Abstract
Aim: The aim of this phase I study was to adjust the dose of cisplatin as adjuvant combination chemotherapy with S-1 in an outpatient setting for gastric cancer. Patients and Methods: The first course was initiated with S-1 monotherapy on days 1-28. From the second to the sixth course, S-1 was administered on days 1-28 and cisplatin was added on days 1, 15, and 29. The dose level of cisplatin was escalated as follows: 20 mg/m2 (level 1); 25 mg/m2 (level 2); 30 mg/m2 (level 3). Dose-limiting toxicity was a delay factor of the start of the next course due to incomplete recovery. Results: The maximum tolerated and recommended doses were confirmed as level 3 and level 2, respectively. Conclusion: Although further clinical trials are recommended to evaluate efficacy, this combination of S-1 plus cisplatin regimen is expected to become a standard adjuvant treatment for gastric cancer in the outpatient setting.
Surgery plays a key role in the treatment of gastric cancer. Until recently, the great challenge of surgeons who treat gastric cancer continued to be improving survival using surgical procedures (1-3). However, the prognosis of advanced cases is not favorable, even if curative resection is achieved. To date, several adjuvant treatment approaches have been used to improve prognosis of patients with advanced gastric cancer (AGC), and their utility has been reported in many regions (4-7). Based on the results of the ACTS-GC trial (Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer), adjuvant S-1 chemotherapy has become a standard treatment following curative resection in patients with stage II or III disease (7). However, the survival benefit associated with S-1 monotherapy in patients with stage III disease remains controversial due to the results of a subset analysis of this trial. Thus, more favorable outcomes are required, particularly in patients with more greatly advanced gastric cancer. One of the standard treatments for unresectable gastric cancer is combination chemotherapy consisting of S-1 plus cisplatin, based on the results of a large randomized controlled trial (8). Therefore, S-1 plus cisplatin as a more potent adjuvant chemotherapy regimen might have clinical significance in stage III gastric cancer. Therefore, we conducted a phase I study to confirm the maximum tolerated dose (MTD) and recommended dose (RD) of cisplatin in an outpatient setting as adjuvant combination chemotherapy with S-1 in patients diagnosed with pathological stage III who have an unfavorable risk of recurrence.
Patients and Methods
Eligibility criteria. Eligibility criteria included histological confirmation of gastric adenocarcinoma, curative resection with D2 lymphadenectomy, confirmation of stage III disease based on the third edition of the Japanese classification of gastric carcinoma (9), age>20 and <80 years, adequate liver and renal function, no prior chemotherapy or radiotherapy, and the ability to take medications orally. All eligible patients provided written informed consent to participate. This study was approved by the Ethics Committee (unique number: 2010-027) at our hospital and thus meets the standards of the Declaration of Helsinki. This study was registered with University Hospital Medical Information Network (UMIN) center (unique trial number: UMIN000004734).
Treatment schedule. Treatment was initiated within six weeks after surgery. The first course consisted of S-1 monotherapy based on previous reports regarding improvement of compliance to adjuvant treatment (10). S-1 was administered orally every day on days 1-28, and the total dose was based on the patient's body surface area as follows: <1.25 m2, 80 mg; 1.25-1.5 m2, 100 mg; and >1.5 m2, 120 mg. From the second to the sixth course, S-1 was administered on days 1-28 in the same manner as the first course, and cisplatin was added on days 1, 15, and 29 for 60 minutes without hydration. Based on our previous study, the starting dose of cisplatin was 20 mg/m2 (defined as level 1) (11). The second dose (level 2) was 25 mg/m2, and the third dose (level 3) was 30 mg/m2. After combination chemotherapy, S-1 monotherapy was continued for up to one year after surgery. The treatment schedule is summarized in Figure 1.
Determination of MTD and RD. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (v 4.0) (12). Dose-limiting toxicity (DLT) was defined as follows during the second course, which included the first dose of combination adjuvant chemotherapy: grade 4 hematological toxicity; grade 3-4 non-hematological toxicity excluding anorexia, nausea, and vomiting; total S-1 administration duration <14 days; delay of cisplatin administration on day 15 or 29 for >7 days; or delay of the start of the next course >21 days. The first three patients were enrolled at level 1. If a DLT occurred in one of the three patients, three additional patients were to be evaluated at the same dose level. If two patients experienced a DLT at the same dose level, that level was defined as the MTD. If no DLT occurred at that level, the next three patients were dose-increased to the following level. The RD was defined as the dose level immediately below the MTD.
