3 vs, 6 MONTHS OF ADJUVANT CHEMOTHERAPY FOR COLORECTAL CANCER

 Thierry André, MD, and colleagues reported the prospective pooled analysis of six phase III trials in the IDEA collaboration in The Lancet Oncology. The analysis showed that noninferiority in overall survival for 3 vs 6 months of adjuvant chemotherapy was not established in patients with stage III colon cancer, and the absolute difference in 5-year overall survival between approaches was 0.4%.

As noted by the investigators, the previous IDEA analysis did not show noninferiority for the primary endpoint of 3-year disease-free survival for 3 months vs 6 months of adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). However, 6 months of treatment did not provide additional benefit in patients receiving CAPOX, with noninferiority being shown, whereas 6 months of FOLFOX was associated with a moderate but significant improvement vs 3 months.

Thierry André, MD

Study Details

The analysis included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients were recruited between June 2007 and December 2015 in 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials who started any treatment (modified intention-to-treat population).

Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant FOLFOX every 2 weeks or CAPOX every 3 weeks, as chosen by the treating physician. FOLFOX regimens consisted of infusional leucovorin at 200 mg/m² for FOLFOX4 (400 mg/m² for FOLFOX6), bolus fluorouracil at 400 mg/m² (400 mg/m²), infusional fluorouracil at 600 mg/m² (2,400 mg/m²), and infusional oxaliplatin at 85 mg/m² (85 mg/m²). The CAPOX regimen consisted of infusional oxaliplatin at 130 mg/m² and oral capecitabine at 1,000 mg/m² twice daily.

The primary endpoint was disease-free survival, with overall survival being the prespecified secondary endpoint. The noninferiority margin for overall survival was set as a hazard ratio (HR) of 1.11. Preplanned subgroup analyses included analysis by regimen and by risk group. Noninferiority was demonstrated if the one-sided false discovery rate adjusted (FDRadj) P value was < .025. The cutoff date for the final overall survival analysis was in January 2020.

Overall Survival

The analysis included 12,835 patients in the modified intention-to-treat population, with 5,064 (39.5%) receiving CAPOX, 7,771 (60.5%) receiving FOLFOX, and 6,425 receiving 3-month and 6,410 receiving 6-month regimens. Overall median follow-up was 72.3 months (interquartile range = 72.2–72.5 months). A total of 2,584 patients died (20.1%).

Among all patients, 5-year overall survival was 82.4% (95% confidence interval [CI] = 81.4%–83.3%) with 3 months of therapy vs 82.8% (95% CI = 81.8%–83.8%) with 6 months of therapy (HR = 1.02, 95% CI = 0.95–1.11; noninferiority FDRadj P = .058; superiority for 6 months FDRadj P = .64). The absolute difference in 5-year overall survival was −0.4%.

Among patients receiving CAPOX, 5-year overall survival was 82.1% (95% CI = 80.5%–83.6%) in the 3-month group vs 81.2% (95% CI = 79.2%–82.9%) in the 6-month group (HR = 0.96, 95% CI = 0.85–1.08; noninferiority FDRadj P = .033; superiority for 6 months FDRadj P = .62). The absolute difference in 5-year overall survival was +0.9%.

Among patients receiving FOLFOX, 5-year overall survival was 82.6% (95% CI = 81.3%–83.8%) in the 3-month group vs 83.8% (95% CI = 82.6%–85.0%) in the 6-month group (HR = 1.07, 95% CI = 0.97–1.18; noninferiority FDRadj P =.34; superiority for 6 months FDRadj P = .38). The absolute difference in 5-year overall survival was −1.2%.

Among 7,507 patients with low-risk disease (T1, T2, or T3 and N1), 5-year overall survival was 89.6% vs 88.9% (HR = 0.95, 95% CI = 0.84–1.08; noninferiority FDRadj P =.033; superiority of 6 months FDRadj P = .58). Among 5,273 patients with high-risk disease (T4, N2, or both), 5-year overall survival was 72.0% vs 74.1% (HR = 1.08, 95% CI = 0.98–1.19; noninferiority FDRadj P = .39; superiority of 6 months FDRadj P = .29). In total, 5-year overall survival was 89.3% in the low-risk group and 73.1% in the high-risk group.

