Commentaries on Articles

Artinyan A, Hellan M, Mojica-Manosa P. Improved Survival with Adjuvant External-Beam Radiation Therapy in Lymph Node-negative Pancreatic Cancer- A United States Population-Based Assessment. Cancer 2008; 112: 34-42.

A study carried out with the aim of determining the effect of adjuvant radiotherapy in patients with locally confined, lymph node-negative (N0) pancreatic cancer was published in Cancer 2008(112: 34-42).The study method utilised the Surveillance, Epidemiology, and End Results registry to identify patients who had undergone cancer-directed surgery for N0 pancreatic adenocarcinoma between 1988 and 2003 and a cohort of 1930 surgical patients with N0 disease was identified. The results showed that patients who received radiotherapy had a better survival as compared to patients who did not receive radiotherapy (20 months vs 15 months, respectively; P <.001). EBRT emerged as an independent predictor of improved survival in the multivariate analysis. The study results support the much debated use of radiation therapy for pancreatic cancer especially in patients who have early-stage N0 disease.

Commentary by:

Dr. Umesh Mahantshetty
MBBS, MD, DNB, DMRT
Associate Professor and Consultant Radiation Oncologist
Department of Radiation Oncology
Tata Memorial Hospital
Dr. Ernest Borges Marg, Parel
Mumbai- 400 012
India.

Despite a multimodal approach, the prognosis of pancreatic cancers is found to be dismal. The 5- year survival rates for resectable pancreatic cancer are in the range of 14% to27% after curative resection. Adjuvant treatment regimens and systemic therapy are equally important due to high rates of loco-regional as well as distant failures. The landmark studies evaluating the role of adjuvant therapy are shown in the table below. The results were conflicting and criticised by inclusion of tumors other than pancreatic head and use of split course RT which is suboptimal radiobiologically by today's standards.

To resolve the issue, Pancreatic Cancer Meta-analysis (BJC 2005, 92, 1372-1381) studied the individual patient data from the above three trials and also previously unpublished data from ESPAC-1 on 261 patients. Results of this were substantially biased towards ESPAC-1 results due to disproportionately large number of patients in this trial. This meta- analysis demonstrated significant benefit for CT without any discernible advantages for CTRT and a trend was noted towards improved survival with concomitant chemoradiation in margin positive and poorly differentiated tumors. However, this probably was underpowered to establish the benefits of adjuvant RT.

Recent Evidence:

The SEER Registry data published by Kim et. al. in Cancer January 1, 2008 / Volume 112 / Page 34-42' reporting more than 650 patients receiving adjuvant RT(largest cohort of patients reported so far) suggests improved survival with adjuvant external radiation therapy in lymph node-negative pancreatic cancers. This SEER data and use of adjuvant RT for T1-T3 N0 patients in 40% of pancreatic adenocarcinoma patients during 1988-2003 is proof in itself that there is definitely some role of adjuvant RT in patients undergoing radical surgery for pancreatic cancers.

The authors report a small but significant benefit of 28% reduction in death (13% reduction after excluding early deaths) exists with the use of adjuvant EBRT in N0 pancreatic cancer patients (MS 20 months Versus 15 months, HR 0.72). This improvement in survival on the largest cohort so far is comparable to that achieved in EORTC and ESPAC-1 trials (both underpowered). Moreover, SEER data reported survival advantage is independent of several established prognostic factors for outcome.

There are few limitations of this SEER data study:

• Data on use of chemotherapy, chemotherapeutic agents etc. is lacking.
• The meta- analysis showed a trend towards improved survival in patients with positive cut margins. However, this data lacks information on it.
• In all the previous mentioned trials, external beam with split course fractionation was used and encountered major criticism in negating the role of adjuvant RT. The external beam details on total dose, fractionation, treated volumes and use of concomitant chemotherapy schedules is lacking in this SEER data.

Radiation therapy as a potential component of adjuvant treatment for future trial setting makes me ponder: How can one identify this select group of patients with pancreatic cancers, who would benefit from adjuvant radiation? Also with ongoing basic and translational research and better understanding of tumor biology the use of targeted therapies like cetuximab, avastin etc. to improve the outcome is evolving. Hence, a thorough evaluation of adjuvant RT in phase III randomised trial may not be possible today. Further, data on the use of adjuvant chemo-radiation in pancreatic cancers might emerge from the institutions treating large number of pancreatic cancers, depending on their policies and practice.