Irinotecan Combined with 5-Fluorouracil and Leucovorin as Second-line Chemotherapy for Metastatic or Relapsed Gastric Cancer (2024)

Article history

Abstract

INTRODUCTION

Gastric cancer is the most common cancer in Korea (1), and the second most common cause of cancer death in the world (2). Although improvements in the early diagnosis have increased the number of curative resections, many patients still have inoperable disease and distant metastases when first diagnosed. Even after complete resection, local and distant relapses are common. Palliative chemotherapy has been shown to improve the quality of life and the overall survival (OS) compared with best supportive care (BSC) alone in patients with metastatic or relapsed gastric cancer (MRGC) (3–6). 5-Fluorouracil (5-FU) and platinum combination chemotherapy have been widely used as first-line chemotherapy for MRGC. However, about one-half of the patients receiving chemotherapy are unresponsive, and the majority of the patients who do respond eventually suffer disease progression. Although many of these patients are candidates for second-line chemotherapy at the time of first-line treatment failure, no established second-line regimen is available (7), and thus selection of patients who may benefit most from second-line treatment is an important issue.

Irinotecan (CPT-11) and its active metabolite (SN-38) bind reversibly to the topoisomerase I-DNA complex and induce cancer cell death by preventing relegation of single-strand DNA breaks (8,9). Irinotecan, 5-FU and leucovorin (LV) combination chemotherapy is an internationally accepted standard chemotherapy for metastatic colorectal cancer. These combination regimens, based on biweekly schedules, are called FOLFIRI regimens. The dosages of irinotecan, LV and 5-FU in FOLFIRI regimens vary. In MRGC, biweekly FOLFIRI chemotherapy as first-line treatment has yielded the response rate (RR) of 36∼42% and a median OS of 10.7∼14.0 months (10–13). Single-agent irinotecan showed an RR of 16% for MRGC patients who had received prior chemotherapy (14). In the salvage treatment setting, only two phase II studies that had strictly restricted the use of FOLFIRI regimen as second-line treatment have been published, and FOLFIRI regimens showed the RR of 21∼29% (15,16). However, there is still need for more data about the salvage effects of FOLFIRI regimens on MRGC and little data exist about the selection of MRGC patients who might benefit most from second-line chemotherapy. Therefore, our study was undertaken to evaluate the toxicity and efficacy of a FOLFIRI regimen as second-line treatment in a clinical practice setting in MRGC patients who had previously received platinum-based chemotherapy. In addition, factors to select patients who may benefit from salvage chemotherapy were also analysed.

MATERIALS AND METHODS

Patient Eligibility

Using prospective databases of two institutions (Seoul National University Hospital and Seoul National University Bundang Hospital), we screened all patients with histologically confirmed adenocarcinoma of the stomach that progressed while receiving, or within 6 months after the discontinuation of prior platinum-based chemotherapy used as an adjuvant or palliative treatment and then those who received FOLFIRI chemotherapy as second-line treatment between May 2003 and July 2007. Sixty-one patients who met such criteria were identified. Of 61, 10 patients who did not have any measurable lesion at the time of FOLFIRI chemotherapy initiation were excluded. A measurable lesion was defined as a mass with demarcated dimensions by physical examination, routine chest radiography or computed tomography (CT). We also had other exclusion criteria; it was planned to exclude patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of >2 or those with insufficient bone marrow [absolute neutrophil count (ANC) <1.5 × 10⁹/l and/or platelet count <100 × 10⁹/l] or with hepatic or renal dysfunction. However, all of these 51 patients did not meet any of the exclusion criteria and were thus included in this study.

Treatment

Patients received intravenous irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then LV (200 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 600 mg/m² in a 22-h continuous infusion) on days 1 and 2 (FOLFIRI regimen) every 14 days. Atropine was not routinely used. All patients received adequate anti-emetic therapy prior to FOLFIRI chemotherapy. Loperamide was prescribed prophylactically and patients were instructed to take loperamide in case of developing diarrhoea. Treatment was continued until documented disease progression, unacceptable toxic effects or patient refusal. All patients gave written informed consent before initiating treatment and this study was approved by the institutional review boards.