Results
Patients' characteristics. Between September 2010 and February 2014, 13 patients (six males, seven females) were entered into the study. Their median age was 65 years (range=55-79 years). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0. Histological types included differentiated (n=6) and undifferentiated (n=7) disease. Nine patients underwent distal gastrectomy and four underwent total gastrectomy with D2 lymphadenectomy. Curative resection was achieved in all patients. Patient characteristics are summarized in Table I.
Confirmation of MTD and RD. The first three patients enrolled at level 1 and none of the three patients experienced DLT (Table II). However, one patient at level 2 was unable to complete administration of cisplatin. Therefore, an additional three patients were entered into level 2. Since these patients did not experience any severe adverse events, level 2 was completed. The first patient enrolled at level 3 had experienced leukocytopenia and elevated bilirubin. These toxicities did not resolve to the level of the starting criteria for the next course within 21 days. For the next patient, the third course could not be started within 21 days because of fatigue and anorexia. Based on these results, the MTD and RD were confirmed as level 3 and level 2, respectively. The DLT was a more than 21-day delay of starting the next course.
Compliance with adjuvant chemotherapy. Three patients at level 1 completed combination adjuvant chemotherapy between the second and sixth course based on the protocol. During these treatments, no hematological or non-hematological toxicities greater than grade 2 were experienced (Table III). At level 2, two out of six patients completed five courses of combination chemotherapy without experiencing severe adverse events. Three out of six patients at level 2 had received four courses of combination chemotherapy. Out of 13 recruited patients, two were unable to receive the second course due to adverse events experienced during the first course of S-1 monotherapy.
Discussion
Although curable resection can be achieved in GC, the risk of recurrence, which is associated with an unfavorable prognosis, cannot be completely avoided (13). More potent adjuvant chemotherapy regimens including S-1 are expected to improve AGC prognosis. Currently, since the best partner of S-1 for AGC is considered to be cisplatin, this combination has the possibility of improving survival in the adjuvant setting (14, 15). For this regimen, hospitalization has been recommended due to the toxicities experienced with high doses of cisplatin. Therefore, we consider that preserving quality of life is important for patients who wish to attain their pre-cancer lifestyle.
The present study was conducted to confirm the dose of cisplatin in combination with S-1 in an outpatient setting. According to the dose-escalation results, the MTD and RD of cisplatin were defined as 30 (level 3) and 25 mg/m2 (level 2) bi-weekly, respectively. Although one patient experienced the DLT, the five remaining level 2 patients were able to receive treatment at more than 80% of the planned schedule. These results support the safety and feasibility of chemotherapy consisting of S-1 and 25 mg/m2 cisplatin as adjuvant chemotherapy for patients with stage III disease.
A key adverse effect of cisplatin therapy is nephrotoxicity, which is caused by molecular damage to renal tubules (16). Therefore, hydration at the time of cisplatin administration is required to avoid cisplatin-induced nephrotoxicity, and hospitalization is required to administer the adequate volume of fluid. However, previous reports have shown that fractional administration of cisplatin does not cause nephrotoxicity, even in the absence of a great volume of hydration (11, 17-20). Such fractional schedules without hydration make it possible to administer cisplatin-containing regimens in an outpatient setting. In the present study, severe nephrotoxicity was not experienced at any level, suggesting that this treatment schedule without hydration does not negatively impact renal function.
Another major toxicity associated with cisplatin is chemotherapy-induced nausea and vomiting (CINV) that can negatively impact quality of life (21). In particular, patients who have undergone gastrectomy sometimes suffer from anorexia caused by postoperative disturbances. Therefore, the addition of emetic chemotherapeutic agents such as cisplatin further increases the risk of nausea and vomiting. Several reports demonstrated the utility of fractional administration of cisplatin for reducing the emetic risk (11, 17-20). In the present study, CINV was manageable in all patients at levels 1 and 2. Therefore, the dose at level 2 is expected to be tolerable as adjuvant chemotherapy in patients following gastrectomy.
In the present study, our purpose was to establish an adjuvant chemotherapy regimen for gastric cancer that not only improves survival but also preserves safety in an outpatient setting. Of course, although further clinical trials are recommended to confirm the efficacy and feasibility of this combination chemotherapy regimen, it appears to be an excellent candidate for a standard adjuvant chemotherapy regimen for stage III gastric cancer in an outpatient setting.
Footnotes
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Disclosure Statement
We declare that the Authors have no conflicts of interest related to this study.
- Received August 22, 2014.
- Revision received September 30, 2014.
- Accepted October 7, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved