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Chemoradiotherapy does not prolong OS in locally advanced pancreatic cancer
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The addition of radiation to chemotherapy failed to improve OS for patients with locally advanced pancreatic cancer, according to the results of the randomized, open-label, phase 3 LAP07 trial.
Further, the addition of erlotinib (Tarceva; Genentech, Astellas Oncology) to gemcitabine also did not extend OS.
Deborah Schrag
“Since 1997, gemcitabine has been the standard of care for patients with metastatic pancreatic cancer,” Pascal Hammel, MD, PhD, of the department of gastroenterology and pancreatology at Beaujon Hospital in Clichy, France, and colleagues wrote. “Thereafter, studies involving gemcitabine in combination with erlotinib found a statistically significant but not clinically meaningful gain of survival.”
The role of radiation therapy in treating patients with pancreatic cancer has been controversial.
“The results of five randomized trials of locally advanced pancreatic cancer patients comparing chemoradiotherapy with chemotherapy were contradictory,” Hammel and colleagues wrote. “Some retrospective studies have suggested that induction chemotherapy administered before radiation concurrent chemoradiotherapy could improve survival.”
Hammel and colleagues sought to determine whether chemoradiotherapy improved OS among patients with locally advanced pancreatic cancer after 4 months of gemcitabine-based induction chemotherapy. The trial also assessed the effect of erlotinib on OS.
The study included data from 442 patients (median age, 63.3 years; range, 57-71; men, n = 232) over two randomization periods. During the first, researchers randomly assigned patients to 1,000 mg/m2 weekly gemcitabine alone (n = 223) or in combination with 100 mg daily erlotinib (n = 219).
Patients who were progression free at 4 months (n = 269) underwent a second randomization to 2 months on the same chemotherapy (n = 136) or chemoradiotherapy (54 Gy plus capecitabine; n = 133).
OS from the date of first randomization served as the primary endpoint. Secondary outcomes included the effect of erlotinib and quality assurance of radiotherapy on OS, PFS from the date of first randomization with the gemcitabine–erlotinib and erlotinib maintenance vs. gemcitabine alone, and toxicity.
Two-hundred twenty-one patients had died (chemoradiotherapy, n = 109; chemotherapy, n = 112) at the time of the interim analysis, causing the trial to end early due to futility.
Median follow-up was 36.7 months.
The median OS from the date of first randomization did not significantly differ between chemoradiotherapy and chemotherapy alone (15.2 months vs. 16.5 months; HR = 1.03; 95% CI, 0.79-1.34).
Patients assigned gemcitabine alone had a median OS of 13.6 months from first randomization, which did not significantly differ from the 11.9-month OS observed among patients assigned gemcitabine plus erlotinib (deaths, 188 vs. 191; HR = 1.19; 95% CI, 0.97-1.45).
Patients assigned gemcitabine plus erlotinib had higher rates of grade 3 or grade 4 anemia (P = .05), febrile neutropenia (P = .03), diarrhea (P = .006) and acneiform rash (P = .007) during the induction phase.
All but six patients assigned chemoradiotherapy experienced grade 3 or grade 4 nausea, compared with no patients in the chemotherapy group (P = .008). Other rates of adverse events did not differ between the groups.
Eighty-seven percent of all study patients (n = 385) experienced tumor progression, 54% (n = 207) of which were metastatic. During the second randomization, locoregional progression occurred less frequently among patients assigned chemoradiotherapy (32% vs. 46%); however, metastatic progression occurred more frequently (60% vs. 44%; P = .04).
The researchers acknowledged study limitations, including their inability to use FOLFIRINOX or nab-paclitaxel chemotherapy, which were not invented when the study was designed. They further noted that the study was not designed for quality-of-life or cost-efficacy analyses.
“In this open-label, randomized trial among patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in OS with chemoradiotherapy compared with chemotherapy alone, and there was no significant difference in OS with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy,” Hammel and colleagues wrote.
