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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 162-164 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.0227
In Reply:David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
Karmanos Cancer Institute, Wayne State University, Detroit, MI Ben-Josef and colleagues make the case for the delivery of full dose chemotherapy and modern radiation therapy in treating patients with newly diagnosed locally advanced unresectable pancreas cancer (LAPC).1 We believe that significant increases in the survival of patients with pancreas cancer are primarily dependent on more effective systemic therapies. Improvements in therapies in LAPC should include better drug combinations based on additive or synergistic components and use of existing drugs in a more effective manner with lesser toxicity. However, systemic therapy should be administered to patients with LAPC regardless of the ability to combine it with radiation therapy or not. Our comments were fully made in that context because we are encouraged by the outcome of our study that demonstrated a median survival of 13.8 months with a systemic therapy regimen that did not include radiation.2 If more than 75% of patients who undergo curative pancreatoduodenectomies have multiple nodal metastases, certainly a greater percentage of patients with locally advanced disease have significant nodal spread. The latter also parallels the presence of occult peritoneal and visceral micrometastases at the time of initial diagnosis in high proportion of patients with LAPC. Nevertheless, we feel that local disease control will remain an important goal for patients with LAPC only in the context of effective treatment of the systemic micrometastatic disease. More novel delivery of radiation to improve its therapeutic index is well noted. However, none of the cooperative group trials reported to date have embraced 3D radiotherapy. Our study was undertaken in a multi-institutional cooperative group setting, and chemotherapy alone appeared to achieve results not observed with combined modality treatment in similar experimental settings.2 A better locoregional control with radiation-based therapy, though expected, may not impact the natural history of the disease or even be a requirement for desired palliation in every patient with LAPC. As Ben-Josef et al appropriately stated in their final sentence, the contribution of local control to survival would become increasingly more evident with improvements in systemic therapies for this disease. Unfortunately, we are not there yet. With this in mind, our intention was not to pit one treatment modality against the other, but instead to highlight the potential benefit of systemic therapy in this disease and its impact on survival. The longer-term benefits of radiation therapy in LAPC are expected to increase, but only when decreasing the systemic burden of disease. Here, we feel that radiation will produce a clinically meaningful impact on the course of the disease in patients selected on the basis of behavior of their systemic disease rather than if applied indiscriminately to each patient with newly diagnosed LAPC. We feel that the literature demonstrates the marked limitations of current approaches utilizing fluoropyrimidines combined with radiation to control micrometastatic disease while only having a modest benefit on local disease. An improvement in survival as a result of concurrent chemoradiation throughout the last three decades has not occurred, to our knowledge, even with the introduction of newer radiosensitizers that have been tested at full therapeutic doses. The innovative work by the University of Michigan on the feasibility of delivering full diseases of conventional cytotoxic therapies concurrent with limited field radiation is an important finding coming from a single institution with well-selected patients.3,4 Unfortunately, none of the currently available systemic therapies has major impact on the natural history of this disease when tested in phase III trials. The more favorable outcomes of concurrent chemotherapy and radiation in other tumor types, such as head and neck and upper aerodigestive tract cancers, were dependent on the noticeably higher sensitivity of such tumors to both treatment modalities. The paucity of complete responses and tumor downstaging in LAPC supports this differentiation. The limited activity of either chemotherapy or radiation therapy in LAPC highlights the concern about the toxicity associated with full doses of chemotherapy combined with radiation and hence the worth of applying such therapy at the present time. Radiation does impact the delivery of effective doses of combination therapy during, and/or after its completion may therefore limit the ability to develop effective systemic treatments for this disease. Interactions may include more enhanced myelosuppression, but also other nonhematological toxicities related to infield normal tissues. The most commonly prescribed dose of radiation therapy is 50.4 Gy given in 28 fractions throughout 5 weeks, using a field size that includes regional lymph nodes. Employing such doses and field sizes that do not improve survival may expose patients to unjustified toxicity. In the cancer and leukemia group B trial, where gemcitabine 40 mg/m2 was given twice weekly