Current Perspectives on Locally Advanced Pancreatic Cancer
Current Perspectives on Locally Advanced Pancreatic Cancer
The article by Drs. Czito and Willett provides a succinct and accurate review of the staging and treatment of patients with unresectable pancreatic cancer. Several additional points regarding the evaluation and management of these patients warrant mention, however, particularly as they pertain to advances that may ultimately result in improved outcome for patients with this deadly disease.
The conclusion that high-speed helical computed tomography (CT) has become the gold standard for the evaluation of resectability is certainly supported by studies from M. D. Anderson and has become our practice as well. As a complementary imaging modality when CT fails to detect distant metastases, endoscopic ultrasound has been shown, in our experience, to be more sensitive than CT in determining vascular invasion. Thus, in institutions with an endoscopist experienced in endoscopic ultrasound, its use has become routine.
As the authors point out, this technique should not replace CT, because evaluation of the liver for metastases is limited. Yet it may spare an additional population of patients surgical exploration. Another advantage of endoscopic ultrasound is its ability to delineate a target for directed fine-needle aspiration, which is more likely than endoscopic retrograde cholangiopancreatography (ERCP) to furnish a cytology sample to confirm the clinical suspicion of pancreatic adenocarcinoma.
Management of Obstruction
The roles of the radiologist and endoscopist in the management of these patients deserve additional mention, because the majority of patients with locally advanced pancreatic cancer present with biliary and/or duodenal obstruction. A plastic biliary stent, placed at the time of ERCP, will relieve symptoms of obstruction. In the event a stent cannot be placed, percutaneous stent placement should be considered. However, after a determination of unresectability is made, replacement of either the biliary or percutaneous stent with expandable metal stents should be considered, as these are far less likely to become obstructed and, thus, reduce the risk of stent occlusion and cholangitis. This measure is critically important when the patient is being considered for systemic therapy, which may result in myelosuppression. The endoscopist may also provide symptomatic relief for those with duodenal obstruction by placing recently developed metal wall stents within the duodenum.
Combined Modality Therapy
Data supporting the use of external-beam radiotherapy with concurrent fluorouracil (5-FU) have led to routine use of this approach, yet the data are surprisingly scanty and dated. The authors acknowledge that 5-FU delivered by continuous infusion has become common practice. It is important to note, however, that the impact of this change in 5-FU administration schedules on pancreatic cancer outcomes is entirely unknown, particularly given the differences between the adjuvant therapy of patients with rectal cancer and the palliative therapy of patients with unresectable pancreatic cancer.
Emphasis on measures to improve local control are described, based on unacceptably high rates of local failure. Yet in the Radiation Therapy Oncology Group (RTOG) series that utilized intraoperative radiation therapy (a technique that is the most likely of those mentioned to improve local control), a survival benefit was not demonstrated. Therefore, in our opinion, trials investigating the use of a radiosensitizer with little or no evidence of systemic activity (eg, paclitaxel [Taxol]), or low-dose gemcitabine (Gemzar) in a twice weekly regimen designed to optimize radiosensitization alone may be of limited overall efficacy.
To improve outcome in this disease, systemic disease control must be maximized using agents at doses and schedules of administration that have some evidence of activity in systemic disease. This tenet becomes particularly apparent when one considers the fact that most patients with locally advanced disease harbor, at the very least, micrometastatic disease. Furthermore, few patients die with isolated local disease.
As the authors point out, gemcitabine has been shown to produce a modest improvement in survival in patients with metastatic disease, compared with 5-FU. Thus, while it doesnt represent a home run, the integration of gemcitabine with radiotherapy into regimens that emphasize systemic activity (rather than radiosensitizing potential) warrants further investigation.
University of Michigan Trials
Efforts at the University of Michigan have centered on this concept. In our recently completed phase I trial in patients with unresectable pancreatic cancer, gemcitabine was administered at the currently recommended dose (1,000 mg/m² weekly ´ 3 every 28 days), with a 3-week course of radiation (15 fractions) delivered during this cycle of chemotherapy. The goal was to maximize systemic drug effect while providing local control through sensitization of a modest radiation dose. Indeed, our preclinical data supported this approach as well, as radiosensitization increases with increasing concentrations of gemcitabine.
