Head and neck cancer

Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.

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Background

In 2021, the American College of Surgeons Commission on Cancer (CoC) approved the initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric.1 This quality metric, which is also included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers, was selected in part because of the robust association between delays in starting guideline-adherent adjuvant therapy and worse oncologic outcomes for patients with HNC.2–7 In addition, the metric was selected because there is a quality-of-care gap, with approximately 50% of patients failing to commence PORT within the recommended 6-week interval.2,3,8,9 Delays in starting guideline-adherent PORT disproportionately burden racial and ethnic minority groups, the underinsured, and other medically vulnerable populations, and contribute to disparities in survival.2,10,11

Patient navigation (PN) is a patient-centered approach that supports patients in overcoming individual barriers and facilitating timely access to quality health care.12–19 The implementation of PN can support cancer care delivery systems in their goal of meeting quality metrics and has been linked to improved clinical, patient-reported, and financial outcomes.12,13,20–25 There is robust evidence demonstrating that PN improves the timeliness and equity of cancer screening, diagnostic resolution, and treatment initiation.12,25–33 In addition, emerging data suggest that PN-based interventions may reduce delays in starting adjuvant therapy for patients with HNC, and thus improve adherence to the new CoC quality metric.34–36

Although PN has the potential to improve the delivery of guideline-adherent PORT for patients with HNC and adherence to this quality metric, the national landscape of PN and barriers to scaling PN-based approaches for patients with HNC undergoing adjuvant therapy are unknown. Therefore, we conducted a national survey to assess the current use of navigators in helping deliver timely, guideline-adherent PORT to patients with HNC, and to identify potential barriers and facilitators to implementing PN as a strategy to improve the delivery of timely PORT.

Materials and Methods

Study Sample

The study sample consisted of health care organizations that participate in the American Cancer Society National Navigation Roundtable (ACS NNRT) email listserv. The ACS NNRT was established in 2017 to advance navigation efforts that eliminate barriers to quality care, reduce disparities, and foster ongoing health equity across the cancer continuum.37 The study was reviewed by the Medical University of South Carolina Institutional Review Board and deemed exempt from human subjects research.

Survey Design and Statistical Analysis

Between September 9, 2022, and November 27, 2022, ACS NNRT disseminated an email invitation to its listserv to complete a survey about the present and future role of navigators in helping cancer centers meet their goal for the new CoC quality metric of time-to-PORT among patients with HNC. The survey consisted of 16 questions (supplemental eAppendix 1, available with this article at JNCCN.org). The survey was pilot-tested and refined by the ACS NNRT Evidence-Based Promising Practices Task Group to assess readability and content accuracy, then disseminated by email to the ACS NNRT listserv. The ACS NNRT listserv includes 186 distinct health care–providing organizations. The email contained instructions and a hyperlink to a web-based data capture tool (REDCap). The survey was anonymous and did not contain any data to link responses to, or identify, the responding institution. Consistent with ACS NNRT best practices, email recipients were instructed to forward the survey link to the person most knowledgeable about navigation services for patients with HNC at their institution. Only one person was instructed to respond from, and on behalf of, each institution. Due to the deidentified nature of the responses and the potential for the survey link to be forwarded to others, the true denominator (and thus response rate) is unknown. Respondents were not compensated for survey completion. Responses were analyzed using descriptive statistics (eg, means and proportions).

Results

Respondent and Facility Characteristics

In total, navigators from 94 institutions responded to the survey. The characteristics of the navigators and the facilities in which they practice are shown in Table 1. Navigators were most commonly located in the South Atlantic (29.8%) or Middle Atlantic (21.3%) regions of the United States. Respondents were from diverse facility types, including comprehensive community cancer programs (35.1%), academic facilities (22.3%), and community cancer programs (21.3%). Most navigators (83.0%) had a nursing background, and nearly half (45.7%) reported 1 to 5 years of experience working as a navigator.

Table 1.

Characteristics of Survey Respondents (N=94)

Table 1.VIEW TABLE

Scope of PN

Of the 94 respondents, 84 (89.4%) reported that at least part of their practice was dedicated to navigating patients with HNC. Of those 84 navigators, 54.8%, 26.2%, and 19.0% reported that 1% to 49%, 50% to 99%, and 100% of their practice was devoted to navigating patients with HNC, respectively (Table 2).

Table 2.

Respondent-Reported Scope of PN Services (N=84)

Table 2.VIEW TABLE

Of the 83 respondents who navigated patients with HNC and reported their navigation along the continuum, 67.5% (n=56) reported specifically helping navigate the initiation of adjuvant therapy. Only 37.3% (n=31) navigated all phases of the HNC treatment continuum (Table 2). The distribution of HNC-related navigation along the continuum is shown in Figure 1. Navigators reported that their facilities tracked metrics for patients with HNC (Table 2), with time to initiation of adjuvant radiation therapy specifically being tracked by 32.5% of facilities. The most commonly tracked metrics were health-related social needs, such as lack of transportation, housing, or food (62.7%), and barriers to care (61.4%).

Figure 1.
Figure 1.

Barriers to Navigation From Surgery Through Adjuvant Therapy

For respondents who did not help navigate patients with HNC initiate adjuvant therapy, the most commonly cited reason (66.7%) was that it was not in their job description but that someone else within the institution had this responsibility. The remaining 33.3% reported that providing navigation services to help patients with HNC start adjuvant therapy was not in their job description and that no one else in the institution had the responsibility. None of the navigators reported being too busy with other responsibilities as a barrier to delivering PN services for timely adjuvant therapy for HNC.

