Abstract
Background: Docetaxel combined with cisplatin and 5-fluorouracil (5-FU) is active in advanced gastric cancer, but not generally accepted because of its substantial toxicities. We conducted a feasibility study of a triplet combination using paclitaxel, cisplatin and S-1 for advanced gastric cancer. Patients and Methods: Patients were given paclitaxel 160 mg/m2 infused over 2 hours on day 1, followed by cisplatin 60 mg/m2 in a 2-hour infusion on day 14, and S-1 80 mg/m2/day for 14 consecutive days, followed by a 2-week rest, repeated every 4 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred, the patient refused the therapy, or a surgical procedure was performed. Results: Twenty-one patients were prospectively enrolled. A total of 53 courses were administered, with a median of 2 courses (range: 1-7). Leucopenia, neutropenia, and anemia of grade 3 or more occurred in 3, 12, and 3 patients, respectively. Non-hematological toxicities were all grade 2 or less. Planned treatment was delivered with relative dose intensity for paclitaxel, cisplatin, and S-1 as 91.1%, 81.1% and 90.6%, respectively. The overall response rate was 67% with 1 complete response, 13 partial responses, and 6 with stable disease, while 6 out of 13 surgically resected specimens showed a histologic response graded ≥1b. Median survivals of all patients and of 13 patients who underwent curative resection were 543 and 871 days, respectively. Conclusion: Triplet combination chemotherapy with paclitaxel, cisplatin and S-1 demonstrated superior feasibility and promising antitumor activity for advanced gastric cancer.
Gastric cancer is the second leading cause of cancer mortality worldwide (1, 2), although its global incidence has been declining in recent years. Surgical resection is the mainstay of curative treatment for gastric cancer, however, not infrequently, the disease is too advanced at initial diagnosis to allow for curative surgery. For such patients, chemotherapy is the mainstream choice for symptom palliation and prolongation of survival. Despite the considerable efforts paid to develop effective chemotherapeutic regimens, advanced gastric cancer (AGC) remains a challenging malignancy for physicians as well as for patients, with a median survival of 9-13 months (3-6). Although no established regimen is yet a global standard for AGC, a doublet combination containing 5-fluorouracil (5-FU) and cisplatin is the most commonly used treatment worldwide (3, 7-9). In Japan, S-1 (an oral 5-FU agent) plus cisplatin has recently been established as a standard regimen for AGC based on the results of the SPIRITS trial (5), in which a response rate (RR) of 54% and a durable overall survival (OS) of 13 months were obtained using S-1 plus cisplatin. However, there still remains room for improving the efficacy of chemotherapy. To develop a more active and efficacious chemotherapy regimen, docetaxel, another cytotoxic agent against AGC, has been added to a doublet combination with 5-FU plus cisplatin (3, 10). Although triplet therapy with these three drugs has demonstrated promising outcomes, it has not been generally accepted as a standard of treatment because of its substantial toxicities, in particular high incidences of grade 3/4 neutropenia and febrile neutropenia (3, 10).
Several phase II trials showed that the taxanes, docetaxel and paclitaxel, when used as single agents for AGC, have different toxicity profiles. In particular, grade 3/4 neutropenia was less frequent with paclitaxel than with docetaxel (40% versus 80-90%, respectively), while the non-hematological toxicity profile, RR, and OS were quite similar between the two (11-15). From these findings, we speculated that substituting pactitaxel for docetaxel could reduce the toxicity of triplet therapy, while preserving its efficacy.
We therefore conducted the present feasibility study to evaluate the safety and efficacy of triplet combination chemotherapy with paclitaxel, cisplatin and S-1 in patients with AGC.
Patients and Methods
Eligibility criteria. Tumor assessment was performed within 4 weeks prior to enrollment, and a complete blood cell count and liver and renal function tests were carried out within 2 weeks prior to enrollment. Patients enlisted in this study were required to fulfill the following criteria: histologically proven gastric adenocarcinoma with measurable lesions; no prior chemotherapy or radiotherapy against any malignancies; age of 80 years or younger; performance status of 1 or less on the Eastern Cooperative Oncology Group (ECOG) scale; adequate bone marrow function (WBC count 3,000-12,000/mm3, neutrophil count ≥1,500/mm3, platelet count ≥100,000/mm3, and hemoglobin ≥8.0 g/dl), hepatic function (total bilirubin ≤2.0 mg/dl and serum aminotransferases ≤5 times the upper institutional limit), and renal function (serum creatinine ≤1.2 mg/dl and creatinine clearance ≥60 ml/min/body); sufficient oral intake or tolerance of enteral tube feeding; no other severe medical conditions; no other concurrent active malignancy; life expectancy of at least 3 months; and provision of written informed consent. This study was approved by the Institutional Ethics Board.
