Pancreatic Cancer: Adjuvant Chemotherapy, but Not Radiation

Alexander M. Castellino, PhD

February 24, 2016

In the treatment of resectable pancreatic cancer, adjuvant chemotherapy (ACT) is a standard of care, whereas the use of adjuvant radiochemotherapy (ARCT) has been controversial.

A large, multicenter, retrospective analysis published online February 13 in the Journal of the American College of Surgeons now indicates that the addition of ACT, but not radiation, reduces the risk for distant recurrences and increases overall survival. These data were first presented in December 2015 at the Southern Surgical Association's 127th Annual Meeting, held at Hot Springs, Virginia.

This is the first large, multi-institutional study that demonstrates differences in recurrence patterns in patients with pancreatic cancer on the basis of type of adjuvant therapy. It shows that ACT increases both local recurrence-free survival and distant recurrence-free survival, with a corresponding benefit in overall survival. By contrast, adjuvant chemoradiation therapy (ACRT) provides a benefit in local recurrence-free survival but not in distant recurrence-free survival or overall survival.

Does this study settle the debate on the use of ACRT in the clinical management of resectable pancreatic cancer?

"The study confirms that adjuvant chemotherapy should be the standard of care following surgery for resectable pancreatic cancer, as has been shown in randomized clinical trials," corresponding author Alexander A. Parikh, MD, MPH, associate professor of surgery and director of the Vanderbilt Pancreas Center at Vanderbilt University Medical Center, Nashville, Tennessee, told Medscape Medical News.

"The use of adjuvant chemoradiation, however, only provided a benefit in local recurrence but not distant recurrence or survival. Its benefit, therefore, remains unclear," he added.

Medscape Medical News contacted medical oncologists not associated with the study for their perspectives on the study.

"This is a thought-provoking study that undertook a thorough analysis to evaluate the role of adjuvant systemic chemotherapy and chemoradiation therapy in local and distant recurrences in patients with pancreatic cancer following surgery," Eileen M. O'Reilly, MD, associate director of the David M. Rubinstein Center for Pancreatic Cancer at the Memorial Sloan Kettering Cancer Center, in New York City, told Medscape Medical News.

"While it endorses the use of adjuvant systemic chemotherapy, it leaves the major question of the use of chemoradiation therapy in this setting not definitively answered," she added.

"This work addresses an important issue regarding the patterns of recurrence and survival following resection and adjuvant treatment for patients with pancreatic cancer," Ryan D. Nipp, MD, of the Massachusetts General Hospital Cancer Center and the Dana-Farber Harvard Cancer Center, Boston, told Medscape Medical News.

The Retrospective Multi-institutional Study

The study is a retrospective analysis of prospectively maintained databases from eight academic centers that make up the Central Pancreatic Consortium (CPC). Participants were patients with pancreatic cancer who underwent surgical resection from January 2000 to December 2010.

Of 1130 patients, 392 (35%) received surgery alone, 291 (26%) received ACT following surgery, and 447 (39%) received ACRT.

Median follow-up was 18 months.

The median age of all participants was 65 years, although patients receiving ACRT were younger, with median age of 63 years (68 years for surgery and 67 years for ACRT; P < 0.001). More men underwent surgery alone (57% vs 46% for ACT and 50% for ACRT). There were some differences across the three groups with respect to tumor size, grade, and stage, as shown in the following table.

  Surgery (n = 392) ACT (n = 291) ACRT (n = 447) P-value
Mean tumor size 2.9 3.3 3.1 0.01
Tumor grade 2 63% 61% 63% 0.61
Tumor stage II 85% 92% 85% 0.03
Positive lymph nodes 42% 70% 58% <.001
Positive margins after surgery 16% 21% 28% <.001

"These differences are important," Dr Nipp commented, "as they underscore the potential for selection bias among treating clinicians and help illustrate the point that patients with pancreatic cancer are a heterogeneous population."

Treatment pattern (surgery vs ACT vs ACRT) across each of the eight institutions varied significantly. "Individual institutions may differ slightly in the way they treat pancreatic cancer patients," Dr Parikh said in a press statement. "When we do a collective, multicenter study, we decrease those differences, which can provide insights that reflect the majority of what good pancreatic cancer care is," he added.

Differences in Disease Recurrence

The researchers analyzed differences in disease recurrence and survival between the ACT and ACRT groups in comparison with the surgery group. After adjusting for variables that included age, tumor size, tumor stage, tumor grade, and margins, on the basis of hazard ratios, the researchers showed that adjuvant ACT or ACRT were both associated with significantly increased local recurrence-free survival.

However, differences in distant recurrence-free survival and overall survival were significant only for patients receiving ACT.

The authors provide a logical explanation of their results. Because most patients die of distant recurrence rather than local recurrence, an improvement in both distant and local recurrence translates to an improvement in overall survival, they point out.

"In the case of ACRT, however, simply reducing local recurrence without affecting distant recurrence may not be adequate to provide a benefit in overall survival," they write.

Dr Nipp commented that worse survival was associated with several factors, including older age, higher tumor grade, longer postoperative hospital length of stay, and lymph node and margin positivity.

The association between older patient age and worse overall survival underscores the importance of the growing field of geriatric oncology and the need for ongoing research in this field. Dr Nipp was of the opinion that future studies should consider controlling for additional prognostic factors, including patients' comorbidities, as well as lymphovascular and perineural invasion.

