A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 55, No. 5, pp. 1305–1310, 2003 Copyright © 2003 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter

doi:10.1016/S0360-3016(02)04399-7

CLINICAL INVESTIGATION

Pancreas

A PHASE I STUDY OF RADIATION THERAPY AND TWICE-WEEKLY GEMCITABINE AND CISPLATIN IN PATIENTS WITH LOCALLY ADVANCED PANCREATIC CANCER JAMES A. MARTENSON, JR., M.D.,* ANTONIO P. G. VIGLIOTTI, M.D.,† HENRY C. PITOT, M.D.,* LOUIS H. GEERAERTS, M.D.,‡ DANIEL J. SARGENT, PH.D.,* MICHAEL G. HADDOCK, M.D.,* CHIRANTAN GHOSH, M.D.,† MICHAEL D. KEPPEN, M.D.,§ TOM R. FITCH, M.D.,¶ AND RICHARD M. GOLDBERG, M.D.* *Mayo Clinic, Rochester, MN; †Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA; ‡Meritcare Hospital CCOP, Fargo, ND; § Sioux Community Cancer Consortium, Sioux Falls, SD; ¶Scottsdale CCOP, Scottsdale, AZ Purpose: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine’s radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. Methods and Materials: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m2 i.v. The starting dose for cisplatin was 5 mg/m2. Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. Results: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3– 4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m2 i.v. and cisplatin 10 mg/m2 i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m2 i.v. and cisplatin 10 mg/m2 i.v.) without dose-limiting toxicity. Conclusion: Gemcitabine 30 mg/m2 i.v. twice weekly and cisplatin 10 mg/m2 i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity. © 2003 Elsevier Science Inc. Cisplatin, Gemcitabine, Pancreatic cancer, Radiation therapy.

INTRODUCTION

prolong survival (1). Disease is usually technically unresectable among patients who do not have distant metastases. Although radiation therapy and 5-fluorouracil (5-FU) may prolong life modestly, median survival in randomized trials with these regimens is only about 9 to 10 months (2– 4), and all patients ultimately die of their disease. Even when sur-

Therapy for pancreatic cancer benefits only a minority of patients. At presentation, most patients have distant metastases and are incurable. Response rates with chemotherapy are low, and even aggressive multiagent regimens do not

participating institutions include the following: Iowa Oncology Research Association CCOP, Des Moines, IA 50309-1014 (Roscoe F. Morton, M.D.); Rapid City Regional Oncology Group, Rapid City, SD 59709 (Larry P. Ebbert, M.D.); Medcenter One Health Systems, Mid Dakota Clinic, Bismarck, ND 58501 (Ferdinand Addo, M.D.); Geisinger Clinical Oncology Program, Danville, PA 17822 (Suresh Nair, M.D.); CentreCare Clinic, St. Cloud, MN 56301 (Harold E. Windschitl, M.D.); Wichita Community Clinical Oncology Program, Wichita, KS 67214-3882 (Shaker R. Dakhil, M.D.); Missouri Valley Cancer Consortium, Omaha, NE 68131 (James A. Mailliard, M.D.). Received May 20, 2002, and in revised form Oct 30, 2002. Accepted for publication Nov 11, 2002.

Address correspondence to: Roberta Schwartz, Section of Scientific Publications, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Tel: (507) 284-3335; Fax: (507) 284-2107; E-mail: [email protected]. Reprint requests to: James A. Martenson, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Data were presented in abstract form at the Annual Meeting of the American Society of Clinical Oncology on May 19, 2002. Supported in part by Public Health Service Grants CA-25224, CA-37404, CA-15083, CA-63826, CA-52352, CA-35103, CA60276, CA-35101, CA-35448, and CA-63849 as well as a grant from the Eli Lilly Corporation. This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Additional 1305