Treatment schedule. Paclitaxel (160 mg/m2) was given as an intravenous infusion over 2 hours on day 1 and cisplatin (60 mg/m2) was administered intravenously over 2 hours on day 14, as shown in Figure 1. S-1 was given orally after meals or via enteral feeding tube twice daily at a standard dose of 80 mg/m2/day for 14 consecutive days, followed by a 2-week rest, repeated every 4 weeks. The initial dose of S-1 was assigned according to the body surface area (BSA) of the patient as follows: BSA<1.25 m2, 80 mg/day; 1.25 m2≤BSA<1.5 m2, 100 mg/day; and BSA≥1.5 m2, 120 mg/day. Dose increases or reductions of paclitaxel, cisplatin, or S-1 were not planned.
The next course was only started if the biological parameters still conformed to the eligibility criteria and any non-hematological toxicity was of grade 1 or less. Otherwise, the treatment was suspended for up to 4 weeks after the last administration of cisplatin.
S-1 was discontinued if the patient developed grade 3 leucopenia and/or neutropenia, grade 3 thrombocytopenia, total bilirubin elevation above 3.0 mg/dl, serum aminotransferase elevation greater than 5 times the upper institutional limit, serum creatinine elevation above 1.5 mg/dl, or other non-hematological toxicity of grade 3 or more.
Cisplatin administration on day 14 was postponed for up to 1 week if the patient developed grade 2 leucopenia and/or neutropenia, grade 2 thrombocytopenia, or serum creatinine elevation above 1.2 mg/dl.
To prevent paclitaxel-induced hypersensitivity, all patients were given dexamethasone (20 mg) and ranitidine (50 mg) intravenously plus diphenhydramine (50 mg) orally or via enteral feeding tube at 30 min prior to the delivery of paclitaxel, and every patient was hydrated on day 14 with 2000 ml of 5% dextrose in 0.9% sodium chloride to avoid cisplatin-induced renal damage. Antiemetic drugs were given prophylactically before each administration of cisplatin. Granulocyte colony-stimulating factor (G-CSF) was used only when grade 4 leucopenia/neutropenia and/or grade 3 neutropenia with fever were observed.
The treatment was continued until disease progression or unacceptable toxicity occurred, the patient refused the therapy, or a surgical procedure was performed.
Treatment schedule used for study patients.
Evaluation of toxicity and efficacy. A complete blood cell count and measurements of liver and renal function were assessed at least every week during the treatment. Non-hematological toxicities were also verified at least every week by patient interview and physical examination. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0 (16).
During the treatment, patients were evaluated with abdominal computed tomography (CT) scans and assessed for an objective response in measurable lesions every 1-2 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (17). A complete response (CR) was defined as complete disappearance of the tumor by CT scan. A partial response (PR) was defined as shrinkage of the tumor diameter by ≥30%. An increase of the tumor diameter by ≥20% or the appearance of new lesions was defined as progressive disease (PD). Cases that did not meet criteria for CR, PR, or PD were defined as stable disease (SD). Disease control rate (DCR) represented the combined percentage of CR, PR and SD.
OS was defined as the time since the initiation of chemotherapy to the last follow-up or the date of death from any cause, and the Kaplan-Meier method was used to draw the survival curve. Patients who were alive at the time of our analysis were censored for survival.
Pathological examination. All resected specimens were examined by two pathologists and the graded histologic response of the primary tumor to the treatment was evaluated according to the guidelines of the Japanese Gastric Cancer Association (18). Histologic response of gastric lesions to the treatment was graded from 0 to 3 based on the amount of residual viable carcinoma in relation to areas of fibrosis or fibroinflammation within the gross lesion. Grade 3 (G3) response was defined as the complete absence of histopathologic evidence of malignancy. Grade 2 (G2) response was defined as <33.3% viable tumor cells seen on serial hematoxylin-eosin-stained sections, and grade 1b (G1b) as 33.3% to 66.6% viable cells. Tumors with 66.6% to less than 100% viable cells and those without any effect of chemotherapy on viable cells were scored as grade 1a (G1a) and grade 0 (G0), respectively.
Results
Patient characteristics. Patients' clinical characteristics are shown in Table I. Twenty-one patients, 14 males and 7 females, with a median age of 63 years (range: 30-79 years), were prospectively enrolled in this study between January 2008 and December 2009. Every patient had a performance status of 0-1. Twelve patients had primary resectable AGC, 6 patients had primary unresectable AGC, and 3 patients had recurrent GC. According to the guidelines of the Japanese Gastric Cancer Association (16), the primary tumor was classified as stage II in 2 patients, stage IIIb in 5, and stage IV in 11. Bulky nodal disease and/or para-aortic nodal metastasis (N3) were found in 10 patients, liver metastasis (H1) and/or distant metastasis (M1) in 7 patients, and T4 tumor, esophageal invasion, and linitis plastica in 4, 1, and 4 patients, respectively. Two patients, numbered 17 and 20 in Table I, received enteral tube feeding because of gastric outlet obstruction due to the primary tumor. Histologically, 10 patients had intestinal-type adenocarcinoma and 11 had diffuse-type adenocarcinoma.