KEY POINTS

• Noninferiority of overall survival was not established for 3 months vs 6 months of adjuvant chemotherapy, but 5-year overall survival differed by only −0.4%.
• Among patients receiving CAPOX, 5-year overall survival differed by +0.9%.

Updated Disease-Free Survival

The hazard ratio for 5-year disease free survival for the 3-month vs 6-month groups among all patients was 1.08 (95% CI = 1.02–1.15; noninferiority FDRadj P= .25; superiority for 6 months FDRadj P = .044). Among patients receiving CAPOX, the hazard ratio was 0.98 (95% CI = 0.88–1.08; noninferiority FDRadj P = .027; superiority FDRadj P = .67). Among those receiving FOLFOX, the hazard ratio was 1.16 (95% CI = 1.07–1.26; noninferiority FDRadj P = .80; superiority for 6 months FDRadj P = .0061). The P value for interaction between regimen and duration was .011. For low-risk vs high-risk patients, 5-year disease-free survival was 78.5% vs 57.7%.

Data on adverse events were not recorded beyond the initial primary analysis. As noted by the investigators, analysis at that time showed that grade ≥ 2 neurotoxicity during active therapy and in the first month after stopping study treatment occurred in 16.0% of patients in the 3-month group vs 44.5% of those in the 6-month group.

The investigators concluded, “Noninferiority of 3 months vs 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0.4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.”

Qian Shi, PhD, of the Department of Health Science Research, Mayo Clinic, Rochester, is the corresponding author for The Lancet Oncology article.  

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

---

ADVERTISEMENT

ADVERTISEMENT

JAN

04

TODAY IN ONCOLOGY

Surgical Intervention May Offer Survival Advantage for Certain Patients With Metastatic Breast Cancer

Nivolumab Indication Withdrawn in Small Cell Lung Cancer in U.S. Market

Final Overall Survival Results of the IDEA Collaboration 3 vs 6 Months of Adjuvant Chemotherapy for Stage III Colon Cancer

Do Adult-Onset Cancer Survivors Have a Higher Risk of Developing a Subsequent Malignancy

Integrated Palliative and Oncology Care for Patients Receiving Treatment for Acute Myeloid Leukemia

VIEW MORE 

ADVERTISEMENT

NOVEL TREATMENT APPROACH FOR RECTAL CANCER-

 As reported in The Lancet Oncology by Bahadoer et al, the phase III RAPIDO trial has shown improved 3-year disease-related treatment failure with preoperative short-course radiotherapy followed by chemotherapy and total mesorectal excision (TME) vs preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in patients with locally advanced rectal cancer.

Study Details

The open-label trial included 912 eligible newly diagnosed patients from sites in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the United States. Patients were randomly assigned between June 2011 and June 2016 to receive short-course radiotherapy followed by chemotherapy and TME (experimental group, n = 462) or preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy (standard of care group, n = 450). Patients had to have high-risk disease defined as at least one of following criteria: clinical tumor stage cT4a or cT4b, extramural vascular invasion, clinical nodal stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes.

Patients in the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX (capecitabine and oxaliplatin) on days 1–14 with a chemotherapy-free interval between days 15–21 or nine cycles of FOLFOX4 (oxaliplatin, leucovorin, fluorouracil) on days 1 and 2 with a chemotherapy-free interval between days 3­­–14 followed by TME; the choice of CAPOX or FOLFOX4 was left to physician’s discretion. Patients in the standard-of-care group received radiotherapy at (per physician discretion or hospital policy) 28 daily fractions (1.8 Gy up to 50.4 Gy) or 25 fractions (2.0 Gy up to 50.0 Gy) with concomitant twice-daily oral capecitabine, followed by TME and optional adjuvant chemotherapy (according to hospital policy) with 8 cycles of CAPOX or 12 cycles of FOLFOX4 (n = 187). The primary endpoint was 3-year disease-related treatment failure—defined as first occurrence of locoregional failure, distant metastasis, new primary colorectal tumor, or treatment-related death—in the intention-to-treat population.

Disease-Related Treatment Failure

KEY POINTS

• Preoperative short-course radiotherapy followed by chemotherapy and TME was associated with reduced disease-related treatment failure vs preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy.
• The 3-year cumulative incidence of disease-related treatment failure was 23.7% vs 30.4%.

