Weekly docetaxel, cisplatin, and irinotecan (TPC): results of a ...

original article

Annals of Oncology 20: 475–480, 2009 doi:10.1093/annonc/mdn658 Published online 12 January 2009

Weekly docetaxel, cisplatin, and irinotecan (TPC): results of a multicenter phase II trial in patients with metastatic esophagogastric cancer P. C. Enzinger1*, D. P. Ryan2, J. W. Clark2, A. Muzikansky3, C. C. Earle1, M. H. Kulke1, J. A. Meyerhardt1, L. S. Blaszkowsky2, A. X. Zhu2, P. Fidias2, M. M. Vincitore1, R. J. Mayer1 & C. S. Fuchs1,4 1 4

Department of Medical Oncology, Dana-Farber Cancer Institute; 2Division of Hematology/Oncology and; 3Biostatistics Center, Massachusetts General Hospital; Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

Received 5 June 2008; revised 4 August 2008; accepted 3 September 2008

Background: Recent studies have examined the addition of docetaxel to fluorouracil and cisplatin in advanced esophagogastric cancer. irinotecan (TPC), given on days 1 and 8 every 3 weeks, in patients with chemonaive solid tumors. Subsequently, we completed a multiinstitutional phase II study of TPC in patients with previously untreated, metastatic esophagogastric cancer. Results: Thirty-nine patients were enrolled in the phase I trial; a weekly schedule of TPC was well tolerated. On that basis, docetaxel 30 mg/m2, cisplatin 25 mg/m2, and irinotecan 65 mg/m2 were selected for the phase II trial, where in the first 18 patients irinotecan 65 mg/m2 caused too much diarrhea and was reduced to 50 mg/m2. Among 56 eligible patients with previously untreated, metastatic esophagogastric cancer enrolled in the phase II trial, three complete and 27 partial responses were observed (overall response rate = 54%), and 15 patients (30%) had stable disease. Median progression-free survival was 7.1 months, and median survival was 11.9 months. At the final irinotecan dose of 50 mg/ m2, grade 3 or higher toxicity included diarrhea (26%), neutropenia (21%), nausea (18%), fatigue (16%), anorexia (13%), and thrombosis/embolism (13%). Conclusions: Weekly TPC is an active and well-tolerated regimen for patients with esophagogastric cancer. Key words: chemotherapy, cisplatin, docetaxel, esophageal cancer, gastric cancer, irinotecan

introduction Despite a myriad of combination chemotherapy regimens available for the treatment of esophageal and gastric cancers, there remains no clear consensus regarding the optimum regimen in patients with advanced disease. A combination of cisplatin and infusional 5-fluorouracil (5-FU), with or without epirubicin, has often been considered a standard approach, with response rates of 25%–29% and median survival durations of 8.6–9.3 months reported in the most recent randomized trials [1–3]. Docetaxel has demonstrated activity against esophageal and gastric cancers as monotherapy and in combination with other agents. A randomized trial added docetaxel to cisplatin and fluorouracil (DCF) and reported a 10% increase in response rate to 37% and a 1-month

*Correspondence to: Dr P. C. Enzinger, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel: +1 (617) 632-6855; Fax: +1 (617) 632-5370; E-mail: [email protected]

improvement in median survival time to 9 months, but at the cost of increased toxicity [1–3]. At the same time, the combination of weekly cisplatin and irinotecan appears well tolerated and has demonstrated comparable efficacy in phase II trials of patients with esophageal and gastric cancers [4, 5]. Examining the combination of a taxane, with cisplatin and a topoisomerase I inhibitor, Chou et al. [6] demonstrated significant in vitro synergy for the three-drug combination; moreover, when these three agents were used in combination, the doses of each compound needed to achieve antitumor activity could be reduced two- to eight-fold. We therefore conducted a phase I dose-escalation study to examine a weekly combination of docetaxel, cisplatin, and irinotecan (TPC) delivered in a 2-week-on-1-week-off schedule (3-week cycle length). Following successful completion of our phase I study, we initiated a subsequent multicenter phase II trial to assess the efficacy and tolerability of TPC in chemonaive patients with advanced esophageal and gastric cancers.

ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

original article

Patients and methods: We carried out a phase I dose-escalation study of weekly docetaxel, cisplatin, and

original article

Annals of Oncology

Herein, we report the results of both the phase I and II trials of the TPC regimen.

patients and methods phase I trial eligibility criteria. For the phase I trial, patients were required to have a histologically confirmed, incurable solid tumor malignancy, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two, adequate bone marrow function (absolute neutrophil or granulocyte counts ‡1500/mm3, platelets ‡100 000/mm3), hepatic function [total serum bilirubin £the institutional upper limit of normal (ULN), aspartate aminotransferase £1.5 · ULN or £2.5 times the institutional upper limit of normal if alkaline phosphatase was normal, alkaline phosphatase £2.5 times the institutional upper limit of normal or £4 times the institutional upper limit of normal if aspartate aminotransferase was normal], renal function (serum creatinine £ 1.5 mg/dl), and no previous chemotherapy for metastatic disease. Measurable disease was not required. Patients were excluded if they had prior radiation therapy >15% of the bone marrow, known central nervous system metastases, myocardial infarction within the past 6 months, major surgery in the past 2 weeks, significant medical or psychiatric comorbidities, uncontrolled diarrhea, or peripheral neuropathy. treatment. Docetaxel was delivered as a 30-min i.v. infusion, followed by cisplatin given as a 30-min i.v. infusion, followed by irinotecan administered as a 30-min i.v. infusion, each delivered on days 1 and 8, followed by a 1-week rest (cycle length = 3 weeks). The first cohort of three patients received docetaxel 25 mg/m2, cisplatin 22 mg/m2, and irinotecan 25 mg/m2. Doses for subsequent cohorts of patients were escalated in an alternating fashion (Table 1).

phase II trial eligibility criteria. For the phase II study, patients were required to have histologically confirmed, metastatic esophageal or gastric carcinoma with measurable disease by response evaluation criteria in solid tumors (RECIST) [7], ECOG PS of zero to one and adequate organ function as defined in the phase I trial. In addition, patients needed to meet the inclusion and exclusion criteria defined by the aforementioned phase I trial. treatment. TPC for the phase II trial consisted of docetaxel 30 mg/m2, cisplatin 25 mg/m2, and irinotecan 65 mg/m2, each delivered on days 1 and 8, followed by a 1-week rest. However, due to high rates of grade 3 or higher diarrhea among the first 18 patients, the starting dose of irinotecan was reduced to 50 mg/m2 in the subsequent 38 patients. On day 1 of each 21-day treatment cycle, full-dose therapy was given if patients had an absolute neutrophil count (ANC) ‡1500/mm3, platelets ‡100 000/mm3, creatinine 1 week or for grade 3 diarrhea of any duration; irinotecan was reduced by 50% for grade 4 diarrhea. Cisplatin was reduced by 50% for creatinine >1.5 lasting >1 week. Docetaxel and cisplatin were each reduced by 15% for grade 2 or 3 peripheral neuropathy. Docetaxel was reduced by 25% for grade 3 or 4 stomatitis. For other grades 3–4 non-hematologic toxicity, both docetaxel and irinotecan were reduced by 15%.

study assessments for both phase I and II trials Baseline evaluations consisted of physical examination, history, ECOG PS, complete blood cell with differential, hepatic and renal function tests. Baseline radiographic tumor assessments were carried out within 28 days before the first study medication dose; during chemotherapy, follow-up radiographic tumor assessments were carried out every 6 weeks until progressive disease (PD) or upon chemotherapy discontinuation. Tumor response classification was based on RECIST guidelines [7]. Adverse events, laboratory test results, and changes in vital signs were recorded at every study visit. Both the phase I and II trials were approved by the institutional review boards of the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, Lowell General Hospital, and Faulkner Hospital; all patients provided signed, informed consent.

