Clinical Response to Systemic Combined Chemotherapy with 5-Fluorouracil and Cisplatin (FP Therapy) in Patients with Advanced Pancreatic Cancer

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1 Clinical Response to Systemic Combined Chemotherapy with -Fluorouracil and Cisplatin (FP Therapy) in Patients with Advanced Pancreatic Cancer Takuji Okusaka, Shuichi Okada, Hiroshi Ishii, Haruhiko ose, Hidekazu akasuka, Hidetsugu akayama and Hiroyasu agahama Department of Internal Medicine, ational Cancer Center Hospital, Tokyo Pancreatic cancer shows high mortality and has a poor prognosis. Although the rate of response to all chemotherapeutic regimens is low, some patients have shown improvement of their symptoms after chemotherapy and/or radiotherapy without obvious tumor regression. We assessed the clinical benefit of systemic combined chemotherapy with -fluorouracil and cisplatin (FP therapy) in patients with advanced cancer of the pancreas. The clinical response to FP therapy was evaluated using two parameters: pain (intensity of pain and consumption of morphine) and performance status. A patient was considered to be a clinical responder if one of two parameters was positive and the other was positive or stable. Four patients (9%) responded. Two of the responders achieved partial response according to the objective tumor response, and the remaining two showed no change. The survival period in responders was significant longer than in the other patients. The clinical response may be one parameter for evaluating the results of treatment for pancreatic cancer, and the longer survival period of the clinical responders in this study supports this notion. (Jpn J Clin Oncol 6: -, 996) Key words: Clinical response Chemotherapy Pancreatic cancer Introduction Pancreatic cancer is the fifth most common cause of death among patients with malignant disease in Japan. The prognosis of this disease is very poor, because it is not easy to find and diagnose patients with resectable tumors, postoperative recurrences are often seen, and there is no effective non-surgical treatment. Many patients with inoperable pancreatic cancer have several symptoms such as severe pain, fatigue and loss of weight, ' ' and therefore improvement of symptoms is clinically beneficial in these patients. " ' Although the rate of response to chemotherapeutic regimens is low, some patients show improvement of symptoms after chemotherapy and/or radiotherapy without obvious tumor regression. The clinical response has been described as one endpoint of clinical trials of treatment for pancreatic cancer. 67 ' In this study, we assessed the clinical benefit of Received: February, 996 Accepted: March 8, 996 For reprints and all correspondence: Takuji Okusaka, Department of Internal Medicine, ational Cancer Center Hospital, - Tsukiji -chome, Chuo-ku, Tokyo -fluorouracil and cisplatin (FP) therapy in patients with pancreatic cancer by measuring changes in pain and performance status (PS) before, during and after chemotherapy. Patients and Methods Eligibility Patients with advanced pancreatic cancer were eligible for this study if they had the following features; histologically confirmed adenocarcinoma, age between and 7 years, at least one measurable lesion, no prior irradiation or chemotherapy, a life expectancy of at least months, adequate hepatic (serum total bilirubin <.mg/dl, serum aspartate aminotransferase (AST) < IU/, alanine aminotransferase (ALT) < IU/), hematologic (white blood cells >/mm, platelets >,/mm, hemoglobins g/ml) and renal function (serum creatinine<l.l mg/dl, blood urea nitrogen< mg/ dl, creatinine clearance > 6 ml/min), gave written informed consent and met at least one of the following criteria: - Karnofsky performance status (KPS) of, 6 or 7.