Radiation dose escalation in this trial was achieved by increasing the fraction size, thereby keeping the duration of radiation at 3 weeks (15 fractions). A reduction in the treatment volume achieved by using three-dimensional planning was critical in attempting to limit the potential for normal tissue radiosensitization. Prophylactic nodal irradiation was eliminated, in light of the potential systemic activity of gemcitabine at this dose. To date, radiation doses in the range of 24 to 42 Gy (1.6 to 2.8 Gy per fraction) have been investigated. Preliminary data reveal a median survival of 12 months in the initial cohort of 21 patients (including 7 with distant metastases). As a result, we are cautiously optimistic about this type of regimen.
Our current trial builds on this approach by incorporating gemcitabine and cisplatin (Platinol) with concurrent radiation therapy (15 fractions). The chemotherapy is based on a phase II experience in which gemcitabine and cisplatin were delivered to 42 patients, 38 of whom had metastatic disease. An objective tumor response was observed in 26% of patients, and the median survival was 7.1 months. The integration of cisplatin may provide additional local control, considering its radiosensitizing potential.
The evaluation of response to combined-modality therapy warrants further investigation as well, particularly as new regimens are studied. Posttreatment changes such as fibrosis and edema make assessment of response based on anatomic imaging difficult. Changes in CA 19-9 and/or functional imaging modalities such as positron-emission tomography (PET) scanning or dynamic-contrast magnetic resonance imaging (MRI) may provide additional information to assess early changes that may correlate with ultimate outcome.
Finally, the therapeutic nihilism that surrounds pancreatic cancer treatment needs to be discussed. There is an admonition to do no harm, considering the advanced age of the patient and the significant morbidity that often exists prior to the initiation of therapy. This attitude has interfered with entry into and completion of clinical trials and contributes to the uncertainty as to what constitutes standard therapy. Advances in the management of symptoms associated with pancreatic cancer suggest this attitude may be inappropriate.
The article concludes with the expressed hope that our increased knowledge of the biology of cancer will translate into logarithmic improvements in the treatment of the disease. While we are hopeful that better days are ahead, we believe that the continued study and application of currently available treatments in combination and sequence can result in progress, and serve as the basis for further improvement with newer therapies.
1. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al: Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 167:104-111, 1994.
2. Tierney WM, Carpenter SL, Bansal R, et al: Accuracy and economic impact of Helical CT and EUS in the local staging of ampullopancreatic tumors. Gastrointest Endosc 45:A183, 1997.
3. Doctor N, Dick R, Rai R, et al: Results of percutaneous plastic stents for malignant distal biliary obstruction following failed endoscopic stent insertion and comparison with current literature on expandable metallic stents. Eur J Gastroenterol Hepatol 11:775-780, 1999.
4. Schmassmann A, von Gunten E, Knuchel J, et al: Wallstents vs plastic stents in malignant biliary obstruction: Effects of stent patency of the first and second stent on patient compliance and survival. Am J Gastroenterol 91:654-659, 1996.
5. Soetikno RM, Lichtenstein DR, Vandervoort J, et al: Palliation of malignant gastric outlet obstruction using an endoscopically placed Wallstent. Gastrointest Endosc 47:267-270, 1998.
6. Lawrence TS, Chang EY, Hahn TM, et al: Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine. Int J Radiat Oncol Biol Phys 34:867-872, 1996.
7. McGinn CJ, Shureiqi I, Robertson JM, et al: Encouraging survival data from a phase I trial of radiation dose escalation with full-dose gemcitabine in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 8(suppl 1):223, 2000.
8. Philip P, Zalupski M, Vaitkevicius VK, et al: Phase II study of gemcitabine and cisplatin in advanced or metastatic pancreatic cancer (abstract). Proc Am Soc Clin Oncol 18:1053, 1999.