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© 2000 American Society for Clinical Oncology
Docetaxel Chemotherapy for Pancreatic Cancer: Do Results Support Certainty?
Hospital of Urbino, Urbino To the Editor:In the June 1999 issue of the Journal of Clinical Oncology, Androulakis et al1 reported the results of a phase II study on the treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor. The authors found a 6% response rate, an impressive median survival of 36 weeks (8.4 months), and an interesting clinical benefit. The median survival time of patients with stable disease (SD) and progressive disease (PD) was 48 and 24 weeks, respectively (P = .0043). In our opinion, the data reported in this trial are debatable, and discrepancies between patients characteristics and results may limit the reliability of conclusions. The number of patients enrolled is limited, and if we exclude four patients with stage II disease, only 29 patients with unresectable locally advanced or metastatic pancreatic cancer were evaluated. The authors stated that at the time of analysis (they do not define when), 15 patients showed PD, five deterioration of performance status, and one early death. On the whole, 21 (63.6%) of 33 patients did not benefit from chemotherapy and worsened, but 18 (54.5%) of 33 patients improved or maintained their baseline performance status. The authors reported the use of analgesics in 27 patients (81.8%), whereas 21 (36.6%) of them were experiencing pain (Table 2). Also, 21 patients (63.6%) had asthenia and 26 patients (78.7%) had anorexia. In our opinion, it is difficult to realize how these data suit the excellent performance status of the majority of patients enrolled (World Health Organization performance status of 0 and 1 in 12 patients (36%) and 16 (49%) patients, respectively). Moreover, it seems quite difficult to imagine such a performance status in a group of 33 patients with pancreatic cancer, 19 (58%) of whom had stage IV disease. It is common knowledge that the clinical presentation of pancreatic cancer is characterized in more than 80% of cases by disease-related symptoms, namely, pain, asthenia, weight loss, anorexia, and impairment of life functions.2 Recently, Burris et al3 reported the results of a randomized trial of gemcitabine versus fluorouracil in pancreatic cancer. In this study, 70% of 63 patients enrolled onto the gemcitabine arm had stage IV disease. Accordingly, most of the patients (70%) showed a Karnofsky performance status of from 50 to 70. Androulakis et al1 reported an overall median survival of 36 weeks in 33 patients, but 21 of them worsened during treatment. Among the 15 patients with PD, the median survival was 24 weeks (5.6 months), which is comparable to the overall median survival of the patients treated with gemcitabine.3 Patients with SD had a 48-week (11.2-month) median survival, and this very long time is double that observed with gemcitabine.3 Curiously, the authors found a median duration of SD of only 14 weeks. In our opinion, these results on the role of docetaxel in pancreatic cancer raise more questions than the trial was prepared to answer. As discussed by Androulakis et al,1 the prolonged survival time was not due to the inclusion in the trial of stage II patients. In our opinion, it is likely related to the astonishing median survival of both SD and PD patients, and the authors should have addressed their discussion to these data. Literature supporting the role of docetaxel in pancreatic cancer is still limited. At least three phase II trials are ongoing4-6; in these experiences, partial responses are in the range of 6% to 22%. So far, the results of these studies have been reported in abstract form and complete data on clinical benefit and survival are not available yet. In a recently published trial,7 docetaxel at 60 mg/m2 every 3 weeks did not produce any objective response, less than half of the patients achieved SD, and the median survival was only 4 months. It may be supposed that the lower dose of docetaxel used in this study could explain these unsatisfactory results. Finally, we do not agree with Androulakis et al,1 who reported a 6-month median survival of untreated pancreatic cancer patients; in control arms of major randomized trials of chemotherapy versus best supportive care, it did not exceed 3.5 months.2 In conclusion, in our opinion, the results reported by Androulakis et al should be interpreted with caution, and docetaxel chemotherapy for pancreatic cancer deserves more careful investigations before it is used in randomized studies. REFERENCES
1.
Androulakis N, Kourosis C, Dimopoulos MA, et al: Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: A multicenter phase II study. J Clin Oncol 17:1779-1785, 1999
2.
Cascinu S, Graziano F, Catalano G: Chemotherapy for pancreatic cancer: It may no longer be ignored. Ann Oncol 10:105-109, 1999
3.
