Abstract

Background: Postoperative chemoradiotherapy with concurrent 5-fluorouracil improves gastric cancer outcome. We previously demonstrated that chemoradiotherapy with a more intensified––and therefore potentially more effective––schedule with daily cisplatin and oral capecitabine is feasible. Because such an intensive schedule requires an extensive logistic infrastructure which is not available in every hospital, we additionally investigated the tolerability of this combined regimen with weekly instead of daily cisplatin in a dose-escalation study.

Patients and methods: After R0 or R1 resection, treatment initiated with capecitabine 1000 mg/m2 b.i.d. for 2 weeks and 1-week rest. Subsequently, patients received capecitabine (575–650 mg/m2 orally b.i.d., 5 days/week) and cisplatin (20–25 mg/m2 i.v., once weekly) according to a predefined dose-escalation schedule concurrent with radiation. Radiotherapy was given to a fixed total dose of 45 Gy in 25 fractions.

Results: Thirty-one patients were eligible and started treatment. During chemoradiotherapy, seven patients developed 10 items of grade III and one episode of grade IV (mainly hematological) toxicity (National Cancer Institute—Common Toxicity Criteria version 3.0). The maximum tolerable dose was determined to be for cisplatin 20 mg/m2 i.v. weekly and for capecitabine 575 mg/m2 b.i.d. orally.

Conclusions: This phase I–II study demonstrated that postoperative chemoradiotherapy with weekly cisplatin and daily capecitabine is feasible in gastric cancer at the defined dose level. This schedule is currently being tested as the experimental arm in a phase III multicenter study (CRITICS: chemoradiotherapy after induction chemotherapy in cancer of the stomach; Clinicaltrials.gov NCT 00407186).

introduction

Surgical resection remains the cornerstone of curative treatment of gastric cancer [1]. However, with surgery only, long-term survival is poor, especially in patients with advanced T3–4 tumors and/or tumor-positive lymph nodes [2, 3]. This is mainly due to high locoregional relapse rates of up to 82% [4]. Randomized studies that compared standard D1 lymph node dissection with more extended D2 resection in the Western world failed to show a significant survival benefit with more extensive surgery [5, 6]. Postoperative chemotherapy also did not improve survival to a clinically significant level, according to several meta-analyses [7–13]. Recently, a Japanese study showed that S1 chemotherapy [oral prodrug of 5-fluorouracil (5-FU)] after a D2 resection increased 3-year overall survival (OS) from 70.1% to 80.1%, which makes it a reasonable treatment option in the Asian world [14]. Furthermore, a substantial increase in survival was found with perioperative chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) study [15]. In this randomized phase III study of 503 patients, three courses of epirubicin, cisplatin and continuous 5-FU (ECF) chemotherapy before surgery and three postoperative courses significantly prolonged progression-free survival and OS (23% for surgery only and 36% with perioperative chemotherapy at 5 years). Earlier, in a trial from the British Stomach Cancer Group, no advantage of postoperative radiotherapy only was found [16]. The Intergroup 0116 study, however, showed in a randomized study of 556 patients that postoperative 5-FU-based chemoradiotherapy prolonged 5-year OS to 40% as compared with 22% with surgery only [17]. This study has been criticized for the suboptimal quality of surgery in both arms with 54% of the patients having a D0 lymph node dissection [18]. In this study, which was initiated in the beginning of the 1990s, concurrent chemotherapy was given only during the first 4 and last 3 days—to a total of 7 days—of radiotherapy. Consequently, the interaction between both treatment modalities was limited, as was the radiosensitizing effect of 5-FU. We previously tested a more intensive and potentially more effective concurrent treatment regimen of conventionally fractionated radiotherapy (45 Gy in 25 fractions, equal to the Intergroup study) combined with daily oral capecitabine (which mimics continuous 5-FU infusion) [19, 20] with or without daily cisplatin in two phase I–II studies [21, 22]. Cisplatin was added to this regime because of its radiosensitizing properties in a number of other malignancies [23–26].

