cancer treatment

Sublobar Resection Is Now Standard of Care for Some Patients with Early-Stage NSCLC

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Sublobar resection is noninferior to lobectomy in patients with carefully staged, peripheral cT1aN0 NSCLC and should be offered to them.

To determine whether sublobar resection (wedge resection or segmentectomy) is noninferior to lobar resection in early-stage stage non–small-cell lung cancer (NSCLC), researchers conducted an international phase 3 trial. Nearly 700 patients with histologically confirmed stage IA node-negative NSCLC were randomized to lobar resection (357 patients) or sublobar resection (340 patients). Node status was confirmed by frozen section examination of level 10 lymph nodes and at least 2 mediastinal stations.

At a median follow-up of 7 years, the primary endpoint — disease-free survival (DFS) — did not differ significantly between groups (hazard ratio, 1.01; 90% CI, 0.83–1.24). The 5-year DFS was 63.6% in the sublobar-resection arm and 64.1% in the lobar-resection arm. There were no significant differences in DFS between the arms in subgroup analyses by tumor size or sites of recurrence. Overall survival (OS) also did not differ significantly between arms (HR, 0.95; 95% CI, 0.72–1.26). The 5-year OS was 80.3% with sublobar resection and 78.9% with lobar resection. There were no significant differences between the arms in lung cancer–related deaths (HR, 0.99) or deaths from other causes (HR, 1.12).

At 6 months, there was a greater reduction from baseline in the median percentage of predicted forced expiratory volume in 1 second (FEV1)in the lobar-resection arm (−6.0; 95% CI, −8.0 to −5.0) than in the sublobar-resection arm (−4.0; 95% CI, −5.0 to −2.0). The reduction in the median percentage of predicted forced vital capacity (FVC) was also greater in the lobar-resection arm (−5.0; 95% CI, −7.0 to −3.0) than in the sublobar resection arm (−3.0; 95% CI, −4.0 to −1.0).

Comment

A recent trial from Japan showed that segmentectomy was noninferior to lobectomy in patients with T1a/bN0 NSCLC (NEJM JW Oncol Hematol May 9 2022 and Lancet 2022; 399:1607). Together, these trials provide conclusive evidence that sublobar resection is the standard of care for patients with small, peripheral, node-negative NSCLC. As computed tomography screening for lung cancer becomes more widespread, the proportion of patients who meet these criteria will continue to increase. As noted by an editorialist, although many patients are cured of their first NSCLC, the risk for metachronous primary tumors remains quite high. Sublobar resection allows more treatment options for these patients.

Total neoadjuvant therapy in oesophageal and gastro-oesophageal junctional adenocarcinoma

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Abstract

Adenocarcinoma of the oesophagus and gastro-oesophageal junction represent a large burden of cancer death in the Western World with an increasing incidence. In the past two decades, the overall survival of patients on a potentially curative treatment pathway has more than doubled due to the addition of perioperative oncological therapies to surgery. However, patients often fail to respond to oncological treatment or struggle to complete their treatment after surgery. In this review, we discuss the current evidence for total neoadjuvant therapy and options for assessment of treatment response.

Background

Oesophageal cancer is the 14th most common cancer in the United Kingdom, with adenocarcinoma being the most common histological subtype, and it is the 7th most common cause of cancer death [1]. The overall benefit of preoperative or perioperative oncological therapy (chemotherapy or chemoradiotherapy) for oesophageal and junctional adenocarcinoma is widely recognised, most notably demonstrated by landmarks trials including OEO2, MAGIC, FLOT4 and CROSS with overall 5-year survival reaching 47% in CROSS, a large improvement from 17–23% for surgery alone [2,3,4,5]. In this review, we discuss the effect of neoadjuvant chemotherapy (nCT) and chemoradiotherapy (nCRT) on surgical resection margin, lymph node downstaging, and primary tumour pathological response and how this impacts survival. We also review the challenges of delivering perioperative therapy and discuss total neoadjuvant therapy as a potential novel treatment regimen for patients with resectable oesophageal cancer.

Total neoadjuvant therapy—is it possible in oesophageal cancer?

Total Neoadjuvant Therapy (TNT), where all oncological treatment is delivered before surgery, is beneficial in other cancer types. This experience should be exploited with regard to potential issues which could arise using the TNT approach for oesophageal cancer, such as increased toxicity and poorer tolerability of neoadjuvant therapy given the higher chemotherapy dose and subsequent failure of progression to surgery.

For example, TNT has gained prominence in the management of locally advanced rectal cancer and has now been incorporated into national rectal cancer guidelines [6]. A summary of key trials of TNT in rectal cancer is shown in Table 1. The RAPIDO trial included high-risk patients with T4 or N2 clinical staging or other high-risk factors, and patients in the TNT group received 6 cycles of CAPOX or FOLFOX4 chemotherapy following a short course of radiotherapy [7]. In the UNICANCER-PRODIGE 23 trial, patients with T3-T4 and N0 clinical disease were included, arguably less advanced disease than in RAPIDO [8]. This trial used the more aggressive FOLFIRINOX chemotherapy before nCRT and showed a better 3-year disease-free survival in the TNT group and the trial concluded that there was a lower toxicity rate in the TNT group despite using FOLFIRINOX. These trials did not show any improvement in overall survival with TNT, but two meta-analyses have supported the improved oncological outcomes using TNT and consensus has shifted in favour of TNT in locally advanced rectal cancer [9, 10]. As well as these trials, there are various other smaller studies of TNT in rectal cancer, which consistently show better tolerability, less toxicity, and higher rates of planned treatment completion when the TNT approach is used [11,12,13]. Furthermore, excellent results have been reported in Phase 2 trials of TNT for borderline resectable pancreatic adenocarcinoma, with 2-year progression-free and overall survival of 43% and 56%, respectively and a median PFS of 48.6 months in those undergoing resection with 2-year OS of 72% [14]. There is evidence to suggest that TNT enables the delivery of intended systemic therapy with a greater chance of pCR and without compromising on surgical resection in pancreatic adenocarcinoma [15]. A recent systematic review and meta-analysis suggest superior oncological and pathological outcomes with TNT compared to standard neoadjuvant therapy [16]. Phase III trials of TNT in pancreatic adenocarcinoma are currently ongoing [17].Table 1 A summary of key trials of total neoadjuvant therapy in rectal cancer.

Full size table

Current evidence for TNT in oesophageal adenocarcinoma is limited to retrospective or small pilot study evidence but is promising and summarised in Table 2. Due to the non-randomised and largely retrospective nature of these studies, it is difficult to draw strong conclusions, however, there appears to be a consistently high disease-free and overall survival with intensified neoadjuvant regimens compared to standard of care. In addition, there are high rates of treatment completion and surgical resection as evidenced by in patients receiving FLOXFOX + CROSS [18]. Although there was an 80% grade 4 toxicity rate in the prospective study by Wo et al., the majority of this was due to subclinical lymphopenia. When patients with M1 nodal disease were excluded, 2-year progression-free survival was 78% in this study [19]. There are several ongoing trials of TNT or enhanced neoadjuvant therapy in patients with oesophageal or oesophagogastric junction adenocarcinoma. These are summarised in Table 3.Table 2 Current evidence for total neoadjuvant therapy oesophagogastric adenocarcinoma.

Full size tableTable 3 Ongoing trials of total neoadjuvant therapy in oesophageal or gastroesophageal junction adenocarcinoma.

Full size table

The, albeit limited, existing evidence in oesophageal and junctional adenocarcinoma, as well as other solid tumours suggests a significant survival benefit for patients receiving TNT and allows more patients to complete all oncological therapy and surgery. Prospective, randomised controlled trials are needed to compare treatment modalities directly using the TNT approach in oesophageal cancer.

Total neoadjuvant therapy—assessing treatment response

If patients are to embark on a prolonged course of preoperative treatment, ideally it should be a precision medicine strategy with mechanisms in place for an as early as possible assessment of response and adaption of treatment accordingly. Again, rectal cancer might help us to address this problem. The OPRA trial compared surgical resection to a “watch-and-wait” approach following TNT in patients with locally advanced rectal cancer [20]. This trial used an extensive surveillance protocol with a combination of digital rectal examination, flexible sigmoidoscopy (every 4 months for the first 2 years, then 6 monthly), CEA, MRI, CT chest/abdomen/pelvis and colonoscopies at year 1 and year 5 and demonstrated that organ preservation is safe and achievable in half of patients. Findings from the International Watch & Wait Database emphasise the importance of endoscopic surveillance [21]. We can also look to oesophageal squamous cell carcinoma, for which definitive chemoradiotherapy (dCRT) is a treatment option. Surveillance after dCRT includes regular OGD and biopsies, EUS, CT scan and Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET-CT) [22, 23]. The SANO trial is ongoing, which investigates the use of active surveillance in an organ-sparing “watch-and wait” approach for patients with oesophageal squamous cell and adenocarcinoma and utilises PET-CT, OGD with biopsies and EUS with FNA of suspicious nodes in its clinical response evaluation [24].

Generally, PET-CT has been shown to be a feasible and accurate modality for detecting response to neoadjuvant therapy in oesophageal cancer [25,26,27,28]. However, its accuracy in detecting non-response is questionable, with one study suggesting reliable detection of non-responders in gastric and Siewert II-III cancers [29], and another suggesting a lack of accuracy in detecting non-response in oesophageal cancer [30]. In the absence of a “one size fits all” endoscopic or radiological surveillance modality and a lack of reliable tumour markers in oesophageal adenocarcinoma, it may be that a multimodality approach is required to assess response, and more importantly, non-response to preoperative treatment. The burden of such an approach for patients and the health care system will need to be understood.

Circulating tumour DNA (ctDNA) is well established as a marker of minimal residual disease and correlates with recurrence and survival in patients undergoing neoadjuvant therapy for rectal cancer [31,32,33,34,35,36]. The use of ctDNA in oesophageal cancer is still being established. The prospective pilot study of TNT in oesophageal adenocarcinoma analysed ctDNA at various time points, including post-chemoradiotherapy and post-surgery [19]. Those with undetectable ctDNA post-chemoradiotherapy and post-operatively had significantly lower recurrence rates compared to those with detectable ctDNA at these time points (8% vs 75% post-CRT, p = 0.004; 0% vs 40% post-op, P = 0.045). ctDNA has been identified in other studies as a useful biomarker of recurrence and treatment response in oesophageal cancer [37,38,39]. This highlights the potential utility of ctDNA as a biomarker of response to treatment, a predictor of recurrence and its utility in planning adjuvant treatment where needed. It is essential that any future trials of TNT incorporate several modalities to monitor response to treatment such as PET-CT, endoscopic surveillance and ctDNA.

Surgical resection margin

The importance of complete surgical excision of oesophageal and gastroesophageal junction (GOJ) cancers is long established. The 3-year survival in those with a complete surgical resection (R0) in OEO2 was 42.4% compared to 18.0% and 8.6% in those with R1 and R2 resections, respectively [40]. Patients who undergo preoperative oncological therapy are more likely to have an R0 resection. This is particularly evident in regimens where all the therapy is delivered pre-operatively, for example, in the CROSS trial, those receiving preoperative chemoradiotherapy had an R0 rate of 92% compared with 69% in those having surgery alone [5]. Neoadjuvant chemoradiotherapy has been shown to deliver better local tumour control (R0 resection rate) than preoperative chemotherapy. In the Neo-AEGIS study, which compared neoadjuvant CRT (CROSS) with perioperative chemotherapy, R0 in the CROSS group was 95% compared to 82% in the perioperative chemotherapy group [41]. Similar results have been shown for R0 rate in the NeoRes I study, where chemoradiotherapy (R0=89%) and chemotherapy (R0=71%) were compared in the neoadjuvant setting alone in patients with T1-T3 disease[42]. However, there were comparable R0 rates between nCRT and nCT in the POET study (72% vs 69%), in patients with T3-T4 disease [43]. It should be noted that in these comparative studies older chemotherapy regimens were largely used in the chemotherapy arm rather than FLOT. The ESOPEC trial is currently ongoing, which directly compares FLOT and CROSS [44]. In the FLOT4 trial, where 83% of patients who received perioperative FLOT chemotherapy had T3/T4 disease and 78% had node-positive disease, there was an R0 resection rate of 92% in those with resected specimens [45]. The recent DANTE trial, in which 93% of patients completed pre-op FLOT cycles, had similarly high R0 rates of 91% in the FLOT arm and 92% in FLOT + atezolizumab [46]. Indirect comparison of the studies above is limited by significant differences in the study population, notably differences in histological type, disease location, disease stage, age, and performance status. This highlights the need for precise patient selection in clinical trials comparing treatment modalities.

