The article by Drs. Czito and Willett provides an excellent overview of our current knowledge of locally advanced pancreatic cancer. In short, patients with locally advanced, unresectable disease have been shown to benefit from combination chemoradiation using fluorouracil(Drug information on fluorouracil) (5-FU)-based therapy. This benefit comes in the form of palliation, whereby 50% to 80% of patients have improved pain control. Moreover, coadministration of 5-FU and radiation prolonged survival, compared to chemotherapy alone or radiation alone.
Importantly, the authors articulate a general approach to management: Patients with adequate performance status to undergo a course of radiation should be considered for combined-modality therapy. For patients with comorbid conditions precluding chemoradiation, or inadequate performance status, treatment with gemcitabine(Drug information on gemcitabine) (Gemzar) or supportive measures represent a realistic alternative.
In addition to the review of the readily available literature, the authors discuss evolving strategies for the future management of locally advanced pancreatic cancer. These include improved staging strategies, newer radiosensitizers, and a vision for exploiting recently defined molecular targets. These newer approaches raise issues that require further discussion, particularly in the context of future clinical trial design.
Clinical Course of Locally Advanced Disease
That said, I do not think the reader is given an adequate sense of the clinical course of patients with locally advanced disease. Generally, these patients present with pain that requires moderate doses of narcotics for control. After completing chemoradiation, the majority of patients will have a reduction in their pain and, typically, a transient period of improved well-being. This is short lived, and followed by either local tumor progression (which is manifested by worsening pain or gastric outlet obstruction) or the onset of metastatic disease.
Thereafter, the disease course is punctuated by pain, obstruction, peritoneal carcinomatosis, wasting, and finally death. Thus, while better radiation techniques and radiosensitizers are needed to improve local control, prolonging the clinically quiescent period after chemoradiation should be a high priority.
Role of Laparoscopy in Staging
The early randomized trials of chemoradiation for locally advanced pancreatic cancer were undertaken at a time when computed tomography (CT) was relatively new. Virtually all enrolled patients were surgically staged and found to be unresectable at the time of laparotomy, with no visible evidence of peritoneal or liver metastases.[1,2]
With the advent of thin-cut contrast-enhanced helical CT, surgical resectability can now be defined nonoperatively. If this technology is routinely applied, should patients who are radiographically determined to have locally advanced disease be subjected to a laparoscopy? Such an intervention will upstage a subset of patients by visualizing small hepatic metastases or peritoneal implants that are not appreciated on CT scan or through cytologic examination of peritoneal lavage fluid.
If these patients are excluded from treatment with definitive radiation, how would they be better managed? They share similar problems of pain control, and based on the estimate of clinical benefit with gemcitabine (24%), systemic therapy alone is less likely to offer palliative benefit compared to chemoradiation.[3,4] For practical purposes, patients with locally advanced tumors have subclinical metastatic disease and, whereas more vigorous staging may allow identification of a subgroup of patients with slightly better survival, laparoscopy may in some sense be deleterious.
Radiosensitization for Pancreatic Cancer
When chemotherapy and radiation are combined, radiotherapy has a singular goalto achieve local control. Chemotherapy has a dual roleradiosensitization and a potential impact on metastatic disease. Gemcitabine, the standard agent for metastatic disease, leads to response rates ranging between 4% and 11%.[3,5] Thus, given the lack of potent systemic agents for pancreatic cancer, it is presumed that most of the benefit from chemotherapy in combined-modality regimens is derived from radiosensitization.
Although often used in a clinical context, radiosensitization is difficult to demonstrate in clinical practice. Radiosensitization with 5-FU, paclitaxel(Drug information on paclitaxel) (Taxol), or gemcitabine can be quantitated in vitro, but determining a measurable effect in the setting of a locally advanced pancreatic cancer is challenging. These tumors are often desmoplastic, with small nests of malignant ductal epithelium existing in large areas of fibrotic tissue. Even with significant cytotoxic activity, radiographic evidence of tumor reduction is often lacking.
Data regarding objective responses to chemoradiation are limited. In the Eastern Cooperative Oncology Group (ECOG) phase I trial of infusional 5-FU combined with radiation, no objective responses were observed. In a phase II trial of infusional 5-FU with radiation, the response rate was 10%.[6,7]
As noted in the article, radiosensitization with paclitaxel has led to an objective response rate of about 20%. Using gemcitabine as a radiosensitizer has proven to be more problematic, based primarily on toxicity. Early trials of gemcitabine and radiation have been quite informative, but inconclusive regarding the optimal doses and schedule of this drug when combined with radiation. When administered with standard fractions of radiation (180 cGy), the maximum tolerated dose of gemcitabine ranges from 40 mg/m² twice a week to more than 500 mg/m² weekly.[8,9] In our trial, when gemcitabine was delivered with a higher dose of radiation per fraction (300 cGy) to a total of 30 Gy, the maximum tolerated dose was 350 mg/m².
The objective response rate with gemcitabine is about 20%, whether using a low-dose, twice weekly regimen or higher weekly doses delivered with a shortened course of radiation.[8,10] Once the optimal dose and schedule of gemcitabine and radiation has been established, it can be anticipated that a randomized trial comparing 5-FUbased chemoradiation to gemcitabine-based and/or paclitaxel-based chemoradiation will be performed. Notably, measures of quality of life pertaining to toxicity, symptom control, and duration of palliation will be important end points, because significant differences in survival are unlikely to be evident.
Future Clinical Trial Design-Exploiting Molecular Targets
As mentioned, locally advanced pancreatic cancer harbors low-volume metastatic disease. While local control remains a high priority, most patients will ultimately succumb with overt evidence of disseminated disease. Unfortunately, experience suggests that the delivery of conventional cytotoxic therapy after chemoradiation is difficult on the patient and not particularly gratifying. Therefore, the interval after completion of chemoradiation is an ideal time to consider novel therapeutic interventions, particularly with agents that are not associated with significant toxicity.
The new agents discussed in the article, which target defined molecular defects, are more apt to have an impact in the setting of low tumor burden. Thus, clinical investigators should consider locally advanced disease a unique entity in which to test these compounds. In my view, such trials should utilize chemoradiation as the foundation, with concurrent or subsequent targeted therapy delivered in an attempt to prolong the time to disease progression.
If a novel agent appears to prolong this interval in phase II studies, placebo-controlled randomized trials would be warranted. In addition, since the majority of patients with resectable pancreatic cancer will relapse, novel biological agents may be applicable to this group of patients as well. However, these compounds are better tested in the larger population of patients with locally advanced disease, in whom the median time to disease progression is short.
In summary, chemoradiation remains the cornerstone of therapy for the management of locally advanced disease. Clinical trials should focus on improving local control using newer radiosensitizers, and prolonging the time to disease progression by exploring novel therapies.