New Data in Colorectal, Neuroendocrine, Gastric, and Hepatocellular Cancers

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THE ANNUAL GASTROINTESTINAL CANCERS SYMPOSIUM took place earlier this year in San Francisco. In addition to important studies captured in our past few issues, The ASCO Post here briefly summarizes additional interesting studies.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Colon Cancer

“Overall, 21% of patients [with stage II and III locally advanced colon cancer undergoing adjuvant chemotherapy] had peritoneal metastases detected after 23 months of follow-up, demonstrating the magnitude of this clinical problem.”
— Pieter J. Tanis, MD, PhD

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ADJUVANT HYPERTHERMIC intraperitoneal chemotherapy did not reduce the risk of peritoneal recurrences in patients with high-risk colon cancer, the phase III Dutch COLOPEC trial showed.1 The idea behind hyperthermic intraperitoneal chemotherapy is to manage the metachronous peritoneal metastases that occur in up to 25% of patients with stage II and III locally advanced colon cancer undergoing adjuvant chemotherapy. By the time they are detected, they are usually difficult to treat, said senior author Pieter J. Tanis, MD, PhD, of the Amsterdam University Medical Centers in Amsterdam. 

“Overall, 21% of patients had peritoneal metastases detected after 23 months of follow-up, demonstrating the magnitude of this clinical problem,” he said.

In the study, 202 patients underwent curative resection of T4 or perforated colon cancers, followed by adjuvant chemotherapy. Patients were randomly assigned also to receive, or not, postoperative hyperthermic intraperitoneal chemotherapy. Adjuvant hyperthermic intraperitoneal chemotherapy consisted of 30 minutes of intraperitoneal oxaliplatin plus intravenous fluorouracil (5-FU) and leucovorin. Hyperthermic intraperitoneal chemotherapy was usually performed 5 to 8 weeks after resection (91%) and was done laparoscopically (71%). Patients in the hyperthermic intraperitoneal chemotherapy and control groups were similarly likely to receive adjuvant systemic chemotherapy (84% vs 89%, P = .385), but it was started after a longer period in the experimental arm (10.2 vs 6.4 weeks, P < .001).

At 18 months, 81% of the hyperthermic intraperitoneal chemotherapy group and 76% of the control group were free of peritoneal recurrence, as assessed by laparoscopy. The 14% reduction in risk with hyperthermic intraperitoneal chemotherapy was not significant (hazard ratio [HR] = 0.86; 95% confidence interval [CI] = 0.51–1.54). “We couldn’t find any superiority of adjuvant [hyperthermic intraperitoneal chemotherapy] with oxaliplatin regarding peritoneal metastasis–free survival in patients with T4 or perforated colon cancer,” Dr. Tanis said.

Think Twice Before Giving Antibiotics to Patients Starting Immunotherapy

ANTIBIOTICS GIVEN within 60 days of starting immunotherapy may blunt the response to cancer treatment, according to research that earned a Merit Award at the meeting.2 Antibiotics can alter the gut microbiome, and this may be the underlying cause of this association, said Uqba Khan, MD, of NewYork–Presbyterian Hospital/Weill Cornell Medicine, New York. 

“The results of our study provide an association between the use of antibiotics and inferior outcomes from immunotherapy. However, we don’t know whether antibiotics somehow directly cause this or other factors are also involved. This question needs to be further explored,” said Dr. Khan. “Meanwhile, we are suggesting that antibiotics should be avoided if there is no clear indication for them.”

Dr. Khan and colleagues performed an institutional retrospective review of all patients with cancer treated with checkpoint inhibitors between 2015 and 2018 and who received an antibiotic within 6 months of immunotherapy (before or after). They identified 76 antibiotic users and 166 nonusers. Half the patients received pembrolizumab and the other half, nivolumab or atezolizumab. The most common antibiotics were piperacillin/tazobactam, vancomycin, and azithromycin.

