Pancreatic Cancer: Chemoradiotherapy vs Chemo Alone

Veronica Hackethal, MD

May 05, 2016

Adding radiation to chemotherapy does not improve overall survival in comparison with chemotherapy alone in patients with locally advanced pancreatic cancer with controlled disease after 4 months of induction therapy, according to results from the phase 3 randomized clinical trial LAP07. The findings were published online May 4 in the Journal of the American Medical Association.

The study also found that adding the targeted agent erlotinib (Tarceva, Osi Pharmaceuticals, Inc) to gemcitabine (Gemzar, Eli Lilly and Company) does not increase overall survival in comparison with gemcitabine alone.

"The overall survival was better than expected, confirming the efficacy of this strategy using induction chemotherapy first. Survival after chemoradiation was not inferior to chemotherapy," study author Florence Huguet, MD, of the Department of Radiotherapy, Tenon Hospital, Paris, France, wrote in an email to Medscape Medical News.

"Chemoradiation and chemotherapy remain two reasonable options in patients with disease control after 4 months of chemotherapy," she added.

There is no consensus concerning the best treatment strategy for locally advanced pancreatic cancer, Dr Huguet explained. Such tumors are not resectable because of invasion into adjacent structures. Although these patients do not yet have metatastic disease, they are at risk for local progression and metatastasis. Such patients usually receive induction chemotherapy followed by chemoradiation (fluorouracil or capecitabine [Xeloda, F. Hoffman/La Roche, Ltd] plus radiation) if the disease has not progressed.

Chemoradiation has the potential to decrease distant metastases and convert inoperable tumors into resectable ones. However, results from at least five randomized, controlled trials that compared chermoradiotherapy with chemotherapy have been conflicting. Some retrospective studies, though, have suggested a survival advantage for patients who receive induction therapy followed by chemoradiotherapy.

Previous studies have also suggested that adding erlotinib to gemcitabine may increase survival. However, the results, though statistically significant, have not proved to be clinically meaningful.

Study Details

The LAP07 trial was an international, open-label, unblinded phase 3 randomized trial that included 449 adults with stage III locally advanced pancreatic cancer. Enrollment occurred between 2008 and 2011 in 80 centers in France, Australia, New Zealand, Belgium, and Sweden.

Researchers first randomly assigned 223 patients to 1000 mg/m2 of gemcitabine alone once a week and 219 patients to 1000 mg/m2 of weekly gemcitabine plus 100 mg/day of oral erlotinib. They then randomly assigned patients who were without disease progression after 4 months of induction therapy to receive two additional months of the same chemotherapy (n = 136) or chermoradiotherapy (54 Gy, 30 daily fractions over 6 weeks) plus capecitabine 800 mg/m2 twice a day (n = 133).

An interim analysis conducted after 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group) led to early cessation of the trial due to futility.

Over a median overall follow-up of 36.7 months, median overall survival rates in the chemotherapy and chemoradiotherapy groups were similar (16.5 months vs 15.2 months, respectively; hazard ratio [HR], 1.03; P = .83). Likewise, progression-free survival rates were similar in the two groups (HR, 0.78, 95% confidence interval [CI], 0.61 - 1.01; P = .06).

In the group that received gemcitabine alone, median overall survival was similar to that of the group that received gemcitabine plus erlotinib (13.6 months vs 11.9 months, respectively; HR, 1.19; P = .09). Progression-free survival rates were also similar for the two groups (HR, 1.12; 95% CI, 0.92 - 1.36; P = .26).

The group that received gemcitabine plus erlotinib experienced significantly more grade 3 or 4 anemia (P = .05), febrile neutropenia (P = .03), diarrhea (P = .006), and acneiform rash (P = .007) compared with the group that received gemcitabine alone.

The chemoradiotherapy group showed no increase in grade 3 or 4 toxicity except for nausea. In addition, this group experienced less local progression than the group that received chemotherapy alone (32% vs 46%; P = .03), and progression-free survival was increased, resulting in a longer treatment-free period (6.1 months vs 3.7 months; P = .02).

"This could translate into a better quality of life, which is in favor of chemoradiation," Dr Huguet pointed out, "On the other hand, radiation therapy is more expensive and time consuming for the patients."

The study included a radiation therapy quality assurance and quality control component to ensure delivery of protocol-compliant radiation therapy. Evaluations showed that 32% of participants received radiation per protocol, 50% had minor deviations, and 18% had major deviations. Major deviations were mainly with regard to variations from the planned schedule. These deviations did not significantly affect overall survival.

The study did not employ the most optimal drugs for chemotherapy ― FOLFIRINOX (leucovorin/fluorouracil/irinotecan/oxaliplatin) and gemcitabine-nab-paclitaxel ― because the trial began in 2005, before these regimens came into use.

Using these more effective regimens could improve the results, Dr Huguet speculated. Also, new radiation techniques, such as intensity-modulated radiation therapy and image-guided radiation therapy, may allow for dose escalation and better sparing of organs at risk.

"These two axes of development should be explored in the future," she concluded.

Progress, but Not Precision

The results represent progress, but the goal of precision medicine was not achieved, Deborah Schrag, MD, MPH, of the Dana Farber Cancer Institute, Boston, Massachusetts, and associate editor of JAMA, writes in a linked editorial.

"The trial does not include information about the molecular correlates of response," she said in an email to Medscape Medical News. "It is quite plausible that there is heterogeneity in response and that some tumors are especially responsive to radiation."

Research is currently underway to identify molecular signatures of tumors that are particularly responsive to radiation or chemotherapy, she noted.

Asked about the clinical implications of the new findings, Dr Schrag wrote: "Chemoradiation need not be a component of standard care based on the LAP07 study results. However, it is also important to realize that radiation was not inferior to continued chemotherapy."

In her editorial, she points out that pancreatic cancer is one of the most difficult-to-treat tumor types and that little progress has been made. "Pancreas cancer mortality rates have not substantially declined over the past decade, and the incidence is increasing in low- and middle-resource countries," she notes.

"If cancer is the emperor of all maladies, then pancreatic adenocarcinoma is the ruthless dictator of all cancers," she comments.

Dr Huguet has received personal fees and nonfinancial support from Merck Serono and Celgene. Several coauthors report relationships with pharmaceutical companies, including Celgene, Merck Serono, Pfizer, Lilly, Sanofi, Amgen, Novartis, Integragen, Nestle, Eisai, Invectys, and/or Roche. Dr Schrag has disclosed no relevant financial relationships.

JAMA. Published online May 4, 2016. Abstract, Editorial

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