Median follow-up was 4.6 years (interquartile range = 3.5–5.5 years). At 3 years after random assignment, the cumulative probability of disease-related treatment failure was 23.7% (95% confidence interval [CI] = 19.8%­–27.6%) in the experimental group vs 30.4% (95% CI = 26.1%–34.6%) in the standard-of-care group (hazard ratio [HR] = 0.75, 95% CI = 0.60–0.95, P = .019).

At 3 years, the cumulative probability of distant metastases was 20.0% (95% CI = 16.4%–23.7%) vs 26.8% (95% CI = 22.7%–0.9%; HR = 0.69, 95% CI = 0.54–0.90, P = .0048) and the cumulative probability of locoregional failure was 8.3% (95% CI = 5.8%–10.8%) vs 6.0% (95% CI = 3.8%–8.2%; HR = 1.42, 95% CI = 0.91–2.21, P = .12). A new primary colorectal tumor occurred in 2% vs 3% of patients.

Among evaluable patients, pathologic complete response was achieved in 120 (28%) of 423 patients in the experimental group vs 57 (14%) of 398 in the standard-of-care group (odds ratio = 2.37, 95% CI = 1.67–3.37, P < .0001). Overall survival at 3 years was 89.1% (95% CI = 86.3%–92.0%) vs 88.8% (95% CI = 85.9%–91.7%; HR = 0.92, 95% CI = 0.67–1.25, P = .59).

Adverse Events

The most commonly reported grade ≥ 3 adverse events during preoperative therapy were diarrhea in both groups (18% vs 9%), and neurologic toxicity during adjuvant chemotherapy in the standard-of-care group (9%). Serious adverse events occurred in 38% vs 34% of patients who did not receive adjuvant chemotherapy and in 34% of 187 patients who did receive adjuvant chemotherapy. Treatment-related deaths occurred in four patients in the experimental group (due to cardiac arrest and pulmonary embolism in one patient each and infectious complications in two) and in four patients in the standard-of-care group (due to pulmonary embolism, neutropenic sepsis, aspiration, and suicide in 1 patient each).

The investigators concluded, “The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer.”

Geke A.P. Hospers, MD, of the Department of Medical Oncology, University Medical Center Groningen, Netherlands, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network. For full disclosures of the study authors, visit thelancet.com.

FIRST LINE PEMBROLIZUMAB FOR MSI-H COLORECTAL CANCER

 Frontline pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) compared with chemotherapy among patients with microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer, according to results from the KEYNOTE-177 study.

At a median follow-up of 32.4 months, PFS was 16.5 months for patients who received pembrolizumab, vs 8.2 months for the chemotherapy group.

"In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer," commented lead author Thierry André, MD, of Hôpital Saint Antoine, Paris, France, when presenting this study earlier this year at the annual meeting of the American Society of Clinical Oncology (ASCO),.

"I think this is setting a new standard of care," said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center, Houston, Texas, who was the invited discussant at the ASCO meeting. However, he also pointed out that despite the higher overall response rate (43.8% vs 33.1% with chemotherapy), the rate of progressive disease was higher in the pembrolizumab arm than in the chemotherapy arm (29.4% vs 12.3% for patients who received chemotherapy).

The study has now been published in The New England Journal of Medicine.

Pembrolizumab is the "preferred choice" for patients with MSI-H/dMMR colorectal cancer because of "the durability of response, better safety profile, and improved quality of life associated with immunotherapy as compared with chemotherapy," comments Axel Grothey, MD, GI Cancer Research, West Cancer Center and Research Institute, Germantown, Tennessee, in an accompanying editorial.

He notes that in colorectal cancer, only 4% to 5% of metastatic cancers show the MSI-H/dMMR phenotype; the prevalence is greater in BRAF V600E–mutated cancers, in cancers originating on the right side, and among female patients.

Immune checkpoint inhibitors have already demonstrated "convincing activity" in MSI-H/dMMR colorectal cancers, and pembrolizumab as well as nivolumab (Opdivo), with or without ipilimumab (Yervoy), are approved for use as salvage therapy in colorectal cancer, he noted.

These results for use as a first-line therapy in his patient population have been "long awaited," he commented.

Study Details

The KEYNOTE-177 trial included 307 patients with confirmed, untreated MSI-H/dMMR metastatic colorectal cancer who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles (n = 153) or the investigators' choice of chemotherapy (n = 154). Chemotherapy regimens included modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab. Patients in the chemotherapy group could cross over to pembrolizumab therapy after disease progression.

The study's two primary endpoints were PFS and overall survival.