From the available evidence, if the objective of preoperative treatment were solely to improve R0 resection rate both CROSS and FLOT offer comparable outcomes, but other important outcomes that have a profound impact on overall survival need to be considered.

Lymph node status, primary tumour pathological response and survival

Systemic disease control in patients with node-positive or micrometastatic disease is important for improving long-term outcomes in patients with oesophageal cancer [47,48,49,50,51,52,53,54,55]. A recent meta-analysis has highlighted the importance of lymph node downstaging after neoadjuvant therapy as a prognostic factor in oesophageal cancer, with those with ypN0 achieving a much-improved survival over those with positive nodes (ypN+) after neoadjuvant therapy [56]. The POET study demonstrated a significantly improved 3-year survival for patients with an R0 resection and ypN0 (64.2%) compared with those who had tumour in the resected lymph nodes (38.8%), P < 0.001 [43]. Other studies have demonstrated the benefit of ypN0 as a prognostic factor in surgery for oesophageal cancer [57], with one study showing response in the lymph nodes and primary tumour to independently improve disease-free survival [58]. Two studies have suggested that adequate lymph node response improves survival, even if there is little response in the primary tumour [59, 60]. Furthermore, lymph node status was the largest determinant of prognosis in a recent machine-learning model predicting long-term survival [61]. Although there is a survival benefit for ypN0 over those with positive lymph nodes in the resected specimen (ypN+), the greatest benefit is seen in those with natural N0 or in those in whom there is concomitant complete regression in the primary tumour (ypT0)[62]. This highlights the importance of adequate pathological response in both the primary tumour and the lymph nodes. Moreover, primary tumour pathological complete response (pCR) has demonstrated 5-year overall survival of 88% vs 39% in those with complete resection (R0) but residual tumour in the resected specimen [63]. In a separate study, pCR was demonstrated as an independent predictor of improved survival following neoadjuvant chemoradiotherapy [64]. However, the Neo-AEGIS study, which compared neoadjuvant chemoradiotherapy to mostly older ECX perioperative chemotherapy, demonstrated higher rates of pCR (16% vs 5%) and ypN0 (60.1% vs 44.5%) after nCRT compared to nCT but this did not translate into improved survival [41]. If the objective of preoperative treatment were solely to improve pCR in the primary tumour and lymph nodes, neoadjuvant chemoradiotherapy would be the clear treatment of choice. However, it is important to consider how this impacts disease-free and overall survival.

Adjuvant therapy

The evidence for adjuvant therapy alone is extremely limited in gastroesophageal adenocarcinoma and is restricted to trials in gastric and gastroesophageal junction adenocarcinoma [65, 66]. In oesophageal adenocarcinoma, specific benefit of adjuvant therapy has only been demonstrated within the context of perioperative chemotherapy. In a large retrospective analysis, patients who received adjuvant chemotherapy had improved median survival over those who did not receive adjuvant chemotherapy (62.7 months vs 50.4 months) [67]. Moreover, the benefit of completing all cycles of FLOT has been shown to improve overall survival, regardless of tumour regression [68]. Adjuvant chemotherapy is also associated with improved median overall survival (40 months vs 34 months) in patients who had preoperative chemoradiotherapy [69]. Other studies suggest that the benefit of adjuvant chemotherapy in this setting is greatest in node-positive disease [70, 71]. Indeed, in their subgroup analysis in patients receiving perioperative chemotherapy Rahman et al. [67] found that patients who had ypN0 had excellent survival outcomes, with no additional benefit from adjuvant chemotherapy whereas those with ypN+ had superior survival if they received adjuvant chemotherapy. The relative benefit of neoadjuvant over adjuvant therapy alone has been shown in patients with gastric cancer in the PRODIGY trial with increased 3-year PFS in those receiving nCT (66.3%) compared to adjuvant CT alone (60.2%) [72]. Retrospective studies also show survival benefit in those with gastro-oesophageal junction adenocarcinoma receiving nCRT over adjuvant CRT [73].

Adjuvant therapy following preoperative oncological therapy can improve survival outcomes for patients with oesophageal adenocarcinoma, particularly those with residual nodal disease and is part of the current standard of care. However, there are challenges in delivering adjuvant chemotherapy in patients who have undergone oesophagogastrectomy and there is some evidence to suggest a relative benefit of neoadjuvant therapy over adjuvant.

Current standard of care and its challenges

Although accepted as a standard of care, the perioperative approach of neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy thereafter is often hampered by failure to complete all chemotherapy cycles. In the FLOT4 trial, only 46% of patients completed all cycles using the perioperative approach [4]. Whereas, in regimens where all treatment is delivered pre-operatively there is a much higher rate of treatment completion without reducing the number of patients proceeding to surgery. An example is the CROSS trial, in which 95% of patients completed oncological treatment and 90% of patients underwent resection, albeit that the amount of chemotherapy delivered in this regimen is much less than in FLOT. However, in the FLOT4 trial, 90% of patients completed all preoperative chemotherapy, suggesting that preoperative treatment is better tolerated than postoperative treatment, in part due to the morbidity following oesophagogastrectomy. Timing of surgery after neoadjuvant therapy is also an important consideration. Patients undergoing nCRT have improved response after delayed surgery (>7–8 weeks after nCRT completion) but have higher 30-day mortality after surgery [74]. A large study of >2000 patients suggests that the optimal timing for surgery is 56 days after nCRT completion to balance increased pathological response with overall survival [75].

Both the perioperative FLOT chemotherapy regimen and the preoperative CROSS chemoradiotherapy regimen plus surgery are accepted standards of care for patients with resectable oesophageal adenocarcinoma and are currently being compared in the ESOPEC trial [44]. Although there is currently no directly comparable clinical evidence to suggest that either is superior to the other, CROSS (nCRT) and FLOT (perioperative chemotherapy) have different effects on the primary tumour and systemic disease. There is a higher rate of pCR with CROSS than preoperative chemotherapy. Due to its radiotherapy component, CROSS gives the opportunity to downstage primary tumours where there is a risk of R1 resection. However, CROSS delivers less systemic treatment than FLOT. As a result, there is a risk of systemic undertreatment in patients allocated to nCRT using CROSS. This has been demonstrated in a recent large cohort study of patients with oesophageal adenocarcinoma all achieving pCR (ypT0N0) after neoadjuvant therapy, which showed that 5-year recurrence-free survival was significantly better in the nCT group (87.1%) compared to nCRT (75.3%), notably with a greater prevalence of distant recurrence in the nCRT group, suggesting potential systemic undertreatment [55]. This has also been demonstrated in 10-year CROSS follow-up, in which CROSS reduced oesophageal cancer-related death by reducing locoregional recurrence but did not reduce the incidence of distant recurrence compared to surgery alone [76].

Regarding pCR in the primary tumour and lymph nodes (ypT0N0), it is important to consider how this translates to into long-term outcomes and the differential outcomes observed after different neoadjuvant regimens. It is evident that whilst achieving ypT0N0 is important, the modality used to achieve this is also important for survival outcomes. Although there were higher rates of ypT0 and ypN0 in those receiving nCRT compared to nCT (using older ECX chemotherapy rather than FLOT) in the NEO-AEGIS study, this did not translate into improved 3-year overall survival (56% vs 57%) [41]. There were similar results in NeoRes I, with higher pCR for nCRT than nCT (28% vs 9%) but similar 5-year OS (42.2% vs 39.6%) [42]. A recent retrospective study directly comparing FLOT vs CROSS shows similar 5-year overall survival in patients receiving FLOT and CROSS despite a higher pCR with CROSS [77]. Other recent smaller studies demonstrate similar survival patterns between CROSS and FLOT but show higher distant recurrence and postoperative respiratory failure with CROSS [78, 79]. Results from the ESOPEC Phase III trial are eagerly awaited [44]. A 2019 meta-analysis makes the conclusion that although the addition of radiotherapy to chemotherapy alone increases the chance of pCR and reduces the risk of locoregional failure, it does not reduce the risk of distant metastases or death [80].

These clinical observations support tumour biology relating to intra-patient heterogeneity. One study has shown discrepancy in genomic alterations between primary tumour and metastatic disease and highlights the limitations of using genetic alterations in biopsies of the primary tumour to guide treatment in other areas of the patient’s disease such as distant metastases [81]. Furthermore, intratumoural heterogeneity exists between tissue from superficial primary tumour, deep primary tumour, and lymph node metastases [82].

The main challenges for the current standards of care are non-completion of perioperative therapy in the context of FLOT, as well as a risk of systemic undertreatment in those receiving CROSS. Whilst pCR is seen as a marker of treatment success, studies comparing patients achieving pCR who received nCT or nCRT lead us to conclude that ypT0N0 does not always translate into the same outcomes in primary endpoints such as disease-free or overall survival between treatment modalities and should not be used as a surrogate primary endpoint. Future comparative randomised trials should focus not only on pCR but also on survival outcomes. By combining both modalities in the preoperative setting using a total neoadjuvant approach, for example using extended preoperative FLOT or a combination of preoperative FLOT plus CROSS, we may be able to achieve both optimal locoregional and systemic disease control, without compromising progression to surgery, enabling more patients to complete all intended treatment.

The role of immune checkpoint inhibitors

Immune checkpoint inhibitors remove the inhibitory signals of T-cell activation that enable tumour-reactive T cells to overcome regulatory mechanisms and mount an effective antitumour response [83]. Although their mechanism of action is different, there are synergies between chemotherapy and immunotherapy and it has been suggested that an effective strategy to harness such synergies is to give immune checkpoint inhibitors after the tumour mass has been optimally reduced with surgery and systemic chemotherapy in the setting of minimal residual disease, where the negative impact of tumour bulk on antitumour immune response is minimised [84]. In the context of TNT, this could theoretically enable best possible response to local and systemic therapy whilst engaging the immune response in the postoperative setting. The positive impact of postoperative checkpoint inhibitors has been demonstrated in the nCRT setting in the CHECKMATE 577 trial, in which patients with residual disease after surgery (ypT+ or ypN+) were randomised to receive adjuvant PD-1 inhibitor, nivolumab, or placebo [85]. Median disease-free survival was 22.4 months in the treatment vs 11 months in the placebo arm (HR 0.69, P < 0.001). These results have changed the paradigm of treatment for oesophageal cancer, giving us a fourth treatment modality in addition to chemotherapy, radiotherapy, and surgery to improve outcomes for patients with locally advanced, high-risk oesophageal cancer. It must be noted that quality of life scores were comparable between the placebo and treatment groups with an acceptable safety profile, which is important when considering patients who might have already received TNT and surgical resection for further treatment [86]. However, recent trial results have failed to show a benefit for the addition of immune checkpoint inhibitors to neoadjuvant and adjuvant chemotherapy. Final results are awaited but KEYNOTE-585 reports a higher pathological complete response rate from the addition of pembrolizumab to perioperative FLOT, but the event-free and overall survival endpoints were not met [87]. Similarly, ATTRACTION-5 reported no recurrence-free survival benefit from the addition of Nivolumab to adjuvant chemotherapy [88]. In both KEYNOTE-585 and ATTRACTION-5 the use of immune checkpoint inhibitors was in biomarker unselected patients, and it is relevant that in CHECKMATE577 a post hoc subgroup analysis indicated that disease-free survival benefit from adjuvant nivolumab was only demonstrated in PDL1 combined positive score (CPS) ≥5 patients and not seen in PDL1 CPS ≤5. In metastatic or advanced-stage unresectable gastroesophageal cancer patients a number of randomised trials have reported the benefit of the addition of immune checkpoint inhibitor to chemotherapy and tumour PDL1 CPS has demonstrated benefit as a biomarker to predict the quantum of benefit from the checkpoint inhibitor. In CHECKMATE 649, patients with metastatic, or unresectable oesophageal, junctional or gastric adenocarcinomas who were not known to be HER2 positive were enrolled regardless of PDL1 CPS result, but the co-primary endpoints were PFS and OS in patients with PDL1 CPS ≥5 where benefit was seen with the addition of nivolumab to oxaliplatin plus capecitabine or 5-FU (OS HR = 0.70 (95% CI 0.61, 0.81), PFS HR = 0.70 (95% CI 0.60, 0.81)) [89]. Similarly in KEYNOTE 859, in metastatic or advanced-stage unresectable gastroesophageal junctional or gastric adenocarcinomas OS and PFS benefit from the addition of pembrolizumab to platinum fluoropyrimidine chemotherapy was demonstrated recently in patients with PDL1 CPS ≥1 with a greater incremental benefit seen in those with PDL1 CPS ≥10 [90]. While KEYNOTE 590 demonstrated benefit of the addition of pembrolizumab to platinum fluoropyrimidine chemotherapy to all randomised patients with oesophageal cancer (squamous and adenocarcinoma) and Siewert type I junctional adenocarcinomas, but greater incremental benefit in those with PDL1 CPS ≥10 [91]. These trials demonstrating the survival benefit of checkpoint inhibitors in unresectable and metastatic gastro-oesophageal malignancy have established new standards of care in biomarker-selected patients with advanced-stage disease and underscore the importance of biomarker-directed use of immune checkpoint inhibitors. Together with the recent results from KEYNOTE-585 and ATTRACTION-5, and post hoc PDL1 CPS analysis from CHECKMATE 577 this suggests that biomarker section for immune checkpoint inhibitors is likely to be important in the neoadjuvant and adjuvant setting as well. This has important relevance for ongoing trials of immune checkpoint inhibitors in the curative setting, including those which incorporate perioperative FLOT such as MATERHORN (FLOT + durvalumab or placebo) (NCT04592913). Microsatellite instability-high (MSI-H) is present in 6–24% of resected gastroesophageal adenocarcinoma and is an established predictive biomarker for immune checkpoint inhibitors [92]. Encouraging results have been reported in non-randomised Phase 2 trials of perioperative immune checkpoint inhibitors without chemotherapy in MSI-H selected patients, for example, the NEONIPIGA trial has shown pCR rates of 59% in patients with MSI-high disease, but survival follow-up is limited at present and larger randomised studies are yet to be undertaken [93].