Burris HA III, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997 4. Abbruzzese JL, Evans D, Gravel D, et al: Docetaxel, a potentially active agent for patients with pancreatic adenocarcinoma. Am Soc Clin Oncol 15:107, 1994 (abstr) 5. Ducreux M, Adenis A, Blanc C, et al: Phase II study of docetaxel in pancreatic adenocarcinoma. Proc Eur Soc Med Oncol 5:82, 1994 (abstr) 6. Preusser P, Niederle N, Harstrick C, et al: Phase II study of docetaxel as first line chemotherapy in metastatic adenocarcinoma of the pancreas. Proc Am Soc Clin Oncol 18:297a, 1999 (abstr 1142) 7. Okada S, Sakata Y, Matsuno S, et al: Phase II study of docetaxel in patients with metastatic pancreatic cancer: A Japanese cooperative study—Cooperative Group of Docetaxel for Pancreatic Cancer in Japan. Br J Cancer 80:438-443, 1999[Medline]
ResponseUniversity General Hospital of Iraklion Iraklion, Crete, Greece In Reply:We read with great attention Dr Graziano’s and Dr Cascinu’s letter concerning our article, "Treatment of Pancreatic Cancer with Docetaxel and Granulocyte Colony-Stimulating Factor: A Multicenter Phase II Study," published in the June 1999 issue of the Journal of Clinical Oncology.1 We believe several of their remarks are due to a misinterpretation or misunderstanding of the results presented in our article. Indeed, based on the reported data on treatment discontinuation, the authors conclude that no benefit was derived from the treatment for 21 patients. However, this conclusion is arbitrary, because based on standard response evaluation criteria among the 15 patients who stopped treatment, one patient experienced a partial response while two others had stable disease lasting for more than 4 weeks (range, 4 to 23 weeks) after the initial three or six cycles of chemotherapy. Therefore, these three patients cannot be considered as having progressive disease. In addition, their comments on the effect of asthenia and anorexia on patients’ performance status (PS) are confusing because anorexia, which was present in 26 patients (78.7%), is not included in the World Health Organization criteria for PS. Conversely, among the 21 patients with a PS of 1 or 2, 16 patients had a PS of 1 and five patients had a PS of 2, as shown in Table 1. Nowhere in the article was our patient population characterized as having "an excellent performance status." At the same time, Graziano and Cascinu are surprised because most patients in our study had a good PS. On the basis of the inclusion criteria of the trial, patients with severe organ dysfunction were excluded, which thus allowed patient selection. Indeed, in several phase II trials of pancreatic cancer, the enrolled patients had a good PS (World Health Organization PS of 0 or 1).1,2 Graziano and Cascinu considered that there was a discrepancy between the number of patients suffering from pain (n = 21; Table 2) and the number of patients receiving analgesics; 10 patients were receiving narcotics and 17 noncorticosteroidal analgesics; thus, they calculated a total of 27 patients were suffering from pain. However, four patients were receiving only opioids, six patients were receiving a combination of narcotics and nonsteroidal anti-inflammatory drugs, and 11 patients were receiving only nonsteroidal anti-inflammatory drugs (a total of 21 patients). The details on the analgesics consumption were presented to emphasize that only one third of our patients needed opioids for pain relief. Graziano and Cascinu consider that a 36-week median overall survival is probably excessive "because 21 patients worsened during treatment." This is not accurate, since only 12 patients had progressive disease. The prolonged survival of patients with stable disease is interesting, and a possible explanation is that these patients represent a subgroup with a more favorable tumor biology as compared with patients presenting with progressive disease. Treatment-mediated stable disease associated with tumor growth control may confer a survival benefit in some tumors, eg, the case of irinotecan in patients with advanced colorectal cancer.3 Conversely, disease progression may be indicative of a more aggressive tumor phenotype with rapid tumor development, distant metastases, and short survival. Finally, median survival of untreated pancreatic carcinoma patients has been reported to range from 3.5 to 6.0 months, mostly depending on PS at diagnosis, and this information is given in our article (first paragraph of the Introduction). A prolonged median overall survival has also been observed in other phase II studies. Hidalgo et al2 and Carmichael et al3 have reported survival rates of 10.3 and 6.8 months, respectively. Moreover, in the former study,2 the 1-year survival rate was 39.5%. Our opinion is that the comparison of median survival of patients with progressive disease or stable disease after docetaxel treatment with that of patients treated with gemcitabine may be misleading. In general, conclusions cannot be drawn in oncology by comparing different phase II studies, as Graziano and Cascinu did. However, we agree with them, and this is clearly stated in the Discussion of the article, that additional studies, including randomized trials, are needed to fully determine the place of docetaxel in the treatment of advanced pancreatic cancer. REFERENCES 1. Androulakis N, Kourousis C, Dimopoulos MA, et al: Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: A multicenter phase II study. J Clin Oncol 17:1779-1785, 1999
2.
Hidalgo M, Castellano D, Paz-Ares L, et al: Phase I/II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol 17:585-592, 1999 3. Carmichael J, Fink U, Russell R, et al: Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer 73:101-105, 1996[Medline] 4. Cunningham D, Pyrhonen S, James RD, et al: Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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