2 OKUSAKA ET AL. none Pain assessment card PAI intolerable Fig.. Pain assessment card. The patients indicated their levels of pain intensity by marking the card. -baseline morphine consumption of more than or equal to mg per day. -baseline pain intensity score of more than or equal to (out of ) as measured by the pain assessment card (Fig. ). Twenty-one patients were enrolled in this study between August 99 and October 99. ine patients were non-eligible because their KPS was better than 7, and their pain was absent or non-evaluable. The patient characteristics before chemotherapy are summarized in Table I. Although one of the eligible patients received palliative gastro-jejunostomy, the rest had no laparotomy before chemotherapy. All the patients had histological confirmation of their disease by fine-needle biopsy. Chemotherapy Patients were treated with a combination of -FU and cisplatin (FP therapy). Cisplatin (8 mg/m ) was given on the first day, and -FU ( mg/m ) by continuous intravenous infusion for days. FP therapy was repeated every weeks until there was evidence of progressive disease (PD) or unacceptable toxicity levels. Tumor response and toxicity were evaluated after each course, according to the standard WHO criteria. 8 ' Response duration was measured from the start of therapy to progression. Evaluation of Pain Each of the patients recorded their pain intensity on a daily pain assessment card (Fig. ). The baseline measurement of pain intensity was the mean of the pain intensity scores for three days just before the start of treatment. The pain intensity measurement was computed each week by taking the mean of the daily pain intensity scores for the previous week. The daily consumption of morphine by the pa- Table I. Age Sex Male Female Karnofsky performance status Baseline morphine requirement (mg/day) Site of primary tumor Head Body Tail Body/Tial Distant metastasis ( + ) CEA (ng/ml) CA9-9 (U/ml) umber of cycles Patient Characteristics 6 (-7) (6%) 8 (8%) (%) (%) (%) (6%) (%) (%) (9%) (%) 6 (9%) 8 (7%) (6%) (%) (9%) (%) (67%) 8 (-) 7 (-) (-6) tient as an analgesic was recorded daily. The dose of morphine taken per os or per anum was converted to the one-third dose that was equivalent to an intravenous dose. The baseline measurement of morphine consumption was the mean of the morphine consumption scores for the three days just before the start of treatment. Morphine consumption was computed each week by taking the mean of the daily morphine consumption scores for the previous week. Pain was evaluated by measuring changes from the baseline in pain intensity and morphine consumption. Each patient was categorized as positive, stable or negative for each of these two pain-related parameters (Table II). If at least one of the two pain-related parameters was positive, without being identified as negative on the other, the overall pain improvement classification was positive. A patient who was stable according to both parameters was classified as stable overall. All others were considered negative (Table HI). 6 Jpn J Clin Oncol 6() 996

3 CLIICAL BEEFIT OF CHEMOTHERAPY Table II., and Criteria for Each Parameter Pain intensity (measured on the pain assessment card, - visual analog scale) An improvement of ^% from baseline, sustained for & weeks, assuming a minimum pain score of ^ A worsening from baseline, sustained for ^ weeks Any other result Morphine consumption (ing) A decrease of ^% from baseline, sustained for s weeks, assuming a minimum morphine consumption of g mg/day Any increase from baseline, sustained for g weeks Any other result Karnofsky performance status An improvement of & points from baseline, sustained for g weeks, for patients with KPS, 6 or 7 A worsening of s points from baseline, sustained for ^ weeks Any other result Table III. Pain intensity Pain-improvement Classification Categorized by Pain Intensity and Analgesic Consumption Morphine consumption P P P, overall pain improvement is positive;, overall pain improvement is negative; S, overall pain improvement is stable. Table IV. P S Clinical Response Classification Categorized by Pain and Performance Status Performance status Pain R R R, clinical responder;, clinical non-responder; S, showing a stable clinical response. R S Table V. Leukocytopenia Granulocytopenia Thrombocytopenia Anemia Total Bilirubin GOT GPT ALP Creatinine BU ausea/vomiting Diarrhea Stomatitis Fever Toxicity of FP Therapy o. of patients with toxicity (WHO grade) GOT, glutamic-oxaloacetic transaminase; GPT, glutamic-pyruvic transaminase; ALP, alkaline phosphatase; BU, blood urea nitrogen. 