Knowledge of Guidelines and Estimated Rates of PORT Delay

Table 3 shows knowledge about NCCN and CoC guidelines for timely PORT and frequency of delays in starting PORT among navigators caring for patients with HNC. Among the 84 respondents who navigated patients with HNC, 44% (n=37) correctly reported that NCCN and CoC guidelines recommend commencing adjuvant radiation within 6 weeks for patients with HNC; 21.4% (n=18) provided a time interval other than within 6 weeks, and 34.5% (n=29) reported that they did not know. When asked to estimate the frequency of delays in starting adjuvant therapy among patients with HNC nationally in the United States, 71.4% (n=60) of respondents who navigated patients with HNC stated that they did not know. Additionally, 63.1% of respondents who navigated patients with HNC (n=53) stated that they did not know the rate of delay at their own institution. Results were similar when data were analyzed only for the 56 respondents who reported navigating PORT initiation for patients with HNC (50% correctly stated the 6-week time-to-PORT interval, 71.4% did not know the national rate of PORT delay, and 57.1% did not know the rate of delays in starting PORT at their institution).

Table 3.

Respondent-Reported Knowledge of Guidelines for Timely PORT and Frequency of PORT Delays (N=84)

Table 3.VIEW TABLE

Barriers Encountered and Navigation Services for Timely Adjuvant Therapy

More than two-thirds of HNC navigators (67.5%; 56/83) reported assisting patients with HNC initiate adjuvant therapy. The most commonly reported barriers were challenges with transportation (70.9%), difficulty coordinating timely dental care (69.1%), difficulty coordinating across health systems (54.5%), insufficient health insurance coverage (54.5%), and lack of patient-perceived importance (50.9%) (Table 4). The most frequently reported PN services included placing referrals or providing transportation assistance (89.1%), coordinating care between providers or clinics (87.3%), assessing patient barriers to timely adjuvant therapy (85.5%), and providing referrals or assisting with financial toxicity or health insurance coverage (85.5%).

Table 4.

Respondent-Reported Barriers to Initiation of Adjuvant Therapy Following Surgery (N=56)

Table 4.VIEW TABLE

Discussion

In this national landscape survey, we found that most institutions report routinely providing navigation for patients with HNC, and most of those institutions use navigators to help patients with HNC start timely adjuvant therapy. We also found potential gaps in knowledge among navigators regarding NCCN and CoC guidelines for starting PORT among patients with HNC and metrics for tracking delays in starting PORT. Although the delivery of timely PORT for patients with HNC is incorporated into NCCN Guidelines and is a CoC quality metric, more than half of patients with HNC continue to experience delays in starting PORT, and these delays disproportionately burden racial and ethnic minority groups, the underinsured, and other medically vulnerable populations.2,10,11 Data from this landscape study have important implications for understanding the current and future role of PN in improving the delivery of timely, equitable adjuvant therapy for patients with HNC, thereby improving survival and decreasing disparities in mortality.

As institutions strive to improve the delivery of timely, equitable, guideline-adherent PORT, PN has emerged as one important intervention. There is substantial evidence showing that PN decreases delays in starting adjuvant therapy and enhances equity in access and timeliness of cancer care delivey.12,26–31,38 For example, Castaldi et al39 demonstrated that PN improved the delivery of guideline-adherent adjuvant chemotherapy and endocrine therapy to patients with breast cancer. A single-arm clinical trial using a PN-based multilevel intervention resulted in a PORT delay rate of 14%,35 which compared favorably to historical institutional delay rates of 45%.8 Similarly, a study from Voora et al34 showed that a PN-based strategy reduced PORT delays from 89.5% to 50% among patients with HNC surgery undergoing free flap reconstruction. Collectively, these studies indicate that PN-based approaches improve the delivery of timely guideline-directed adjuvant therapy for patients with cancer and motivate the hypothesis that PN can also decrease delays for patients with HNC and improve performance on this CoC metric.

Our findings have a number of practical implications for how institutions can harness PN-based approaches to deliver timely, equitable adjuvant therapy for patients with HNC. First, our data suggest that efforts to scale PN in this area should focus on enhancing the effectiveness of existing PN programs, not extending existing PN programs to a new point along the HNC care continuum, because our data suggest that navigators are already widely used in routine clinical practice to facilitate timely adjuvant therapy for patients with HNC. In addition, the implementation of PN for HNC in a number of institutions across the country suggests that there is a model for PN for HNC that is, on some level, financially viable and sustainable. However, it has been well characterized that inadequate hospital resources dedicated to PN services, especially for HNC, are the single largest barrier to implementation, effectiveness, and scaling.13,40,41 Findings from this landscape study, in alignment with the new CoC quality metric for HNC and existing data about the efficacy of navigation for timely oncology care, provide a compelling basis for the provision of additional resources to support and grow HNC-based patient navigation organizations. In addition, this organizational infrastructure highlights an opportunity for institutions to collaborate and understand the logistics behind these services to enhance access, equity, and quality throughout the country for patients with HNC.

Second, we found that navigators in this study reported low levels of knowledge regarding guidelines for timely PORT and institutional performance with regards to the CoC quality metric. Although the low levels of knowledge about the guidelines for timely PORT and institutional performance on the timely PORT metric could be explained by the fact that the CoC-accredited institutions have only been collecting and reporting data for the CoC quality metric since March 2022, initiation of adjuvant radiation therapy within 6 weeks of surgery has been recommended in the NCCN Guidelines for HNC for nearly 10 years. Capitalizing on the recent approval of the CoC metric, institutions could develop pocket guidelines/cheat sheets or provide focused education and training to address the knowledge gap among navigators, which would, in turn, facilitate education of patients and communication between patients, navigators, and providers. These educational initiatives could occur at the institution level or through collaboration with national navigation (eg, NNRT) and/or HNC (eg, American Head and Neck Society) organizations.