Overall, the role of immune checkpoint inhibitors in perioperative treatment of gastroesophageal adenocarcinomas is not yet established and emerging trial results highlight the importance of biomarker-directed use of these agents. This emphasises the importance of optimising the conventional perioperative treatments with chemotherapy and chemoradiotherapy for those patients who are immune checkpoint inhibitor biomarker negative and the incorporation of treatment with checkpoint inhibitors in a biomarker-directed manner into trials of TNT where patients have residual disease despite optimal local and systematic therapy.

Conclusion

In Summary, the addition of perioperative oncological therapies to surgery have greatly improved overall and progression-free survival in patients with oesophageal and junctional adenocarcinoma, achieving higher R0 resection rates and pathological response in the primary tumour and involved lymph nodes. However, more than 50% of patients do not complete all planned therapy if receiving perioperative chemotherapy. Furthermore, whilst pCR is important, intra-tumour heterogeneity impacts how this translates into long-term disease-free survival, and the impact of FLOT and CROSS on survival does not appear to be directly related to pCR alone. Total neoadjuvant therapy has shown promising results with high pCR rates together with impressive disease-free and overall survival in the retrospective setting. This warrants a randomised controlled trial of total neoadjuvant therapy approaches, incorporating methods of treatment response.

Aspirin and cancer treatment: systematic reviews and meta-analyses of evidence: for and against

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Abstract

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence ‘for’ and ‘against’ the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

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Abstract

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence ‘for’ and ‘against’ the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

Introduction

In 1965, Sir Austin Bradford Hill set nine criteria against which a causal relationship between a presumed cause and an observed effect could be assessed [1]. These criteria are still useful, but Hill’s comment on his eighth criterion: ‘Experiment’: ‘Occasionally it is possible to appeal to experimental evidence’ is somewhat dated. Now, thanks to Cochrane and others [2] the randomised controlled trial (RCT) is widely accepted as a ‘gold-standard’ within the hierarchy of evidence, and discussions about clinical interventions tend now to be dominated by whatever RCT evidence of clinical benefit is available. Randomised trials however have their own limitations and cannot give absolute certainty, so they therefore need to be considered in balance with other sources of evidence, including observational studies.

Hill’s criteria for a causal relationship also includes ‘Plausibility’ and in relation to aspirin and cancer, plausibility has been extensively established by the identification of effects of aspirin upon platelets and upon the many biological mechanisms relevant to cancer initiation, cancer metabolism, metastatic cancer spread, and thromboembolic complications in cancer [2].

In this review, we put together the published evidence from a wide range of sources which is favourable to the use of aspirin in cancer, and evidence that is unfavourable to its use. Finally, we urge the rights of patients with cancer to be sufficiently well informed about the risks and benefits of aspirin to enable them to raise the topic with members of their healthcare team, and to enable them, within discussion with their healthcare advisors, to decide whether or not to take the drug.

For aspirin use in cancer

Aspirin, biological mechanisms and clinical outcomes

The primary mechanism of aspirin is inhibition of the cyclooxygenase (COX) enzyme responsible for the formation of key signalling lipids known as prostanoids. While this is an important pathway in cancer signalling, recent evidence highlights additional targets for aspirin in tackling cancer progression directly, irrespective of COX activity [3, 4]. Such targets include energy metabolism involved in cancer proliferation, cancer associated inflammation [5] and platelet driven pro-carcinogenic activity [2].

Aspirin was also shown to affect DNA repair pathways, which is a mechanism of particular interest in colorectal cancers. Defects in DNA mismatch repair genes are responsible for hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome [6], as well as other types of colorectal cancer by causing the occurrence of instability of simple repeat sequences (termed ‘microsatellite instability’) [7, 8] Colon cancers which exhibit a high microsatellite instability are currently targeted by immunotherapy treatment to a good effect [8].

However, aspirin has also been shown to play a role in reducing the occurrence of these microsatellite instabilities in cancer cell lines independent of COX activity, supporting a direct role for aspirin in DNA repair pathways in cancer [7]. These findings were further supported by a recent study by Nonu et al. [9] which combined proteomics and Mendelian randomisation to demonstrate a beneficial effect of aspirin on colon cancer risk through an enhancement of DNA-repair mechanisms [2].

Beyond genetic repair, aspirin has also been shown to influence epigenetic mechanisms relating to inflammation-associated cancer progression. In many cancers, inflammation leads to the promotion of carcinogenesis via direct mutagenesis or activation of a cytokine response, leading to the formation of ‘tumour microenvironments’ which are characterised by the presence of immune cells, stromal cells and extracellular matrix which together serve to promote cancer progression [10, 11].

One way in which inflammation leads to this cancer promotion is through epigenetic changes, the heritable transcription alterations that do not include changes in DNA sequence [12]. Aspirin has been shown to interfere with these epigenetic cancer-related changes by mediating histone methylation, leading to an in vivo decrease of tumour growth and metastasis in animal models of metastatic cancer through interfering with cells in the tumour microenvironment [12, 13].

Together, these observations provide mechanistic evidence for the causal involvement of aspirin in modifying cancer pathways, DNA repair mechanisms as well as epigenetic mechanisms which jointly provide a ‘basic science’ basis to justify using aspirin as an adjunct to other pre-existing therapies (e.g., immunotherapy and cytotoxic chemotherapy) in the treatment of cancer progression and metastasis [2, 14].

Aspirin and vascular complications in cancer

Aspirin has been shown repeatedly to reduce thromboembolism, including in patients with cancer [15], and the biological mechanisms through which this is achieved have been well described [2].

In the UK records for 108,000 survivors of cancer were examined. Venous thromboembolism and other vascular causes of death were found to be substantially elevated in patients with almost all the cancers and were most pronounced in patients who had received chemotherapy [16].

In the USA the SEER programme on mortality in cancer patients reported that 11% of deaths amongst patients with twenty different cancers had been certified as due to vascular disease, most of which (76%) was heart disease [17]. This led the American Society of Clinical Oncology to recommend that prophylactic anticoagulants be considered for all hospitalised cancer patients [18]. Although aspirin use has to some extent been superseded by recently developed drugs for vascular protection, aspirin is still effective against thrombosis, including venous thrombosis [19].

Aspirin and metastatic cancer spread

The effect of aspirin on metastatic spread is of importance because metastases are responsible for much of the pain and the complications of cancer [20] and many of the deaths are attributable to metastases [21]. Platelets play a significant role in metastatic spread, and the relationship between these effects and the clinical outcomes has been detailed elsewhere [2, 22].

There appears to have been no systematic literature search and meta-analysis of clinical data on metastatic cancer, but many studies and overviews give evidence of substantial reductions by aspirin (ranging from about RR 0.48 (95% CI 0.30 to about 0.75), to RR 0.62 (0.52 and 0.75) [23, 24].

It is important to note that an effect on cancer spread indicates a value of aspirin that is independent of its effects upon cancer mortality [24,25,26]. Indeed any delay in the diagnosis and initiation of treatment would seem to make a reduction in metastatic spread of increased value.

Aspirin and cancer mortality

An effect of aspirin of particular interest is its enhancement of the mismatch repair of DNA [3], a protective mechanism against cancer within all of us. Failure of this mechanism leads to Lynch Syndrome, with a high risk of colon and other cancers and with an estimated prevalence of one in 279, or 0.35% in the general population [27].

Following the report of a reduction in mortality by aspirin in patients with this syndrome [28], the National Institute of Clinical Excellence in the UK judged the safety and effectiveness of aspirin favourable and recommends aspirin for the reduction of cancer in patients with the Syndrome [29].

A systematic literature search in 2016, together with two replicate searches in 2018 and in 2021 identified 118 published observational studies of cancer patients, representing about 1 million patients with 18 different cancers [30]. About a quarter of these patients reported taking aspirin at diagnosis (most usually for vascular protection, and therefore 75 or 81 mg daily) and a pooled analysis showed a reduction of 21% in all-cause mortality (HR 0.79; 95% CI 0.74, 0.86 in 56 reports that used hazard ratios and OR 0.57 (0.36, 0.89) in seven papers that reported odds ratios). Table 1 provides a summary of the key data.Table 1 Aspirin taking and mortality: meta-analysis of 118 published observational reports [30].

Full size table

Publication bias, arising from the selective publication of positive findings for an intervention such as aspirin, is a most important issue in meta-analyses such as the above. A ‘trim and fill’ testing procedure to restore symmetry in forest plots was therefore applied extensively to the data, and although the benefits of aspirin were reduced, significance of almost all the reductions remained [30].

In their report the authors identified 23 publications which had focused upon fifteen less studied cancers (naso- and oropharyngeal, oesophagus, gastrointestinal, gastric, rectal, liver, gallbladder, bladder, pancreas, bladder, endometrium, ovary, glioma, head and neck, lung, melanoma). Meta-analysis of these gave pooled reductions of around 30% in deaths associated with aspirin taking (HR 0.67; 0.60, 0.75 in 21 studies, and OR 0.47; 0.26, 0.83 in five studies) [30]. Together with the evidence of favourable effects of aspirin upon a wide range of biological mechanisms relevant to cancer mortality [3], these clinical outcomes suggest that aspirin is likely to be of benefit to patients within a very wide range of different cancers.

Unfortunately, in contrast to observational studies, very few randomised trials of aspirin and mortality have been reported. The pooled results of four early trials based upon a total of 722 patients with cancer gave a suggestive pooled reduction associated with aspirin of about 9% in cancer deaths [30]. Currently, a number of randomised trials which test aspirin and mortality are in progress. These focus upon the common cancers: colon, breast, prostate and one in lung cancer. One of these trials, based upon 3021 selected patients in remission from a HER2-negative breast cancer, has already reported [31]. This trial was ended prematurely because aspirin was associated with a possible increase of about 25% in deaths.