"Prior research has shown that patient age and comorbidity are both independent predictors of early mortality following pancreatic cancer resection, thus highlighting the need for models of care integrating geriatric evaluation and management perioperatively for older cancer patients," Dr Nipp said.

"Collectively, these findings highlight the need for prospective, randomized trials to assess the efficacy of adjuvant treatment strategies for patients with pancreatic cancer," Dr Nipp told Medscape Medical News.

Implications for Clinical Practice

The study authors indicate that category I evidence gathered from several clinical trials supports the use of ACT in patients with pancreatic cancer who undergo surgery with curative intent. The use of radiation in this setting has mixed reviews.

Dr Parikh told Medscape Medical News that the study suggests that a full course of chemotherapy should be administered, rather than chemoradiotherapy, following surgical treatment of pancreatic cancer.

The authors point out that the chemoradiotherapy option uses a much lower dose, because "the chemotherapy received during the radiation therapy portion of the adjuvant treatment is only radiosensitizing."

Dr Parikh said: "The reason we think ACRT is not as effective is that, in general, when combined with ACT, only 4 months of ACT are given with the 6 weeks of ACRT.

"All patients should get at least 6 months of chemotherapy. If there is a role for chemoradiotherapy, it should not be given at the expense of giving less chemotherapy," he said.

Commenting on the study, Dr O'Reilly agreed with the authors. She explained that one of the issues surrounding ACRT is that, in the past, it was a "split course" treatment. This meant that patients received several months of chemotherapy, followed by chemoradiation therapy, after which they received the remainder of chemotherapy. She pointed out that during the combined modality period, a less than optimal dose of chemotherapy was used.

"Currently, our sense is that patients should receive the full course of systemic chemotherapy followed by ACRT, if combined-modality therapy is going to be administered, and again, the absolute value of the addition of chemoradiation remains unanswered," Dr O'Reilly told Medscape Medical News. Knowing the exact details of how patients were treated in this analysis would have helped in understanding this further, she said.

The study authors concede. They write: "[D]etails of treatment regimens, including the type and duration of adjuvant therapy, were not always available because many patients received their adjuvant treatment at institutions other than the primary facility where the resection was performed."

However, they explain that the multi-institutional study overcomes limitations associated with small patient cohorts and single-institution studies, with the added advantage that patients were treated at high-volume tertiary referral centers with expertise in multimodal treatment.

Does Not Settle the Debate

This latest study does not settle the debate, according to Dr O'Reilly.

Dr Parikh indicated that recommendations for the treatment of pancreatic cancer from the National Comprehensive Cancer Network support the use of ACT but provide no clear guidance on the use of ACRT, which is suggested for patients at high risk for local recurrence. However, an accepted definition of what constitutes high risk is lacking. For some oncologists, patients at high risk for local recurrence include those with node-positive disease or margin-positive disease, Dr O'Reilly noted.

"The question of where ACRT fits in the treatment algorithm is a complex one," Dr O'Reilly said. "While patients with positive lymph nodes and positive margins following surgery are considered at higher risk, data from this study do not support the use of ACRT in these patients," she told Medscape Medical News.

How do practicing oncologists manage patients in their own clinical practice?

Dr Parikh explained that at the Vanderbilt Pancreas Center, a multidisciplinary team, which includes pathologists and surgical, medical, and radiation oncologists, formulates a treatment plan. Although patients undergo surgical resection at the center, often the adjuvant treatment suggested by the team is provided by community oncologists.

Dr Parikh explained that when possible, all CPC centers attempt to enroll patients in clinical trials as the first priority. "If not eligible or possible, our center recommends 6 months of adjuvant chemotherapy for all. For patients with positive lymph nodes, additional ACRT is usually recommended," Dr Parikh said.

At Memorial Sloan Kettering, systemic chemotherapy is a standard of care, Dr O'Reilly said, but enrollment in clinical trials is considered for all patients. For patients who do not wish to participate in clinical trials, ACT is typically recommended for those with a high burden of positive lymph nodes. "It is unlikely that these patients meaningfully benefit from ACRT," Dr O'Reilly said.

"However, the use of ACRT in patients with positive or negative margins remains unanswered," she told Medscape Medical News. Approximately 60% to 70% of patients receive adjuvant therapy at Memorial Sloan Kettering or within its network; the remainder receive adjuvant therapy in a community setting, Dr O'Reilly indicated.

The ongoing RTOG 4808 trial (NCT01013649) aims to enroll 950 patients with resectable pancreatic cancer. Patients are randomly assigned to receive gemcitabine (Gemzar, Eli Lilly and Company) with or without erlotinib (Tarceva, Osi Pharmaceuticals, Inc) followed by the same chemotherapy regimen with or without radiation therapy and capecitabine (Celoda, F. Hoffman-La Roche, Ltd) or fluorouracil (multiple brands).

Dr O'Reilly noted that in that trial, randomization to receive erolotinib was recently discontinued, but the radomization to receive radiotherapy or not to receive radiotherapy continues.

"Results from this study should hopefully settle the debate on the value of ACRT in pancreatic cancer," Dr O’Reilly told Medscape Medical News.

Dr Nipp commented that in designing studies of the impact of any treatment for patients with pancreatic cancer, consideration should be given to incorporating patient-reported outcomes in order to determine how different treatment strategies affect patients' quality of life and symptoms.

The study authors, Dr O'Reilly, and Dr Nipp have disclosed no relevant financial relationships.

J Am Coll Surg. Published online February 13, 2016. Abstract


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