Studies Explore Colon Tumor Sidedness, Lung Radiation Dose in Esophageal Cancer, Pembrolizumab in Liver Cancer, and More


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Along with full coverage of key presentations from the 2018 Gastrointestinal Cancers Symposium, The ASCO Post brings our readers this additional news roundup. 

Side Matters in Colon Cancer

One of the studies included in the global IDEA trial, which compared 3 vs 6 months of adjuvant chemotherapy in stage II/III colorectal cancer, has confirmed that when it comes to prognosis, side matters. Patients with tumors in the right side of the colon had a significantly worse disease-free survival, irrespective of chemotherapy duration, than those with tumors elsewhere, a retrospective analysis of the SCOT trial has shown.1 

Mark P. Saunders, MD, PhD

Mark P. Saunders, MD, PhD

Mark P. Saunders, MD, PhD, of the Christie National Health Service Foundation Trust in Manchester, England, who reported the findings, noted that registry studies and meta-analyses have shown that patients with locoregional right-sided tumors have a worse overall survival than those with left-sided tumors. One such study was a retrospective analysis of the landmark CALGB/ SWOG 80405 (Alliance) trial that compared two chemotherapy regimens.2 Patients with primary tumors on the right side of the colon were at a 55% higher risk for death compared with patients with their primary tumor location on the left side. Other studies have made similar findings. 

In an unplanned analysis of 3,219 patients in the SCOT trial, those with right-sided tumors had a 3-year disease-free survival rate of 73% compared with 80% for patients with left-sided tumors (P < .0001). This 7% absolute difference translated into a 40% increase in the hazard ratio for patients with right-sided tumors. After adjustment for T and N stage, a statistically significant 21% increase in the risk remained (P = .009). 

“This is the first study to show that unselected patients with right-sided tumors had a worse disease-free survival compared to left-sided tumors,” Dr. Saunders and his colleagues concluded.

Tumor sidedness did not impact the comparison of 3 vs 6 months of chemotherapy in the trial, he noted. Patients with right-sided tumors were significantly older, less likely to be men, more likely to have stage T4 disease, and less likely to have T2 disease. 

The findings imply, Dr. Saunders said, “that prognosis is influenced primarily by greater recurrence rather than the contributing factors that influence overall survival.” 

Negative Results for Catumaxomab

Final results of the randomized phase II AIO trial conducted in patients with peritoneal carcinomatosis from gastric cancer provided mixed results—but not positive enough for the manufacturer to continue to market catumaxomab in the European Union.3 

Florian Lordick, MD

Florian Lordick, MD

Stephen Leong, MD

Stephen Leong, MD

Intraperitoneal immunotherapy with this bispecific anti–epithelial cell adhesion molecule (EpCAM)/anti-CD3 monoclonal antibody yielded a 27% macroscopic complete remission rate in patients who received it before chemotherapy. Although this exceeded the 20% threshold for a positive study, Florian Lordick, MD, of the University Cancer Center Leipzig, Germany, said the study was closed prematurely, with 31 patients enrolled after catumaxomab became unavailable in the European Union. The drug is currently not marketed.

Catumaxomab features a unique molecular design. In essence, its trifunctional structure draws immune cells to the tumor site to enhance the efficiency of tumor-killing. Intraperitoneal catumaxomab had previously proven effective in treating malignant ascites from EpCAM-positive epithelial tumors and was approved for this indication by the European Commission in 2009. 

The current AIO study evaluated intraperitoneal catumaxomab prior to intravenous FLOT chemotherapy (fluorouracil, leucovorin, oxaliplatin, docetaxel) vs FLOT alone, as a means of reducing peritoneal metastasis associated with gastric cancer. The primary endpoint, macroscopic complete remission, was assessed via laparoscopy; if macroscopic disease remained, gastrectomy and peritonectomy were allowed to achieve complete resection of all malignant lesions.

The addition of catumaxomab prior to FLOT administration did not significantly increase the macroscopic complete remission rate over FLOT alone (27% vs 19%; P = .69). In addition, no significant differences between the catumaxomab-FLOT and FLOT-alone arms were found for median progression-free survival (6.7 vs 5.4 months; hazard ratio [HR] = 0.85, P = .71) or median overall survival (13.2 vs 13.0 months; HR = 0.98, P = .97) based on a median follow-up duration of 52 months.

“Although the primary endpoint was not met, the results are promising for future trials investigating intraperitoneal immunotherapy in this patient population,” the investigators commented in their abstract.

“The study’s small sample size and the premature termination of the study make it difficult to interpret the data,” said discussant Stephen Leong, MD, of the University of Colorado Cancer Center, Aurora.

In Esophageal Cancer, Radiation Dose to Lung Affects Survival

Among patients undergoing chemoradiation therapy for localized esophageal cancer, the radiation dose to the lung—specifically lung V20 (the volume of the lung receiving ≥ 20 Gy)—is an independent predictor of survival, according to a large cohort retrospective analysis.4 

Patrick Oh, a second-year medical student at Stony Brook University School of Medicine, New York, reported the results of a study he conducted along with researchers from Memorial Sloan Kettering Cancer Center and the University of Colorado.

Multiple lung metrics have correlated strongly with overall survival, and V20 is the most widely used in practice. “We speculated that higher lung dose may increase the risk of fatal cardiopulmonary and postsurgical events,” he said.

Patrick Oh

Patrick Oh

The researchers reviewed the records of 453 consecutive patients with stage I to III esophageal cancer treated between 2007 and 2015 with definitive or preoperative chemoradiation; the median dose was 50.4 Gy in 28 fractions, given mostly via intensity-modulated radiation therapy. Radiation plans were reviewed, and multiple dose-volume histogram metrics for heart and lung were extracted for the analysis. Surgery was also performed on about half the patients. The median follow-up was 28.4 months.