At the second interim analysis, at a median follow-up (from randomization to data cutoff) of 32.4 months, pembrolizumab proved superior to chemotherapy with regard to PFS (hazard ratio, 0.60; P = .0002).

At 12 months and at 24 months, the estimated percentages of those alive without disease progression were 55.3% and 48.3%, respectively (95% CI, 39.9 – 56.2) in the pembrolizumab group and 37.3% and 18.6%, respectively, in the chemotherapy group.

The mean PFS after 24 months of follow-up was 13.7 months for patients who received pembrolizumab, vs 10.8 months for those who received chemotherapy. PFS was consistently longer with pembrolizumab across key prespecified subgroups. Complete responses were achieved in 11% of patients treated with pembrolizumab and in 4% of those treated with chemotherapy. At 24 months, 83% of patients in the pembrolizumab group had ongoing responses, as compared with 35% in the chemotherapy group.

Overall survival data continue to evolve, the authors comment. They note that 56 patients in the pembrolizumab group and 69 in the chemotherapy group have died. The independent data monitoring committee has recommended that the trial continue without any changes to the final analysis for assessment of overall survival until 190 overall deaths have occurred or until 12 months after the second interim analysis.

Crossover will be a factor when overall survival is assessed, the authors note. At the time of data cutoff, 56 of 154 patients (36%) who received chemotherapy had crossed over to the pembrolizumab group after their disease had progressed. In addition, 35 patients in the chemotherapy group received anti–PD-1 or PD-L1 therapies outside the trial. This extrapolates to a crossover rate of 59% in the intention-to-treat population.

Treatment-related adverse events of grade 3 or higher were more common in the chemotherapy group (66% vs 22%). Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than with chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.

Preferred Choice

In the accompanying editorial, Grothey points out that the results of this trial "deserve some scrutiny," because disease progression was higher in the pembrolizumab group. This is mirrored by early poorer performance among patients treated with pembrolizumab vs chemotherapy until about 6.5 months after onset of therapy, he notes. After that, the "pembrolizumab group showed protracted improvement — a phenomenon seen in various other trials with PD-1 antibodies in gastrointestinal cancers.

"It appears that a subgroup not yet clearly defined within the MSI-H–dMMR population does not have a response to immune checkpoint inhibitors," Grothey writes.

The study was funded by Merck. André has received honoraria from Amgen, GlaxoSmithKline, and Pierre Fabre Pharmaceuticals; consulting fees and travel support from Bristol-Myers Squibb; advisory board fees and honoraria from F. Hoffmann–La Roche; advisory board fees from Gritstone Oncology, Halliodx, and Tesaro; grant support, paid to Hôpitaux de Paris; advisory board fees, honoraria, and travel support from Merck Sharp and Dohme; consulting fees and honoraria from Servier; and honoraria and travel support from Ventana Medical Systems. Grothey has received grants and nonfinancial support from Bayer; grants from Boston Biomedicals; grants from OBI Pharmaceuticals, Array/Pfizer, Natera, Merck, and Bristol-Myers Squibb and grants and nonfinancial support from Roche/ Genentech outside the submitted work.

N Engl J Med. 2020;383:2207-2218, 2283-2285. Abstract, Editorial

For more from Medscape Oncology, join us on Twitter and Facebook

ADDITION OF IRINOTECAN TO NEOADJUVANT CHEMORADIOTHERAPY FOR RECTAL CANCER

 

In a Chinese phase III trial reported in the Journal of Clinical Oncology, Zhu et al found that the addition of irinotecan to neoadjuvant capecitabine chemoradiation (CapIriRT)—with irinotecan dosing guided by UGT1A1 genotype—followed by capecitabine/irinotecan (XELIRI) significantly improved pathologic complete response rate vs capecitabine chemoradiation (CapRT) followed by capecitabine/oxaliplatin (XELOX) in patients with locally advanced rectal cancer.     