Third, our results suggest a need for better data collection systems and methods of tracking/reporting outcomes back to navigators about the delivery of timely PORT to patients with HNC. In this study, only one-third of respondents who navigated PORT for patients with HNC reported collecting data to track the corresponding CoC metric. It is important to note that there is a difference between navigator awareness of the clinical importance of timely PORT and navigator awareness of the CoC quality metric for timely PORT for patients with HNC. However, because one purpose of quality metrics is to address gaps in clinical care and drive subsequent improvements, the development of enhanced data collection and tracking infrastructure could facilitate the delivery of real-time data that could be leveraged to improve timely PORT. A recent study by Hudson et al42 described an intervention incorporating early ancillary referral placement, a metric-tracking tool to identify gaps in patient care along the HNC continuum, and closed-loop communication to intervene at the gaps. They found that the combination of closed-loop communication and real-time tracking was associated with an increase in timely PORT for HNC from a historical 42%43 to 75%.42 Similarly, a quality improvement study by Divi et al36 found that an intervention incorporating real-time tracking of a care pathway checklist could improve the delivery of timely, guideline-adherent PORT for patients with HNC. Although these studies did not incorporate patient navigation, it is likely that navigation could enhance, and be enhanced by, a real-time tracking and communication system. Real-time tracking and improved data collection infrastructure around this quality metric could also be leveraged for audit and feedback, a strategy that has been effective for prior quality improvement initiatives in HNC.44

Finally, it is also likely that, when feasible, having navigators whose practice is specifically dedicated to patients with HNC could improve the delivery of timely, equitable care. In this study, only 1 in 5 navigators who care for patients with HNC reported navigating exclusively for this patient population. However, delivery of timely, equitable PORT to patients with HNC requires overcoming a unique and complex set of barriers and doing so in a highly compressed time interval. In this study, navigators reported having to address barriers of transportation insecurity, timely dental care, coordinating across health systems, insufficient health insurance coverage, and low patient knowledge. These multilevel barriers align with what has previously been reported34,45,46 and also reflect barriers targeted in recent PN-based interventions to improve timely PORT in this patient population.36,47,48 Of these barriers, the challenges associated with preradiation dental care are unique to patients with HNC and thus potentially outside of the standard scope of practices for navigators who have a broad oncology practice. Preradiation dental care could potentially be more efficiently and effectively addressed with PN dedicated to patients with HNC that prioritizes these types of barriers.35,36,49,50 In addition, navigating timely PORT for patients with HNC requires operating within a highly compressed time interval. Unlike the target 6-week interval between surgery and initiation of PORT for patients with HNC, the time interval for other CoC quality measures for timely adjuvant therapy is much longer, ranging from 4 months to 1 year following diagnosis or surgery for non–small cell lung cancer, colon cancer, and breast cancer.51–54 Specialization of navigators within HNC might help them understand and work within the more urgent timeline necessary to identify and resolve barriers to timely care in this patient population.

This landscape analysis has multiple strengths, including its national scope and inclusion of navigators from various facility types with different amounts of PN experience. However, there are limitations. First, the true response rate is unknown as survey recipients could have forwarded the link to others. Second, it is likely that there is response bias. Institutions who were included on the ACS NNRT listserv or those who responded may be more heavily invested in PN practices (particularly for patients with HNC) or more inclined to report according to best practices rather than actual practices. As a result, our findings may overestimate the true proportion and scope of PN practices with regard to starting adjuvant therapy for patients with HNC. Third, the study lacked details regarding potentially important characteristics of the navigators or their institutions, including the patient populations served (eg, rurality, insurance coverage, racial or ethnic diversity), geographic location, CoC accreditation status, clinical volume of HNC, program-specific outcomes, or navigator caseload. Therefore, the generalizability of findings to the overall practices of PN for HNC within the United States is unknown. Fourth, although email recipients were instructed to forward the survey to the person with the most knowledge about PN for HNC at their institution, we cannot verify that the respondent was truly the most well informed at the facility. However, it is reassuring that most respondents were HNC navigators, because they would likely be knowledgeable about their own practices. Fifth, the heterogeneous nature of PN as a profession limits our ability to estimate the time dedicated to navigation versus other activities and the amount of time dedicated to initiating PORT versus other HNC continuum intervals. Although we explored whether navigators provided a given service, we did not evaluate the breadth or quality of the navigation.

Conclusions

In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC begin timely, guideline-adherent adjuvant therapy. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, institutions could focus on providing better education and support for their navigators. Further research is necessary to evaluate the efficacy and implementation of navigation-based approaches to improving timeliness, equity, and quality for patients with HNC.

Radiotherapy with or without chemotherapy for locally advanced head and neck cancer in elderly patients: analysis of the Head and Neck Cancer Registry of Japan

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Abstract

Background

Whether concurrent chemotherapy with radiotherapy (CRT) is effective for elderly patients with head and neck cancer is a controversial topic. This study aimed to analyze the effectiveness of CRT vs. radiation therapy (RT) among elderly patients in Japan.

Methods

Data from the Head and Neck Cancer Registry of Japan were extracted and analyzed. Patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who received definitive CRT or RT between 2011 and 2014 were included.

Results

CRT was administered to 78% of the 1057 patients aged ≥ 70 years and 67% of the 555 patients aged ≥ 75 years. For the patients aged ≥ 75 years, the overall survival (OS) rate was significantly better in the CRT group than in the RT group (P < 0.05), while the progression-free survival (PFS) rate was not significantly different (P > 0.05). The add-on effect of CRT was significantly poor in elderly patients (P < 0.05), and it was not a significant factor in the multivariate analysis for patients aged ≥ 75 years. After propensity score matching, there were no significant differences in the OS and PFS rates between the patients aged ≥ 70 years and those aged ≥ 75 years (all, P > 0.05).

Conclusion

Although aggressive CRT is administered to elderly patients in Japan, its effectiveness is uncertain. Further prospective randomized trials are needed to verify whether CRT is superior to RT alone for elderly patients.

A ‘new gold standard’ for head and neck cancer radiotherapy.

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Phase III trial results on a precision radiotherapy technique support a ‘new gold standard’ for treating head and neck cancer patients.

The research suggests the new approach can reduce the risk of swallowing problems after radiotherapy, without impacting the success of treatment. The Dysphagia-Aspiration Related Structures (DARS) trial, which was sponsored by The Royal Marsden and coordinated by the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, with funding from Cancer Research UK, compared dysphagia-optimised intensity modulated radiotherapy (DO-IMRT) with standard IMRT. 

Final results from the trial were published in The Lancet Oncology.