In the meantime, we have started a––currently accruing––phase III study [Chemoradiotherapy after induction chemotherapy in cancer of the stomach (CRITICS;) Clinicaltrials.gov NCT 00407186] in which patients are randomly assigned to receive three courses of epirubicin, cisplatin and capecitabine (ECC) and surgery followed by three more courses of ECC (arm 1) and three courses of ECC and surgery followed by chemoradiotherapy with cisplatin and capecitabine (arm 2). The ECC regimen was proven to be equally effective but more convenient as compared with ECF in metastatic gastric cancer [27]. In order to reduce logistical barriers for participation in this study, we have investigated whether weekly cisplatin is feasible in this patient group as well.

patients and methods

Detailed description of inclusion criteria and treatment parameters has been published previously [21, 22].

patients

In summary, patients with macroscopically radically resected adenocarcinoma of the stomach or gastroesophageal junction according to American Joint Committee on Cancer stage Ib–IV (M0) were eligible for this study [28].

All patients underwent a (partial or total) gastrectomy with preferably at least a D1 lymph node dissection. No routine splenectomy or pancreatic tail resection was done. Whenever possible, jejunostomies were left in situ for the entire postsurgical treatment period to facilitate adequate caloric intake. Furthermore, the surgical specimens were reviewed at the Department of Pathology of The Netherlands Cancer Institute. Patients had to be >18 years old, with a World Health Organization performance status of two or less and normal blood counts and kidney and liver tests. Baseline investigations included Tc99m-thiatide renography for evaluation of the relative function of the left and right kidney, physical examination, chest X-ray, chest and abdominal computed tomography (CT) scans, electrocardiogram and evaluation of caloric intake by a dietician. A caloric intake of at least 1500 kcal/day had to be ensured. During treatment, patients had weekly physical examination, testing of hematological, liver and renal function and determination of body weight, caloric intake and toxicity (National Cancer Institute—Common Toxicity Criteria v3.0).

The study was approved by the Medical Ethical Committee of The Netherlands Cancer Institute, and all patients gave written informed consent.

treatment design

The objectives of this phase I–II study were to determine the maximum tolerable dose (MTD) of two chemotherapeutic agents, cisplatin and capecitabine, with a fixed radiotherapeutic regimen of 45 Gy and to define a treatment schedule to be used as experimental arm in the subsequent phase III study. Dose-limiting toxicity (DLT) was defined as any greater than or equal to grade III event at any time up to 4 weeks after treatment in more than two of six patients per dose level. The DLT for neutropenia was defined as dose limiting only when reaching grade IV, with neutropenic fever or infection or when it occurred within the first 14 days (capecitabine monotherapy) of treatment. Because in our experience with postoperative chemoradiotherapy in gastric cancer, the prominent role of adequate caloric intake emerged, all greater than or equal to grade III weight loss and anorexia was also defined as DLT. In agreement with the Southwest Oncology Group study and to bridge waiting time for radiotherapy, all patients started with 2 weeks (days 1–14) of monotherapy with capecitabine 1000 mg/m2 b.i.d., after which a nontreatment week (day 15–21) followed. On day 22, radiotherapy started which consisted of 25 fractions of 1.8 Gy to a total dose of 45 Gy in 5 weeks (five fractions/week).

The MTD in our previous phase I study with daily capecitabine and daily cisplatin proved to be 650 mg/m2 for capecitabine and 5 mg/m2 for cisplatin. It was planned to escalate doses of cisplatin (20, 25, 30 and 40 mg/m2 i.v. once weekly with standard pre- and posthydration) in groups consisting of six patients each. Capecitabine was given in doses of 575–650 mg/m2 b.i.d., with the first dose before radiotherapy, using complete tablets only.

The clinical target volume (CTV) for radiotherapy consisted of the gastric bed (with stomach remnant when present), anastomoses and the draining lymph nodes, as was described in the Intergroup 0116 study [17]. Multiple field 3D conformation techniques and/or intensity-modulated radiotherapy (IMRT) techniques were used in all patients.

All patients had CT-based dose calculation with construction of dose volume histograms. Dose constraints for critical organs were mean liver dose <30 Gy and for kidneys, at least two-thirds of one kidney should receive a dose of <40% of the total dose. All patients were treated in a supine position without immobilization measures on linacs. Patients were weekly seen both by their radiation oncologist and gastrointestinal (GI) oncologist. Twice weekly blood counts and serum creatinin were checked. All patients were also strictly monitored by a dietician. Antiemetics were given on a prophylactic basis; antiacid and antidiarrheic drugs were prescribed on indication.

results

From March 2006 to July 2008, 32 patients were entered in the study. One patient went off study before start of treatment because of progressive disease at the celiac trunk and paraaortic lymph nodes. Thus, 31 patients started treatment and could be evaluated for acute toxicity. Patient characteristics are summarized in Table 1.