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gical resection is possible, survival is generally less than 10% at 5 years (5). One Phase III clinical trial suggested that adjuvant radiation therapy and 5-FU modestly but significantly prolonged survival (6), and a second Phase III trial demonstrated a nonsignificant trend (p ⫽ 0.099) toward better survival in a subgroup of similarly treated patients after resection of pancreatic head cancer (7). Even with adjuvant treatment, however, the vast majority of patients experience recurrence and die of their disease. Clearly, investigation of better methods of treatment is warranted. A Phase III clinical trial was performed in a group of patients with advanced pancreatic cancer to assess the value of gemcitabine compared with 5-FU. Patients received gemcitabine (1,000 mg/m2 i.v. weekly for 7 weeks, followed by 1 week of rest, and then weekly every 3 of 4 weeks) or 5-FU (600 mg/m2 weekly). Patients treated with gemcitabine experienced a modest improvement in both survival and a complicated measure of clinical benefit (8). This trial was the first Phase III study to suggest a possible benefit of chemotherapy in advanced pancreatic cancer. Because of this, the use of gemcitabine is now accepted as standard first-line therapy for patients being considered for systemic treatment of pancreatic cancer. Studies of gemcitabine’s mechanism of action suggest that more frequent administration or more prolonged administration might result in additional therapeutic gains with this drug. The biochemistry of gemcitabine has been reviewed in detail elsewhere (9, 10) and is summarized briefly here. Gemcitabine is a prodrug that is activated by a phosphorylation pathway to form gemcitabine triphosphate. Gemcitabine triphosphate is incorporated in the elongating DNA strand in a way that is directly competitive with deoxycytidine triphosphate. Incorporation of gemcitabine triphosphate into the DNA strand effectively abrogates further elongation of the DNA by DNA polymerases. Both gemcitabine triphosphate and its immediate precursor, gemcitabine diphosphate, seem to influence metabolic pathways, which results in enhancement of incorporation of gemcitabine triphosphate into DNA. For example, gemcitabine diphosphate is an inhibitory alternative substrate for ribonucleotide reductase, the enzyme that produces deoxynucleotides required for DNA replication and repair, including deoxycytidine triphosphate. Gemcitabine triphosphate inhibits deoxycytidine monophosphate deaminase, an enzyme that commits gemcitabine to a biochemical pathway resulting in its deactivation. The preclinical finding that prolonged exposure to gemcitabine results in a dramatically increased antitumor effect is consistent with the hypothesis that accumulation of gemcitabine triphosphate, as a result of these and other (9) mechanisms for self-potentiation, is critical for its antitumor effect. Laboratory experiments suggest that gemcitabine may enhance radiation cytotoxicity for prolonged periods after drug exposure. Cells from the HT-29 human carcinoma cell line were exposed to 100 nM gemcitabine, which is noncytotoxic. Radiosensitization was observed for 48 h after drug washout, possibly because of the prolonged half-life of

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gemcitabine’s active phosphorylated metabolites (11). Accordingly, it may be possible to achieve prolonged sensitization during a course of radiation therapy with the use of dosing schedules that call for drug administration more frequently than once weekly. Theoretically, cisplatin might be expected to enhance the effect of gemcitabine. Cisplatin, like gemcitabine diphosphate, inhibits ribonucleotide reductase (12). Laboratory models showed that gemcitabine and cisplatin are synergistic in the ADDP and A2780 tumor cell lines (13). Cisplatin was shown to produce synergistic cytotoxicity with gemcitabine in human pancreatic cell lines without affecting gemcitabine-mediated radiosensitization (14). The North Central Cancer Treatment Group has undertaken an investigation of the possible therapeutic gains that might be achieved with external radiation therapy given with a novel chemotherapy regimen of twice-weekly gemcitabine and cisplatin. The first step in this effort was to conduct a Phase I study to determine the maximum tolerated dose of these drugs when given with radiation therapy. METHODS AND MATERIALS Adult patients with unresectable, incompletely resected, or locally recurrent adenocarcinoma of the pancreas or stomach with a neutrophil count ⱖ2,000 cells/␮L, a platelet count ⱖ100,000/␮L, and Eastern Cooperative Oncology Group performance status 0 –1 were eligible for this study. Specific parameters for unresectability were not included in the protocol and were left to the judgment of the treating physicians. Patients with stomach cancer were considered appropriate for this Phase I study, because the general area irradiated and the size of the irradiated fields are sufficiently similar to those used for pancreatic cancer. Required pretreatment evaluations included history, physical examination, chest radiograph, and computed tomographic scan of the abdomen. The protocol did not include specific requirements for computed tomography parameters, such as the use of a helical scanner. Adequate hepatic function (bilirubin within normal limits and alkaline phosphatase and aspartate aminotransferase less than 3 times the upper normal limit) and renal function (creatinine less than 1.3 times the upper normal limit) had to be demonstrated before study entry. Patients had to maintain ⱖ1,200 calories of oral nutrition per day before study entry. Patients who had undergone a surgical procedure recently could not be placed on study less than 21 days after their operation. Patients with distant metastases, nausea, or vomiting at the time of study registration, medical problems that would preclude protocol therapy, a history of prior conventional external beam radiation therapy to the planned radiation field, or prior chemotherapy were ineligible. Pregnant or lactating women were also excluded from this study. Written informed consent and local Institutional Review Board approval were required before entry of any patient to this study. Radiation therapy consisted of 45 Gy in 25 fractions to a

