Real-World Data Favor Doublets in Esophageal/Gastric Cancer

An analysis of real-world use of first-line palliative treatment for metastatic esophagogastric cancer supports the use of doublet regimens over triplet chemotherapy protocols. The odds of survival are similar for both, but toxicity is less with fewer drugs.

The study also showed a strikingly large degree of heterogeneity in the drugs chosen to treat this incurable malignancy, which could have negative consequences for patient outcomes, the authors suggest.

The findings were published online on July 24 in the International Journal of Cancer.

"Palliative treatment represents an important part of esophagogastric cancer care, since approximately one-third of esophagogastric cancer patients have metastases at initial diagnoses, and curative treatment options are not available," senior author Hanneke van Laarhoven, MD, PhD, University of Amsterdam, the Netherlands, and colleagues observe.

"We found a strikingly wide variation of 45 different systemic therapy regimens that were administered," they continue.

"This heterogeneity in treatment is undesirable, especially in the case of unconventional treatment combinations [because] the use of an unusual treatment regimen may limit opportunities for second-line treatment and subsequent OS (overall survival) benefit," they add.

Data From National Cancer Registry

For the study, the team identified 2204 patients with synchronous metastatic esophgogastric cancer who underwent treatment with some form of systemic chemotherapy from 2010 to 2016 from the Netherlands Cancer Registry.

Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus or the gastroesophageal junction of the stomach were included in the analysis.

First-line treatment was defined as the first systemic treatment patients were given, either as monotherapy or as a combination regimen, until discontinuation.

"Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy," van Laarhoven and colleagues note.

Regimens containing trastuzumab (multiple brands) were singled out as a singular treatment strategy.

Some 45% of patients received doublet chemotherapy, and another 34% received triplet chemotherapy, the authors note. Monotherapy and trastuzumab-containing regimens were each given to 10% of the cohort.

The most commonly used regimen in this Dutch cohort was capecitabine (Xeloda, Genentech) plus oxaliplatin (Eloxatin, Sanofi-Aventis), received by 21% of patients, followed by the triplet consisting of epirubicin (Ellence, Pfizer), oxaliplatin, and capecitabine at 20%.

For the overall cohort, median OS was 7.5 months, the authors note.

OS was best in patients who were treated with a trastuzumab-containing regimen, at 11.9 months, and was worse for those who received monotherapy, they add.

The authors recommend that best supportive care be offered to patients who cannot tolerate a dual chemotherapy regimen. They argue that survival is significantly diminished when only single-drug therapy is used and that toxicity is only marginally less with single-drug therapy than with doublet regimens.

Survival odds as well as time to treatment failure (TTF) were identical for patients who were treated with a doublet or a triple regimen, at an adjusted hazard ratio of 0.92 for both endpoints, the investigators note.

With regard to different combinations of drugs, the investigators did not find any survival advantage for cisplatin, gemcitabine, or platinum-taxane doublets over fluoropyrimidine doublets.

Nor was there any survival advantage for anthracycline triplets over fluoropyrimidine doublets.

On the other hand, both OS and TTF were significantly better with taxane triplets than with fluoropyrimdine doublets. Taxane triplets extended OS by 37% and TTF by 33%.

"Both trastuzumab- and targeted therapy–containing regimens showed significantly better OS and TTF than fluoropyrimidine doublets," the authors observe.

Details of Toxicity Profiles

A subgroup of 1221 patients were diagnosed with metastatic esophagogastric cancer from 2010 to 2014. In this cohort, toxicity of grades 3 to 5 was reported in 27% of patients overall.

"Trastuzumab-containing regimens induced the highest complication rate (45%), followed by triplets (33%), doublets (21%) and monotherapy (17%)," the authors note.

Eighteen patients died from complications due to the treatment. Seven of these patients were treated with a triplet, five were treated with a doublet, two with monotherapy, and three with a trastuzumab-containing regimen.

"Population-based data represent a wide variation of patients, including frail patients and patients with comorbidity who are usually not included in conventional clinical trials," the authors observe.

"Real-world evidence, if well analyzed and interpreted, is therefore highly potent in efficiently adding information about systemic treatment alongside the results of these trials," they conclude.

The study was funded by a grant from Lilly Oncology. Laarhoven has served as a consultant for Bristol-Myers Squibb, Celgene, Lilly, and Nordic and has received research funding from Bayer, Bristol-Myers Squib, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips, and Roche. Several coauthors also have relationships with pharmaceutical companies, as detailed in the original article.

Int J Cancer. Published online July 24, 2019. Full text

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