Table 1.

Patient characteristics (n = 31)

Sex (male/female) 23/8 
Mean age (range; years) 56 (33–73) 
Histology  
    Adenocarcinoma 28 
    Signet cell carcinoma 
Surgery  
    Partial gastrectomy 18 
    Esophagocardiac resection 
    Total gastrectomy 
Lymph node dissection  
    D0 
    D1 20 
    D2 
pT stagea  
    T1 
    T2 
    T3 20 
    T4 
pN stagea  
    N0 
    N1 13 
    N2 13 
    N3 
Sex (male/female) 23/8 
Mean age (range; years) 56 (33–73) 
Histology  
    Adenocarcinoma 28 
    Signet cell carcinoma 
Surgery  
    Partial gastrectomy 18 
    Esophagocardiac resection 
    Total gastrectomy 
Lymph node dissection  
    D0 
    D1 20 
    D2 
pT stagea  
    T1 
    T2 
    T3 20 
    T4 
pN stagea  
    N0 
    N1 13 
    N2 13 
    N3 
a

According to AJCC staging manual (sixth edition).

All patients completed the 2 weeks of capecitabine monotherapy. In the first dose level, no DLTs were seen (Table 2). In the second dose level (cisplatin 25 mg/m2; capecitabine 575–650 mg/m2 b.i.d.), in three patients, five items of greater than or equal to grade III toxicity were seen, of which four met the DLT criteria of neutropenia (one), weight loss (one), anorexia (one) and leucopenia (one). One patient developed both dose-limiting neutropenia and leucopenia; another patient developed both dose-limiting weight loss and anorexia. After this dose level had shown too many DLTs, the cisplatin dose was deescalated to the former dose level and 19 extra patients were treated in this dose level to obtain more insight in the toxicity profile of this dose regimen before embarking on the subsequent phase III study. At the same time, in all patients, the capecitabine dose was set as 575 mg/m2. So, in fact, 25 (6 + 19) patients were treated according to the first dose level with cisplatin 20 mg/m2 and capecitabine in a dose of 575–650 mg/m2 b.i.d. For clarity reasons, these patients are grouped together in Table 2. In this subsequent dose level, four patients developed six items of grade III toxicity. One of these patients developed grade III nausea and vomiting followed by an endoscopy-related bowel perforation that required surgery in the first week of treatment at which occasion early recurrence with peritoneal carcinomatosis was confirmed histologically. This patient stopped radiotherapy after only four fractions and the perforation was considered not related to treatment. A few weeks later, this patient died of progressive disease. In another patient, intra-abdominal abscesses became manifest in the first week of chemoradiotherapy. These were treated conservatively with percutaneous drainage but further chemoradiotherapy was stopped. In the following weeks, this patient fully recovered. The MTD therefore was for cisplatin 20 mg/m2 i.v. once weekly and for capecitabine 575 mg/m2 b.i.d orally on radiotherapy days. The other patients in this dose level with grade III toxicity (nausea and vomiting) could be managed conservatively and was judged not to be dose limiting.

Table 2.

Grade III/IV toxicity in relation to chemotherapy dose level during chemoradiotherapy in 31 patients who completed treatment as planned

Patient Cisplatin dose (mg/m2Capecitabine dose (mg/m2 b.i.d.) Grade III toxicity Grade IV toxicity DLT 
25 575 Leucopenia Neutropenia Yes 
25 575 Weight loss, anorexia  Yes 
11 25 575 Neutropenia  No 
14 20 575 Nausea, vomiting  Yes 
19 20 575 Syncope  No 
22 20 575 Nausea  Yes 
31 20 575 Nausea, vomiting  Yes 
Patient Cisplatin dose (mg/m2Capecitabine dose (mg/m2 b.i.d.) Grade III toxicity Grade IV toxicity DLT 
25 575 Leucopenia Neutropenia Yes 
25 575 Weight loss, anorexia  Yes 
11 25 575 Neutropenia  No 
14 20 575 Nausea, vomiting  Yes 
19 20 575 Syncope  No 
22 20 575 Nausea  Yes 
31 20 575 Nausea, vomiting  Yes 

b.i.d., twice a day; DLT, dose-limiting toxicity.