Radiation therapy, gemcitabine, and cisplatin for pancreatic cancer

Table 1. Dose escalation scheme for twice-weekly gemcitabine and cisplatin given concurrently with radiation therapy (50.4 Gy) Dose level

Gemcitabine dose, mg/m2*

Cisplatin dose, mg/m2*

0 1 2 3 4 5 6

5 5 10 20 30 30 45

0 5 5 5 5 10 10

* Twice-weekly intravenous administration for the first 3 weeks of radiation therapy. The starting point for the study was dose Level 1.

field designed to encompass the tumor and draining celiac axis, pancreaticoduodenal, and porta hepatis nodes. The use of three-dimensional treatment planning was allowed but not required. This was followed by a boost to the tumor of 5.4 Gy in 3 fractions. Gemcitabine and cisplatin were given on Tuesdays and Fridays for 3 weeks, beginning with the first week of radiation therapy. Chemotherapy doses were escalated, beginning with dose Level 1 (Table 1). National Cancer Institute Common Toxicity Criteria were used for grading of adverse effects (15). Prospectively defined dose-limiting toxicities are shown in Table 2. The protocol called for initial treatment of 3 patients at each dose level. If a dose-limiting toxicity was not observed in any of these 3 patients, 3 patients were treated at the next dose level. If a dose-limiting toxicity was observed in 1 of the initial 3 patients, 3 additional patients were entered at that dose level. Escalation was permitted if no further doseTable 2. Prospectively defined dose-limiting toxicities Toxic response Neutrophil count Platelet count Fatigue or flu-like symptoms Vomiting or anorexia

Nausea Diarrhea

Skin Fevers Renal

Dose-limiting toxicity ⱖGrade 4 toxicity (⬍500 cells/␮L) for ⱖ5 days ⱖGrade 4 toxicity (⬍25,000 cells/␮L) for ⱖ5 days ⱖGrade 4 toxicity (decline in performance status to 4) for ⱖ5 days Grade 4 toxicity resulting in admission to the hospital (the use of outpatient i.v. fluids shall not be considered a DLT) or any Grade 5 toxicity Nausea resulting in hospital admission Grade 4 toxicity resulting in admission to the hospital (the use of outpatient i.v. fluids shall not be considered a DLT) or any Grade 5 toxicity ⱖGrade 4 ⱖGrade 4 ⱖGrade 4

Abbreviations: DLT ⫽ dose-limiting toxicity; i.v. ⫽ intravenous.

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Table 3. Patient characteristics (n ⫽ 26) Characteristic

Number of patients

Age (years) Median (64.5) Range (49–76) Gender, male/female Primary cancer Pancreas Stomach Disease status Primary unresectable Incompletely resected Locally recurrent Performance score 0 1

17/9 26 0 21 3 1 7 19

limiting toxicities were observed in these 3 additional patients. The protocol required de-escalation if dose-limiting toxicity was observed at any time in 2 or more patients at a given dose level. In that circumstance, the protocol required treatment of a total of 6 patients at the previous dose level. The maximum tolerated dose was deemed to have been reached when 6 patients had been treated at a de-escalated dose level with ⱕ1 patient experiencing dose-limiting toxicity. Survival was calculated from the date of study registration, according to the Kaplan–Meier method (16). RESULTS Between March 1998 and April 2001, 26 patients, all with pancreatic cancer, entered this study. Characteristics of these patients are summarized in Table 3. Two patients did not complete protocol treatment for reasons other than doselimiting toxicity. A patient at dose Level 2 refused further therapy after receiving only half of the treatment. A second patient, treated at dose Level 3, experienced abdominal pain before treatment. This problem continued during treatment, and a decision was made not to treat the patient according to protocol, based on a clinical judgment that this would not be in the patient’s best interest. These 2 patients were replaced, according to a specific protocol provision, and are not included in the analysis of toxicity. Both of these patients are included in the survival analysis. The predominant form of hematologic toxicity was neutropenia and thrombocytopenia (Table 4). The only other potentially significant hematologic toxicity occurred in a patient at dose Level 1, who experienced Grade 4 lymphopenia. No clear relationship was apparent between the dose of chemotherapy and hematologic toxicity. Significant symptomatic toxicity is summarized in Table 5. In some cases, symptomatic toxicity did not seem to be related to use of the study drug. A serious, but self-limited, case of hepatic toxicity in 1 patient, for example, was caused by a malfunctioning stent rather than the patient’s protocol therapy. The frequency of Grades 3 and 4 toxicity

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Table 4. Neutropenia and thrombocytopenia according to dose level

Table 6. Nonhematologic toxicity according to dose level No. of patients

Dose level*

Patients, no.

