A Daunting Task: How to Treat Gemcitabine-Refractory Pancreatic Cancer?

Gemcitabine (Gemzar)-based regimens have been the mainstay of front-line treatment for patients who present with advanced pancreatic cancer over the past decade, but most medical oncologists throw their hands up in frustration when considering what therapeutic options a patient is left with once he or she has progressed beyond first-line therapy. This is not without reason-as nicely summarized in the review article by Almhanna and Kim, studies in the published medical literature focusing on treatment of pancreatic cancer in the salvage setting have generally been small and have shown very modest clinical efficacy, characterized by low response rates and progression-free survival of a few months at best.

Moreover, it is important to recognize that these studies already incorporate an inherent favorable selection bias-ie, they include only patients who are well enough to even receive second-line treatment. According to one recently reported cooperative group trial in advanced pancreatic cancer (Cancer and Leukemia Group B [CALGB] 80303), less than 45% of patients went on to receive additional therapy following progression on front-line study treatment.[1] Thus, when analyzing survival data associated with any salvage regimen, one must take into account the fact that these patients are (relatively speaking) the fitter of the fit, and more favorable tumor biology may be playing as great a role in clinical outcomes as the antitumor activity of the regimen in question.

These results, therefore, cannot reliably be extrapolated to a broader pancreatic cancer population. A well-designed, randomized phase III trial could partially help overcome this problem, but such a study is difficult to conceive and conduct. Hence, single-arm phase II studies are the norm and provide the majority of the data we have to go by.

Promising Regimens

We do have some recent results from Germany suggesting that a weekly combination known as OFF (oxaliplatin [Eloxatin], fluorouracil [5-FU] given as a 24-hour infusion, and folinic acid) may be a reasonable option for patients whose disease has progressed on gemcitabine. The efficacy of this combination was originally tested in a small single-arm study of gemcitabine-refractory patients, reported in abstract form in 2002.[2]

Subsequently, these investigators developed an ambitious randomized phase III trial to evaluate this regimen compared to best supportive care. Best supportive care is a difficult sell to include as an arm in any study-although in the absence of better therapeutic options in this particular disease context, it is not necessarily inappropriate-and the investigators soon discovered that such a control arm was not an acceptable option for patients.

They therefore modified the trial (Charit Onkologie [CONKO] 003) to compare OFF to 5-FU/folinic acid in one of the largest studies addressing this subject to date. Final results were reported at this year’s annual meeting of the American Society of Clinical Oncology (ASCO),[3] and clearly showed a significant advantage of OFF in terms of both progression-free and overall survival. Thus, for now, the combination of a fluoropyrimidine plus oxaliplatin appears to be a good choice in this setting, with reasonable data to justify this selection.

As Almhanna and Kim describe, other studies have investigated a wide variety of alternative cytotoxic regimens, both as single-agent therapy and as part of two-drug (or more) combinations. These have included not only completely non–cross-resistant regimens, but also strategies that involve adding additional drugs to gemcitabine in the hope of “overcoming” gemcitabine resistance. The considerable toxicity reported in these regimens is an important consideration in such a fragile patient population, in whom the risk-benefit ratio of any treatment must be carefully weighed.

Targeted Therapy

What about an approach to salvage therapy using exclusively targeted agents that might circumvent some of the above issues? Our institution has almost completed accrual to a phase II study looking at the combination of bevacizumab (Avastin) and erlotinib (Tarceva) in patients who had received up to three prior regimens (at least one gemcitabine-based) for metastatic pancreatic cancer. The clinical efficacy of this strategy, reported at this year’s ASCO meeting,[4] could be described as modest at best, with a median time to progression of less than a month and a half, and an overall survival of 3.3 months.

What is particularly striking is how similar these results were to a larger, multicenter trial (cooperative group trial CALGB 80603) in gemcitabine-refractory disease reported at the same meeting, using the oral vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) alone (median progression-free survival: 1.35 months; overall survival: 3.2 months).[5] Clearly, these “targeted therapy–only” strategies offer relatively little for the majority of patients and, at least for now, do not appear to be as efficacious as regimens that include traditional cytotoxic agents as a component.

Conclusions

So where does that leave us? The above-mentioned analysis[1] of postprogression patterns of treatment highlights the sobering fact that only 2% of individuals entered a clinical trial after disease progression on first-line study treatment. One must keep in mind that this was a patient population already inclined to clinical trial participation. More therapeutic studies specific to this disease setting are clearly needed, with Almhanna and Kim correctly pointing out that correlative pharmacoeconomic and quality-of-life analyses would also be useful to incorporate in future study designs.

Furthermore, the same overreaching principles apply in the salvage setting as in first-line treatment-that is, a focus on patient- and tumor-specific characteristics, both clinical and molecular, that might allow for refinement in the selection of patients most likely to derive benefit from a particular novel therapy. This represents a difficult goal to achieve, to be sure, but one that may be necessary if we are to make any significant headway in this disease.

-Andrew H. Ko, MD

The main article can be found here.

Disclosures:

Financial Disclosure: Dr. Ko has received research support from Lilly and Genentech and is a member of the speakers bureau for Roche.

References:

References

1. Schrag D, Archer L, Wang X, et al: A patterns-of-care study of post-progression treatment among patients with advanced pancreas cancer after gemcitabine therapy on Cancer and Leukemia Group B study #80303 (abstract 4524). J Clin Oncol 25(18S):203s, 2007.

2. Pelzer U, Hempel C, Stieler J, et al: Oxaliplatin in combination with high dose 5-FU (24h)/folinic acid as salvage therapy in patients with gemzar-refractory advanced pancreatic cancer (abstract 684). Proc Am Soc Clin Oncol 21:172, 2002.

3. Pelzer U, Kubica K, Stieler J, et al: A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study (abstract 4508). J Clin Oncol 26(15S):215s, 2008.

4. Ko AH, Dito E, Schillinger B, et al: A phase II study of bevacizumab plus erlotinib in patients with gemcitabine-refractory metastatic pancreatic cancer (abstract 4516). J Clin Oncol 26(15S):217s, 2008.

5. O’Reilly EM, Niedzwiecki D, Hollis DR, et al: A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603 (abstract 4515). J Clin Oncol 26(15S)216s, 2008.