Some promising news on the cancer front

*Usual disclaimer* Small sample size and much more study is required, but when you read this, you're gonna go "DAYUM!!!"

1. As you said it needs to be replicated but my initial reaction is FUCK YEAH!

2. The disturbing part was that none of the big players would finance the study (too risky) it took a small startup to chance it and that firm got bought up (for other reasons) before the study was completed. Yay for consolidation!

Dang. That's awesome. I'd love to know more about the mechanism. Does it have the potential to be a universal cancer-killer and they just chose colon cancer for the trial, or is it colon cancer-specific?

I was wondering the same thing.

Same question I had. The article doesn't go into that. Of course, the desert of medical research is littered with the bleaching bones of "promising" and/or "radical" treatments for cancer that in the end amounted to nothing or just incremental progress, so maybe it's just as well not to speculate on possible spinoffs.

This commentary on the implications of this new treatment is taken from the New England Journal of Medicine. It's paywalled, but I'm copying and pasting it since it answers some of the questions that we all have.

• Hanna K. Sanoff, M.D., M.P.H.

The cure rate for nonmetastatic rectal cancer has been improving for decades. Treatment for stage II and III rectal adenocarcinomas now routinely includes surgery, radiation therapy, and chemotherapy. The results of recent phase 3 trials have led to an increase in the intensity of treatment to include multiagent chemotherapy in addition to radiation therapy before proctectomy is performed; such treatment has resulted in a 3-year disease-free survival rate as high as 77%.1,2 Unfortunately, this treatment approach is grueling and can cause substantial long-term sequelae, including neuropathy, infertility, and bowel and sexual dysfunction. However, this more aggressive preoperative treatment also opens the door for a paradigm-shifting way to mitigate some of the long-term consequences — nonoperative management.

With nonoperative management, treatment begins with chemotherapy and radiation therapy. Thereafter, in patients without detectable residual cancer, treatment consists of only careful observation, with surgery reserved for patients with cancer regrowth. Implementation of this strategy avoids the functional consequences of proctectomy in patients who have a sustained response to chemotherapy and radiation. In the OPRA (Organ Preservation of Rectal Adenocarcinoma) nonoperative management trial, at 3 years, the percentage of patients in whom the rectum was preserved was 43% in the group that received chemotherapy followed by chemoradiotherapy and 59% in the group that received the same treatments in reverse.3

Unfortunately, for the 5 to 10% of patients with cancers that are molecularly characterized as deficient in DNA mismatch-repair enzymes, the chance of rectal preservation may be lower because of a diminished response to chemotherapy and radiation therapy.4,5 A second paradigm shift in colorectal cancer — the transition from chemotherapy to immunotherapy as primary treatment for metastatic mismatch repair–deficient cancers — presents a potential means to allow these patients to consider nonoperative approaches. In the KEYNOTE-177 trial, in which the immune checkpoint inhibitor pembrolizumab was compared with standard chemotherapy, treatment with pembrolizumab resulted in a longer duration of cancer control and a greater chance for cancer regression than standard chemotherapy.6

Cercek and colleagues7 now report in the Journal the results of a small but compelling study that brings these two treatment advances together. In this study, immunotherapy with the programmed death 1 (PD-1) inhibitor dostarlimab was followed by nonoperative care in patients with mismatch repair–deficient stage II or III rectal cancer. Twelve patients received dostarlimab for 6 months with careful monitoring of clinical response by magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, and endoscopy. Patients who did not have a complete response were to receive subsequent standard radiation therapy and chemotherapy; however, all 12 patients had complete tumor resolution with dostarlimab. At a median follow-up of 1 year, none of the 12 patients had needed other treatment, and none had had cancer regrowth. None of the patients had adverse events of grade 3 or higher.

These results are cause for great optimism, but such an approach cannot yet supplant our current curative treatment approach. The end point presented, clinical complete response, is an imperfect surrogate for long-term cancer control. Patients who have a clinical complete response after chemotherapy and radiation therapy have a better prognosis than those who do not have a clinical complete response, yet cancer regrowth occurs in 20 to 30% of such patients when the cancer is managed nonoperatively.4,8 Furthermore, although responses to PD-1 inhibition can last for years, only 55% of patients treated with pembrolizumab for mismatch repair–deficient metastatic colorectal cancer in the KEYNOTE-177 trial were reported to be alive without cancer progression at 12 months; responses lasted longer among the patients who had an initial strong response, but only approximately 70% had an ongoing response 3 years later.6 These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early- and late-stage disease. In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure.

Whether the results of this small study conducted at Memorial Sloan Kettering Cancer Center will be generalizable to a broader population of patients with rectal cancer is also not known. In order to provide more information regarding which patients might benefit from immunotherapy, subsequent trials should aim for heterogeneity in age, coexisting conditions, and tumor bulk. Enrollment of patients from diverse communities could address variations in the composition of the gut microbiome, which are known to influence response to immunotherapy.9 Diversity in the clinical practice setting is also critical to ensuring that this is a safe approach to implement on a large scale. Safe nonoperative management involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging. Such expertise is not available in all communities, and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.

Despite these uncertainties, Cercek and colleagues and their patients who agreed to forgo standard treatment for a promising but unknown future with immunotherapy have provided what may be an early glimpse of a revolutionary treatment shift. Although the incidence of severe toxic effects (i.e., adverse events of grade 3 or higher) with PD-1 inhibitors is usually higher than that seen in this study — closer to 10% — lasting consequences are uncommon.10 Thus, if immunotherapy can be a curative treatment for rectal cancer, eligible patients may no longer have to accept functional compromise in order to be cured.

Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.

This editorial was published on June 5, 2022, at NEJM.org.

From the Division of Oncology and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.

Notice that the call for tests among a "broader population of patients" is for rectal cancer sufferers. There's no mention of possible applications to other cancers. This is understandable since we've come to gradually understand that the term "cancer" applies to a variety of diseases, not just one. That said, I have to believe that researchers are at least considering whether there might be implications for treatment of other types of cancer.