Oncologists and physicists spend some additional time designing the treatment based on the size and position of the tumour. A computer will then plan the dose and route[…]. These tweaks to the treatment can significantly improve quality of lifeChris Nutting

DO-IMRT optimises IMRT to reduce the risk of swallowing difficulties, known as dysphagia. This common side effect of radiotherapy for head and neck cancer can, in some cases, leave patients needing a permanent feeding tube. DO-IMRT lowers the risk of dysphagia by reducing radiation to the pharyngeal muscles, which support swallowing. The DARS study included 112 newly diagnosed participants with oropharyngeal and hypopharyngeal cancers (tumours of the throat) from centres across the UK and Ireland. Half received standard IMRT and half received DO-IMRT for six weeks. 

The trial revealed that: 

  • After two years, patients treated with DO-IMRT were more likely to report better swallowing function than those treated with IMRT. 
  • After a year, around three fifths (62%) of DO-IMRT patients reported high normalcy of diet – meaning they were still able to eat at least some foods that require chewing – and over 8 in 10 (85%) said they felt comfortable eating in public, compared with just under 45% and 75% of those treated with standard IMRT respectively.  
  • After just over three years of follow up, there was no evidence of a difference in survival rates between the two approaches.

Study lead Professor Chris Nutting, Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust and Professor of Radiation Oncology at The Institute of Cancer Research, London, said: “The final results from this study support a new gold standard for treating head and neck cancer patients with radiotherapy. We have demonstrated that this targeted form of radiotherapy can spare the swallowing muscles of patients without impacting the success of their treatment. This approach involves oncologists and physicists spending some additional time designing the treatment based on the size and position of the tumour. A computer will then plan the dose and route which turns the radiation into lots of smaller, more precise beams that help to protect the throat where possible. As these tweaks to the treatment can significantly improve quality of life, we hope more centres will implement this practice.”  

We’re delighted our trial has shown it is possible to tailor how we deliver cutting-edge radiotherapy to minimise damage to key muscles and structures involved in swallowingEmma Hall

Professor Justin Roe, Consultant Speech and Language Therapist and Joint Head of the Department of Speech, Voice and Swallowing at The Royal Marsden NHS Foundation Trust, said: “The vast majority of patients I support have had a head and neck cancer diagnosis and many unfortunately experience swallowing problems during and following treatment, which often includes radiotherapy. I regularly see people who no longer enjoy food and drink, or feel too embarrassed to consume them around others, which can lead to depression and isolation. Dysphagia can also cause other serious medical problems such as malnutrition, dehydration and, in some cases, respiratory complications. It has been a privilege to support this study and I hope to see many more patients benefit from this tailored form of radiotherapy in the future.”

Professor Emma Hall, Co-Director of the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, which coordinated the trial, said: “Maintaining the ability to eat and drink normally following treatment for head and neck cancer is incredibly important for patients’ wellbeing. We’re delighted our trial has shown it is possible to tailor how we deliver cutting-edge radiotherapy to minimise damage to key muscles and structures involved in swallowing, and help more people continue to enjoy eating and drinking following therapy. This is just one example of how advanced radiotherapy techniques like Do-IMRT can help more patients live well, with fewer side effects, after receiving cancer treatment.” 

Martin Ledwick, Cancer Research UK’s head nurse, said: “Behind the results of each clinical trial, there are real people who deserve the best possible quality of life. It’s important the interventions not only work, but can be kinder so they are still able to enjoy life’s pleasures. It’s difficult for many of us to imagine not being able to swallow properly, but this can be the reality for head and neck cancer patients post-treatment. These promising results could make life after treatment brighter for head and neck cancer patients, and we look forward to seeing this kinder form of radiotherapy make its way to the clinic.”

Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment

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Abstract

Targeted immunotherapy has improved patient survival in head and neck squamous cell carcinoma (HNSCC), but less than 20% of patients produce a durable response to these treatments. Thus, new immunotherapies that consider all key players of the complex HNSCC tumour microenvironment (TME) are necessary to further enhance tumour-specific T cell responses in patients. HNSCC is an ideal tumour type in which to evaluate immune and non-immune cell differences because of two distinct TME aetiologies (human papillomavirus (HPV)-positive and HPV-negative disease), multiple anatomic sites for tumour growth, and clear distinctions between patients with locally advanced disease and those with recurrent and/or metastatic disease. Recent technological and scientific advancements have provided a more complete picture of all cellular constituents within this complex TME and have evaluated the interplay of both immune and non-immune cells within HNSCC. Here, we include a comprehensive analysis of the complete ecosystem of the HNSCC TME, performed utilizing data-rich resources such as The Cancer Genome Atlas, and cutting-edge techniques, such as single-cell RNA sequencing, high-dimensional flow cytometry and spatial multispectral imaging, to generate improved treatment strategies for this diverse disease.

Source: Nature

Results of Phase III Randomized Trial for Use of Docetaxel as a Radiosensitizer in Patients With Head and Neck Cancer, Unsuitable for Cisplatin-Based Chemoradiation.

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PURPOSE: There is a lack of published literature on systemic therapeutic options in cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) undergoing chemoradiation. Docetaxel was assessed as a radiosensitizer in this situation.

METHODS: This was a randomized phase II/III study. Adult patients (age = 18 years) with LAHNSCC planned for chemoradiation and an Eastern Cooperative Oncology Group performance status of 0-2 and who were cisplatin-ineligible were randomly assigned in 1:1 to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The primary end point was 2-year disease-free survival (DFS).

RESULTS: The study recruited 356 patients between July 2017 and May 2021. The 2-year DFS was 30.3% (95% CI, 23.6 to 37.4) versus 42% (95% CI, 34.6 to 49.2) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.673; 95% CI, 0.521 to 0.868; P value = .002). The corresponding median overall survival (OS) was 15.3 months (95% CI, 13.1 to 22.0) and 25.5 months (95% CI, 17.6 to 32.5), respectively (log-rank P value = .035). The 2-year OS was 41.7% (95% CI, 34.1 to 49.1) versus 50.8% (95% CI, 43.1 to 58.1) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.747; 95% CI, 0.569 to 0.980; P value = .035). There was a higher incidence of grade 3 or above mucositis (22.2% v 49.7%; P < .001), odynophagia (33.5% v 52.5%; P < .001), and dysphagia (33% v 49.7%; P = .002) with the addition of docetaxel.