The opportunity to conduct long-term follow-up studies of deaths in subjects who had already participated in randomised trials of aspirin and vascular disease was taken by Rothwell and colleagues in Oxford. Subjects who had been involved in up to 51 randomised vascular trials were followed-up for up to 20 years. Consistently, a reduction in cancer deaths was shown in these studies: (OR 0.58; 95% CI 0.44, 0.78 in an overview of six vascular trials [23], and OR 0.84; 0.75, 0.94) in an overview of 51 randomised vascular trials) [32].

An opportunistic trial was conducted in a subset of subjects who were participants in a randomised trial of prophylactic aspirin. During the study 502 subjects developed cancer of the prostate, and follow-up of these showed a 30% relative reduction attributable to aspirin (HR 0.68, 95% CI 0.52, 0.90 in cancer deaths and HR 0.72; 0.61, 0.9 in all-cause deaths) [33], and the evidence given by aspirin taken by patients with the Lynch syndrome [27], together with Mendelian randomisation studies, powerfully supplement the evidence available from conventional randomised trials.

Aspirin and the duration of survival

A few authors report estimates of the length of additional survival associated with aspirin taking by patients with cancer. A number of different summary statistics of survival have been used, and these defy pooling, but the additional survivals range from about 3 months up to 3 years [30].

Using a different approach, a group in Liverpool extracted extensive baseline data, including aspirin taking, from the records for 44,000 patients with colon cancer. With these they constructed a formula giving predicted estimates of survival [34]. Entering into the formula the details for a typical non-diabetic patient aged 70 with colon cancer, the inclusion of aspirin increases the estimate of survival by about 5 years for a man, and about 4 years for a woman.

Against aspirin use in cancer

Additional gastrointestinal bleeding

A bleed, either gastrointestinal or intra-cerebral, is a crisis for a patient and especially for patients who are already seriously ill [35,36,37]. Yet the seriousness of bleeds attributable to aspirin, and not just their frequency, should be evaluated against the benefits attributable to the use of aspirin [38]. The most serious bleeds are those that are responsible for death, and survival/death is a clear dichotomy, requiring no value judgement.

In a systematic literature search eleven randomised trials which included data on fatal bleeding were identified [39]. These 11 RCTs included together a total of 121,094 subjects, followed for an average of 2.8 years, as shown in Table 2.Table 2 GI bleeding in a meta-analysis of data from 11 RCTs [39] (average duration 2.8 years).

Full size table

These data confirm the usual excess risk of all ‘major’ bleeds for aspirin (RR 1.55), equivalent to about one per bleed per 1000 persons per year. Note however that the 50% increase above the background risk of bleeding from a peptic ulcer, stomach infection or other pathology, means that amongst patients who are taking aspirin the risk of a GI bleed being truly attributable to aspirin is only one in every three bleeds.

However, the proportion of ‘major’ bleeds in subjects who had been randomised to aspirin that led to death was 4% in those who had been randomised to aspirin while 8% of bleeds in subjects randomised to placebo were fatal. Clearly, this implies that overall, the bleeds truly attributable to aspirin must be of a much lower severity than other bleeds attributable to stomach pathology. This is further confirmed by the absence of any increased risk of a fatal bleed associated with aspirin taking, as shown in the third cell in the above table (RR 0.77), and this final conclusion has been confirmed in overviews of bleeding reported by other authors [39].

It is unfortunate however that the scientific literature on the issue of aspirin and bleeding appears to have been swamped by a host of statements about serious dangers of aspirin, most unsupported by any evidence while some are total misinterpretations. Probably the most misleading and most influential item on the web was a report issued by Reuters on the 14th June 2017, stating: ‘daily aspirin causes 3000 deaths from bleeding in Britain every year’ [40]. This claim was taken up and very widely and repeatedly publicised in the web and the media across the world. The report by Reuters was however a totally invalid, having been based on a prospective study of 3166 older patients, all of whom (93–97%) were taking aspirin. There were therefore no control subjects and no valid estimate of the independent contribution of aspirin to the fatal bleeds can be made.

In addition to this, there have been reports of so-called ‘neurogenic’ bleeding in patients with acute ischaemic strokes. A report from six thousand patients in the Fukuoka Stroke Registry describes 89 patients (1.4%) who experienced a GI bleed within a week of admission for acute ischaemic stroke [41]. O’Donnell et al. reported an incidence rate of 1.5% within a week of admission for acute ischaemic stroke, associated with a high rate of death [42] and Davenport et al. estimated an incidence of 3% [43]. In the study which led to the Reuters claim of 3000 deaths 2000 (65%) of the patients had had a stroke!

Additional cerebral bleeding

Unlike a gastrointestinal bleed, the consequences of a cerebral bleed, whether or not fatal, can be of a severity comparable to a cancer or a myocardial infarct in a risk/benefit evaluation. Estimates of additional risk in patients on aspirin are around one or two events per ten thousand (10,000) subject-years [35, 44, 45]. The major factor in cerebral bleeding however is hypertension [46], and in an RCT of aspirin based on more than 18,000 hypertensive patients—all of whom were receiving ‘optimal’ antihypertensive treatment—there were no additional cerebral bleeds in patients randomised to aspirin [47].

Inadequate support from randomised trials of aspirin

At present, the strength of the case for the use of aspirin in cancer lies in the wealth of evidence of benefit in observational cohort and case-control studies of aspirin taken by patients with cancer, while support from RCTs is seriously limited to a small number of trials, and there are serious inconsistencies between these.

There are calls by many for a delay on the promotion of aspirin until there is better and more consistent evidence from randomised trials. However, one seriously questions how much evidence, from how many randomised trials, in how many different cancers, will be required to resolve the uncertainties in the pooled observational studies.

Discussion

The first ethical principle in clinical practice is: do no harm: non-maleficence. In the evaluation of excess bleeding attributable to aspirin, the absence of any valid evidence of fatal bleeding (see Table 2 and the related references) is reassuring and indicates that evaluated against cancer, or a thrombotic vascular event, aspirin is a reasonably safe drug. This conclusion is supported by the recommendation of aspirin by NICE as a treatment for some patients at risk of cancer [29].

Beneficence—perhaps the second most important ethical principle of relevance to clinical interventions—has been established with difference levels of probability for the three main clinical effects of aspirin. A reduction in thromboembolic events has been widely and repeatedly established with a high level of certainty, and a reduction in metastatic cancer spread seems to be a reasonable expectation based upon both clinical reports and the effect of aspirin upon relevant biological mechanisms. While the evidence for a reduction in mortality lacks consistent support from RCTs, both the evidence of benefit in Lynch syndrome [12], and further evidence from Mendelian randomisation studies [2] give considerable support.

Furthermore, the effect of aspirin on both the biological mechanisms relevant to thromboembolism and to metastatic cancer spread, are different to the biological mechanisms of aspirin and cancer growth and survival. This seems to indicate that aspirin is a useful cancer treatment whether or not the drug does truly affect survival.

However, the wealth of favourable evidence on aspirin and mortality in observational cohort and case-control studies of patients with cancer cannot be lightly dismissed. Granted, confounding by unknown factors independent from aspirin is possible and perhaps even likely, yet the evidence from Mendelian randomisations studies powerfully supplements the few results from randomised trials.

The situation with cancer in the poorer countries is clearly ethically unjust. One in every six deaths worldwide is due to cancer [48], giving an estimated 9.6 million deaths in 2018, with around 70% of the deaths in low- and middle income- countries [49]. WHO points out that most cancers in the poorer countries are diagnosed at a very late stage, when most treatments are no longer effective—even if treatments were available, which they are not in many countries [50]. Against that background the promotion of aspirin would be of enormous benefit in developing countries.

The ethical issue of autonomy concerns the right of a patient to be involved in every aspect of his or her care and treatment [51, 52]. Aspirin is inexpensive and readily available globally. It is easily taken with none of the highly distressing effects that accompany some of the cancer therapies. While aspirin should best be considered as a possible adjunct treatment for cancer, yet for those patients who refuse the more aggressive treatments, and for patients for whom palliative care is judged to be appropriate, aspirin should be considered.

Given the relative safety of aspirin; given its likely reduction in metastatic cancer spread; given its associated reduction in thromboembolic complications and given the support by NICE for aspirin use in a subset of cancers, is it ethically reasonable for patients to be kept in ignorance about the probable risk/benefit balance of aspirin?

Early in this work, in 2010, a challenge was published in the BMJ: “The debate about aspirin has consumed the medical profession for over 30 years, [now, almost 50 years!] yet almost no public participation or consultation has occurred” [53]. In response, a 3-day far ranging enquiry—a ‘Citizens’ Jury—under the general title: ‘My Health—whose responsibility?’ was held in Cardiff with members of the general public who had no vested interest in the topic [54]. Over several days, the jury listened to a range of (sometimes contradictory) expert evidence, and the evidence of ‘experts by experience’, and vigorously debated amongst themselves the various issues raised. An immediate outcome of this initiative was a verdict by the sixteen members of the ‘jury’ that patients and the public should be directly involved in the evaluation of the outcomes of research, and in the assessment of its relevance to clinical practice and to public health policy…. and to this last the jurors unanimously added the phrase: ‘even before there is agreement between doctors’ [54].

In the UK, the NHS Ethical Clinical Guidelines establish that people have a right to be involved in discussion and have a right to make informed decisions about their care [55]. However the law in the UK goes further and in a ‘Landmark Decision’ given by the UK supreme court in 2015 it was stated: ‘If information is material, doctors should generally disclose it. They should not wait for the patient to ask’ [56]. Surely evidence on the possible benefits of aspirin are highly ‘material’ to patients with cancer and to their carers!

‘Medicine is a science of uncertainty and an art of probability.’

Sir William Osler (1849-1919)

Frequently described as the father of Modern Medicine. (1849-1919)

Conclusions

A major strength of the case for the promotion of aspirin as a treatment of cancer lies in the consistent evidence of a reduction in the thromboembolic complications of cancer and in the consistent evidence of a reduction in metastatic cancer spread. The main weakness, however, lies in the lack of support of a reduction in deaths from trials with random allocation of aspirin. However, the suggestive evidence from observational studies, together with evidence from Mendelian randomisation powerfully favour the use of low-dose aspirin.

Finally: aspirin is inexpensive, readily available and has none of the highly aggressive side effects of some of the cancer treatments. It would therefore seem to be only fair and reasonable that knowledge of the true risk and probable benefits of the drug should be widely publicised amongst cancer patients and their carers—so that, as one oncologist has predicted:

There could be benefit ‘…both to the affluent and the indigent within developed and under-developed countries’… and…’a truly global impact on cancer mortality could be realised

Childhood Leukaemia May Be Linked to Residential Exposure to Electrical Transformer Stations

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TOPLINE:

A study from Northern Italy has found weak evidence for an association between residential proximity to electrical transformer stations and childhood leukaemia in children aged 5-14 years. No association was found in younger children.

METHODOLOGY:

  • A population-based, case-control study of 182 patients with childhood leukaemia (age, 0-14 years) from two Northern Italian provinces (with diagnosis during 1998-2019) identified using an Italian registry and 726 age-, sex-, and province-matched control individuals.
  • Residential exposure to the nearest transformer station was calculated for all patients and control individuals using a geographic information system.
  • Exposure was evaluated based on residing within a 15- or 25-m radius from the transformer station, which is often located on the ground floor or in the basement of houses. The transformer converts the distribution line’s 15 kV to the end user’s 380 V.

TAKEAWAY:

  • There was no overall association between the risk for leukaemia (all subtypes) or acute lymphoblastic leukaemia and living close to a transformer station.
  • There was some evidence on this relationship for children aged ≥5 years. The odds ratio showed a 30% increase in the risk for both leukaemia and acute lymphoblastic leukaemia among those living within 15-m radius from the transformer but the confidence interval (CI) was too wide to confer statistical significance (eg, odds ratio, 1.3; 95% CI, 0.1-12.8 for leukaemia).
  • Among children aged ≥5 years living within the 25-m radius, there was a 70% increase in the risk for leukaemia but again the CI was too wide to confer statistical significance (odds ratio, 1.7; 95% CI, 0.4-7.0 for leukaemia); no increase in the risk was seen for acute lymphoblastic leukaemia.
  • No association was found among children <5 years of age for leukaemia or acute lymphoblastic leukaemia.

