For the first time, an effective and safe regimen to treat biliary tract cancer has been established, researchers say.
Adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine showed definite promise in the treatment of two rare forms of biliary cancer: extrahepatic cholangiocarcinoma (EHCC) and gallbladder carcinoma (GBCA).
The combination was well tolerated and provides clinicians with a well-supported regimen they can use going forward, lead author Edgar Ben-Josef, MD, from the University of Pennsylvania, Perelman Center for Advanced Medicine, in Philadelphia, told Medscape Medical News.
The findings from the phase 2 intergroup Southwest Oncology Group (SWOG) S0809 trial were published online May 11 in the Journal of Clinical Oncology.
"They fill an important gap in the knowledge of how best to treat these uncommon cancers," Dr Ben-Josef said. "They are important because, until now, there have been no reliable data on outcomes for these cancers."
"There was a lot of confusion and disagreement on how to treat patients after surgery. Some physicians used chemotherapy, others a combination of chemo and radiation," he explained. In addition, "a variety of different drugs and regimens were being used, and no one really knew if any one regimen was better than the others or, in fact, if any worked. Furthermore, being an uncommon disease, there was no attempt to study these cancers systematically in prospective clinical trials, so there was no hope for progress."
Study Details
The SWOG 0809 trial involved 79 patients (median age, 62 years) with a pathologic diagnosis of EHCC or GBCC after radical resection.
The primary disease site was bile duct in 54 patients (68%) and gallbladder in 25 patients (32%). Most patients (n = 54) had undergone R0 resections, and 25 patients had undergone R1 resections.
Treatment consisted of four 21-day cycles of chemotherapy with intravenous gemcitabine 1000 mg/m² on days 1 and 8 and capecitabine 1500 mg/m² — divided into twice-daily doses — on days 1 to 14.
Patients who did not progress after reimaging went on to receive capecitabine 1330 mg/m² — divided into twice-daily doses — 7 days per week, concurrent with radiotherapy (45 Gy to regional lymph nodes and 54 to 59.4 Gy to the preoperative tumor bed).
Treatment was completed by 86% of patients.
Two-year survival was 65% for all patients, 67% for R0 patients, and 60% for R1 patients.
Median overall survival was 35 months for all patients, 34 months for R0 patients, and 35 months for R1 patients.
Fourteen patients experienced local relapse. Of these, nine also experienced concurrent distant relapse. Twenty-four patients experienced distant-only relapse.
Grade 3 adverse effects were observed in 52% of patients, and grade 4 adverse events were observed in 11% of patients.
The most common grade 3/4 adverse effects were neutropenia, seen in 44% of patients, hand–foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%).
Noteworthy Findings
There were some particularly noteworthy findings from this study.
"The overall rate of R0 resection was quite high — 68% — compared with the best contemporary retrospective series. We would have expected to find a lower rate of R0 resection in a national cooperative group trial," Dr Ben-Josef explained. "This suggests dissemination of good surgical practices nationwide."
Another surprise was that overall survival and local control were similar after R0 and R1 resections.
"Previous reports have consistently documented inferior outcomes after R1 resection in both EHCC and GBCA. This apparent improvement in outcomes in the R1 stratum may be cautiously interpreted as a sign of efficacy of the treatment regimen," he said.
In addition, the local failure rate, at just 11%, was low. "This argues that radiotherapy is an important component of the adjuvant regimen," he noted.
Of course, an important limitation of the trial was the lack of a concurrent control group.
The SWOG investigators did consider a randomized design, but their concerns about sample size, availability of patients with these rare cancers, and therefore their ability to complete the trial in a timely fashion, prevailed and led them to carry on with the single-group design.
That design does limit the conclusions that can be drawn from SWOG S0809, write Robin K. Kelley, MD, from the Helen Diller Family Comprehensive Cancer Center and The Liver Center at the University of California, San Francisco, and Nabeel Bardeesy, PhD, from the Centers for Cancer Research and Regenerative Medicine at the Massachusetts General Hospital and Harvard Medical School in Boston, in an accompanying editorial.
However, it does not diminish the trial's importance, they explain.
"To place this trial into context, it is the first multicenter clinical trial of adjuvant chemotherapy plus chemoradiotherapy in biliary tract cancers, and it was conducted in the Cooperative Group setting with rigorous surgical, pathology, and radiation quality control," they point out.
In addition, restricting the trial to the EHCC and GBCA subsets of biliary tract cancer is a "key strength," they note, because it proves that "prospective, anatomically selected trials are possible in this heterogeneous family of cancers."
To Lump or to Split?
A longstanding issue in clinical trial design for biliary tract cancers "has been whether to lump or split eligibility on the basis of anatomic site of tumor origin, Drs Kelley and Bardeesy report. "Proponents of lumping cite the challenges of trial accrual in a rare cancer and the difficulty of discerning actual site of origin in some cases, whereas those in favor of splitting raise concerns about confounding by lead time bias, heterogeneous rates of complications of biliary obstruction, and the long-perceived differences in patterns of recurrence and prognosis by anatomic site."
But emerging evidence suggesting differences in tumor biology by anatomic subset lends support to splitting, they note.
It stands to reason that biologic subsets affect prognosis and response, or lack of response, to different systemic therapies, they write.
But just how this understanding of the biology of biliary tract cancers will be integrated into the existing clinical subdivisions of biliary tract cancers is not clear.
Although the incidence of intrahepatic cholangiocarcinomas is increasing, "this cancer remains rare, and the prospect of both anatomic and genomic selection for ever-narrower subsets of patients simply does not allow for clinical testing of each subset individually," the editorialists explain.
One answer could be to create a foundation of biliary cancer cell lines, patient-derived xenografts, and genetically engineered mouse models that will represent the "diversity of patient subsets," they suggest.
They also suggest that the data and tumor samples banked from the S0809 trial could be analyzed to help inform future clinical trial stratification by genotype, improve designs of trials looking for targeted therapies, and identify new candidate biomarkers or targets.
"It is essential that we take these bedside findings back to the bench to place them into the context of the emerging new molecular taxonomy of biliary tract cancer and define new molecular subtypes that encompass and transcend our historical splitting and lumping by anatomic location alone," they conclude.
The study was supported by the National Institutes of Health, the National Cancer Institute, the National Clinical Trials Network, and the Community Oncology Research Program. Dr Ben-Josef has disclosed no relevant financial relationships. Dr Kelley reports financial relationships with Eli Lilly, Exelixis, Acceleron Pharma, Regeneron, Celgene, Merck Sharp & Dohme, Tekmira Pharmaceuticals, and Sanofi. Dr Bardeesy reports royalties from intellectual property related to modulating AMPK activity in cancer.
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