CONCLUSION: The addition of docetaxel to radiation improved DFS and OS in cisplatin-ineligible patients with LAHNSCC.

The Burning Question: Prophylactic Gabapentin for Mucositis-Related Pain in Patients Undergoing Chemoradiation Therapy for Head and Neck Cancer?

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Head and neck cancer (HNC) patients endure a gamut of physical sequelae while undergoing a course of radical chemoradiation therapy (CRT). Of these, mucositis and its related symptoms, including pain, remain particularly troublesome for both the patients and their treating clinicians. Current strategies to manage mucositis-related pain rely heavily on opioids; however, this strategy is frequently inadequate, and consequently, many patients will still experience significant discomfort and pain throughout their treatment. The typical escalation of opioids also introduces a host of additional unwanted challenges, such as nausea and vomiting, sedation, and constipation. These concerns have driven mounting interest in the use of adjunct medications such as gabapentin to increase pain control and possibly reduce the need for high-dose opioids. The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology recently updated their evidence-based clinical practice guidelines for managing mucositis.

1

,

2

 The recommendations provided for mucositis-related pain relief are focused mainly on systemic opioids and topical morphine, as a paucity of randomized data has prohibited the development of guidelines specifically addressing the role of adjunct analgesics such as gabapentin.

3

In the article that accompanies this editorial, Cook et al

4

 report the results of a randomized, placebo-controlled, double-blind phase 3 study evaluating the role of prophylactic gabapentin in reducing treatment-related oral mucositis symptoms in patients with oropharyngeal cancer treated with definitive CRT. Eligible patients had stage III to IV disease (American Joint Committee on Cancer Cancer Staging Manual, seventh edition) and could be either human papillomavirus (HPV) positive (49 of 58 [84%]) or negative. All patients received concurrent platinum-based chemotherapy, including carboplatin (7 of 58 [12%]) or high- (32 of 58 [55%]) or low-dose (19 of 58 [33%]) cisplatin. There were competing cooperative group trials enrolling during this period, which were prioritized, and of the 112 study-eligible patients, 65 consented; 58 patients were included in the per-protocol analysis.

The 2 arms were well balanced across relevant demographic, disease, and treatment variables, including baseline opioid use, disease staging, primary and nodal target volumes, and dosimetric factors (mean pharyngeal constrictor and oral cavity doses). Gabapentin was commenced at 300 mg thrice daily during the first week of treatment and increased to 600 mg thrice daily in week 2 (total daily dose 1800 mg)—a dose that was continued through to the week after treatment, at which point patients were quickly weaned off. The placebo was scheduled in a similar fashion, and compliance was documented at weekly interviews, with 12 of 21 doses in any given week considered protocol compliant. Noncompliant patients in the first 2 weeks of treatment (n = 3) were excluded from the final analysis. All patients were recommended lidocaine oral rinses, and opioids were prescribed at the discretion of individual physicians when self-reported pain scores were in excess of 4 of 10 on a numerical scale. The timing and insertion of a feeding tube were individualized and at the discretion of the multidisciplinary team.

This study documented patient-reported outcome measures, opioid use, weight loss, and frequency and duration of feeding tube use. The primary endpoint evaluated the change in the Patient-Reported Oral Mucositis Symptom (PROMS) total score over the entire treatment period (baseline to 6-week post-CRT follow-up). The PROMS scale was developed and validated in the bone marrow transplant setting and includes 10 items assessing mouth pain (single item), the functional impact of mucositis (8 items), and taste change (single item) using a visual analog scale. Secondary outcomes included a prespecified analysis of PROMS item 1 (mouth pain) and a composite score of items 4, 5, 6, and 9; health-related quality of life assessed by the Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN); and a composite score of 4 items on the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) relevant to the study toxicities. Repeated-measures analysis of variance demonstrated no between-arm differences in the primary or secondary PROMS endpoints. Interesting, however, was that throughout the study, the primary endpoint scores numerically favored the placebo arm, differences that at times approached but did not reach statistical significance. Importantly, opioid use was also similar for both arms. Similar quality-of-life outcomes were observed with the exception of a smaller negative change from baseline to follow-up in the functional well-being domain of the FACT-HN in favor of the placebo arm (gabapentin −6.0 vs placebo −1.0; P = .03). An increase in the composite PRO-CTCAE score also favored the placebo arm (gabapentin 6.5 vs placebo 1.0, P = .01). Keeping in mind that investigators were blinded to arm allocation, feeding-tube placement was more frequent in the gabapentin arm (18 of 29 [62.1%] vs 6 of 29 [20.7%]; P < .01); however, the median duration of placement was not statistically different (47.5 vs 39.0 days; P = .82). Weight loss from baseline to the last week of treatment was also similar (−11.4% vs −10.7%; P = .81). Overall, this study concluded that gabapentin was ineffective in reducing mucositis-related symptoms and suggested that patients may be adversely affected across several clinically relevant measures.

This study provides arguably the strongest data to date in evaluating the role of prophylactic gabapentin in HNC patients undergoing CRT, given its homogeneous inclusion criteria and placebo-controlled, double-blind design. A number of published retrospective

3

 and prospective

5

,  

6

,  

7

 studies have also reported their outcomes, with mixed results (Table 1). In placing the current study in context, one needs to consider the variations in study design, inclusion criteria (adjuvant/definitive intent, mixed HNC subsites, utilization of induction chemotherapy), gabapentin dosing (protocol specified and received dosing), concomitant analgesics, and the primary assessment of efficacy. A strength to the Cook et al

4

 study is the reporting of radiation doses to the mucosa (pharyngeal constrictors and oral cavity), a surprising omission in the other reported series.