IN PRACTICE:

The authors concluded that they have evidence of a “modest positive but imprecise association” particularly for older children, but “larger studies are needed to confirm our findings.” The findings support results from most systematic reviews and meta-analyses.

SOURCE:

The study was led by Marcella Malavolti, University of Modena and Reggio Emilia, Modena, Italy. It was published online in Environmental Research.

LIMITATIONS:

The major limitations of the study were its observational, case-control design and the very low number of patients living within close proximity to transformer stations.

When bad cells go good: Harnessing cellular cannibalism for cancer treatment

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Scientists have solved a cellular murder mystery nearly 25 years after the case went cold. Following a trail of evidence from fruit flies to mice to humans revealed that cannibalistic cells likely cause a rare human immunodeficiency. Now the discovery shows promise for enhancing an up-and-coming cancer treatment.

“This paper takes us from very fundamental cell biology in a fly, to explaining a human disease and harnessing that knowledge for a cancer therapy,” said UC Santa Barbara’s Denise Montell. “Each one of those steps feels like a major discovery, but here they are, all in one paper.”

Researchers in Montell’s lab published their findings in the Proceedings of the National Academy of Sciences and are now investigating the mechanisms and implications.

An ancient gene

The primary character in this story is a gene, Rac2, and the protein it encodes. Rac2 is one of three Rac genes in humans. “Rac is very ancient in evolution, so it must serve a fundamental function,” said senior author Montell, Duggan Professor and Distinguished Professor of Molecular, Cellular, and Developmental Biology.

Rac proteins help build a cell’s scaffolding, called the cytoskeleton. The cytoskeleton is made of dynamic filaments that allow cells to maintain their shape or deform, as needed. In 1996, while studying a small group of cells in the fruit fly ovary, Montell determined that Rac proteins are instrumental in cell movement. Since then, it has become clear that Rac is a nearly universal regulator of cell motility in animal cells.

Back in the ’90s, she noticed that a hyperactive form of the Rac1 protein, expressed in only a few cells in a fly’s egg chamber, destroyed the whole tissue. “Just expressing this active Rac in six to eight cells kills the entire tissue, which is composed of about 900 cells,” explained lead author Abhinava Mishra, a project scientist in Montell’s lab.

Why did this happen? How does it work? “This was our 25-year-old cold case,” Montell said.

A few years ago, evidence began to mount implicating cell eating, also known as cannibalism, in tissue destruction. There’s a step in normal fly egg development where certain cells similar to the border cells consume their neighbors because they are no longer needed. Indeed, cellular cannibalism is not as rare as you might expect: Millions of old red blood cells are eliminated from the human body this way every second.

Rac2 is one component of the complex eating process. Rac helps the eating cell to envelop its target. The team was curious if a hyperactive form of the protein was causing border cells to prematurely consume their neighbors.

For this to occur, the border cells need to recognize their targets, which requires a particular receptor. Indeed, when Mishra blocked this receptor, the border cells expressing activated Rac didn’t consume their neighbors, and the egg chamber remained alive and healthy.

“Our 25-year-old cold case was solved, and that was very satisfying for us,” Montell exclaimed. “But this is a fairly niche area of Drosophila egg development.” The implications would soon grow, though.

A mysterious immune condition

Around the time that her lab made their breakthrough, Montell caught wind of an intriguing study in the journal Blood. This paper found that three unrelated people suffering from recurrent infections had the exact same mutation, which hyperactivates Rac2, a Rac protein produced in blood cells. She suspected her lab’s recent revelation in fruit flies might shed light on this enigma.

The patients’ mutation was just mildly activating, and yet it was enough that they all suffered from multiple infections and ultimately needed bone marrow transplants. Blood tests revealed that these patients had nearly no T cells, a specialized kind of white blood cells crucial to the immune system. The team at the National Institutes of Health inserted the Rac2 mutation into mice and found the same mysterious loss of T cells. They also found that the T cells with hyperactive Rac developed normally in the animals’ bone marrow, and migrated to the thymus, where they continued to mature without incident. But then they just seemed to disappear. So, the paper ended with a mystery: what was causing the T cells to disappear?

The authors of that journal study had noticed that many of the patients’ neutrophils—another type of white blood cell—were enlarged. They seemed to be consuming quite a lot of material, unusual behavior in an otherwise healthy person. Many aspects of the immune system are involved in these findings. Credit: Matt Perko, UC Santa Barbara

Montell wondered if the patients’ T cells were disappearing because their innate immune cells like neutrophils with active Rac2 were eating them, much like the fruit fly border cells with active Rac were eating the egg chamber. Her team turned their attention to macrophages—the neutrophil’s more voracious counterpart—to investigate. Mishra cultured human macrophages with and without hyperactive Rac2 together with T cells. He observed that macrophages with hyperactive Rac consumed more cells, confirming the group’s hypothesis from their work with fruit flies.

To test whether this might cause the observed immunodeficiency, co-author Melanie Rodriguez (a graduate student in Montell’s lab) took bone marrow samples from mice with the same hyperactive Rac2 mutation found in the patients. She then grew the marrow stem cells into macrophages, and performed a similar experiment to Mishra, but this time mixing both macrophages and T cells with and without the Rac2 mutation.

She found that macrophages with active Rac2 consumed significantly more T-cells than their normal counterparts. However, T-cells with active Rac2 were also more vulnerable to consumption from either kind of macrophage. So the most likely explanation for the patients’ missing T cells was a combination of increased consumption by macrophages as well as increased vulnerability of the T cells themselves. A human medical mystery was solved based on fundamental observations in fruit flies.

Harnessing haywire cells

The implications of these insights expanded in January 2020, when co-author Meghan Morrissey interviewed for a faculty position at UCSB. In her talk she described programming macrophages to eat cancer cells as a novel treatment for the disease, an approach called CAR-M. Morrissey had found that adding a CAR receptor to macrophages promoted this behavior. But it was also clear that inducing the macrophages to eat more would make the approach more effective—especially if they would specifically consume, and kill, entire cancer cells.

Well, if there was one thing that Montell and her lab had learned, it was how to make macrophages eat and kill whole, living cells. So they collaborated with Morrissey, now an assistant professor of molecular, cellular and developmental biology, to determine if adding activated Rac2 would increase the effectiveness of the CAR-M approach.

Rodriguez grew macrophages from the bone marrow of normal and mutant mice with activated Rac2. In each of these groups, Morrissey expressed either a dummy receptor or the CAR receptor, which recognizes B cells (another type of white blood cell). They found that the normal and hyperactive Rac cells with the dummy receptors did not eat many B cell targets. The normal macrophages with CAR receptors consumed far more B cells, as Morrissey had previously shown. However, the macrophages with both hyperactive Rac and the CAR receptors ate twice-again as many B cells as the CAR-only group. Activated Rac2 also seemed to increase the number of so-called “super eaters”—ravenous macrophages that eat and kill multiple cancer cells.

The results made it clear that activated Rac and the receptor were both necessary for the enhanced effect. “If you add active Rac without the right receptor, it doesn’t do anything,” Montell explained.

This level of control is good news for any potential treatments because it would give doctors a way to focus the modified macrophages’ attack on cancerous cells. Clinicians hopefully won’t need to worry about the engineered cells eating the patient’s T-cells either, because the T-cells wouldn’t have the active Rac2 mutation making them more vulnerable to this, as Rodriguez had previously discovered.

There is a current cancer treatment called CAR-T, which uses the CAR receptor and a patient’s own T-cells to attack and destroy cancers. It is highly effective against some cancers, but there are many that do not respond. CAR-M, a newer cousin to CAR-T, has recently entered into clinical trials in humans and so far seems safe. Montell and her group are interested in harnessing Rac-enhanced CAR macrophages to increase the efficacy of CAR-M treatments. They’ve filed a provisional patent for the technique—which they call Race CAR-M—and are inviting biotech companies to partner in further developing the approach.

This new multifaceted paper raises both basic science and practical questions, which the lab has begun to tackle. They’re investigating whether the technique, which is so effective in the lab, will also work in freshly collected human immune cells and in animal cancer models, in mice and zebrafish. The team is also exploring how Rac2 is making this all happen at the molecular level, deep inside the cells.

Further down the line, Montell wants to know how many kinds of cancer the RaceCAR-M treatment might successfully target. For comparison, CAR-T has been effective against cancers like leukemia and lymphoma, but not against solid-tumor cancers like breast, lung or colon.

The results have amazed Montell, an esteemed cell biologist with well over 100 papers to her name. “This is my favorite paper so far,” she said.

“We had this 25-year-old cold case in fruit flies, and we solved it,” Montell added. “And that helped us solve the mystery of an unexplained human immunodeficiency. And then we harnessed that knowledge to enhance a potential cancer immunotherapy.

“It was just one mystery after another, and Rac turned out to be the answer to each of them.”

Treatment Approaches for Platinum-Resistant Ovarian Cancer

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ABSTRACT

ChooseTop of pageAbstract <<CASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

CASE PRESENTATIONChooseTop of pageAbstractCASE PRESENTATION <<CHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES

A 59-year-old woman presents with recurrent high-grade serous ovarian carcinoma. At initial diagnosis, she underwent an optimal cytoreductive surgery and was diagnosed with stage IIIC, BRCA wild-type, homologous recombination deficiency (HRD) test–positive disease. She completed six cycles of adjuvant carboplatin and paclitaxel chemotherapy with normalization of her cancer antigen (CA)-125 and subsequently received olaparib maintenance. Five months after her last treatment with carboplatin and paclitaxel, she reported new abdominal bloating; her CA-125 was found to be 353. Computed tomography imaging revealed multiple new peritoneal nodules, serosal implants, and ascites, indicative of disease progression.

CHALLENGES IN DIAGNOSIS AND MANAGEMENTChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A… <<SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES

After initial diagnosis and treatment with platinum-based chemotherapy, 85% of patients with epithelial ovarian cancer will experience recurrence and eventual treatment resistance. The platinum-free interval (PFI) is defined as the time from last platinum treatment to detection of recurrence. A PFI of <6 months has been historically used to identify patients who have <20% response rate with rechallenge with platinum-based therapy.1,2 Patients with a PFI of <6 months are considered to have platinum-resistant ovarian cancer (PROC). Given the limited efficacy of platinum in these cancers, treatment with nonplatinum therapy is often considered.

However, the introduction of maintenance therapies such as bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitors has added additional complexity into the interpretation of platinum resistance. For example, several retrospective studies, including retrospective analyses of the SOLO2 and PAOLA1 trials, have reported that receipt of previous PARP inhibitor treatment may modify the clinical relevance of the PFI.3–6 Additionally, patients with nominal PROC may still have disease response to platinum therapy. Recognizing that platinum sensitivity is therefore not a binary condition but a spectrum, the Gynecologic Cancer Intergroup (GCIG) moved away from a strict definition of platinum resistance in both the fifth and sixth Ovarian Cancer Consensus Conferences7,8 and recommends considering whether platinum remains a treatment option.7 Similarly, although the National Comprehensive Cancer Network (NCCN) Ovarian Cancer guidelines preserve a division between platinum-sensitive and platinum-resistant ovarian cancers, they caution that definitions of platinum sensitivity are imprecise, and that clinical judgment and flexibility should be used in determining treatment options.9

SUMMARY OF THE RELEVANT LITERATUREChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L… <<NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M…REFERENCES

Initial Studies

The mainstay of treatment for PROC has been sequential use of cytotoxic agents with monotherapy activity including pegylated liposomal doxorubicin (PLD), gemcitabine, paclitaxel, and topotecan. In general, the reported response rates in recent PROC trials have been 10%-15%, with a median progression-free survival (PFS) of approximately 3.5 months (Table 1).19–22

TABLE 1. Reported Response Rates in Recent PROC Trials

View larger version (361K)

Use of Bevacizumab in PROC

A significant advance in PROC treatment occurred with the AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) study, which investigated the value of adding bevacizumab to nonplatinum chemotherapy in recurrent PROC. In this phase III study, 361 patients received either investigator’s choice chemotherapy (paclitaxel 80 mg/m2 once weekly, PLD 40 mg/m2 once every 4 weeks, or topotecan 4 mg/m2 once weekly) or investigator’s choice chemotherapy with bevacizumab.10 The primary end point was PFS, with secondary end points of objective response rate (ORR) and overall survival (OS). Eligible patients had PROC and no more than two previous anticancer treatments. The study met its primary end point of improved PFS, with patients in the chemotherapy plus bevacizumab arm demonstrating a statistically significant improvement of 6.7 months versus 3.4 months (hazard ratio [HR], 0.48 [95% CI, 0.38 to 0.60]) and ORR of 27.3% versus 11.8% (P = .001). No significant improvement in OS was observed.