with radiation therapy, grade 3 and 4 toxicities were 35% and 50%, respectively. The median survival was 8.5 months with no apparent benefit over fluorouracil (FU) and radiation.5 Crane et al compared the efficacy and toxicity of current gemcitabine-based chemoradiation with that of FU and identical radiotherapy. Of the patients who received gemcitabine, 32% were hospitalized for supportive care resulting from treatment related toxicity. Fifty-five percent of patients receiving gemcitabine, and 54% of patients who received FU had objective evidence of local disease progression. Toxicity was significantly higher in patients treated with gemcitabine compared with FU with no benefit in local disease control or survival.6 Misha et al,7 as part of a multi-institutional trial, evaluated the use of induction chemotherapy with gemcitabine and irenotecan followed by twice-weekly gemcitabine and concurrent radiation. Because 35% of patients experienced disease progression after a count of the first 20 patients, the study was stopped. The median survival time for all patients was 8.8 months. The outcome was felt to be comparable with those observed with FU-based chemoradiation. Krishnan et al8 compared induction chemotherapy followed by chemoradiation alone. Rates of locally progressive disease were 41% and 47%, respectively. In the group that was treated without induction chemotherapy, but received gemcitabine and radiation, 27% of patients required hospitalization because of severe acute toxicity. Haddock et al9 as part of a North Central Cancer Treatment Group study treated 48 patients with gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. Following radiotherapy, the patients received maintenance gemcitabine. The median survival time was 10.2 months. Nearly half of the patients (51%) initially had locoregional progression. Collectively, these studies highlight the potential toxicity of combined approach of chemotherapy and radiation and question the gain in better local control. We have yet to test the hypothesis that full dose systemic therapy given without interruption (ie, without radiation) will provide a greater degree of palliation and overall outcome and be associated with fewer toxic adverse reactions. A recent prospective phase III trial comparing initial chemoradiotherapy followed by gemcitabine to gemcitabine alone supports our opinion on the relative roles of chemotherapy and radiation, recognizing some of the limitations of that study.10 Furthermore, a retrospective analysis of data from randomized trials in LAPC led the authors to conclude that after control of disease by initial chemotherapy, chemoradiation could significantly improve survival in patients with LAPC compared with chemotherapy alone.11 Therefore, the way forward for treating LAPC is the development of systemic therapies that are tested in study designs that reliably evaluate their benefit when delivered in doses and schedules that are well tolerated. Radiation therapy can complement systemic therapy in the patients whose tumors’ clinical and biologic behaviors demonstrate that disease is truly localized. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Ben-Josef E, Lawrence TS, Zalupski MM: Radiotherapy for locally advanced pancreatic cancer. J Clin Oncol 25:4861, 2007 2. Isacoff WH, Benedetti JK, Philip PA, et al: Phase II Trial of Infusional Fluorouracil, Leucovorin, Mitomycin-C and Dipyridamole in Locally Advanced Unresectable Pancreatic Adenocarcinoma: SWOG 9700. J Clin Oncol 25:1665-1669, 2007 3. Desai SP, Ben-Josef E, Normolle DP, et al: Phase I: Study of oxaliplatin, full-dose gemcitabine, and concurrent radiation therapy in pancreatic cancer. J Clin Oncol 25:4587-4592 2007 4. McGinn CJ, Zalupski MM, Shureiqi I, et al: Phase I: Trial of Radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19:4202-4208, 2001 5. Blackstock AW, Tepper JE, Niedwiecki D, et al: Cancer and Leukemia Group B (CALGB) 89805: Phase II chemoradiation trial using gemcitabine on patients with locoregional adenocarcinoma of the pancreas. Int J Gastrointestin Cancer 34:107-116, 2003[CrossRef] 6. Crane CH, Abbruzzese JL, Evans DB, et al: Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiology Oncology Biol Phys 52:1293-1302, 2002[CrossRef] 7. Mishra G, Butler J, Ho C, et al: Phase II trial of induction gemcitabine/cpt-11 followed by twice-weekly infusion of gemcitabine and concurrent external beam radiation for the treatment of locally advanced pancreatic cancer. Am J Clin Oncol 28:345-350, 2005[CrossRef][Medline] 8. Krishnan S, Rana V, Janjan MA, et al: Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer 110:47-55, 2007[CrossRef][Medline] 9. Haddock MG, Swaminathan R, Foster NR, et al: Gemcitabine, cisplatin and radiotherapy for patients with locally advanced pancreatic carcinoma: Results of a North Central Cancer Treatment Group Phase II study N9942. J Clin Oncol 25:2567-2572, 2007 10. Chauffert B, Mornex F, Bonnetain F, et al: Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs gemcitabine alone in patients with locally advanced non–metastatic pancreatic cancer: A FFCD-SFRO study. J Clin Oncol 24:180, 2006 11. Huquet F, André T, Hammel P, et al: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25:326-331, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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