Uqba Khan, MD

Uqba Khan, MD

Patients who received an antibiotic within 30 or 60 days of starting a checkpoint inhibitor had significantly lower response rates. Response rates for patients who received antibiotics within 60 days after starting immunotherapy were 29% among antibiotic users vs 47% for nonusers (P = .005); response rates for patients who received antibiotics within 30 days were 26% vs 46%, respectively (P = .01). There were no significant differences when patients received antibiotics before starting immunotherapy, he reported.

The use of antibiotics within 60 days also seemed to negatively impact progression-free survival. Median progression-free survival was 60 days for antibiotic users vs 126 days for nonusers. The enrollment of additional patients has not altered these outcomes. The researchers plan to conduct studies in mouse models to further evaluate the correlation between the timing of antibiotic use and outcomes.

High Response Rates Achieved With Lenvatinib in Neuroendocrine Tumors

IN THE PROSPECTIVE phase II European TALENT trial, 40.4% of patients with heavily pretreated grade 1 to 2 pancreatic neuroendocrine tumors responded to lenvatinib (by central radiographic review), as did 18.5% with gastrointestinal neuroendocrine tumors, according to Jaume Capdevila, MD, of Vall d’Hebron University Hospital and Institute of Oncology in Barcelona.3 “To my knowledge, these are the highest response rates ever reported in [neuroendocrine tumors] with a targeted agent and central radiology assessment,” he said. With other targeted agents, he said, response rates are less than 10%, and no progression-free survival benefit has been shown in patients previously treated with targeted agents.

Jaume Capdevila, MD

Jaume Capdevila, MD

Lenvatinib inhibits vascular endothelial growth factor receptors 1 to 3 and fibroblast growth factor receptors 1 to 4. “We think this may increase efficacy and revert the primary and acquired resistance to targeted agents,” he said.

This prospective phase II study evaluated lenvatinib at 24 mg daily in 55 patients with grade 1 to 2 (mostly grade 2) pancreatic neuroendocrine tumors and 56 with grade 1 to 2 gastrointestinal neuroendocrine tumors. Patients with pancreatic neuroendocrine tumors had to have had disease progression on targeted agents (some also had disease progression on somatostatin analogs and chemotherapy); for gastrointestinal neuroendocrine tumors, disease progression on somatostatin analogs was required. Most patients had shown disease progression within 1 year of their last treatment. “We selected patients with aggressive disease,” Dr. Capdevila said.

With a median follow-up of 17 months, median progression-free survival for both cohorts exceeded 15 months. “This is longer than would be expected,” he said. Benefit was seen in all subgroups.

The most frequent grade 3/4 adverse events were hypertension (21%), asthenia (13%), diarrhea (7%), and abdominal pain (5%). “With lenvatinib in thyroid cancer, we see grade 3 to 4 hypertension in about 50% of patients, but here it’s about 20% because we treat it aggressively,” he said. “This drug is quite toxic if you don’t manage it appropriately. Almost all patients need dose reductions, but in this study, most patients only needed one.”

For Rectal Surgery, Safe to Wait Longer After Neoadjuvant Treatment—but Useless

WAITING TO PERFORM surgery up to 11 weeks after radiochemotherapy has no influence on the oncologic outcomes of T3/ T4 rectal cancers, French investigators reported.4 The findings of the GRECCAR-6 trial help to settle the question of whether a prolonged interval between radiochemotherapy and resection affects complete pathologic response and oncologic prognosis, said Jérémie H. Lefevre, MD, PhD, of the Hôpital Saint Antoine, Assistance Publique–Hôpitaux de Paris.

Jérémie H. Lefevre, MD, PhD

Jérémie H. Lefevre, MD, PhD

Dr. Lefevre presented the 3-year survival results of the phase III, multicenter, randomized trial of 265 patients with cT3/T4 or Tx, N+ tumors of the mid or lower rectum who received neoadjuvant radiochemotherapy. Patients were randomly assigned between two waiting periods: 7 weeks or 11 weeks between radiochemotherapy and resection (primarily total mesorectal excision).