Table 1Randomized studies evaluating the role gabapentin in head and neck cancer populations undergoing chemoradiation therapy

StudyNo.Disease siteTreatment receivedRT and chemo scheduleStudy designProtocol-specified gabapentin dosingReceived gabapentin dosingOther analgesic informationPrimary endpoint/pain assessmentOutcomeOpioid use
Current study458OPCAll definitive CRT70 Gy/35 fractionsRandomized, placebo controlled, double blindWeek 1: 300 mg tid

Week 2: 600 mg tid

through to 1 wk after treatment; then 300 mg tid for 1 d		1 Noncompliant (placebo arm); 3 patients excluded in per-protocol analysisOpioids at discretion of treating physician (once >4 of 10 pain)Total PROMS scoreNo improvement in treatment-related oral mucositis symptoms or painNo difference
Kataoka et al522Mixed:

OC 45%; OPC 23%; LC/HPC 27%; NPC 5%		Mixed;

Sx + aCRT 45%; NACT 9%		≥60 GyRandomized, open labelD1: 300 mg daily;

D4: 600 mg daily;

D7: 900 mg daily maintained to 4 wk post		2 Patients reduced doseAnalgesic ladder from acetaminophen to incorporation of short- and then long-acting opioids (type not stipulated)Maximum VAS pain scoreNo benefit (numerically worse scores in gabapentin arm)Not reported
Hermann et al660Mixed; OC 62%;

OPC 25%; LC/HPC 18%;

CUP 7%;

NPC 7%		All definitive CRT70 Gy/35 fractionsRandomized, open labelArm 1: up titrate from D1 evening 300 mg to 900 mg tid over 9 d as tolerated; arm 2: D1: 300 mg; D2 300 mg bid; D3: 300 mg tid and continued;

up titrate

methadone as long acting		Arm 1: 87%; arm 2: 93% compliantArm 1, BT: acetaminophen 325 mg, hydrocodone 7.5 mg qid;

long acting: fentanyl transdermal patch (titrated from 25 μg/h); arm 2, BT: oxycodone 5-10 mg Q4h;

long acting: methadone 5 mg bid up to 15 mg bid		OMWQ-HN*No difference in mouth or throat symptoms or painArm 2 had nonsignificant lower MME; more patients in arm 1 did not use any opioids (42% vs 7%)
Smith et al7,†71Mixed;

OPC 55%; LC/HPC 13%; OC 10%; NPC 5%; other 5%		Mixed;

Sx + aCRT 23%; NACT 28%		69-70 Gy definitive; 50-60 Gy adjuvantRandomized, open labelWeek 1: 100 mg tid;

Week 2: 300 mg tid;

Week 3: 600 mg tid;

Week 4: 900 mg tid		Most patients were maintained on 300 mg tidBT and long acting as needed (type not stipulated)VHNSSv2 pain scaleReduction in pain (OR = 0.55)‡No difference in breakthrough opioid pain medication

Abbreviations: aCRT = adjuvant CRT; bid = twice daily; BT = breakthrough; CRT = chemoradiation therapy; CUP = carcinoma unknown primary; HPC = hypopharyngeal cancer; LC = laryngeal cancer; MME = morphine milligram equivalent; NACT = neoadjuvant chemotherapy; NPC = nasopharyngeal cancer; OC = oral cavity cancer; OMWQ-HN = oral mucositis weekly questionnaire-head and neck cancer; OPC = oropharyngeal cancer; OR = odds ratio; PROMS = Patient-Reported Oral Mucositis Symptom; Q4h = every 4 hours; qid = 4 times a day; RT = radiation therapy; Sx = surgery; tid = 3 times a day; VAS = visual analog scale; VHNSSv2 = Vanderbilt Head and Neck Symptom Survey version 2.

low asterisk Primary endpoint was clinician reported.

† Interim analysis.

‡ suggests that patient on the gabapentin arm would have approximately 55% chance of exceeding a given pain score compared to a patient in the standard therapy arm.

To date, only the planned interim analysis by Smith et al

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 has demonstrated any efficacy in pain reduction with prophylactic gabapentin. In this study, 71 HNC patients undergoing CRT (either definitive or adjuvant) had their pain assessed with the 4-item composite pain subscale of the Vanderbilt Head and Neck Symptom Survey.

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 With the use of a proportional odds model adjusted for time and baseline pain scores, the authors reported that gabapentin resulted in a significant reduction in the composite pain subscale (odds ratio = 0.549; 95% confidence interval, 0.364-0.827; P = .004). However, when the analysis was restricted to mucositis-related pain, gabapentin failed to show ongoing efficacy. Furthermore, the authors did not observe any reduction in opioid use, an outcome reported in only 1 of the 4 prospective studies. In that study, Hermann et al

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 reported a reduction in the number of patients requiring opioids when treated with high-dose gabapentin. Conversely, patients in the low-dose gabapentin and methadone arm were reported to have lower total opioid requirements. Drawing definite conclusions from this study is difficult owing to differences in gabapentin dosing and the use of different short- and long-acting opioids in the 2 study arms.

One criticism of the current study may be the protocol-specified dosing of gabapentin (1800 mg daily). Daily gabapentin maintenance doses ranged from 900 mg to 2700 mg across the 4 prospective studies. Patients may not tolerate dosages at the higher end of this range, largely due to somnolence and fatigue, and this may be compounded by cisplatin-induced kidney injuries, given gabapentin is exclusively renally eliminated. Although Smith et al

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 recommended titrating to a maximal daily dose of 2700 mg, most patients were maintained at the lower dose of 900 mg daily, providing support for the use of the dose specified by Cook et al.

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 In addition, >80% of participants in the current study had HPV-positive oropharyngeal cancer, a group shown to experience higher rates of acute and subacute mucositis and more severe mucositis-related pain.

9

,

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 Although HPV status was balanced between the 2 arms in the current study, it is possible that gabapentin is simply too weak a remedy for this kind of pain.