statistical considerations phase I trial. Dose-limiting toxicity (DLT) was defined as toxicity (National Cancer Institutes—Common Toxicity Criteria, Version 1.0) experienced during the first cycle of chemotherapy and at least possibly related to chemotherapy. DLT was defined as follows: grade 4 neutropenia >3 days, grade 4 neutropenia with fever, grade 4 neutropenia requiring colonystimulating factor, grade 4 thrombocytopenia, grades 3–4 diarrhea despite aggressive loperamide therapy, or any other grades 3–4 non-hematologic toxicity, excluding nausea and vomiting. Maximum tolerated dose (MTD) was defined as the dose level before the one where two or more of three patients had DLT. If only one of three patients had DLT, another three patients were treated at this dose level. If any of these patients had DLT, the previous dose level was considered the MTD. Following determination of the MTD, an additional 10 patients were treated at the MTD to assess toxicity more accurately. phase II trial. The primary objective of the phase II study was to assess the response rate associated with TPC among 35 eligible patients with advanced esophagogastric cancer. Secondary objectives included determination of progression-free survival (PFS), overall survival (OS), and toxicity. PFS was measured from the date of initial treatment to first objective documentation of PD or date of death, whichever occurred first. Follow-up

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time was measured from the start of therapy to the date of death. PFS and OS were estimated using Kaplan–Meier methodology [8]. Patients with advanced esophagogastric cancer were admitted in a standard two-stage design [9] to test the null hypothesis, with 82% power and 6% significance level, that the true objective response rate was 40%. As predefined by the protocol, at least five responses were required among the first 17 assessable patients for the study to continue to a total of 35 assessable patients. At that point, the treatment would be considered promising if a total of 11 or more responses were observed.

results From January 2000 to July 2002, 40 patients were entered into the phase I dose-escalation study. One patient on the phase I trial withdrew before initiation of treatment; the remaining 39 patients received treatment and were included in subsequent analysis. Baseline characteristics of the treated phase I population are shown in Table 2. The majority of patients on the phase I study had an ECOG PS of either zero or one,

Table 2. Patient characteristics for phase I and phase II trials Characteristics

Phase I

Phase II

Total no. of evaluable patients Males Females Age Median (range) Race White Black Asian Baseline ECOG performance status 0 1 2 Disease status Measurable Evaluable Location of primary malignancy Esophagus Gastroesophageal junction Stomach Unknown primary Pancreas Other (gastrinoma, islet cell carcinoma, breast small cell carcinoma, mesothelioma) Histology Adenocarcinoma Squamous cell carcinoma Location of metastases Lung Liver Lymph nodes Bone Other

39 29 (74%) 10 (26%)

56 46 (82%) 10 (18%)

55 (23–75)

59 (29–79)

38 (97%) 0 1 (3%)

47 (91%) 4 (7%) 0

19 (42%) 25 (56%) 1 (2%)

22 (39%) 34 (61%) 0

34 (87%) 5 (13%)

All

10 4 13 6 2 4

21 (37%) 10 (18%) 25 (45%) 0 0 0

ECOG, Eastern Cooperative Oncology Group.


(26%) (10%) (33%) (15%) (5%) (10%)

N/A N/A

55 (98%) 1 (2%)

6 18 23 2 19

12 29 41 3 15

(15%) (46%) (59%) (3%) (49%)