In the overall population, the pathologic complete response rate was 18.6%. At 3 years the survival rate was 89.6%, disease-free survival rate was 67.7%, local recurrence rate was 8.3%, and distant recurrence rate was 22.0%. No differences in these endpoints was observed by treatment arm (ie, according to waiting time), he reported.

“Patients achieving a pathologic complete response had an excellent prognosis,” Dr. Lefevre noted. For these 43 patients, the overall survival rate was 95%, vs 89% for the remaining patients (P = .2597), and disease-free survival was 90% vs 63% (P = .0023). No patients had a local recurrence, and only 5% had a metastatic recurrence—outcomes that were also significantly better than what was seen in the remaining patients, he said.

“In the absence of a rectal-sparing strategy, surgery should be performed 7 to 8 weeks after the end of radiochemotherapy,” he suggested.

Trifluridine/Tipiracil Prolongs Survival in Heavily Pretreated Metastatic Gastric Cancer

THE PHASE III TAGS trial in patients with heavily pretreated metastatic gastric cancer showed the benefit of trifluridine/tipiracil over best supportive care.5 By finding a 2.1-month improvement in overall survival (HR = 0.69, P = .00029), the study met its primary endpoint, according to David H. Ilson, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York.

“The data from this analysis reinforce the benefit for trifluridine/tipiracil at prolonging survival vs placebo [in patients with metastatic colorectal cancer], and this is regardless of prior gastrectomy.”
— David H. Ilson, MD, PhD

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The randomized, double-blind study was conducted in 507 patients with metastatic gastric or gastroesophageal junction adenocarcinoma who had previously received at least 2 chemotherapy regimens. Benefit was shown in a preplanned subgroup analysis of the 221 patients who underwent prior gastrectomy, thus indicating that the benefit of trifluridine/tipiracil applies to all patients receiving the novel chemotherapy combination, regardless of whether they had prior surgery.

Many patients undergo gastrectomy at some point in their disease, which could affect the pharmacokinetics of oral chemotherapy drugs. It is important, therefore, to determine whether gastrectomy influences the response to systemic treatment, Dr. Ilson explained.

Trifluridine/tipiracil combines the antineoplastic activity of trifluridine with the thymidine phosphorylase inhibitory activity of tipiracil. The coformulation is currently approved for patients with metastatic colorectal cancer who have had disease progression on other regimens, as it is active against tumors resistant to 5-FU.

“The data from this analysis reinforce the benefit for trifluridine/tipiracil at prolonging survival vs placebo, and this is regardless of prior gastrectomy,” Dr. Ilson said.

Among patients who had undergone prior gastrectomy, median overall survival was 6.0 months with trifluridine/tipiracil vs 3.4 months with placebo (HR = 0.57, 95% CI = 0.41–0.79), and median progression-free survival was 2.2 months and 1.8 months, respectively (HR = 0.48, 95% CI = 0.35–0.65).

Although patients with and without prior gastrectomy benefited from trifluridine/tipiracil, adverse events were more frequent in patients with prior gastrectomy, including grade ≥ 3 neutropenia, leukopenia, and decreased white blood cell count. Patients in this subgroup, however, were not more likely to discontinue treatment.

Response to Lenvatinib or Sorafenib Predicts Survival in Hepatocellular Carcinoma

A POST HOC retrospective analysis from the phase III REFLECT trial found tumor response to be an independent predictor of overall survival in patients with hepatocellular carcinoma treated with either lenvatinib or sorafenib.6

“Objective response by modified [Response Evaluation Criteria in Solid Tumors based on a reduction of viable tumor burden, rather than overall tumor shrinkage] was an independent predictor of overall survival in patients with [hepatocellular carcinoma], regardless of treatment,” said Masatoshi Kudo, MD, PhD, of Kindai University Faculty of Medicine in Osaka, Japan. This finding is consistent with earlier studies, he noted, meaning that “patients who achieve an objective response can potentially expect a longer survival.”