There are some caveats to this study. The analysis was per protocol rather than intention to treat, and arguably patients who were noncompliant (n = 3) or who experienced acute renal impairment during treatment (n = 1) should not have been excluded from the analysis. The study may also have been slightly underpowered; however, any effect seen in this study was in favor of the placebo arm, and it is very unlikely that a slightly larger study would have yielded a benefit in favor of gabapentin. Although the instrument (PROMS) used for primary assessment of efficacy has not been specifically validated in the studied population, its validity has been tested in patients with oral mucositis in other settings and seems highly likely to be fit for this purpose.

So, where to go from here? Dr Cook and colleagues

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 should be commended for conducting this important study and providing the most compelling evidence to date on the efficacy of prophylactic gabapentin in managing mucositis-related symptoms and pain during HNC-CRT. Although this study comes with several caveats, it is the only placebo-controlled, double-blind study available, thus providing results that are likely to be the least biased. Although larger, well-designed studies would be welcome in the future, there is, at present, little evidence to recommend prophylactic gabapentin during HNC-CRT. Treatment of mucositis-induced pain in HNC patients receiving CRT remains an unmet need, and preclinical and clinical research efforts are required to find novel solutions to this highly demanding symptom.

Five-MicroRNA Signature: Predicting Outcomes in HPV-Negative Head and Neck Cancer

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The prognosis for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma is generally poorer than for those with HPV-positive disease. Dr. Julia Hess, of the German Research Center for Environmental Health GmbH in Neuherberg, and colleagues sought to find prognostic markers to help predict the risk of recurrence in this patient population and thus create personalized treatments with radiation, targeted drugs, and immune checkpoint inhibitors. They may have succeeded: By retrospectively performing microRNA (miRNA) expression profiling, they discovered a “five-miRNA signature [that] is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative head and neck squamous cell carcinoma,” the authors reported. Of note, added Dr. Hess in Clinical Cancer Research, “its prognostic significance is independent from known clinical parameters.”

The five-miRNA signature, when combined with established risk factors, allowed four prognostically distinct groups to be defined. Recursive-partitioning analysis classified 162 patients into being at low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < .001).

“[The five-miRNA signature] represents the basis for a more focused search for molecular therapeutic targets,” which would potentially improve “therapy success for appropriate patients,” the researchers stated. Currently, even when given state-of-the-art, standard-of-care therapy, patients with HPV-negative head and neck squamous cell carcinoma cancer have an overall survival rate of only about 50%.

Predictors of Long-Term Opioid Treatment Among Patients Who Receive Chemoradiation for Head and Neck Cancer

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Abstract

Introduction. The factors associated with successful opioid discontinuation after cancer treatment are not well-known. We determined the proportion of patients with advanced head and neck cancer who continued using opioids 3 months after the completion of radiation therapy with or without chemotherapy.

Methods. We included 70 patients with head and neck cancer referred to our institution’s supportive care center between January 1, 2008, and December 31, 2010. Patients who no longer used opioids 3 months after the completion of radiation therapy were classified as stoppers; patients who continued using opioids were considered nonstoppers. We compared demographics, cancer-related characteristics, alcoholism, substance abuse history, use of psychoactive drugs, and opioid-related factors between stoppers and nonstoppers.

Results. In all, 44 of 70 patients (63%) and 23 of 70 patients (33%) continued opioids 3 months and 6 months after the completion of radiation therapy, respectively. A total of 18 of 44 nonstoppers (41%) and 3 of 26 stoppers (12%) were positive for alcoholism based on the CAGE questionnaire (i.e., Cut down, Annoying, Guilty, Eye opener; odds ratio: 5.3). Demographic and clinical characteristics did not differ between stoppers and nonstoppers. The median duration of any type of opioid use of CAGE-positive patients was significantly longer than that of CAGE-negative patients (median: 261 days vs. 93 days; hazard ratio: 2.5).

Conclusion. CAGE positivity is a risk factor for opioid use beyond 3 months after the completion of radiation therapy and for duration of opioid treatment. Routine CAGE screening and meticulous follow-up are needed for these patients.

RT for Head and Neck Cancer: Humidifier Cuts Hospital Stay.

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For patients with head and neck cancer who are undergoing radiotherapy, using a nasal mask to deliver humidified air to the mouth and throat region while they were sleeping appears to have reduced symptoms, and significantly shortened their hospital stay.

The results come from the RadioHUM study, a phase 3 trial conducted in 210 patients reported here at a plenary session during the 2014 Multidisciplinary Head and Neck Cancer Symposium. This study has just been published in the March 1 issue of theInternational Journal of Radiation Oncology * Biology * Physics.

Radiotherapy for head and neck cancer often results in mucositis, with patients developing painful inflammation and ulceration of the mouth and throat that can negatively affect their quality of life, explained principal investigator Andrew McCann, MBcHB, a radiation oncologist at Auckland City Hospital in New Zealand.

The trial investigated daily humidification of the mouth and throat region (using the Fisher & Paykel Healthcare MR880 humidifier) starting on the first day of radiotherapy. The humidified air is delivered through the nose via a mask-type of apparatus, which patients wear while they are sleeping or sitting. “This provides a greater level of humidification than has previously been available,” he said.“The rationale for humidification is based on the fact that moisturizing wounds generally helps them to heal faster,” he said during a press briefing.

In this trial, patients used this device for a mean of 3.6 hours per day (range, 1 – 14 hours).

However, the authors note that only 43 patients (42%) in the humidification group met a defined benchmark for humidifier compliance. Only these patients contributed to the per protocol analysis, so although the results were in the direction of less symptom severity, most of the time points did not reach significance. Nevertheless, they say there were “efficacy signals consistent with a role for humidification in reducing symptom burden from mucositis,” and this included the patient reports in a self-assessment questionnaire.

However, several of the results did reach statistical significance.

Patients who used the humidifier had a significantly shorter hospital stay (mean of 2.3 vs 4.1 days in the control group; P = .017), and fewer of them required hospital readmission (0.31 vs 0.55; P = .013).

This effect of reducing hospitalization may make this approach cost-effective, the authors comment.