(20%) (49%) (69%) (5%) (25%)

and gastric and esophageal adenocarcinomas represented the most common primary malignancies. From November 2001 to February 2005, 58 patients were entered into the multicenter phase II trial for patients with previously untreated metastatic gastric or esophageal cancer. Two patients withdrew before receiving any treatment. The remaining 56 eligible patients received at least one treatment and were eligible for assessment of toxicity. Primary analyses were on the basis of an intent-to-treat; thus, all 56 eligible patients were included in efficacy and toxicity analyses. Baseline characteristics of the eligible phase II population are shown in Table 2. Twenty-five (45%) patients presented with gastric adenocarcinoma, 21 (37%) presented with esophageal cancer (20 of whom had adenocarcinoma), and 10 (18%) presented with adenocarcinoma of the gastroesophageal junction.

phase I trial The phase I trial enrolled 39 patients at eight dose levels (Table 1). Only one patient (dose level 6) experienced a DLT (grade 3 diarrhea) during the first cycle of treatment. An additional patient at dose level 6 had to be replaced due to the development of PD before completing the first cycle. Since clinically significant doses of all three agents were achieved at dose level 8 and since patients experienced cumulative toxicity in subsequent cycles of therapy, the investigators chose not to pursue further dose escalation beyond dose level 8, despite the absence of protocol-defined DLTs. Thereafter, an additional 10 patients were treated at dose level 8. Data on toxicity for all 39 patients are provided in Table 3. The toxic effects

Table 3. Maximum toxicity grade for each toxicity per patient in phase I trial Toxicity type No. of patients Hemoglobina Absolute neutrophil count Neutropenic fevera Platelets Thrombosis/embolisma Fatiguea Anorexia Stomatitis/pharyngitis Nauseaa Vomitinga Dehydrationa Diarrheaa Abdominal pain or crampinga Constipation Allergic reaction/ hypersensitivity Alopecia Neuropathy—sensory

Grade

3 3 4 3 3–4 3 3 3–4 3–4 3 3 3 3 3

Dose level 1 2 3 4

5

6

7

8

All

4

3

7

3

13 1 4 1 2

39 2 6 3 2 0 2 2 0 0 3 3 1 8 2

3

1

3

3 1

1 1

1

1

1 1

1 1

1

1

1

1 1

2 1

1 1 1 4 1

3–4 3–4 1–2 3–4

0 0 2

1

1

2

1

9

16 0

a

No grade 4 toxicity.

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recorded represent the maximum grade toxicity observed for a given patient for the entire course of therapy. At the highest dose level (dose level 8), the most frequent grade 3 or higher toxic effects were neutropenia (38%), neutropenic fever (15%), diarrhea (31%), thrombosis/embolism (15%), and nausea/ vomiting (8%). Two complete and six partial responses were recorded in 34 patients with measurable disease. Partial responses were noted in 4 of 15 patients with measurable esophagogastric cancer treated at dose levels 5, 6, 7, and 8, which approximated the dose levels given in the subsequent phase II study. Stable disease for at least 6 weeks was noted in an additional 16 patients (41%). Most patients came off study for progression of disease (33%) or at the patient’s or physician’s discretion (41%).

phase II trial Among all 56 eligible patients in the phase II trial, a total of 361 cycles of TPC were administered. The median number of 3-week cycles per patient was 7 (range 1–16). Twenty-two patients (39%) were withdrawn from therapy due to disease progression, 15 patients (27%) as a result of treatment-related toxicity, and 13 patients (18%) due to physician or patient discretion; one patient (2%) died while on therapy (see below). After 10 of the first 18 patients (designated as group 1) experienced grade 3 diarrhea, the dose of irinotecan was reduced from 65 to 50 mg/m2 in the subsequent 38 patients (designated as group 2). Subsequently, very few patients (18%) discontinued their therapy due to toxicity or withdrawal of consent during the first six cycles (18 weeks) of therapy. Data on toxicity for the phase II trial are provided in Table 4; this table represents the maximum grade toxicity observed for a given patient for the entire course of therapy. Eleven