9 9 r l Evaluation of KPS KPS was recorded weekly. The baseline KPS was recorded just before the start of treatment. Each patient was categorized as positive, stable or negative (Table II). Clinical Response To be classified as a clinical responder, a patient had to achieve a positive status for at least one of the measures of pain or KPS, without being identified as negative for the other (Table IV). A patient who was stable for the two measures was classified as showing a stable clinical response. All others were considered clinical non-responders. Clinical response duration was measured from the start of therapy to worsening from the baseline for at least one of the measures of pain or KPS. Survival Survival curves were calculated by the Kaplan- Meier methods, 9 ' and the difference between survival curves was evaluated using the log-rank test. - 7

4 OKUSAKA ET AL. Table VI. Results of Pain-improvement Classification () Table VIII. Results of Clinical Response Classification () Morphine consumption Performance status Pain intensity Total Pain Total Total 8 9 Total Table VII. Results of Pain-improvement Classification () Pain improvement classification Results umber of patients 8 % 8 8 Tumor Response and Toxicity of FP Therapy All the patients were evaluated for response and toxicity. The number of treatment courses in this study ranged from to 6, with a median of. Partial responses were observed in two (%) of the patients, the durations of the responses being 6. and. months, respectively. Eight patients showed no change, while patients had progressive disease. Treatment-related toxicities are summarized in Table V. There was no lifethreatening toxicity. and no patients had to discontinue treatment because of toxic effects. Pain The results of pain improvement are shown in Tables VI and VII. Three patients (%) were classified as positive in the overall pain improvement classification. Eight patients (8%) were stable and (8%) were negative. Clinical Response Tables VIII and IX show the results for clinical response. Four patients (9%) were clinical responders, and the durations of their responses were.9 (still continuing at final analysis),.9,. and. months, respectively. Two patients (%) were classsified as stable, and (7%) as nonresponders. Relationship between Clinical Response and Tumor Regression Two of the clinical responders attained a partial tumor response (PR), and the remaining two showed no change (C). Both patients with PR Table IX. Results of Clinical Response Classification () Clinical befefit classification umber of patients 9 7 Table X. Clinical Response and Tumor Response Clinical response Response on-response Total Tumor response PR C PD Total 8 PR, partial response; C, no change; PD, progressive disease. were clinical responders, whereas none of those with progressive disease (PD) were clinical responders (Table X). Survival Of the patients studied, 9 had died by the time of this analysis. The survival curves for clinical responders and the others (non-responders and stable patients) are shown in Fig.. The 6-month and -year survival rates and the median survival time were % and 67% and 6.8 months, respectively, in the responders, and 9% and % and. months, respectively, in the others. There was a significant difference in survival between the two groups (i J <.). Discussion Many patients with inoperable pancreatic cancer have various symptoms such as severe pain, rapid wasting and loss of strength. Therefore, these symptoms need to be improved by suitable therapy. Some patients do obtain some relief of these symptoms by chemotherapy, even though objective tumor responses are not recognized. 8 Jpn J Clin Oncol 6() 996