AURELIA established the addition of bevacizumab to chemotherapy as a standard of care in PROC. Patients receiving chemotherapy plus bevacizumab experienced expected toxicity on the basis of previous studies including a 2% risk of GI perforation. Notably, the typical toxicity profiles for each chemotherapy cohort, including neuropathy with paclitaxel and hand-foot syndrome with PLD, were accentuated with the addition of bevacizumab. However, patients receiving bevacizumab with chemotherapy remained on treatment longer and reported a 15% or more improvement in patient-reported outcome measures of GI symptoms at 8 weeks, suggesting a patient-specific approach to choosing when to include bevacizumab with therapy.23

OVAL: A Randomized Trial of Ofranergene Obadenovec With Weekly Paclitaxel

Beyond the addition of bevacizumab to chemotherapy, therapeutic advances in PROC have been a challenge. The companion to this article16 reports the OVAL study, a phase III international randomized trial of ofranergene obadenovec (Ofra-vec) versus placebo in combination with weekly paclitaxel in PROC. In this trial, 409 patients with PROC were randomly assigned 1:1 to receive once weekly paclitaxel with placebo or Ofra-vec, a nonreplicating adenovirus-based therapy that promotes disruption of vascular growth and tumor immune infiltration, once every 8 weeks. Despite promising evidence of efficacy from the preceding phase I/II study,24 OVAL was closed early after failing to meet the coprimary end points of OS and PFS at the first unblinded analysis. The reported PFS for Ofra-vec in combination with paclitaxel was 5.29 months versus 5.36 months in the control arm (HR, 1.03 [95% CI, 0.83 to 1.29]), while OS for Ofra-vec plus paclitaxel was 13.13 months versus 13.14 months with paclitaxel alone (HR, 0.97 [95% CI, 0.75 to 1.27]).

A unique aspect of this trial was the inclusion of a planned unblinded interim futility analysis of CA-125 response in the study on the basis of GCIG consensus criteria.25 The end point for this analysis was included on the basis of the favorable CA-125 response rate of 58% with Ofra-vec plus weekly paclitaxel in the initial phase I/II study.24 In the OVAL interim futility analysis, which was conducted in the first 60 evaluable patients in the phase III study, 53% of patients had a CA-125 response, including 15% with a complete CA-125 response. The unblinded results were available only to the Data Safety Monitoring Committee, which recommended continuation of the study; of note, the prespecified criterion for continuation was an absolute percentage advantage in CA-125 response of 10% or higher for Ofra-vec with weekly paclitaxel compared with paclitaxel alone. Nonetheless, exploratory analyses at the conclusion of the study concluded no association between PFS or OS and CA-125 response. Although disappointing, the OVAL study results thus provide valuable evidence that CA-125 is not a reliable trial-level surrogate for survival outcomes.

Ongoing Studies and Approaches

Beyond the OVAL study, there are multiple ongoing clinical trials that look to improve therapeutic options for patients with PROC (Table 2). Just recently, however, the randomized phase III AXLerate-OC trial (ClinicalTrials.gov identifier: NCT04729608) of the GAS6/AXL decoy protein batiraxcept reported negative results for the combination of batiraxcept or placebo with once weekly paclitaxel in PROC. Notably, the PFS with weekly paclitaxel alone in the AXLerate-OC study was reported to be 5.5 months, similar to that observed in OVAL, and longer than the 3.5 months historically considered the benchmark for PFS with single-agent therapy in PROC. Interestingly, the activity observed with once weekly paclitaxel has consistently outperformed other single-agent regimens in numerous completed clinical trials, boasting response rates of approximately 30% and a PFS of 5.5 months irrespective of the number of previous lines of therapy.26 The results from OVAL and AXLerate-OC therefore reset the benchmark for expectations for standard-of-care weekly paclitaxel in PROC and should be considered in the development of clinical trials within this space.

TABLE 2. Recent or Ongoing Phase III Trials in Platinum-Resistant Ovarian Cancer

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NOVEL AGENTS FOR PROCChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROC <<SUGGESTED APPROACHES TO M…REFERENCES

Antibody-Drug Conjugates

Antibody-drug conjugates (ADC) are a rapidly evolving area of oncology drug development, and there has been high interest in developing these drugs in PROC. ADC targets of interest in PROC have included folate receptor alpha (FRα), NaPi2b, trophoblast cell surface antigen 2, mesothelin, and human epidermal growth factor receptor 2 (HER2). In November 2022, mirvetuximab soravtansine (MIRV) became the first ADC to receive accelerated approval from the US Food and Drug Administration (FDA) for ovarian cancer.

MIRV consists of a FRα-directed antibody conjugated to the cytotoxic maytansinoid effector molecule DM4, a tubulin-targeting antimitotic agent. In the phase II SORAYA study, 105 patients with FRα-high PROC (defined as 75% of viable tumor cells exhibiting at least 2+ membrane staining intensity by immunohistochemistry [IHC]) received MIRV at 6 mg/kg using adjusted ideal body weight administered intravenously once every 3 weeks. MIRV demonstrated substantial clinical activity, with an ORR of 32.4% (95% CI, 23.6 to 42.2; P < .0001) and a median duration of response (DOR) of 6.9 months.27 The confirmatory phase III trial MIRASOL randomly assigned 453 patients with FRα-high PROC and up to three previous lines of therapy to MIRV or investigator’s choice chemotherapy (paclitaxel, PLD, or topotecan). The primary end point of the study was PFS, with secondary end points of ORR, OS, and PROs. Excitingly, MIRASOL reported a PFS of 5.62 months with MIRV versus 3.98 months with chemotherapy (HR, 0.65 [95% CI 0.52 to 0.81]) and the first report of improved OS in a PROC trial, with an OS of 16.46 months with MIRV versus 12.75 months with chemotherapy (HR, 0.67 [95% CI, 0.50 to 0.88]).17 Low-grade ocular toxicities were reported in both studies, with blurry vision and keratopathy being the most common symptoms; 96% of cases resolved with dose hold or reduction.

Other ADCs remain under active development in PROC. The HER2-directed ADC trastuzumab deruxtecan (T-DXd) is approved in breast, gastric, and lung cancers, and has shown efficacy across multiple solid tumor types. Recent results from the DESTINY-PanTumor02 trial, a phase II trial of T-DXd in various cohorts of HER2-expressing advanced-stage solid tumors including ovarian cancer, reported an ORR of 57.5% and a DOR of 11.3 months in the ovarian cohort of 40 patients.28 These results are intriguing; however, development of T-DXd within the ovarian space will require further understanding of HER2 expression and biology in ovarian cancers. The results from an ovarian cancer expansion cohort of a separate FRα-directed ADC, luveltamab tazevibulin, were recently presented and reported an ORR of 37.5% with a median DOR of 5.5 months in 32 patients who had ovarian cancer with FRα of at least 25% by tumor proportion score.29 As more data become available, these ADCs or others may become part of the armamentarium for PROC, and this is an exciting and active area of ongoing investigation.

DNA Damage Response and Cell-Cycle Targeting Agents

DNA damage response (DDR) has been a target of growing interest, and agents under investigation in PROC include DDR and cell-cycle targeting drugs such as WEE1 kinase inhibitors, ATR inhibitors, and CDK2 inhibitors. In early-phase trials, inhibitors of WEE1, which modulates the G2/M cell-cycle checkpoint, have had reported activity as monotherapy in CCNE1-amplified ovarian cancers30 as well as in the setting of cyclin E-high PROC.31 A phase II study also reported significant activity of the WEE1 inhibitor adavosertib in patients with ovarian cancer who had previously received a PARP inhibitor, with an ORR of 23% as monotherapy and 29% when combined with olaparib.32 Significant clinical activity has also been reported with the combination of WEE1 inhibitors such as adavosertib or azenosertib with chemotherapy in PROC,33,34 and a phase II study of adavosertib together with gemcitabine reported improved PFS and OS compared with gemcitabine alone in PROC.35 Similarly, a study of the ATR inhibitor berzosertib together with gemcitabine reported improved PFS compared with gemcitabine alone.36

Immunomodulatory Approaches

Early studies suggested that the presence of tumor-infiltrating lymphocytes was a prognostic factor in epithelial ovarian cancer (EOC)37,38 and led to the hope that immunotherapy could be leveraged effectively in this disease. However, subsequent studies have found that the tumor microenvironment within EOCs is profoundly immunosuppressive,39,40 and thus far, trials involving immunotherapy either as a sole intervention (eg, NINJA) or in conjunction with chemotherapy (eg, JAVELIN 200 Ovarian) have failed to exhibit benefits for immunotherapy in PROC.14,15 Although these initial approaches to immunomodulatory strategies in PROC have not been successful, several phase I/II (ClinicalTrials.gov identifiers: NCT01685255, NCT04042116)41,42 and phase III trials (refer to Table 2) are currently in progress or have concluded, focusing on novel strategies to manipulate the composition of immune cells infiltrating the tumor. It remains to be seen whether such immunomodulatory strategies will be able to improve on our current therapies for PROC.

SUGGESTED APPROACHES TO MANAGEMENTChooseTop of pageAbstractCASE PRESENTATIONCHALLENGES IN DIAGNOSIS A…SUMMARY OF THE RELEVANT L…NOVEL AGENTS FOR PROCSUGGESTED APPROACHES TO M… <<REFERENCES

Although novel treatment modalities and approaches to PROC are under active study, the sequential use of noncarboplatin chemotherapy remains the standard of care for PROC. Considering the low response rates to available therapeutics, effective treatments for PROC continue to be an urgent unmet need, with the recent addition of MIRV in FRα-high PROC representing the first FDA approval in this space in almost 10 years. Consensus guidelines, including NCCN, European Society for Medical Oncology, and GCIG, encourage participation in clinical trials at all phases of PROC management.7,9,43

When considering therapy for patients with PROC, the determination to proceed with a particular treatment approach and the selection of therapeutic agents should be tailored to each patient, taking into account their individual symptoms and preexisting comorbidities. With the increasing accessibility of biomarker-guided therapies, consensus guidelines advocate for the consideration of tumor molecular analysis including but not limited to BRCA1/2 testing, HRD status, microsatellite stability status, mismatch repair deficiency, tumor mutational burden (TMB), and FRα testing.9 We routinely perform somatic tumor sequencing, if not already performed, as well as FRα IHC in our patients with PROC to direct therapeutic decision making. Where applicable, additional molecular testing and IHC (eg, HER2 testing) may be performed to guide trial eligibility.

The results of the MIRASOL trial, demonstrating improved PFS and OS of MIRV over other standard-of-care chemotherapies, emphasize the importance of understanding FRα status for all patients with PROC. For patients with FRα-high tumors, treatment with MIRV should be strongly considered, given the MIRASOL results. The FDA indication for use of MIRV is in patients with epithelial ovarian cancer with less than three previous lines of therapy; data suggest that approximately 35%-40% of ovarian cancer will be FRα-high and that FRα expression levels do not change significantly with increasing lines of treatment.17,27 Mitigation of ocular toxicity with this regimen requires ophthalmic or optometry examination with every other cycle and a strict regimen of daily eye drops. In addition to MIRV, several therapeutic approaches can be considered for PROC per the NCCN guidelines, including preferred therapies such as weekly paclitaxel, PLD, or topotecan (each with or without bevacizumab), or gemcitabine monotherapy. Consideration around side effects, including hair loss or worsened neuropathy, schedule of treatment, and patient preference may influence choice and order of these regimens. Additionally, given the overall limited activity of standard of care agents in PROC, we advocate for continuously reevaluating opportunities for clinical trial participation at decision-making junctures.