Study Details

The open-label multicenter trial included 356 patients (modified intent-to-treat population) with clinical T3-4 or N1 rectal adenocarcinoma and UGT1A1 genotype *1*1 or *1*28. Patients were randomly assigned between November 2015 and December 2017 to receive neoadjuvant CapRT followed by XELOX (n = 178) or CapIriRT followed by XELIRI (n = 178). The CapRT group received radiotherapy at 50 Gy/25 fractions with concurrent capecitabine at 825 mg/m²  twice daily 5 days/week, followed 2 weeks after completion of chemoradiation by a cycle of XELOX consisting of capecitabine at 1,000 mg/m²  twice daily on days 1–14 plus oxaliplatin at 130 mg/m² on day 1. The CapIriRT group received radiotherapy at the same dose with capecitabine at 625 mg/m² twice daily 5 days/week and weekly irinotecan at 80 mg/m² in patients with the UGT1A1*1*1 genotype and 65 mg/m² in those with the UGT1A1*1*28 genotype, followed 2 weeks after completion of chemoradiation by a cycle of XELIRI consisting of capecitabine at 1,000 mg/m² twice daily on days 1–14 and irinotecan at 200 mg/m² on day 1. The primary endpoint was pathologic complete response rate in the modified intent-to-treat population.

KEY POINTS

• The addition of irinotecan with dose guided by UGT1A1 genotype to capecitabine chemoradiation was associated with improved pathologic complete response rate.
• Grade 3 or 4 toxicity was more common in patients receiving chemoradiation with capecitabine plus irinotecan.

Pathologic Complete Response Rate

Surgery was performed in 87% of patients in the CapRT group vs 88% of the CapIriRT group. Pathologic complete response was observed in 27 (15%) of 178 patients in the CapRT group vs 53 (30%) of 178 in the CapIriRT group (risk ratio = 1.96, 95% confidence interval [CI] = 1.30–2.97, P = .001). Complete clinical response was observed in four vs six patients. Among patients who underwent surgery, pathologic complete response was achieved in 18% vs 34% (risk ratio = 1.93, 95% CI = 1.28–2.89, P =.001).

Adverse Events

Grade 3 or 4 toxicity occurred in 6% of the CapRT group vs 38% of the CapIriRT group (P < .001), with the most common in the CapIriRT group being leukopenia (25% vs 3%), neutropenia (20% vs 2%), and diarrhea (13% vs 2%). Grade ≥ 3 postoperative complications occurred in 11% vs 15% of patients (P = .268). No deaths within 60 days of surgery were reported.

The investigators concluded: “Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.”

Zhen Zhang, MD, of Fudan University Shanghai Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Fudan University Shanghai Cancer Center, National Natural Science Foundation of China, and Natural Science Foundation of Shanghai. For full disclosures of the study authors, visit ascopubs.org.

STATINS LOWER RISK OF COLORECTAL CANCER-START SCREENING AT 45

Statin use may significantly lower the risk of colorectal cancer (CRC) in patients with or without inflammatory bowel disease (IBD), based on a meta-analysis and systematic review.

In more than 15,000 patients with IBD, statin use was associated with a 60% reduced risk of CRC, reported lead author Kevin N. Singh, MD, of NYU Langone Medical Center in New York, and colleagues.

"Statin use has been linked with a risk reduction for cancers including hepatocellular carcinoma, breast, gastric, pancreatic, and biliary tract cancers, but data supporting the use of statins for chemoprevention against CRC is conflicting," Singh said during a virtual presentation at the annual meeting of the American College of Gastroenterology.

He noted a 2014 meta-analysis by Lytras and colleagues that reported a 9% CRC risk reduction in statin users who did not have IBD. In patients with IBD, data are scarce, according to Singh.

To further explore the relationship between statin use and CRC in patients without IBD, the investigators analyzed data from 52 studies, including 8 randomized clinical trials, 17 cohort studies, and 27 case-control studies. Of the 11,459,306 patients involved, approximately 2 million used statins and roughly 9 million did not.

To evaluate the same relationship in patients with IBD, the investigators conducted a separate meta-analysis involving 15,342 patients from 5 observational studies, 1 of which was an unpublished abstract. In the 4 published studies, 1,161 patients used statins while 12,145 did not.

In the non-IBD population, statin use was associated with a 20% reduced risk of CRC (pooled odds ratio, 0.80; 95% confidence interval, 0.73–0.88; P less than .001). In patients with IBD, statin use was associated with a 60% CRC risk reduction (pooled OR, 0.40; 95% CI, 0.19–0.86, P = .019).

Singh noted "significant heterogeneity" in both analyses (I2 greater than 75), most prominently in the IBD populations, which he ascribed to "differences in demographic features, ethnic groups, and risk factors for CRC."

