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Today's Forecast for the Adjuvant Treatment of Pancreatic Cancer: Clear or Cloudy?: Page 2 of 2

Today's Forecast for the Adjuvant Treatment of Pancreatic Cancer: Clear or Cloudy?: Page 2 of 2

In light of the high risk of distant recurrence following surgery for localized pancreatic cancer, it is clear that this is a systemic disease from the outset, irrespective of whether complete surgical resection is achieved. It is not a question of whether systemic therapy should be given, but how best to do it. All of the major randomized trials cited in this review showed a survival advantage for the use of chemotherapy alone (either fluorouracil [5-FU]-based treatment or single-agent gemcitabine [Gemzar]) vs observation as adjuvant treatment for pancreatic cancer (remembering that the EORTC trial did not employ chemotherapy postchemoradiation and is considered by some to be statistically underpowered to show a survival advantage for treatment). The Radiation Therapy Oncology Group (RTOG) 9704 trial suggests an advantage for gemcitabine over infusional 5-FU as adjuvant therapy. The ESPAC-3 trial, which directly compares gemcitabine with bolus 5-FU/leucovorin, will provide a more definitive answer to this question.

Therapeutic advance in pancreatic cancer depends upon improved systemic therapy. Although chemotherapy combinations have produced only marginal incremental success in advanced pancreatic cancer, they appear to work best for good-performance patients with minimum disease volume—exactly the situation postresection.[5] To date, epidermal growth factor inhibitors (bevacizumab [Avastin], cetuximab [Erbitux], erlotinib [Tarceva]) have also produced only marginal gain in pancreatic cancer, but over 20 new drugs employing a variety of molecular strategies are currently in clinical trials for pancreatic cancer. The potential for prediction of drug response exists via techniques such as molecular profiling, tumor xenografts, and genetically manipulated animal models. Also, the recent report of the use of antitumor vaccination as part of adjuvant therapy for pancreatic cancer postchemoradiation by Laheru and colleagues[6] heralds the potential addition of immunotherapy to our systemic approach to pancreatic cancer.

Radiation Therapy

Unlike systemic therapy, the ultimate role of radiation therapy as part of adjuvant treatment for pancreatic cancer is uncertain. The goal of radiation therapy as adjuvant treatment is to reduce the rate of local recurrence. The logic behind its use is straightforward. Patients have a high incidence of local recurrence even with chemotherapy in resected pancreatic cancer (in the CONKO-001 trial, 34% in gemcitabine-treated patients vs 41% in the observation arm). Recurrence rates in patients with R1 resections are typically even higher, in excess of 60%. Improved local control could improve cure rates in the case of isolated local recurrence; even if systemic recurrence takes place, it could reduce significant morbidity from local complications (eg, pain, biliary/gastric outlet obstruction, vascular occlusion/thrombosis).

5-FU-based chemoradiation after curative surgery for resected pancreatic cancer has significant toxicity. In the RTOG 9704 trial, the incidence of grade 3/4 toxicity was over 60% in the 5-FU arm, and almost 80% in the gemcitabine arm, including a 14% rate of grade 4 hematologic toxicity. Gastrointestinal toxicity (anorexia, nausea/vomiting, diarrhea, mucositis) can be both severe and difficult to control, even in experienced centers. A dedicated staff and supportive care strategy are essential to successful adjuvant chemoradiation for pancreatic cancer.

The role of radiation therapy in the adjuvant treatment of pancreatic cancer invariably sparks passionate debate. Proponents cite the aforementioned logic behind radiation therapy, its utility in other gastrointestinal malignancies (eg, rectal cancer), and technical issues (dose, schedule, quality control) associated with therapy delivery in the major European (EORTC and ESPAC-1) trials. The ESPAC-1 had an astonishing 62% local failure rate; Abrams and colleagues showed in the RTOG 9704 experience that suboptimal delivery of radiation therapy can be a more significant prognostic factor than the identity of the adjuvant chemotherapeutic agent.[7] Detractors cite the formidable toxicity associated with chemoradiation (eg, in RTOG 9704) and the inability of standard chemoradiation, compared with chemotherapy only, to improve disease-free or overall survival in resected pancreatic cancer.

The beauty of radiation therapy is very much "in the eye of the beholder." It may be that sophisticated chemoradiation, given with skillful supportive care, is an asset in the adjuvant treatment of pancreatic cancer; ineffective or toxic chemoradiation that compromises systemic treatment is likely a liability to a successful outcome.

The Future

The future of adjuvant therapy for pancreatic cancer will be characterized by more optimism, more standardized patient selection, and better supportive care. Future options for the adjuvant treatment of pancreatic cancer include resequencing therapeutic modalities (eg, Moutardier et al),[8] novel approaches to local control (eg, the Virginia Mason chemoradiation protocol),[9] and improved systemic agents. The future forecast for the adjuvant treatment of pancreatic cancer calls for "increasing sunshine."

—Vincent J. Picozzi, MD, MMM

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References

1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56:106-130, 2006.

2. Sener S, Fremgen A, Menck H, et al: Pancreatic cancer: A report of treatment and survival trends for 100,313 patients using the National Cancer Database. J Am Coll Surg 189:1-7, 1999.

3. Pisters P, Picozzi V, Abrams R: Therapy for localized pancreatic adenocarcinoma: One, Two or Three Modalities? ASCO Educational Book, pp 397-418. Alexandria, Va; American Society of Clinical Oncology, 2003.

4. Birkmeyer J, Siewers A, Findlayson E, et al: Hospital volume and surgical mortality in the United States. N Engl J Med 346:1128-1137, 2002.

5. Heinemann V, Hinke A, Boeck S, et al: Benefit from gemcitabine-based combination treatment in advanced pancreatic cancer: A meta-analysis of randomized trials (abstract 129). Proceedings of the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; January 19-21, 2007.

6. Laheru D, Yeo C, Bierdrzycki B, et al: A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas (abstract 106). Proceedings of the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; January 19-21, 2007.

7. Abrams R, Winter K, Regine W, et al: RTOG 9704-radiotherapy quality assurance and review (abstract 39). Int J Radiat Oncol Biol Phys 66(3 suppl):S22, 2006.

8. Moutardier V, Turini O, Huiart L, et al: A reappraisal of postoperative chemoradiation for localized pancreatic head ductal adenocarcinoma in a 5-year single institution experience. J Gastrointest Surg 8:502-510, 2004.

9. Picozzi V, Kozarek R, Traverso L: Interferon-based adjuvant chemoradiation after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 285:476-480, 2003.

 
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