After somatic tumor testing, our patient’s genetic profile revealed a TP53 R223C mutation, along with loss of CDKN2B and CDKN2A. The TMB was measured at eight mutations per megabase, and her tumor was confirmed to be microsatellite stable. IHC demonstrated high FRα expression in 78% of cells and HER2 expression 1+.

Given a PFI of only 5 months, we opted to defer platinum-based therapy and considered single-agent nonplatinum regimens. In light of her tumor’s FRα-high status and after a thorough discussion about available treatment options, the patient made an informed decision to commence MIRV treatment. She reported significant improvement in abdominal bloating after her first cycle of treatment. Imaging after seven cycles (Fig 1) demonstrated near-resolution of abdominal ascites and improvement in peritoneal-based disease, and her CA-125 decreased to 14. On treatment, she reported mild neuropathy but no ocular symptoms with strict adherence to the recommended eye care regimen. She continues on MIRV treatment with good control of her PROC and excellent functional status.

FIG 1.Computed tomography images before treatment (left) and after seven cycles of MIRV treatment at 6 mg/kg (right). MIRV, mirvetuximab soravtansine.

How Aspirin, Worming Medicines, and Other Repurposed Drugs Join the Fight Against Cancer

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How Aspirin, Worming Medicines, and Other Repurposed Drugs Join the Fight Against Cancer

In the world of medicine, where we spend a fortune looking for new and better ways to tackle diseases, could it be there’s a cool trick up our sleeves? It turns out that many researchers are taking everyday drugs you’ve probably heard of, like aspirin and some worming medicines, and finding new ways they can help fight cancer. And the results are fascinating.

Today we’re exploring this idea with particular regard to aspirin and anti-worming medicines such as fenbendazole (or its close relative, mebendazole) as they relate to cancer.

Drug Repurposing: Old Drugs With a New Purpose

Repurposing drugs, also referred to as drug repositioning or reprofiling, involves using medicines approved by the U.S. Food and Drug Administration (FDA) for one medical condition to examine their potential in treating another medical condition. This approach has become popular as it offers several advantages, such as reduced development costs and faster time to clinical use.

Repurposing existing medications has a rich and fascinating history dating back centuries, from clinical trials and rigorous scientific methods to innovative use cases discovered through patient testing. Even today, we continue to discover new uses for old drugs as part of medical practice. Here we explore some key milestones in its long history as it relates to two particular pharmaceuticals.

Aspirin: From Pain Relief to Potential Cancer Treatment

Aspirin, a household name for pain relief and fever reduction, has a long history of medicinal use. However, its potential in cancer treatment is a relatively recent discovery.

  • Origins: Aspirin was initially licensed as a painkiller but is now predominantly used as a blood thinner. However, ongoing clinical trials are exploring its role in cancer therapy.
  • Mechanism: Researchers believe that aspirin’s anti-inflammatory and anti-platelet effects might also inhibit the growth of cancer cells and reduce the risk of metastasis.
  • Challenges: The main challenge in repurposing aspirin lies in determining the optimal dosage and treatment duration for different cancer types. Researchers are working to establish clear guidelines for its use in oncology.

Aspirin’s Role in Cancer Prevention

One of the most thoroughly investigated areas pertaining to aspirin use is its effect on colorectal cancer. While studies have suggested regular aspirin use is associated with decreased risks of colorectal cancer development in particular, its exact mechanisms are still under review. However, many researchers agree that aspirin may play an essential role in inhibiting precancerous cell proliferation while decreasing inflammation within the colon.

  • Other cancers: Beyond colorectal cancer, studies have explored aspirin’s potential in preventing various other cancers, including breast, prostate, and lung. While the results have been mixed and more research is needed, some findings suggest that aspirin may offer protective benefits in these contexts as well.
  • Metastasis prevention: Aspirin’s potential in preventing cancer metastasis (the spread of cancer to other parts of the body) has garnered attention. Some studies suggest that aspirin might inhibit the adhesion of cancer cells to blood vessel walls, potentially reducing their ability to spread.
  • Adjuvant therapy: In certain cases, aspirin is being explored as an adjuvant therapy alongside standard cancer treatments like chemotherapy. It’s believed that aspirin’s anti-inflammatory effects may enhance the effectiveness of these treatments and potentially reduce the risk of cancer recurrence.

Aspirin’s Challenges and Considerations

While the potential of aspirin in cancer prevention and treatment is exciting, it’s important to acknowledge some challenges and considerations:

  • Dosing and duration: Determining the optimal dosage and duration of aspirin therapy for cancer prevention and treatment remains a subject of ongoing research.
  • Risks and side effects: Aspirin is not without risks, particularly in terms of gastrointestinal bleeding. Therefore, the decision to use aspirin for cancer prevention or treatment should be made in consultation with a health care provider, weighing potential benefits against risks.
  • Patient variability: Individual responses to aspirin may vary, and not all patients may benefit equally from its use.

Aspirin’s journey from pain reliever to potential cancer fighter is an example of the complexity and diversity of drug repurposing. While substantial progress has been made, more research needs to be conducted to establish its role in cancer prevention and treatment as well as develop clear guidelines on its usage in health care settings worldwide.

Anti-Parasitic Medications and Their Role in Fighting Cancer

You might be amazed to learn that medications used to combat intestinal parasites, both human and animal alike, have recently been investigated as possible cancer treatments—specifically, fenbendazole and mebendazole, which are making significant inroads into fighting cancer. Let’s take a closer look at their efforts against cancer.

and Mebendazole: Promising Candidates

Anti-worming medicines like fenbendazole and mebendazole have entered the spotlight as potential cancer-fighting agents. What are they, and what role do they play in fighting cancer?

  • Origins: These drugs were originally designed to treat intestinal parasites in animals and humans. Their potential anti-cancer properties have sparked interest in recent years.
  • Mechanism: Researchers speculate that these medicines might disrupt cancer cell division or interfere with their metabolic processes.
  • Clinical trials: Early-stage clinical trials are underway to evaluate the safety and efficacy of fenbendazole and mebendazole in cancer treatment. These trials are essential to determine the drugs’ true potential.

Challenges and Opportunities

While drug repurposing offers promise, several challenges must be overcome:

  • Patent issues: Many existing drugs are no longer under patent protection, making pharmaceutical companies less incentivized to invest in costly clinical trials for new indications.
  • Medical hesitancy: Doctors are often reluctant to prescribe drugs for conditions they weren’t initially designed for, as they bear responsibility for potential side effects.
  • Clinical evidence: It’s crucial to rely on robust clinical evidence before the widespread adoption of repurposed drugs in cancer treatment. This necessitates well-designed trials and rigorous research.

Bottom Line

Repurposing existing drugs to treat cancer is a tantalizing prospect. The discovery of faster, more cost-effective treatments that could ultimately save lives should be of interest to all of us. While challenges remain, promise lies in unlocking the unknown potential within existing medications, and changing policy accordingly may unlock these drugs’ full potential in fighting cancer.

Fenbendazole and mebendazole anti-worming medications offer an exciting avenue of exploration when it comes to treating cancer. While research remains in progress and clinical data still emerging, these medicines present us with an opportunity for drug repurposing. As we uncover their mechanisms of action and conduct more comprehensive trials, we may gain valuable insights into their potential role in improving cancer treatment options.

(PeopleImages.com, Yuri A/Shutterstock)
(PeopleImages.com, Yuri A/Shutterstock)

Vitality, viability, long-term clonogenic survival, cytotoxicity, cytostasis and lethality: what do they mean when testing new investigational oncology drugs?

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Abstract

In the field of experimental therapeutics for oncology purposes researchers are continuously evaluating the toxicity of novel treatment approaches against cancer cells. Within this topic of research, it is highly critical to define parameters of toxicity that denote when cancer cells are perturbed in their functionality by a new investigational drug. As the goal for these approaches is to achieve cellular demise, then what approaches to use and what do they mean in terms of assessing such cell death is of critical importance. In this comment article we highlight the definition of vitality and differentiate it from viability, and further define clonogenic survival in a chronic fashion. Additionally, we highly recommend the use of the term cytotoxicity as a general descriptor indicating toxicity towards a cell, but within that we encourage to sub-classify it as either cytostasis (i.e., when a treatment does not allow a cell to grow but it does not kill it either), or lethality (when a cell dies in response to the treatment). A more precise use of these terms should help advance the field of experimental therapeutics in oncology towards better defining the mechanisms of action of novel investigational drugs.

Conclusions

The concept of cell death and the ability to assess cell death is crucial for the field of pharmaceuticals and drug testing. Therefore, it is critical that the terminology being used to describe cell death accurately reflects the fate of the cells. In this commentary we expanded the nomenclature surrounding cell death to include the lesser-known term, vitality, alongside viability. Vitality provides flexibility when discussing cellular toxicity, as it considers the health of the cell as described by metabolic capacity and cellular respiration. Viability, however, should refer only to cases of cell death specifically denoted by damaged or compromised plasma membranes. Assays that assess vitality or viability share a common disadvantage that is the oversight of long-term toxicity. Drugs that do not strongly affect vitality or viability in short-term studies may have significant effects on the long-term reproductive capacity of the cells. Clonogenic survival assays are methods that can be used to assess the reproductive capacity of drug-treated cells. Here, we suggest the use of a “long-term” clonogenic survival, which is better able to assess the residual toxicity of the drug when compared with the traditional clonogenic survival assay. A potential toxic drug should not be discarded as a candidate therapeutic agent against cancer using methods that evaluate vitality or viability only. They can have a long-lasting toxic effect that is only manifested in their long-term reproductive capacity tested in long-term clonogenic survival assays. Finally, when discussing drug toxicity, it is important to note that the term cytotoxicity is an umbrella term which encompasses the more specific descriptors: cytostasis and lethality.

Immunotherapy and… Nothing Else? Studies Test Potential Paradigm Shift in Cancer Treatment

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For some people with cancer, is 6 months of immunotherapy the only treatment they might ever need? Or just 4 weeks of immunotherapy followed by minor surgery?

An older man in a recliner receiving outpatient IV cancer medication
Results from several clinical trials suggest that, for some people with earlier-stage cancers, a short course of treatment with immune checkpoint inhibitor may be all they need to eliminate their cancer.

Results from several small clinical trials suggest that these scenarios may be bona fide possibilities for some people with what are called locally advanced cancers. That means their tumors are largely restricted to their original location but there may be some cancer in nearby lymph nodes. 

The leaders of those trials and other experts stressed that much more research is needed before this treatment approach becomes part of everyday cancer care. But they agreed that the findings so far are highly encouraging.

The most recent results come from a 35-patient clinical trial conducted at MD Anderson Cancer Center. Most patients in the trial had locally advanced colorectal cancer. Perhaps most important, however, was that all participants’ tumors had specific genetic changes—known as MSI-high or dMMR—that make them particularly good candidates for immunotherapy.

About half of the trial participants received the immune checkpoint inhibitor (ICI) pembrolizumab (Keytruda) for up to 6 months and then chose to have surgery to remove whatever tumor tissue remained after the immunotherapy treatment. More than half of these patients had no evidence of cancer in the tissue removed during surgery, called a pathologic complete response.

The other participants were treated with pembrolizumab for up to a year but, otherwise, had no further treatment. All but one of the 18 patients in this group had at least a substantial reduction in the size of their tumors—based on imaging scans—within 24 weeks of starting immunotherapy. Many had no evidence of cancer at all.

Overall, regardless of which treatment path patients pursued, only a handful had some progression or return of their cancer during the study’s follow-up period, the trial investigators reported January 9 in the Journal of Clinical Oncology.

Taken together with the results of several other similar trials, the findings point to a future where, for some people with these earlier-stage cancers, a short course of immunotherapy may be their entire treatment, said James Gulley, M.D., Ph.D., co-director of NCI’s Center for Immuno-Oncology.

More studies are needed to answer many important questions, Dr. Gulley said, including how to identify the best candidates for this approach and how best to follow patients after they stop treatment, including the frequency of follow-up visits and what those visits should entail (e.g., imaging scans, blood work). 