Grade 3 neutropenia,† no.

1 2 3 4 5 6

3 3 6 3 6 3

0 1 0 0 1 0

Grade 3 thrombocytopenia,† no.

Dose level*

Total

With Grade 3–4 toxicity

With dose-limiting toxicity

0 0 0 0 2 0

1 2 3 4 5 6

3 3 6 3 6 3

1 1 3 1 3 3

0 1 1 0 0 2

* See Table 1 for drug and radiation therapy doses according to dose level. † No patient experienced Grade 4 or 5 neutropenia or thrombocytopenia.

and a summary of dose-limiting toxicities according to dose level are shown in Table 6. Nausea and vomiting were dose limiting in all cases. The maximum tolerated dose was determined as follows. After treatment of 3 patients without dose-limiting toxicity at dose Level 5, 3 patients were treated at dose Level 6. Nausea and vomiting requiring hospitalization and i.v. administration of fluid occurred in 2 of these 3 patients. Three additional patients were then treated at dose Level 5 without dose-limiting toxicity. The maximum tolerated dose was Level 5 (twice-weekly gemcitabine, 30 mg/m2 i.v., and twice-weekly cisplatin, 10 mg/m2 i.v., for 3 weeks given with concurrent radiation therapy, 50.4 Gy in 28 fractions). Dose escalation from Level 2 to Level 3 occurred despite dose-limiting toxicity (Grade 4 vomiting resulting in hospitalization) in 1 of 3 patients at dose Level 2. In retrospect,

Table 5. Frequency of Grade 3– 4 nonhematologic toxicity in 24 evaluable patients No. of patients Toxic response

Grade 3 toxicity

Grade 4 toxcity

Vomiting Nausea Anorexia Abdominal pain Diarrhea Hepatic† Constipation Dysphagia† Enteritis Lethargy Infection Dehydration Pain† Dizziness Hypotension Hyperglycemia†

1 7 3 2 1 0 1 1 1 2 1 2 0 0 0 1

6 Not applicable* 0 0 1 1 0 0 0 0 0 0 1 1 1 0

* No category exists for Grade 4 nausea in the National Cancer Institute’s Common Toxicity Criteria (15). † Toxicities that were not clearly related to use of the study drug.

* See Table 1 for drug and radiation therapy doses according to dose level.

it was determined that the decision to escalate from Level 2 to Level 3 was made based on incomplete information in 1 of the Level 2 patients. Measures were subsequently put in place to ensure availability of complete information on all patients before dose escalation. Because 15 patients were treated at dose Levels 3–5 with only 1 case of dose-limiting toxicity, we do not believe that this problem in the conduct of the protocol compromised the reliability of our estimate of the maximum tolerated dose for this regimen. The median survival for all 26 patients was 11.7 months (95% confidence interval: 10.0 –14 months) (Fig. 1). DISCUSSION Results from this study suggest that radiation therapy (50.4 Gy in 28 fractions) can be given with concurrent twice-weekly gemcitabine (30 mg/m2 per dose i.v. for 3 weeks) and cisplatin (10 mg/m2 per dose i.v. for 3 weeks) with acceptable toxicity. When gemcitabine is given without concurrent radiation, the standard dose is 1,000 mg/m2 weekly every 3 of 4 weeks (8). It is likely that several factors contributed to the substantially lower maximum tolerated dose for gemcitabine when it was given twice weekly in combination with radiation therapy and cisplatin. The rate-limiting step in the conversion of the gemcitabine to its active form, gemcitabine triphosphate, is phosphorylation by the enzyme deoxycytidine kinase (9). Phar-

Fig. 1. Survival for all patients with advanced pancreatic cancer.