In addition, significantly fewer patients who had used a humidifier needed an eating tube, and a nutritional status assessment at 20 weeks after the radiotherapy showed that significantly more patients in this group had returned to near-normal eating patterns.

“The results are encouraging, particularly given the signal favoring humidification was seen across clinician-reported outcomes, patient-reported outcomes, and independent data such as hospitalizations,” the authors note.

“This is important,” Dr. McCann suggested, “because when you see signals across these different types of outcomes, there is some independent corroboration there.”

Patients didn’t use the humidifier as much as we had hoped, Dr. McCann commented. Some of the issues with compliance are similar to those seen with the use of continuous positive airway pressure machines in patients with sleep apnea, he said. “Our next step is to work to increase the proportion of patients who use the humidifier effectively,” he added.

Household Spice Protects Against Radiation Treatment’s Horrible

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The humble spice turmeric, in doses available for pennies a day, has been found to reduce one of the most devastating side effects of radiation treatment for head and neck cancer.

Each year, 60,000 patients are diagnosed with ‘head and neck cancer,’ which includes cancer of the mouth, tongue, pharynx, larynx, oral cavity, and thyroid.[i] Sadly, within the conventional medical model, radiation therapy is the ‘standard of care’ for this type of cancer, which involves the use of up to 50-70 Grays of radiation over a 5-7 week period.  To put this dose into perspective, a whole-body exposure to 8 Grays of high-energy radiation in a single dose has a 100% mortality rate within two weeks.[ii] This is a major (if not the primary) reason why radiation oncologists use ‘fractionation,’ breaking the total dose up into smaller fractions over time (1.8-2 Grays per day), in order to prevent the rapid death of the patient from acute radiation poisoning.

The primary adverse symptoms experienced by post-radiation treatment survivors is known as ‘oral mucositis,’ involving tissue destruction and functional problems in the oral cavity, which is painful, affects nutrition, contributes to local and systemic infections and greatly reduces the quality of life.[iii]  There are other lesser known and potentially more lethal problems associated with radiotherapy, not the least of which is its ability to transform non-tumorigenic cancer cells into tumor-initiating ones (exhibiting cancer stem cell-like properties), but the medical establishment rarely if ever touches upon these downstream effects, many of which can not easily be linked to the treatment, or are conveniently written off as being caused by the recurrence of “treatment-resistant” cancer and not the inherent carcinogenicity of radiotherapy itself.

While in many ways the treatment of head and neck cancer through solely conventional means is tragic today, the medical establishment is beginning to wake up to the utility of natural compounds in at least reducing or preventing unnecessary harm caused by the use of chemotherapy and radiation. There is no denying that a massive body of research has now accumulated showing that spices as common as turmeric are capable of both increasing the effectiveness of conventional treatment while at the same time reducing the collateral damage to the patient caused by them. [Read: Integrative Cancer Research: Surviving Chemo & Radiation for more information]. From the perspective of a patient faced with the inevitable side effects of radiotherapy, it is clearly unethical for practicing physicians to ignore, or worse, deny the evidence that better outcomes are available using an integrative approach.

All the more reason why a new study published in the journal Integrative Cancer Therapies, should move the oncology community closer in this direction. Titled,”The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study,”[iv] researchers evaluated the efficacy of turmeric in preventing radiation-induced mucositis.

In the single-blinded, randomized, controlled clinical trial conducted with head and neck cancer patients requiring 70 Gray of radiation or chemoradiotherapy (daily radiotherapy plus carboplatin once a week), 80 eligible patients were randomly assigned to receive either turmeric gargle (40) or povidone-iodine (40) during chemo/radiotherapy during the period of treatment.

Oral mucositis was assessed before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The primary endpoint of this study was the incidence of mucositis every week during the 7-week period. The secondary endpoint was the effect of turmeric gargle on the incidence of treatment breaks, loss of scheduled treatment days, and decrease in body weight at the end of the treatment.

The study produced the following results:

“This study clearly suggests that when compared with the cohorts using povidone-iodine gargle, the group using turmeric as a mouthwash had delayed and reduced the levels of radiation-induced oral mucositis and was statistically significant at all time points ( : < 0.001 to : < 0.0001). Additionally, the cohorts using turmeric had decreased intolerable mucositis ( : < 0.001) and lesser incidence of treatment breaks in the first half of the treatment schedule before 4 weeks ( : < 0.01) and reduced change in body weight ( : < 0.001).”

They concluded:

“Gargling with turmeric by head and neck cancer patients undergoing radiation therapy provided significant benefit by delaying and reducing the severity of mucositis. Turmeric is readily available, relatively inexpensive, and highly accepted making it useful in cancer treatment.”

While this study focused primarily on turmeric’s ability to reduce the side effects of conventional treatment, and not the intrinsic anti-cancer properties of the spice itself, there is a good amount research indicating that turmeric is one of Nature’s most powerful, affordable, safest and easily accessible anti-cancer agent.  For a review of the literature we have accumulated on its health benefits read: 600 Reasons Why Turmeric May Be The World’s Most Important Herb. With over 1500 studies indicating its health value, many of which focusing on turmeric’s (and its primary polyphenol curcumin) ability to kill over 100 different types of cancer cell lines, it is no surprise to find research on its ability to kill head and neck cancer:

We can only hope that the growing body of experimental, preclinical and clinical support for the use of natural substances in cancer treatment will break throw into the practice of so-called ‘evidence-based’ medicine. It would seem that given its self-definition, modern medicine has an obligation to do exactly that; especially when the result will be the reduction of human suffering.

[i] Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin. 2002; 52( 1): 23-47.

[ii] “Radiation Exposure and Contamination”. Merck Manuals. Retrieved 2 June 2013.

[iii] Plevovia P. Prevention and treatment of chemotherapy and radiotherapy induced oral mucositis: A review. Oral Oncol. 1999;35:453–70. [PubMed]

[iv] Suresh Rao, Chetana Dinkar, Lalit Kumar Vaishnav, Pratima Rao, Manoj Ponadka Rai, Raja Fayad, Manjeshwar Shrinath Baliga. The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study.