Characteristics of patients with advanced gastric cancer taking part in this study.
Toxicity and treatment compliance. Toxicity profiles are shown in Table II. All patients were assessable for toxicity. A total of 53 courses were administered in 21 patients, and the median number of delivered treatment courses was 2 (range: 1-7). Hematological toxicity of grade 3 or more consisted of leucopenia, neutropenia, and anemia occurring in 3 (14%), 12 (57%), and 3 (14%) patients, respectively. Non-hematological toxicities were generally mild and manageable, with no grade 3/4 toxicities observed. There were no treatment-related deaths.
Details of treatment compliance are shown in Table III. Treatment was completed in 13 patients, all of whom subsequently underwent surgery, whereas treatment was discontinued in the remaining 8 patients for the following reasons: grade 2 neutropenia lasting more than 4 weeks after cisplatin administration in 1 patient, physician's decision to discontinue treatment due to cisplatin administration being skipped twice in 1 patient, patient choice arising from depression in 2 patients and grade 2 fatigue in 1 patient, and disease progression in 3 patients. Cisplatin administration on day 14 was delayed in 12 out of 53 courses (22.6%) due to grade 3 neutropenia in 6 courses, grade 4 neutropenia in 5 courses, and grade 2 fatigue in 1 course, while it was skipped in 6 courses (11.3%) because of grade 3 neutropenia in 5 courses and patient refusal in 1 course on day 21. Although no dose reductions were planned, the dose of paclitaxel was reduced by 20% twice and that of cisplatin by 20% once (patient no. 2) based on the physician's decision. S-1 dosing was also reduced by 20% for 20 days in 1 patient (patient no. 4) and skipped for 6 days in 1 patient (patient no. 15) at the discretion of a physician. The relative dose intensities (RDIs) of paclitaxel, cisplatin, and S-1 were 91.1%, 81.1%, and 90.6%, respectively, throughout all 53 courses.
Toxicities throughout all 53 courses on a patient basis.
Treatment compliance.
Clinical efficacy of triplet combination chemotherapy for advanced gastric cancer.
Overall survival of the all patients (left) and of patients undergoing curative resection with no residual tumor (right). Closed circles indicate censored cases.
Clinical efficacy. Best objective responses to treatment are shown in Table IV. The overall RR was 67% with 1 CR and 13 PRs, while 6 patients maintained SD, yielding a DCR of 95%.
Histologic responses to treatment of 13 surgically resected specimens were grades 3, 2, 1b, 1a, and 0 in 2, 2, 2, 5, and 2 patients, respectively, with 6 patients (46%) demonstrating grade 1b or greater.
At a median follow-up of 505 (range: 67-1167) days (322 days in 14 dead patients and 778 days in 7 living patients) after the initiation of triplet chemotherapy, median survival time (MST) of all patients was 543 days, and that of 13 patients who underwent curative resection with no residual tumor subsequent to the triplet chemotherapy was 871 days, as shown in Figure 2.
Discussion
Doublet chemotherapy with cisplatin and 5-FU (CF) is currently considered a reference standard worldwide, with overall response rates of 25-51% and MSTs of 7.3-9.3 months (3, 7-9). However, because of the modest RR and limited OS derived from the CF regimen, there exists a clear need to develop more active chemotherapy regimens. Docetaxel, another active agent used for AGC, has been added to a doublet combination with CF in randomized phase II (10) and phase III trials (3); this novel triplet therapy of docetaxel plus CF (DCF) has demonstrated a survival benefit over the CF doublet. In addition, the substitution of oral 5-FU drug for continuous infusion of 5-FU in the CF regimen has successfully avoided the inconvenience associated with infusional chemotherapy without jeopardizing the efficacy or safety of the CF therapy (4, 6, 9). Therefore, a new combination of docetaxel, cisplatin plus capecitabine or S-1, an oral alternative to infusional 5-FU, has recently been tried in several phase I/II studies (19-22).