patients (61%) in the first group and 18 patients (47%) in the second group required at least one dose reduction for toxicity. Toxic effects for the two groups were similar except that, when compared with group 2, group 1 experienced a higher incidence of grade 3 or higher diarrhea (56% versus 26%), fatigue (22% versus 16%), and vomiting (17% versus 8%). Among all 56 patients, only three patients (5%) had febrile neutropenia requiring hospitalization. There was one treatment-related death; one patient died from complications arising from treatment-related diarrhea and dehydration. The primary end point of the phase II trial was objective response rate. By an intent-to-treat basis, three complete and 27 partial responses were observed, for an overall response rate of 54% [95% confidence interval (CI) 41% to 66%]. Fifteen patients (30%) had stable disease as their best response and five (10%) had PD. Response rates did not differ materially between the two irinotecan dose groups (50% and 55% for group 1 and 2, respectively). Major responses were recorded in 21 of 31 patients [67% (95% CI 50% to 82%)] with esophageal or gastroesophageal junction cancer and nine of 25 patients [37% (95% CI 20% to 56%)] with gastric cancer. The median PFS for all 56 patients was 7.1 months (95% CI 6–8.4; Figure 1), the median survival for the entire cohort was 11.9 months (95% CI 9.6–16; Figure 2), and the probability of survival after 6, 12, and 24 months was 74%, 48% and 22%, respectively. Among the 25 patients with gastric cancer, the median PFS was 6.9 months (95% CI 3.7–8.5) and median OS was 9.0 months (95% CI 5.9–16.8). For the 31 esophageal and gastroesophageal junction cancer patients, median PFS and OS were 7.6 months (95% CI 5.7–9.8) and 14.3 months (95% CI 10.1–18.2), respectively. The difference in survival between the two histologic sites was not statistically significant (P = 0.89 for OS).

discussion Table 4. Grades 3–5 toxicity in phase II trial

Hemoglobin Absolute neutrophil count Neutropenic fevera Plateletsa Thrombosis/embolism Fatiguea Anorexiaa Stomatitis/pharyngitisa Nauseaa Vomitinga Dehydrationa Diarrheaa Abdominal pain crampinga Constipationa Allergic reaction Alopecia (grades 1–2)a Neuropathy—sensorya a

No grade 4 toxicity.

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In these sequential multiinstitutional phase I and II trials, we found that docetaxel can be safely added to weekly cisplatin and

Percent of group 1 (n = 18)

Percent of group 2 (n = 38)

Percent of all patients (n = 56)

6 22 6 – 6 22 – – 22 17 17 56 – – – 33 –

13 21 5 – 13 16 13 – 18 8 3 26 8 5 13 34 –

11 21 5 – 11 18 9 – 20 11 7 36 5 4 9 34 – Figure 1. Progression-free survival for all 56 patients in the phase II trial treated with docetaxel, cisplatin, and irinotecan.


Annals of Oncology

Figure 2. Overall survival for all 56 patients in the phase II trial treated with docetaxel, cisplatin, and irinotecan.

irinotecan for patients with previously untreated solid tumor malignancies, and the regimen appears to be active and well tolerated in patients with previously untreated metastatic esophagogastric cancer. Among 56 patients with previously untreated, metastatic esophagogastric cancer enrolled in the phase II trial, the objective response rate was 54%, PFS was 7.1 months, and median survival was 11.9 months. Despite an excellent toxicity profile in a large phase I trial (39 patients), disproportionate gastrointestinal toxicity was noted in the first 18 patients who received irinotecan at 65 mg/m2 in the phase II trial. However, among the subsequent 38 patients treated at 50 mg/m2 of irinotecan, the regimen was well tolerated. Patients with esophageal and gastroesophageal junction cancer appeared to show a trend to improved response rate and survival compared with patients with gastric cancer in our trial (67% and 14.3 months versus 37% and 9.0 months). This difference was not statistically significant since the number of patients in each group was relatively small and should be viewed with caution. Although a trend to improved response and/or survival in patients with esophageal and gastroesophageal junction cancer has been demonstrated in other small studies [4, 5, 10, 11], a pooled analysis (n = 771 patients) of two large randomized studies in advanced esophagogastric cancer found no significant difference in either response or survival among the three tumor locations; response rates were similar for patients with esophageal (39%), gastroesophageal junction (40%), and gastric (33%) cancer. Median survival was nearly identical for these groups (esophagus 8.5 months, gastroesophageal junction 8.2 months, gastric 8.2 months) [12]. Nonetheless, future randomized studies in advanced gastroesophageal cancer should be stratified for tumor location. Our findings compare favorably with other combination regimens in first-line treatment of metastatic esophagogastric cancer [1–5]. In a randomized trial of patients with chemotherapy-naive locally advanced or metastatic gastric cancer, Van Cutsem et al. [2] added docetaxel to cisplatin and


