Adjuvant and Neoadjuvant Therapy for Pancreatic Cancer

There are a number of important issues regarding neoadjuvant and adjuvant therapy for pancreatic cancer that must be considered as we design clinical trials in an effort to improve survival for this disease. Cancer of the pancreas most often occurs in older age groups, which may exhibit significant comorbidities that impact the patients’ ability to tolerate therapy. The location of these tumors-for example the head of the pancreas-may have an impact on therapy, and there can also be important complications associated with these tumors, including biliary duct issues, which can result in infections and delay the onset of therapy. This is particularly critical in the neoadjuvant setting. Also, the delivery of chemotherapy in the neoadjuvant and possibly postoperative setting may be compromised due to a lack of vascular supply to these tumors as a result of fibrosis, a characteristic of this type of malignancy.[1,2] Finally, there is cause for concern surrounding the use of combined radiation therapy and gemcitabine (Gemzar): there are reports that indicate an increased toxicity (including life-threatening side effects) associated with combining these modalities. As a result, many clinical trials have recommended lower doses of gemcitabine, which may doom the treatment to failure.

In general there is a high level of awareness about the poor prognosis of pancreatic cancer, and this has created a great deal of national support and a number of advocate groups. To some extent, this motivates patients to consider receiving treatment either on- or off-protocol in the adjuvant or neoadjuvant setting. Also, because of this poor prognosis, physicians are more likely to consider adjuvant clinical trials in order to impact the natural course of the disease. Because of physician and patient motivation, there is potential for rapid accrual to adjuvant studies for pancreatic cancer.

The role of radiation therapy remains controversial, as is discussed in the article by Castellanos et al. Practically speaking, radiation therapists are more likely to recommend this modality if the surgical margins are positive or if there is lymph node involvement in the postoperative setting. Preoperative radiation therapy is commonly used in borderline resectable patients.

There is also concern that single-agent adjuvant or neoadjuvant therapy results in only a small clinical benefit. There has been a major focus on gemcitabine as the basis of treatment for pancreatic cancer. However, the widespread idea that since we can’t cure this disease, we should not make patients sick from toxicity should be changed, and many clinicians feel that it is time to abandon the use of single, kinder, gentler agents because of their limited success. Frustration also arises from the fact that combination chemotherapy results in increased response rates (especially in patients with good performance status) but not in improved overall survival. Multiagent chemotherapy courses, including gemcitabine, docetaxel (Taxotere), and capecitabine (Xeloda) (GTX), and most recently combination oxaliplatin, 5-FU, leucovorin, and irinotecan (FOLFIRINOX), are active combinations that are begging for clinical trials in the adjuvant and neoadjuvant setting.[3] Pilot studies of these regimens in the pre- and postoperative setting will be necessary to evaluate their tolerance either at full or modified doses. There has also been interest in NAB paclitaxel because of its association with the SPARC protein and the preferential uptake of this agent in pancreatic cancer cells.[4,5] Ideally, in the borderline resectable patient with pancreatic cancer, combination chemotherapy with active agents will have a significantly beneficial effect in cytoreducing the tumors and correcting them to resectability.

Clearly the future for pancreatic cancer lies in the development of new targeted therapies, and their development must be based on the biology of these specific cancer cells. New biologic agents are also needed since our experience with the established agents (bevacizumab [Avastin], erlotinib [Tarceva], and cetuximab [Erbitux]) have shown limited benefit in clinical trials.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Pandol S, Edderkaoui M, Gukovsky I, et al. Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroent Hep. 2009;7(11 Suppl):44-47.

2. Garber, K. Stromal depletion goes on trial in pancreatic cancer. JNCI. 2010;102:448-450.

3. Conroy, T, Desseigne, M. Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. J Clin Oncol. 2010;28:15s.

4. Von Hoff DD, Ramanathan R, Borad M, et al. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: A phase I/II study. J Clin Oncol. 2009;27:15s.

5. Hosein PJ, Lopes GD Jr., Gomez CM, et al. ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol. 2010;28(15 Suppl):4120.