What a superior IDEA!
The IDEA collaboration tested an important and topical question of the non-inferiority of a 3-month course of adjuvant oxaliplatin based chemo versus 6 month after surgery for stage III colon cancer. Although the hazard ratio for the 3-year disease free survival rates did not satisfy the criteria for non-inferiority, I do think this study provides us important ideas on the feasibility of using a shorter course of chemo for selected patients as I had discussed last year. The take home message for me is that for low risk disease a 3-month course of CAPEOX is sufficient whereas for high risk disease, if using FOLFOX, a 6-month course is essential. For high risk disease, I would discuss the benefits, harms and goals of treatment with the patient and decide together on the duration of CAPEOX treatment. 'What about FOLFOX for a low risk disease' you may ask. I say, get CAPEOX instead! In this modern age where we can manage side effects of immunotherapies, I don’t think the anecdotal higher toxicities with capecitabine in American patients should stop us from using this regimen at all. The same is true for S-1 in pancreatic cancer as I have argued time and again. I don’t understand how a patient who has seen these trial results would not want to receive a 3-month course of CAPEOX for low risk colon cancer or S-1 for pancreatic cancer in the adjuvant setting.
What happens when a drug is too toxic to develop as a monotherapy? Should it be combined with another toxic drug? Amazingly, this appears to be the justification for this study testing nivolumab plus ipilimumab as first-line treatment in renal cell cancer. In the introduction, the authors write: “Although ipilimumab at a dose of 3 mg per kilogram of body weight was associated in one trial with an objective response rate of 13% among patients with metastatic renal-cell carcinoma, its toxic effects precluded further development as monotherapy for this disease.” Given this knowledge, why should it be tested in combination with another immunotherapy in nivolumab? Notably, nivolumab is already approved as second-line therapy in renal cell cancer based on a showing of improved overall survival against everolimus. So why not test nivolumab as first-line monotherapy? In patients with melanoma, adding a toxic drug (ipilimumab) to nivolumab didn’t add much to nivolumab alone in terms of efficacy.
Oncology: The Original Infectious Disease
The old concept of cancer being an infectious disease, as we have now come to understand, was not completely wrong after all. Some cancers are strongly correlated with infectious agents, such as gastric cancer and Helicobacter pylori. In a big undertaking, investigators at the National Cancer Center in South Korea conducted an important double-blind, placebo-controlled randomized controlled trial to test whether eradicating H. pylori using triple therapy (amoxicillin, clarithromycin, and rabeprazole) in patients with early gastric cancer helped prevent the development of metachronous gastric cancer (cancer detected 1 year or later). They found that eradicating H. pylori reduced the risk of developing a future gastric cancer by half (7.2% v 13.4%, HR 0.5, 95% CI 0.26 to 0.94). This should be a practice-changing trial, however, additional questions remain. For example, I think we should investigate the increased rate of all-cause deaths in the experimental arm of the trial, even though the absolute number of deaths was small and difference not statistically significant (deaths from any cause: 11 v 6, HR 1.95, 95% CI 0.72 to 5.27).
Concord Continues to Fly
All is not bleak, as this analysis (CONCORD-3) of individual records for 37,513,025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries shows that survival rates are increasing for most cancers. Another lesson is the importance of maintaining such population-based registries, because without them, data-informed cancer policy cannot be implemented and may lead astray cancer control efforts. As we have previously explained in this editorial, development of a population-based cancer registry should be a fundamental component of cancer control efforts in low- and middle-income countries.
In an innovative approach to addressing the financial toxicity of cancer treatment, an international group of researchers explored whether drug/food interactions can be exploited to achieve comparable outcomes with lower doses of the drug. Abiraterone, a commonly used and effective drug in prostate cancer, has interactions with food and is recommended to take on an empty stomach. In this phase 2 trial, researchers found that taking one-quarter of the dose with a low-fat meal was non-inferior in terms of the amount of reduction in PSA. This idea should now be tested in a phase 3 trial, as the potential economic implications are huge. We need to test other similar ideas in oncology: A previous study has hinted that taking erlotinib with Coca-Cola might allow for lower doses of erlotinib.
Let me take a selfie
In a new viewpoint piece, Daniel Goldstein and I review the FDA’s recent decision to approve sunitinib as adjuvant treatment for high-risk renal cell cancer despite the drug not improving overall survival in two trials, and not improving even disease-free survival in a meta-analysis of these two trials. One important issue is what minimum standards we should expect key drug regulators to employ in reviewing oncology drugs, an issue I discuss in further detail here.
Dr. Gyawali is a medical oncologist from Nepal who is now working as a research fellow at Program On Regulation, Therapeutics And Law (PORTAL) at Brigham and Women’s Hospital/Harvard Medical School. The opinions expressed herein are his own. You can read his previous blogs here.