While publication bias was absent from the non-IBD analysis, it was detected in the IBD portion of the study. Singh said that selection bias may also have been present in the IBD analysis, due to exclusive use of observational studies.

"Prospective trials are needed to confirm the risk reduction of CRC in the IBD population, including whether the effects of statins differ between ulcerative colitis and Crohn's disease patients," Singh said.

Additional analyses are underway, he added, including one that will account for the potentially confounding effect of aspirin use.

According to David E. Kaplan, MD, of the University of Pennsylvania, Philadelphia, "The finding that statins are associated with reduced CRC in IBD provides additional support for the clinical importance of the antineoplastic effects of statins. This effect has been strongly observed in liver cancer, and is pending prospective validation."

Kaplan also offered some mechanistic insight into why statins have an anticancer effect, pointing to "the centrality of cholesterol biosynthesis for development and/or progression of malignancy."

The investigators and Kaplan reported no relevant conflicts of interest.

American College of Gastroenterology (ACG) 2020 Annual Scientific Meeting.

This article originally appeared on MDEdge.com.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

It's not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates (ORR) and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs compared with patients who weren't taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking angiotensin converting enzyme (ACE) inhibitors — but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute (NCI) in Bethesda, Maryland.

All study patients received PD-1/PD-L1 inhibitors and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have also suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β), he explained.

"Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack," Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-β through binding to the AT₁ receptor, but has the opposite effect when it binds to the AT₂ receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT₁ and AT₂ receptors.

In contrast, ARBs block only the AT₁ receptor and leave the AT₂­ counter-regulatory receptor alone, said Strauss.

More Data, Including on Overall Survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year overall survival rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT₁ blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.

Hypothesis-Generating Study

Meeting co-chair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, Spain, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting co-chair, agreed with Calvo.

"Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate," Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are NCI employees. Calvo disclosed no relevant financial relationships.

32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics: Abstract 7. Presented in a briefing October 20 and in a plenary session October 25, 2020.

ASTRO GUIDELINES FOR RECTAL CANCER

A new clinical guideline from the American Society for Radiation Oncology (ASTRO) provides guidance for physicians who use radiation therapy to treat patients with locally advanced rectal cancer. Recommendations outline indications and best practices for pelvic radiation treatments, as well as the integration of radiation with chemotherapy and surgery for stage II/III disease. The guideline, which replaces ASTRO's 2016 guidance for rectal cancer, was published in Practical Radiation Oncology.

Colorectal cancer is the second most common cause of cancer death in the United States, and half of new colorectal cancer diagnoses are in people age 66 or younger. Rectal cancer diagnoses account for nearly one-third of colorectal cancers; an estimated 43,340 adults will be diagnosed with rectal cancer in 2020. Although rectal cancer incidence and mortality rates have dropped among older adults in recent years, they have increased for those younger than age 55.

Standard treatment for locally advanced rectal cancer generally involves chemoradiation therapy or short-course radiation without chemotherapy, followed by tumor removal surgery and additional chemotherapy. More recently, several trials have shown potential for emerging paradigms, such as changing the sequencing of treatments or omitting portions of treatments for select patients.

Key Recommendations

The guideline addresses patient selection for radiation therapy, delivery of pelvic radiation treatments, options for nonoperative management of locally advanced rectal cancer, and guidance for follow-up care:

• Neoadjuvant radiation therapy is strongly recommended for patients with clinical stage II/III rectal cancer to reduce their risk of locoregional recurrence. Radiation therapy for locally advanced rectal cancer should be performed before rather than after surgery. Radiation may be omitted in favor of upfront surgery for some patients at low risk of recurrence, after discussion by a multidisciplinary care team. Clinical staging involving a physical exam and pelvic magnetic resonance imaging is critical to determine which patients should receive neoadjuvant radiation therapy.
• For patients who require neoadjuvant radiation therapy, both conventionally fractionated radiation and short-course radiation are recommended equally, given high-quality evidence for similar efficacy and patient-reported quality of life outcomes with each treatment. The guideline specifies optimal dosing, fractionation, and delivery techniques for radiation therapy.
• Recommendations address how to incorporate chemotherapy into the preoperative setting for patients who are at high risk of recurrence and who would likely benefit from the additional treatment using a total neoadjuvant therapy approach. Recommendations also address other sequencing and timing issues for radiation, chemotherapy, and surgery, with specific attention to treatment tolerability and potential downstaging.
• Organ preservation approaches (ie, nonoperative management and local excision) may present an alternative to radical surgery for select patients, especially those who would have a permanent colostomy or inadequate bowel continence after surgery. The guideline outlines specific criteria for situations where surgery can be avoided, as well as long-term surveillance and care for these patients.