Triplet therapy with DCF showed a survival benefit over a standard doublet therapy with CF in patients with AGC, but was associated with severe hematological toxicities including grade 3/4 neutropenia in 80-82% of patients and febrile neutropenia/neutropenic infectionin in 29-41% (3, 10). These high incidences of G3/4 neutropenia and febrile neutropenia limit the use of DCF as a standard of care for AGC. A new combination of docetaxel and cisplatin plus S-1 (DCS) or capecitabine (DCX) also demonstrated substantial hematological toxicities, with grade 3/4 neutropenia in 69-77% of cases and febrile neutropenia in 4-16% (20-22). In contrast, the overall toxicity of our triplet combination with paclitaxel, cisplatin, and S-1 (PCS) was highly acceptable, as shown in Table II. Grade 3/4 neutropenia occurred in 57% of patients, with no febrile neutropenia observed. Our results are consistent with recent phase II studies of PCS showing that the incidence of grade 3/4 neutropenia was 26-47% and that of febrile neutropenia was 0-9% (23, 24). Although variations in the types, doses, and schedules of delivered taxanes limit the degree to which different treatments can be compared, the hematological toxicities associated with PCS regimens seem to be milder and less frequent compared to the DCS and DCX regimens. In terms of non-hematological toxicities with the PCS regimen, Iwase et al. reported that no grade 3/4 non-hematological toxicities were observed when patients with AGC received intravenous paclitaxel (160 mg/m2) on day 1 plus cisplatin (60 mg/m2) as a 24-h infusion on day 14, and S-1 (70 mg/m2/day) on days 1-14 of every 28-day cycle (23). Kim et al. also showed a low incidence of non-hematological toxicities greater than grade 3, including nausea (2.4%), vomiting (4.8%), stomatitis (2.4%), and diarrhea (4.8%) when patients received intravenous paclitaxel (80 mg/m2) plus cisplatin (30 mg/m2) on days 1 and 8, and S-1 (70 mg/m2/day) on days 1-14 based on a 3-week cycle (24). These findings are consistent with our results, in which no grade 3/4 toxicities were observed. Such a low toxicity profile favors the administration of paclitaxel when combined with cisplatin and 5-FU.
With respect to the compliance with triplet combination chemotherapy with taxane (docetaxel or paclitaxel), cisplatin, and S-1, the RDIs of taxane, cisplatin, and S-1 were reported to be 84-96.5%, 83-97.3%, and 84-97.2%, respectively (21, 24). Our triplet PCS regimen showed equivalent tolerability, with RDIs of paclitaxel, cisplatin, and S-1 of 91.1%, 81.1% and 90.6%, respectively.
Compared to the modest overall RR of 25-51% and limited OS of 7.3-9.3 months delivered by the CF doublet (3, 7-9), PCS regimens demonstrated an RR of 59-63% and OS of 11.2-15.0 months in patients with AGC (23, 24), and DCS regimens achieved an RR of 81-87% and OS of over 18 months (20, 21). DCS triplets seem to be more active than PCS triplets, including our PCS regimen, which showed an RR of 67% and OS of 17.9 months.
Of note, in the present study, 13 patients who underwent curative resection following the PCS triplet demonstrated a prolonged MST of 871 days, as shown in Figure 2, despite advanced disease at initial diagnosis. A durable OS of 700 days or more was also obtained for AGC patients who received curative resection subsequent to the DCS/DCX chemotherapy (21, 22). Triplet combination chemotherapy with taxane, cisplatin, and S-1 is likely to be an appropriate neo-adjuvant treatment as well as palliative treatment for AGC. A Swiss group advocated this possibility for a DCF regimen in a study where the DCF regimen led to a rapid tumor shrinkage with a shorter time to response of 1.6 months (10). In addition, a histologic response of grades ≥1b was obtained in 46% of all resected specimens in the present study. A graded histologic response of 1b or greater was found in approximately 50% of patients who showed promising outcomes after receiving preoperative chemotherapy for AGC in other studies (25, 26), and a high graded histologic response of the primary tumor was identified as a predictor of durable survival in patients receiving preoperative chemotherapy or chemoradiotherapy (27, 28). Our PCS triplet might become a promising regimen in the neo-adjuvant setting.
In conclusion, although the present study was a small-scale analysis performed at a single institution, our triplet combination chemotherapy with paclitaxel, cisplatin and S-1 demonstrated superior feasibility with manageable toxicity and encouraging antitumor activity for patients with AGC. These promising results warrant further study to establish the role of this triplet combination regimen.
- Received May 24, 2011.
- Revision received June 27, 2011.
- Accepted June 28, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- Intraperitoneal and Systemic Chemotherapy for Patients with Gastric Cancer with Peritoneal Metastasis: A Phase II Trial
- The Relationship Between Antitumor Effects and Relative Dose Intensity of S-1 plus Cisplatin Treatment for Metastatic Gastric Cancer
- The Approval of TeysunoTM/S-1 by the European Medicines Agency: A Potentially Important Advance for Gastric Cancer Patients