The results of this trial are still worthwhile research, despite the negative outcome, Deborah Schrag, MD, MPH, professor of medicine at Harvard Medical School, chief of the division of population sciences at Dana-Farber Cancer Institute and an associate editor of JAMA, wrote in an accompanying editorial.
“Clinical trials that find no difference between groups never garner as much excitement as trials with positive findings,” Schrag wrote. “However, clear negative results chart the path forward by informing the design of next-generation studies and hastening retirement of ineffective therapies. The results of the LAP07 trial are persuasive that contemporary chemoradiation does not add a survival advantage to chemotherapy alone.” – by Cameron Kelsall
Disclosure: Roche and the French National Institute of Cancer provided funding for this study. Hammel reports consultant fees from Celgene. Please see the full study for a list of all other researchers’ relevant financial disclosures. Schrag reports no relevant financial disclosures.
Perspective
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Philip A. Philip, MD, PhD, FRCP
The LAP07 study by Hammel and colleagues questions the role of radiotherapy in the treatment of locally advanced pancreatic cancer and confirms the lack of benefit from erlotinib (Tarceva; Genentech/Roche, Astellas Oncology). The absence of a survival benefit from chemoradiotherapy in LAP07 occurred despite being designed to allowed selection of patients at the point of randomization who had favorable features, such as an absence of disease progression and good performance status. The lack of a survival benefit by giving 54 Gy conventional radiotherapy along with capecitabine challenges the practice of incorporation of chemoradiotherapy into the multimodality therapy of newly diagnosed patients with locally advanced pancreatic cancer when survival is a treatment goal.
However, one cannot dismiss a clinical value for chemoradiotherapy in a subgroup of patients who may differentially benefit from controlling locoregional disease progression. The potential benefit would be to reduce disease-related morbidities (such as pain and biliary obstruction), prolong time to disease progression and possibly improve survival. Unfortunately, we have no algorithm to follow in selecting those patients who would accrue a survival or other clinical benefit from radiotherapy. Several years ago, it was suggested that SMAD4 tumor suppressor gene status may predict the predominant disease behavior (locoregional vs. systemic) and help select patients with intact SMAD4 who may benefit from locoregional therapy. SMAD4’s role remains to be prospectively validated.
Absence of disease progression after 4 months of gemcitabine in the LAP07 trial was not sufficient to select patients who would survive longer, although local disease progression was improved with subsequent chemoradiotherapy. The latter may be of clinical value, but no serial data on quality of life or disease-related symptoms were reported, nor any other information to support the value of disease control with chemoradiotherapy. The availability of better drug regimens (FOLFIRINOX and gemcitabine/nab-paclitaxel) may allow the demonstration of a benefit from radiotherapy in the context of controlled systemic disease. Patients in LAP07 did not receive inferior systemic therapy. Conversely, drug combinations with objective responses two- to three-times (and deeper) than that of gemcitabine may reduce the need for radiotherapy. Nevertheless, with more effective and safer delivery of newer modalities of radiotherapy — such as stereotactic body or proton beam radiotherapy — its role in the care of selected patients with locally advanced pancreatic cancer may be established.
These results add to the controversy surrounding radiotherapy in pancreatic cancer. LAP07 indicates that radiotherapy is unlikely to benefit most patients with locally advanced pancreatic cancer. Unlike in Europe, chemoradiotherapy remains a standard of care in treating locally advanced pancreatic cancer in the United States. Based on accumulating evidence, it must now be more of a research question than an established treatment.
To support this point, the nationally available RTOG-1201 study elegantly interrogates the role of radiotherapy in locally advanced pancreatic cancer in the context of gemcitabine/nab-paclitaxel systemic therapy and with a prospective SMAD4 evaluation. Outside of a clinical trial, the decision for using chemoradiotherapy must be based on the likelihood of benefit (or lack of it) in a given patient. The current consensus for treating locally advanced pancreatic cancer is to use upfront multicycle combination chemotherapy to best tumor response before considering chemoradiotherapy. This may reduce overall tumor burden and excuse patients who are unlikely to benefit from radiotherapy.
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