Disclosure: For full disclosures of the study authors, visit practicalradonc.org.

NO BENEFIT OF INTENSIVE SURVELLENCE FOR COLORECTAL CANCER PATIENTS

ntensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, "none of the follow-up modalities resulted in a difference," said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Lepage said the study's results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. LePage called CEA surveillance "useless" and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance "was still fairly aggressive."

Because of that, the study does not "suggest we should decrease our intensity," Price said.

He added that the study's major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. "We need to remember that, in 2020, care is very different," Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier "may well have an impact on survival."

Perhaps patients would live longer with "earlier diagnosis in today's setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy]," Price said in an interview.

Study Details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it's based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

EPIDEMIOLOGY OF GI CANCERS

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer's main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study's corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

"Factors such as more widespread electrification and refrigeration tend to drive the rates down," he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. "Premature" deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.

Results of the Analysis

"Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death," Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

"The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men," the investigators summarized.

Explaining the GI Cancer Results

"There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures," observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn't modifiable, "we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline," he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. "The prophylactic effect against gastric cancer is massive, cutting risk by roughly half," he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

"One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer," Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.

Reducing NCD Deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

"To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare," Dr. Ezzati said in a statement. "Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems."

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

"This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment," the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

"COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us," said Katie Dain, CEO of the NCD Alliance.

"The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a 'nice to have.' It must be considered as part of pandemic preparedness," she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018's first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018's data didn't focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Medscape Medical News © 2020 

COLORECTAL CANCER -TRIPLET BETTER THAN DOUBLET?

In a patient-level meta-analysis reported in the Journal of Clinical Oncology, Chiara Cremolini, MD, PhD, and colleagues found that infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab was associated with significantly greater overall survival vs chemotherapy doublets plus bevacizumab as first-line treatment of patients with unresectable metastatic colorectal cancer.

Chiara Cremolini, MD, PhD

Study Details

The study included individual patient data from five trials (CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2) comparing FOLFOXIRI plus bevacizumab with chemotherapy doublets plus bevacizumab. The doublets consisted of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX); fluorouracil, leucovorin, and irinotecan (FOLFIRI); irinotecan and capecitabine (XELIRI); or capecitabine and oxaliplatin (XELOX).

Key Findings

Data from 1,697 patients randomly assigned to receive FOLFOXIRI plus bevacizumab (n = 846) or doublets plus bevacizumab (n = 851) were included in the analysis. Median follow-up was 39.9 months.

Median overall survival was 28.9 months in the FOLFOXIRI group vs 24.5 months in the doublets group (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.72–0.91, P < .001). No significant heterogeneity among trials was observed (P = .39; I² = 2%). No overall survival benefit of FOLFOXIRI plus bevacizumab was observed among the 9% of patients with BRAF-mutant tumors (HR = 1.11, 95% CI = 0.75–1.73).

Median progression-free survival was 12.2 months vs 9.9 months (HR = 0.74; 95% CI = 0.67–0.82, P < .001). Objective response rates were 64.5% vs 53.6% (P < .001). Among 139 vs 100 patients undergoing secondary surgery for metastases with radical curative intent, the R0 resection rates were 16.4% vs 11.8% (P = .007).  

Patients in the FOLFOXIRI plus bevacizumab group had higher rates of grade 3 or 4 neutropenia (45.8% vs 21.5%, P < .001), febrile neutropenia (6.3% vs 3.7%, P = .019), nausea (5.5% vs 3.0%, P = .016), mucositis (5.1% vs 2.9%, P = .024), and diarrhea (17.8% vs 8.4%, P < .001). Death due to toxicity occurred in 2.3% vs 1.4% of patients (P = .277).

The investigators concluded, “FOLFOXIRI [plus] bevacizumab significantly and meaningfully improves survival of patients with metastatic colorectal cancer compared with doublets [plus] bevacizumab and provides advantage in progression-free survival, objective response rates, and R0 resection rate at the price of a moderate increase in toxicity. No increased benefit is observed among patients with BRAF-mutant tumors.”

Dr. Cremolini, of the Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.