The REFLECT trial compared lenvatinib and sorafenib in 954 patients with hepatocellular carcinoma. The median overall survival in the full study was 13.0 months (13.6 months with lenvatinib, 12.3 months with sorafenib). The objective response rate was 16.7%, with more responses seen with lenvatinib (24.1%) than with sorafenib (9.2%). Lenvatinib was deemed noninferior to sorafenib.

Masatoshi Kudo, MD, PhD

Masatoshi Kudo, MD, PhD

Among responders, median overall survival rose to 22.4 months, compared with 11.4 months in nonresponders, for a hazard ratio of 0.61 (P < .001). Landmark analyses showed a separation of the survival curves at 2, 4, and 6 months, Dr. Kudo reported.

On multivariate analysis, objective response was one of several factors that were significantly associated with survival; others included macroscopic portal vein invasion, baseline alpha-fetoprotein, and number of tumor sites at baseline.

DISCLOSURE: Drs. Tanis and Khan reported no conflicts of interest. Dr. Capdevila is a consultant/advisor or has served on the speakers bureau for Advanced Accelerator Applications, Amgen, Bayer, Eisai, Ipsen, Merck Serono, Novartis, Pfizer, and Sanofi and has received institutional research funding from AstraZeneca, Bayer, Eisai, Novartis, and Pfizer. Dr. Lefevre has received honoraria from Takeda and is a consultant/advisor for SafeHeal. Dr. Ilson is a consultant/advisor for AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly/ ImClone, Merck, Pieris Pharmaceuticals, Taiho, and Roche/Genentech; and has received research support from Taiho. Dr. Kudo has received honoraria from or is a consultant/advisor for AbbVie, Bayer, Bristol-Myers Squibb Japan, EA Pharma, Eisai, Gilead Sciences, Merck Serono, MSD, Novartis, Pfizer, and Taiho Pharmaceutical and has received research funding from AbbVie, Astellas Pharma, Bristol-Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Otsuka, and Taiho Pharmaceutical.


1. Klaver CEL, Wisselink DD, Punt CJA, et al: Adjuvant HIPEC in patients with colon cancer at high risk of peritoneal metastases: Primary outcome of the COLOPEC multicenter randomized trial. 2019 Gastrointestinal Cancers Symposium. Abstract 482. Presented January 19, 2019.

2. Khan U, Pena C, Brouwer J, et al: Impact of antibiotic use on response to treatment with immune checkpoint inhibitors. 2019 Gastrointestinal Cancers Symposium. Abstract 143. Presented January 17, 2019.

3. Capdevila J, Fazio N, López-López C, et al: Progression-free survival and subgroups analyses of lenvatinib in patients with G1/G2 advanced pancreatic and gastrointestinal neuroendocrine tumors: Updated results from the phase II TALENT trial (GETNE 1509). 2019 Gastrointestinal Cancers Symposium. Abstract 332. Presented January 18, 2019.

4. Lefevre JH, Mineur L, Cachanada M, et al: Does a longer waiting period after neoadjuvant radiochemotherapy improve the oncological prognosis of rectal cancer? Three-year follow-up of the GRECCAR-6 randomized multicenter trial. 2019 Gastrointestinal Cancers Symposium. Abstract 483. Presented on January 19, 2019.

5. Ilson DH, Prokharau AP, Arkenau H-T, et al: Efficacy and safety of trifluridine/tipiracil in patients with metastatic gastric cancer with or without prior gastrectomy: Results from a phase III study (TAGS). 2019 Gastrointestinal Cancers Symposium. Abstract 3. Presented January 17, 2019.

6. Kudo M, Finn RS, Qin S, et al: Analysis of survival and objective response in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). 2019 Gastrointestinal Cancers Symposium. Abstract 186. Presented January 18, 2019.