, whereas tetracycline is only 50 percent absorbed. In June of 1990, a pelletized version of Minocin also became available, which improved absorption when taken with meals.
This form is only available in the non-generic Lederle brand, and is a more than reasonable justification to not substitute for the generic version.
Clinical experience has shown that many patients will relapse when they switch from the brand name to the generic. In February, 2006 Wyeth sold manufacturing rights of Minocin to Triax Pharmaceuticals (866-488-7429).
Clinically, it has been documented that it is important to take Lederle brand Minocin as most all generic minocycline are clearly less effective.
A large percentage of patients will not respond at all, or not do as well with generic non-Lederle minocycline.
Traditionally it was recommended to only receive the brand name Lederle Minocin. However, there is one generic brand that is acceptable, and that is the brand made by Lederle. The only difference between Lederle generic Minocin and brand name Minocin is the label and the price.
The problem is finding the Lederle brand generic. Some of my patients have been able to find it at Wal Mart. Since Wal Mart is one of the largest drug chains in the US, this should make the treatment more widely available for a reduced charge.
Many patients are on NSAID’s that contribute to microulcerations of the stomach, which cause chronic blood loss. It is certainly possible to develop a peptic ulcer contributing to this blood loss.
In either event, patients are frequently receiving iron supplements to correct their blood counts.
IT IS IMPERATIVE THAT MINOCIN NOT BE GIVEN WITH IRON!
Over 85 percent of the dose will bind to the iron and pass through your colon unabsorbed.
If iron is taken, it should be at least one hour before Minocin, or two hours after.
A recent, uncommon, complication of Minocin is a cell-mediated hypersensitivity pneumonitis.
Most patients can start on 100 mg of Minocin every Monday, Wednesday, and Friday evening. Doxycycline can be substituted for patients who cannot afford the more expensive Minocin.
It is important to notgive either medication daily, as this does not seem to provide as great a clinical benefit.
WARNING: Tetracycline type drugs can cause a permanent yellow-grayish brown discoloration of your teeth.
This can occur in the last half of pregnancy, and in children up to eight years old. You should not routinely use tetracycline in children.
If you have severe disease, you can consider increasing the dose to as high as 200 mg three times a week. Aside from the cost of this approach, several problems may result from the higher doses.
Minocin can cause quite severe nausea and vertigo, but taking the dose at night tends to decrease this problem considerably.
However, if you take the dose at bedtime, you must swallow the medication with TWO glasses of water. This is to insure that the capsule doesn’t get stuck in your throat. If that occurs, a severe chemical esophagitis can result, which can send you to the emergency room.
For those physicians who elect to use tetracycline or doxycycline for cost or sensitivity reasons, several methods may help lessen the inevitable secondary yeast overgrowth. Lactobacillus acidophilus will help maintain normal bowel flora and decrease the risk of fungal overgrowth.
Aggressive avoidance of all sugars, especially those found in non-diet sodas, will also decrease the substrate for the yeast’s growth. Macrolide antibiotics like Biaxin or Zithromax may be used if tetracyclines are contraindicated.
They would also be used in the three pills a week regimen.
Clindamycin
The other drug used to treat rheumatoid arthritis is clindamycin. Dr. Brown’s book discusses the uses of intravenous clindamycin, and it is important to use the IV form of treatment if the disease is severe.
In my experience nearly all scleroderma patients require a more aggressive stance and use of IV treatment. Scleroderma is a particularly dangerous form of rheumatic illness that should receive aggressive intervention.
A major problem with the IV form is the cost. The price ranges from $100 to $300 per dose if administered by a home health care agency. However, if purchased directly from Upjohn, significant savings can be had.
If you have a milder illness, the oral form of clindamycin is preferable.
With a mild rheumatic illness (the minority of cases), it is even possible to exclude this from your regimen. Initial starting doses for an adult would be a 1,200 mg dose once a week.
Please note that many people do not seem to tolerate this medication as well as Minocin. The major complaint seems to be a bitter metallic type taste, which lasts about 24 hours after the dose.
Taking the dose after dinner does seem to help modify this complaint somewhat. If this is a problem, you can lower the dose and gradually increase the dose over a few weeks.
Concern about the development of C. difficile pseudomembranous enterocolitis as a result of the clindamycin is appropriate. This complication is quite rare at this dosage regimen, but it certainly can occur.
It is also important to be aware of the possibility of developing a severe and uncontrollable bout of diarrhea. Administration of acidophilus seems to limit this complication by promoting the growth of the healthy gut flora.
If you have a resistant form of rheumatic illness, intravenous administration should be considered. Generally, weekly doses of 900 mg are administered until clinical improvement is observed.
This generally occurs within the first 10 doses.
At that time, the regimen can be decreased to every two weeks with the oral form substituted on the weeks where the IV is not taken.
What to Do if You Fail to Respond
The most frequent reason for failure to respond to the protocol is lack of adherence to the dietary guidelines.
Most people eat too many grains and sugars, which disturbs insulin physiology. It is important that you adhere as strictly as possible to the guidelines.
A small minority, generally under 15 percent of patients, will fail to respond to the protocol described above, despite rigid adherence to the diet. These individuals should already be on the IV clindamycin.
It appears that hyaluronic acid, which is a potentiating agent commonly used in the treatment of cancer, may be quite useful in these cases. It seems that hyaluronic acid has very little to no direct toxicity but works in a highly synergistic fashion when administered directly in the IV bag with the clindamycin.
Hyaluronic acid is also used in orthopedic procedures. The dose is generally from 2 to 10 cc into the IV bag. Hyaluronic acid is not inexpensive, however, as the cost may range up to $10 per cc. You also need to use some caution, as it may precipitate a significant Herxheimer flare reaction.
An observational European study shows that corticosteroids increased risk for pneumonia and conferred no mortality benefit in patients with severe H1N1 infection.
Use of corticosteroids to mitigate the cytokine storm that might contribute to poor outcomes in otherwise healthy people with pandemic H1N1 influenza infection is controversial, even in those with acute respiratory distress syndrome (ARDS). In a prospective observational study, investigators evaluated the effect of corticosteroids on outcomes in 220 intensive care unit (ICU) patients who were enrolled in the European Society of Intensive Care Medicine H1N1 registry from June 2009 through February 2010. H1N1 influenza A infection was confirmed in 194 patients, probable in 2, and suspected in 24. All patients received antivirals, and 78% were mechanically ventilated.
The 126 patients (57%) who received corticosteroids on ICU admission (dosages equivalent to >24 mg/day of methylprednisone or >30 mg/day of prednisone), compared to patients who did not, were significantly older, more likely to have comorbid pulmonary conditions, and more likely to be chronic corticosteroid users. Although patients who received corticosteroids on ICU admission were significantly more likely to contract hospital-acquired pneumonia (26% vs. 14%; odds ratio, 2.2) and to die in the ICU (46% vs. 18%; OR, 3.8), the association with mortality was no longer present after adjustment for severity of disease and other confounding variables (age, asthma, chronic obstructive pulmonary disease, chronic corticosteroid use). Results were similar when the analysis was limited to the 74% of patients with ARDS.
Comment: This study is limited by its observational nature, variable dosing of oseltamivir, and that patients who received “rescue” corticosteroids after ICU admission were not considered part of the corticosteroid group. For now, corticosteroids do not seem helpful — and might be harmful — in patients with H1N1 influenza.
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