But the potential upside is substantial, he continued. “If we can avoid all the potential harms of surgery and other treatments, that could be a game changer for patients.”

Moving the boundaries of when to use immunotherapy

Immunotherapy is no longer the new kid on the block of cancer treatment. It’s now a standard treatment that oncologists turn to for treating an ever-expanding host of cancers.

Similar to what occurred with targeted therapies over the last few decades, immunotherapy’s role in treatment has evolved, and quickly, said Kaysia Ludford, M.D., who led the MD Anderson clinical trial. 

Initially, ICIs like pembrolizumab were used only to treat people with very advanced cancers that were no longer responding to standard treatments. Several are now used as initial treatments for advanced cancers, including historically hard-to-treat cancers like lung and kidney. 

“But now immunotherapy is pushing the boundaries of even earlier [stages of disease],” she said.

Of particular interest to researchers is using immunotherapy before surgery in people with locally advanced cancers, known as neoadjuvant treatment. 

Neoadjuvant therapy with ICIs is not new. For example, pembrolizumab combined with chemotherapy is already approved by the Food and Drug Administration (FDA) as a neoadjuvant therapy (followed by surgery and more pembrolizumab) for some women with early-stage triple-negative breast cancer. And nivolumab (Opdivo) combined with chemotherapy is approved as neoadjuvant therapy (followed by surgery) for early-stage lung cancer.

An anatomic illustration of stage 2b nonsmall cell lung cancer

A large part of the rationale for neoadjuvant therapy is that if the treatment shrinks the tumor, that may mean less extensive and more successful surgeries. In addition, some studies have suggested that immunotherapy generates a more robust response against the tumor if it’s given while the tumor is in the body, rather than after it’s been removed by surgery.

And there are additional reasons to think that, in certain people—primarily whose tumors have certain genetic alterations/characteristics—giving immunotherapy prior to surgery may be particularly effective. Among those are people with MSI-high and dMMR tumors, which is the case for about 15% of people with colorectal cancer.

MSI-high and dMMR tumor cells tend to have more mutated genes than most cancer cells. Those genes, in turn, can cause the tumor cells to make more mutant proteins that the immune system might recognize as foreign and attack.

In other words, the large number of mutated genes in MSI-high and dMMR tumor cells “means that you have a ton of targets for the immune system to go after,” Dr. Gulley said, “and at least one of them is likely to be clinically relevant.”

Studies test immunotherapy alone or followed by surgery

In the MD Anderson trial, patients—in consultation with their doctors—made the decision to have surgery after immunotherapy or continue with immunotherapy only. 

Overall, tumors shrank substantially in 27 patients (82%) following treatment with pembrolizumab. Among the 17 patients who opted for surgery, 10 had a pathologic complete response.

Of the 18 patients who didn’t get surgery, 10 completed the full year of pembrolizumab and most had no evidence of cancer on routine imaging scans during the study period. The cancer returned or progressed in several patients, most of whom went on to have “salvage surgery” to remove the tumor.

The findings, Dr. Ludford and the team wrote, suggest that a short course of immunotherapy could be a “definitive approach” for people with locally advanced MSI-high or dMMR tumors—that is, it could be their sole treatment.

Last year, even more impressive results were reported from a similar but smaller trial conducted at Memorial Sloan Kettering Cancer Center (MSKCC). That trial included 12 people with rectal cancer whose tumors were MSI-high or dMMR. 

All 12 participants were treated for 6 months with the ICI dostarlimab (Jemperli). That treatment was supposed to be followed by chemotherapy, radiation, and surgery. But that didn’t happen.

That was because all 12 patients had what the investigators called a clinical complete response—that is, based on several different assessments, including an endoscopy, there was no evidence of cancer. So none opted to receive further treatment.

On February 9, the study’s lead investigator, Andrea Cercek, M.D., reported updated results from the MSKCC trial to the FDA’s Oncologic Drugs Advisory Committee. The meeting was held to discuss a proposed clinical trial that would form the basis for a potential FDA approval of dostarlimab as a definitive treatment for locally advanced, MSI-high/dMMR rectal cancer.

In total, 30 patients have participated in the MSKCC study, Dr. Cercek told the committee. All 30 have “achieved and maintained a complete clinical response,” she reported. Four patients still have no evidence of cancer at least 2 years after their last dose of dostarlimab “and no patient has experienced disease progression or recurrence,” she told the committee.

Results from a larger trial of neoadjuvant immunotherapy in people with MSI-high or dMMR colorectal cancer were presented last fall at the European Society for Medical Oncology (ESMO) annual meeting. Called NICHE-2 and conducted in the Netherlands, the trial enrolled 112 patients with cancer that was largely restricted to the colon or rectum.

Patients in the trial received a single dose of the ICI ipilimumab (Yervoy) and two doses of the ICI nivolumab over 4 weeks. After completing that treatment, all patients had surgery to remove any remaining tumor.

During a presentation of the trial’s results at the ESMO meetingExit Disclaimer, the lead investigator, Myriam Chalabi, M.D., of the Netherlands Cancer Institute, showed a slide with a waterfall plot—so

A waterfall plot showing the tumor responses of patients in the NICHE-2 trial.
Credit: Used with permission from Myriam Chalabi, M.D.

called because it shows a line for each patient in a study that runs from 0 at the top to 100 at the bottom. On the plot, 0 represents no pathologic response to immunotherapy (meaning the tumor didn’t shrink at all after treatment) and 100 represents a complete response (based on imaging).

With a handful of exceptions, nearly every line went very close or all the way to 100. Two-thirds of participants had a pathologic complete response, Dr. Chalabi reported. Those in attendance gave a loud round of applause.

Becoming part of standard cancer care?

With the evidence emerging from trials like this, Dr. Chalabi said she believes colorectal cancer treatment may soon change.

“I believe that neoadjuvant immunotherapy has a very strong potential to become the standard of care for people with dMMR colon cancer,” she said during her presentation at the ESMO meeting.

But despite the promising data, Dr. Ludford cautioned, there are still some important questions to address.

An important issue, she said, is determining how long neoadjuvant immunotherapy should be given. One patient in the MD Anderson trial appeared to have had a complete response (based on an endoscopy) after just one cycle of pembrolizumab. 

“Did that patient need to go on [receiving treatment] for one year?” Dr. Ludford asked. “We don’t know those answers.”

The path for immunotherapy as a stand-alone cancer treatment

Other researchers agreed that it’s premature for immunotherapy to be considered a potential stand-alone treatment. 

Elizabeth Mittendorf, M.D., Ph.D., who specializes in treating breast cancer at Brigham and Women’s Hospital in Boston, stressed that, for the time being, it should only be used “in the context of a clinical trial.”

Trials like NICHE-2 involved “a highly selected” group of patients for whom immunotherapy is most likely to work, Dr. Mittendorf said. There are also cancers like melanoma that are considered to be “immunogenic,” she said, where this approach might be particularly effective.

Based on the results from several studies, that may indeed be the case.

For example, findings from an NCI-funded trial presented at the 2022 American Society of Clinical Oncology (ASCO) annual meeting showed that adding neoadjuvant immunotherapy to the standard treatment of locally advanced melanoma substantially reduced the risk of the cancer returning.

Types of Responses

Complete response: No evidence of cancer on imaging scans.

Clinical complete response (used in MSKCC trial): No evidence of cancer on multiple analyses (e.g., PET scans, endoscopy), but no pathology assessment performed.

Pathologic complete response: No evidence of cancer in tissue surgically removed from the tumor site.

Major pathologic response (used in PRADO trial): A 90% or greater reduction in the amount of cancer in the largest lymph node with cancer nearest to the original tumor (the “index lymph node”).

Results from another study of neoadjuvant therapy for melanoma, called PRADO, were also presented at the ASCO meeting. The 99 patients in the PRADO trial received just a few treatments with ipilimumab and nivolumab over 6 weeks, 60 of whom had what the trial leaders called a major pathologic response. 

In these 60 patients, at a median of 2 years after receiving the immunotherapy treatment, only three patients had a recurrence of their cancer at or near its original location, and only one had a recurrence elsewhere in the body.

It will be important for these and future studies of either immunotherapy alone or immunotherapy followed by minimal additional treatments to show that it improves how long people live, Dr. Mittendorf said. 

“That will be the bar they will be held to,” she said. And based on the findings thus far, she added, “I think they’ll meet that bar.”

New imaging method could help make better decisions on personalized cancer treatment

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Decisions on cancer treatment could become better tailored to individual patients with the adoption of a new imaging method being developed by University of Michigan researchers that maps the chemical makeup of a patient’s tumor.

Today, treatment methods for cancer—whether surgery, radiation therapy or immunotherapy—are recommended based mainly on the tumor’s location, size and aggressiveness. This information is usually obtained by anatomical imaging—MRI or CT scans or ultrasound and by biological assays performed in tissues obtained by tumor biopsies.

Yet, the chemical environment of a tumor has a significant effect on how effective a particular treatment may be. For example, a low oxygen level in the tumor tissue impairs the effectiveness of radiation therapy.

Now, a team of scientists from the University of Michigan and two universities in Italy has demonstrated that an imaging system that uses special nanoparticles can provide a real-time, high-resolution chemical map that shows the distribution of chemicals of interest in a tumor.

It could lead to a way to help clinicians make better recommendations on cancer therapy tailored to a particular patient—precision medicine.

Their research, published in ACS Nano, reports on the first demonstration of an in vivo chemical imaging method generalizable to any chemical of interest, according to U-M chemistry professor Raoul Kopelman, one of the senior authors on the paper.

The researchers used a method for “chemical imaging” of tissues called photo-acoustic chemical imaging, or PACI.

“The novelty of this method is that it is performed in vivo, directly inside the body,” Kopelman said.

The team tested their system in mice that were implanted with tissue from a biopsy of a patient’s tumor, called a xenograft. Patient-derived xenografts recapitulate the genetic and biological characteristics of the patient’s tumor.

PACI employs nanoparticles that have been developed in the past decades, by Kopelman and others, that can be injected into the mouse to target the tumor and sense a particular chemical of biomedical interest, such as oxygen, sodium or potassium.

When this nanosensor is activated by infrared laser light that is able to penetrate into the tumor tissues, an ultrasound signal is generated that can be used to map the concentration and distribution of that particular chemical.

The PACI method could be used in a mouse xenograft to repeatedly follow the characteristics of a particular patient’s tumor to evaluate the chemical environment of the tumor over time.

This would allow for optimization of treatment methods for a particular patient—precision medicine.”

Raoul Kopelman,U-M chemistry professor

Kopelman and colleagues employed the PACI with a nanoparticle targeted to sense oxygen. Following radiation therapy of the tumor in the mouse, the researchers found a significant correlation between oxygen levels in each part of the tumor and how well radiation therapy destroyed tumor tissue—the lower the local oxygen in the tissue, the lower the local radiation therapy efficacy.

“We thus provide a simple, noninvasive, and inexpensive method to both predict the efficacy of radiation therapy for a given tumor and identify treatment-resistant regions within the tumor’s microenvironment,” Kopelman said.

“Such chemical mapping would help the clinical team prescribe a personalized, optimal treatment for a given patient’s tumor, based on the new diagnostics from the tumor xenograft’s chemical mapping.”

In this research, PACI has been employed in patient-derived xenografts. The ultimate goal would be the ability to make the chemical maps in patients directly.

That would be feasible, says Kopelman, with fiber optics that could be threaded through the patient’s venous system, as is done in cardiac procedures, to get near the tumor. The nanosensor could then be activated by the laser, but it requires nanosensors developed for each chemical of interest, and each nanosensor would need to be approved by the Food and Drug Administration.

In addition to Kopelman, U-M researchers include Janggun Jo, Jeffrey Folz, Celina Kleer, Xueding Wang, Maria Gonzalez, Ahmad Eido, Shilpa Tekula and Roberta Caruso.

Italian collaborators are Sebastiano Andò of the University of Calabria and Alessandro Paolì of the University of Calabria and University of Padua. The work was supported by National Institutes of Health grants to Kopelman, Wang and Kleer.

Source:

University of Michigan