Radiation therapy, gemcitabine, and cisplatin for pancreatic cancer

macologic studies suggest that this is a saturable process (17, 18) and that a gemcitabine infusion rate of 10 mg/m2 results in an intracellular gemcitabine concentration above that required to achieve maximum intracellular accumulation of gemcitabine triphosphate (19 –21). It is possible that methods of gemcitabine administration that do not saturate the phosphorylation pathway may result in a greater effect on the tumor or greater toxicity, or both. Our findings and those of others (22–25)—that the dose of gemcitabine must be markedly decreased with more than once-weekly administration—are consistent with this hypothesis. Others found that substantially lower doses of gemcitabine had to be administered when it was given more frequently than once per week. A Phase I trial demonstrated that a daily Monday through Friday schedule of 9 mg/m2per day resulted in unacceptable sporadic fever and hypotension (23). The maximum tolerated dose for a twice-weekly schedule of gemcitabine was 65 mg/m2 in a Phase I trial from Wayne State University. Fatigue, malaise, and loss of appetite were common with a twice-weekly regimen at doses ⱖ20 mg/m2. Fevers were observed on a sporadic basis. The dose-limiting toxicity was thrombocytopenia, but flu-like syndrome, weakness, rash, and leukopenia were observed, too (25). Studies of twice-weekly gemcitabine and radiation therapy for pancreatic cancer suggested that the maximum tolerated dose for gemcitabine was 40 –50 mg/m2 (22, 24). A second possible reason for the low maximum tolerated dose of gemcitabine in this study is this drug’s powerful radiosensitizing properties, as observed in several laboratory studies (18, 26). A study of radiation therapy and gemcitabine in mice with flank tumors suggested that radiation sensitization and therapeutic efficacy may be enhanced by the use of twice-weekly gemcitabine, despite the need for a substantial decrease in total gemcitabine dose with twice-weekly administration (26). In this study, the total dose of gemcitabine had to be reduced by approximately a factor of 4 for an equitoxic effect when it was administered twice weekly. Despite this, the therapeutic effect of the twice-weekly regimen was greater than that observed for the once-weekly regimen. Data from human studies also suggested that gemcitabine is a powerful radiosensitizer. The degree of normal-tissue sensitization seems to vary, depending on the area irradiated. The mucosa of the head and neck, for example, seems to be sensitized by extremely low doses of gemcitabine. A Phase I study of

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gemcitabine and radiation therapy in patients with advanced head-and-neck cancer demonstrated that it was necessary to decrease the dose of gemcitabine progressively from 300 mg/m2 per week to 10 mg/m2 per week before unacceptable dose-limiting toxicity was no longer observed (27). A comparison of systemic doses that can be given either alone or in combination with upper abdominal irradiation suggested that more modest dose reductions in gemcitabine or radiation dose are needed in this setting (8, 22, 24, 25, 28 –30). A recent study of twice-weekly gemcitabine, amifostine, and radiation therapy in pancreatic cancer demonstrated a maximum tolerated dose for gemcitabine of 90 mg/m2 (31), which is approximately double the maximum tolerated dose in studies that have not used amifostine (22, 24). This strongly suggested that administration of the radiation protector amifostine might allow administration of higher doses of gemcitabine during radiation therapy. A third reason for the low maximum tolerated dose of gemcitabine in this study is the use of cisplatin. As discussed previously, cisplatin is synergistic with gemcitabine in some tumor cell lines (13), a finding that is consistent with the known inhibitory effect of cisplatin on ribonucleotide reductase (12). Other factors besides the chemotherapy dose may have contributed to treatment-related toxicity. Examples include the initial condition of the patient and the size of the radiation fields used to treat the patient. In the context of a Phase I study, it is not possible to account for the potential influence of variables such as these on the outcome of a study. The results of this or any Phase I study must therefore be interpreted with caution. At this time, the treatment with gemcitabine, cisplatin, and radiation therapy should not be used outside the context of a clinical trial. On the basis of the current findings, the North Central Cancer Treatment Group has initiated a Phase II study of radiation therapy (50.4 Gy in 28 fractions) and twiceweekly cisplatin (10 mg/m2 i.v.) and gemcitabine (30 mg/m2 i.v.). Because many locally advanced pancreatic cancers are not measurable, survival, rather than response, will be used as the end point for this study. Prior clinical trials have shown that treatment with radiation therapy and 5-FU results in 1-year survival rates of approximately 40% (3, 4). If our Phase II study can demonstrate a 60% 1-year survival rate, the potential efficacy of this regimen is worthy of further study in a randomized clinical trial.

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