At time of analysis, after a median follow-up of 11 (1–27) months, 23 patients are alive and eight have died, all because of progressive disease. A Kaplan–Meier plot of OS is depicted in Figure 1. No patient has died due to treatment-related toxicity.

Figure 1.

Overall survival curve.

Figure 1.

Overall survival curve.

discussion

Currently, the treatment of choice for operable gastric cancer has not yet been defined. Although both the Intergroup 0116 and the MAGIC study have contributed in improving the results of gastric cancer treatment, many questions remain about the optimal treatment. When the Intergroup 0116 trial was initiated at the beginning of the nineties, the concept of concurrent chemoradiotherapy was not as widespread as it is nowadays. Especially, cisplatin-based chemoradiotherapy in a daily or weekly schedule has proven to be effective in a wide range of malignancies like head and neck, lung and uterine cervix cancer [24–26]. Furthermore, oral fluoropyrimidines such as capecitabine have shown to be at least as effective and to have a favorable side-effect profile when compared with i.v. 5-FU in metastatic colorectal cancer capecitabine [20, 27]. Capecitabine-based chemoradiotherapy has shown to be feasible and capable of inducing relevant tumor responses in both upper GI and rectal cancer [29, 30].

We investigated whether more intensive concurrent chemoradiotherapy after gastric surgery was feasible. Therefore, two phase I–II studies were carried out where a standard radiotherapy regimen comparable to the Intergroup 0116 trial was combined with daily capecitabine with or without cisplatin on radiotherapy days [21, 22]. The ECC regimen had already proven its use in gastric cancer with adequate and rapid absorption of capecitabine with peak metabolites after 2 h in patients with or without gastric resection [19].

These studies demonstrated that postoperative chemoradiotherapy with daily capecitabine with or without cisplatin and during weekdays combined with 45-Gy radiotherapy in 25 fractions is feasible (after 2 weeks of capecitabine monotherapy). Because it is logistically challenging to apply cisplatin on a daily basis for most centers, the current study was carried out to find out whether weekly administration of cisplatin was feasible in this patient group. As is reported above, we encountered manageable toxicity with cisplatin 20 mg/m2 i.v. once weekly and capecitabine 575 mg/m2 b.i.d. orally during radiotherapy. The mainly hematological and GI toxicity we encountered was comparable to what we found with daily cisplatin. In the radiotherapy part of treatment only modifications in CTV delineation have been introduced. More sophisticated 3D conformal and IMRT techniques are used in comparison with anterior-posterior posterior-anterior (AP–PA) techniques being used in the past and in the Intergroup 0116 study. Because studies established that 2D AP–PA techniques could cause a decrease in left kidney function, we were able in a dose-planning study to decrease the dose to the (left) kidney while adequately covering the planning target volume [31, 32].

The relative contribution for improved results in gastric cancer treatment outcome with postoperative chemoradiotherapy primarily aiming at improving locoregional control as opposed to perioperative chemotherapy aiming at reduction of both systemic and locoregional failures cannot be determined from the INT0116 and MAGIC studies [15, 17]. Hence, questions remain about the optimal type and sequencing of chemotherapy and the implementation of new radiotherapy and surgical techniques. Therefore, we are currently accruing patients in the CRITICS study, a multicenter phase III study (http://www.clinicaltrials.gov/ct/show/NCT00407186 and www.critics.nl), in which all patients receive three preoperative courses of ECC, then have gastric surgery followed by another three courses of ECC or chemoradiotherapy. In the experimental arm (chemoradiotherapy), cisplatin and capecitabine dosages are used that were defined in this phase I–II study. Furthermore, surgery requires at least a D1 resection with a minimum of 15 lymph nodes removed in this study. In addition, quality assurance of surgery (Maruyama index) and radiotherapy will be part of this study.

In conclusion, the combination of modern radiotherapy with weekly cisplatin and daily capecitabine is safe with manageable toxicity in patients who have had curative gastric surgery. This treatment regimen is currently being tested in a large randomized phase III study.

Part of this study has been presented at the American Society of Clinical Oncology Gastrointestinal symposium, January 2008, Orlando, FL.

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