original article fluorouracil (DCF) and reported a response rate of 37%, a median time to progression of 5.6 months, and a median survival of 9.2 months. However, toxicity on this trial appeared considerable with 82% of patients experiencing grade of 3 or higher neutropenia and 49% of patients experiencing grade of 3 or higher gastrointestinal toxicity. Several phase II trials have examined the combination of irinotecan and cisplatin among patients with advanced esophagogastric cancer. Response rates in chemonaive patients have ranged from 36% to 57% and median survivals have been estimated from 9 to 15 months [4, 5, 13–15]. In a singleinstitutional study of 38 patients with esophagogastric adenocarcinoma treated with irinotecan and cisplatin, Ajani et al. [5] reported a 55% response rate, 5.5 month time to progression, and 9 month median survival as compared with a 54% response rate, 7.1 month PFS, and 11.9 month median survival in our multicenter trial of TPC. In a singleinstitutional phase II trial of 35 patients with esophageal or gastroesophageal junction cancer (excluding patients with gastric cancer), Ilson et al. [4] reported a 57% response rate and 14.6 month median survival with irinotecan and cisplatin; however, in a subsequent multicenter trial of 28 patients with esophageal or gastroesophageal junction cancer, Ilson et al. reported a response rate of 36% (survival data were not reported). In comparison, our follow-up, multiinstitutional phase II trial found a 67% response rate and 14.3 month median survival among the 31 patients with esophageal and gastroesophageal junction cancers (excluding gastric cancer patients). Additionally, comparisons across multiple studies suggest that toxicity was similar for our TPC triplet as for the previously studied irinotecan/cisplatin doublet: neutropenia (21% versus 27%–46%), diarrhea (26% versus 11%–22%), fatigue (16% versus 3%–41%), vomiting (8% versus 3%–6%), or febrile neutropenia (5% versus 4%–9%) [4, 5]. Unfortunately, promising results in phase II trials of esophagogastric cancer have not always translated into significant advances in the phase III setting [16]. However, our sequential phase I/II effort was multiinstitutional and included 95 patients. Nonetheless, our results should be confirmed in a randomized effort with other promising regimens, particularly those combinations that have proven themselves in the phase III setting. Our regimen does not include 5-FU, the traditional foundation for chemotherapy in esophagogastric cancer. This is part of a general trend to combine newer agents, particularly docetaxel and irinotecan, in an effort to improve response and survival over the historically poor results seen with 5-FU-based therapy [17–19]. Results from a randomized study [20] and from a meta-analysis [21], presented at the 2008 American Society of Clinical Oncology Meeting, suggest that docetaxel may be an important alternative backbone for future chemotherapy combinations in esophagogastric cancer. Overall, we conclude that the TPC regimen is a well-tolerated and efficacious regimen, an ideal base to which biologic agents may be added. In a recently completed multiinstitutional phase II study, we have added bevacizumab 10 mg/kg every 3 weeks to the TPC regimen [22]. Additional studies may seek to examine the addition of other promising biologic agents to our TPC regimen.

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original article funding Pfizer Oncology; Sanofi-Aventis; National Institutes of Health (P50 CA127003).

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