5 CLIICAL BEEFIT OF CHEMOTHERAPY - st 8 ' I 6 " - "I w. o Months after treatment Fig.., survival curves for clinical responders;, survival curves for others (non-responders and stable patients). The survival time for responders was significantly longer than that for the others (P<.). In the present study, four of patients (9%) who received FP therapy were classified as clinical responders. Although the number of responders was only four, their survival periods were significantly longer than those of the other patients. This indicated that clinical response is a good parameter with which to evaluate the therapeutic effect of chemotherapy for pancreatic cancer. Objective tumor response has usually been used as the primary endpoint in clinical trials of chemotherapy. However, as we have already reported, it is difficult to accurately measure the size of pancreatic tumors using imaging modalities, because pancreatic cancer is invasive and the tumor margin is obscure. ' In addition, pancreatic tumors consist of not only cancer cells but also abundant fibrosis. Therefore whether or not a tumor response really occurs has yet to be determined. Under these circumstances, clinical response may be an important endpoint for further clinical trials of treatment for pancreatic cancer. Rothenberg et al. n) have reported that the rate of clinical response to gemcitabin in -FU-refractory pancreatic cancer patients was 7.% (7/6). Moore et a/. ) have also shown that the rate of clinical response to gemcitabin as a first-line therapy for advanced pancreatic cancer was.8% (/6). Their methods of evaluating the clinical benefit were similar to ours. Although their clinical response rates for gemcitabin were slightly better than ours for FP therapy, these treatments seem to be insufficient for palliation in patients with pancreatic cancer. In conclusion, the clinical response was shown to be assessable simply and rapidly, and the longer survival time among the clinical responders supported the notion that clinical response is a reliable parameter for evaluating the results of treatment for pancreatic cancer. Further clinical trials of chemotherapy for pancreatic cancer are needed in order to develop new anti-cancer agents or regimens that produce meaningful palliation in most patients with advanced pancreatic cancer. Acknowledgments This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan. References ) Brennan MF, Kinsella T, Friedman M: Cancer of the pancreas. In Cancer: Principles and Practice of Oncology, rd ed, Debita VT, Hellman S, Rosenberg SA, eds, Lippincott, Philadelphia. p8oo-8, 989 ) Lebovits AH, Lefkowitz M: Pain management of pancreatic carcinoma: a review. Pain 6: -, 989 ) Schipper H, Clinch J, McMurray A, Levitt M: Measuring the quality of life of cancer patients: the Functional Living Index-Cancer: development and validation. J Clin Oncol : 7-8, 98 ) Hansen R, Quebbeman E, Ritch P, Chitambar C, Anderson T: Continuous -Fluorouracil (FU) infusion in carcinoma of the pancreas: a phase II study. Am J Med Sci 9: 9-9, 988 ) Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, Trochanowski B, Tarassoff PG: Phase II trial of gemcitabine (,'- difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest ew Drugs : 9-, 99 6) Fishman B, Pasternak S, Wallenstein SL, Houde RW, Holland JC, Foley KM: The Memorail Pain Assessment Card: a valid instrument for the evaluation of cancer pain. Cancer 6: -8, 987 7) Andersen JS, Burris HA, Casper E, dayman M, Green M, elson RL, Portenoy R, Rothenberg M, Tarassoff PG, Von Hoff DD: Development of a new system for assessing clinical benefit for patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol : 6, 99 (abstract) 8) World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment: offset publication 8, World Health Organization, Genova ) Kaplan EL, Meier P: onparametric estimation from incomplete observations. J Am Stat Assoc 6: 7-8, 98 ) Mantel : Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep : 6-7, 966 ) Peto R, Pike MC, Armitage P, Breslow E, Cox DR, Howard SV, Mantel, McPherson K, Peto J, Smith PG: Design and analysis of randomized 9

6 OKUSAKA ET AL. clinical trial requiring prolonged observation of each patient: I, introduction and design Br J Cancer : 8-6, 976 ) Aoki K, Okada S, Moriyama, Ishii H, ose H, Yoshimori M, Kosuge T, Ozaki H, Wakao F, Takayasu K, Mukai K: Accuracy of computed tomography in determining pancreatic cancer tumor size. Jpn J Clin Oncol : 8-87, 99 ) Rothenberg ML, Bums HA III, Andersen JS, Moore M, Green MR, Portenoy RK, Casper ES, Tarassoff PG, Storniolo AM, Von Hoff DD: Gemcitabine: effective palliative therapy for pancreas cancer patients failing -FU. Proc Am Soc Clin Oncol : 98, 99 (abstract) ) Moore M, Andersen J, Burris H, Tarassoff P, Green M, Casper E, Portenoy R, Modiano M, Cripps C, elson R, Storniolo A, Von Hoff D: A randomized trial of gemcitabine versus -FU as first-line therapy in advanced pancreatic cancer. Proc Am Soc Clin Oncol : 99, 99 (abstract) Jpn J Clin Oncol 6() 996