On the multivariable analysis, age (HR = 1.01, P = .034), surgery (HR = 0.60, P < .001), stage III disease at baseline (HR = 1.98, P < .001), and lung V20 (HR = 1.03, P = .0389) predicted survival; the cardiac radiation dose, on the other hand, was not predictive. Patients who had less than 20% of the lung exposed to 20 Gy of radiation had a significantly longer survival—nearly double that of patients with exposures ≥ 20% (44 vs 24 months; P = .01).

“In this large cohort retrospective analysis, lung dose was an independent predictor of survival after chemoradiotherapy. This suggests a role for improving outcomes by lowering lung dose,” Mr. Oh said. Outcomes might also be improved with the use of more conformal radiation techniques, such as proton therapy, or smaller target volumes, such as reduced margins or elective nodal radiation therapy, he added.

Theodore Hong, MD

Theodore Hong, MD

Study discussant Theodore Hong, MD, Director of Gastrointestinal Radiation Oncology at Massachusetts General Hospital, Boston, emphasized that while chemoradiation is the standard of care in esophageal cancer, it can have unintended consequences. While it downstages disease and therefore reduces the rate of positive margins and metastatic spread, “when we look across the landscape of multiple neoadjuvant chemoradiotherapy trials, we can see there has been a mix of positive and negative effects [in addition to the modality’s] anticancer effect,” Dr. Hong said.

The question is why the survival benefit is “so inconsistent,” he commented. “We are left with a conundrum.” While toxicity is an issue, he argued, “there may also be unintended adverse consequences on disease progression.” 

Dr. Hong emphasized that hard, mechanistic data are still lacking on why a survival benefit is lost “in light of how much effect we get at the primary tumor. It is very important to tease out whether we are losing patients to toxicity or to loss of systemic control.” 

Pembrolizumab in Advanced Liver Cancer

In the phase II KEYNOTE-224 trial, the use of pembrolizumab (Keytruda) in patients with advanced hepatocellular carcinoma previously treated with sorafenib (Nexavar) led to an overall response rate of 16.3%, Andrew X. Zhu, MD, PhD, Director of Liver Cancer Research at Massachusetts General Hospital Cancer Center and Professor of Medicine at Harvard Medical School, reported.5 

Andrew X. Zhu, MD, PhD

Andrew X. Zhu, MD, PhD

“The durable responses observed with pembrolizumab monotherapy in this difficult-to-treat cancer are encouraging,” he commented. The findings from the open-label study were based on 104 evaluable patients previously treated with sorafenib who received 1 or more doses of pembrolizumab (200 mg every 3 weeks). The 16.3% response rate included complete responses in 1%. The disease control rate was 61.5%.

The response rate was similar across subgroups with different etiologies, including hepatitis B– and hepatitis C–positive patients. At the time of analysis, the median duration of response was 8.2 months, with 94% of responses ongoing for 6 months or longer, Dr. Zhu reported.

Median progression-free survival was 4.8 months, with a 6-month progression-free survival rate of 43.1%. The median overall survival had not been reached at the time of analysis, with 77.9% of patients alive at 6 months. ■

DISCLOSURES: Dr. Saunders has received honoraria from and has been a consultant or advisor for Amgen, Merck, Roche, and Servier. Dr. Lordick has received honoraria from Amgen, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Nordic Group, and Roche Pharma AG, has been a consultant or advisor for BioNTech AG, Bristol-Myers Squibb, Ganymed Pharmaceuticals, Lilly, Merck Sharp & Dohme, and Roche, has received research funding from Boehringer Ingelheim and Fresenius Biotech, and has received travel and/or accommodation expenses from Bayer, Merck Sharp & Dohme, Roche, and Taiho Pharmaceutical. Dr. Leong… Dr. Hong has been a consultant or advisor for Clinical Genomics and has received research funding from Novartis and Taiho Pharma. Dr. Zhu has been a consultant or advisor for Bristol-Myers Squibb, Lilly, Merck, Bayer, Novartis, Eisai, and Roche. Mr. Oh and Dr. Leong reported no conflicts of interest.

REFERENCES

1. Saunders MP, Paul J, Crosby J, et al: SCOT: Tumor sidedness and the influence of chemotherapy duration on disease-free survival. 2018 Gastrointestinal Cancers Symposium. Abstract 558. Presented January 20, 2018.

2. Venook AP, Niedzwiecki D, Innocenti F, et al: Impact of primary tumor location on overall survival and progression-free survival in patients with metastatic colorectal cancer: Analysis of CALGB/SWOG 80405 (Alliance). 2016 ASCO Annual Meeting. Abstract 3504. Presented June 5, 2016.

3. Lordick F, Kunzmann V, Trojan J, et al: Intraperitoneal immunotherapy with the bispecific anti-EpCAM x anti-CD3 directed antibody catumaxomab for patients with peritoneal carcinomatosis from gastric cancer: Final results of a randomized phase II AIO trial. 2018 Gastrointestinal Cancers Symposium. Abstract 4. Presented January 18, 2018. 

4. Oh P, Zhang M, Brady P, et al: The impact of lung and heart dose on survival after radiotherapy for esophageal cancer. 2018 Gastrointestinal Cancers Symposium. Abstract 3. Presented January 18, 2018.

5. Zhu AX, Finn RS, Cattan S, et al: KEYNOTE-224: A phase 2 study of pembrolizumab in patients with previously treated advanced hepatocellular carcinoma. 2018 Gastrointestinal Cancers Symposium. Abstract 209. Presented January 19, 2018.


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