Response to Treatment and Adverse Effects

Physical examination, complete blood counts and biochemical tests were carried out before each cycle of therapy. A CT scan was performed every three cycles to document the extent of disease and to evaluate the response to treatment. The response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST). Toxicities were evaluated using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC, version 3.0) before each treatment. Dose modifications and treatment delays were recommended according to the extent of haematological and non-haematological toxicities. Drug doses were reduced by 20% in the case of severe neutropenia (ANC < 0.5 × 10⁹/l), thrombocytopenia (platelet count < 25 × 10⁹/l), febrile neutropenic fever or other severe non-haematologic toxicities of NCI-CTC ≥ grade 3 (except alopecia). Additional 20% reduction of drug doses was indicated for recurrent febrile neutropenic fever, grade 4 neutropenia, grade 4 thrombocytopenia or ≥grade 3 non-haematologic toxicities. Treatment was delayed for a minimum of 1 week if the ANC was <1.5 × 10⁹/l, the platelet count <100 × 10⁹/l or non-haematologic toxicities were not improved to ≤grade 1. Data on treatment, toxicity and disease status were prospectively recorded on specially designed forms.

Statistical Analysis

Progression-free survival (PFS) was calculated from the first day of FOLFIRI chemotherapy until the time of the first occurrence of progression, death from any cause or to the date of last follow-up if none of the preceding events had occurred. OS was calculated from the first day of FOLFIRI therapy to the date of death or to the date of the last follow-up visit. Analyses of PFS and OS curves were performed using the Kaplan–Meier method. Univariate analysis of OS or FFS was performed using the log-rank test. Factors independently associated with disease control rate (DCR) and survival were identified by multivariate analyses using the logistic and Cox proportional hazards regression models, respectively. The forward conditional method was used in the multivariate analysis. Two-sided P values of <0.05 were considered significant. All statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA).

The dose intensity (DI) was calculated as the ratio of the total dose (expressed in mg) per square meter of the patient, divided by the total treatment duration expressed in days. In this calculation, the end of treatment was considered to be 14 days after day 1 of the last cycle of chemotherapy. The relative DI was calculated as the ratio of the DI actually delivered to the DI planned by the protocol.

RESULTS

Patient Characteristics

Patient characteristics of 51 patients enrolled from two institutions are given in Table1. Median age of patients were 55 year (range, 29–79 year), and the majority of the study population was male [76% (39 of 51)]. Sixteen patients (31%) had an ECOG PS of 2.

Thirty-eight patients (75%) had previously received 5-FU-containing chemotherapy and 13 patients (25%) had received non-5-FU-containing chemotherapy. Of 51 enrolled patients, 47 patients (92%) had received first-line treatment in a palliative setting, and 4 (8%) had received previous chemotherapy [5-FU plus cisplatin (FP)] in an adjuvant setting. At the time of enrolment, 42 patients (82%) had progressive disease (PD) during first-line chemotherapy. Nineteen patients had PD after achieving partial remission (PR) or stable disease (SD) during the first-line palliative chemotherapy. Twenty-three patients had PD after the initiation of first-line treatment; all 4 patients who had received adjuvant chemotherapy had PD during FP treatment. Of 51 patients, nine (18%) progressed within 6 months of discontinuing previous chemotherapy and all these 9 patients had received first-line therapy as a palliative setting.

All patients had measurable tumour lesions at the initiation of FOLFIRI chemotherapy. Lymph nodes (63%), liver (51%) and peritoneum (41%) were the most common metastatic sites. Ten patients (20%) had ≥3 organs involved by gastric cancer metastasis.

Drug Delivery and Objective Tumour Responses

Two hundred and eighty-two treatment cycles were delivered, with a median of four cycles per patient (range, 1–12). Dose reduction was required in 14 patients (86 cycles). The relative DIs of irinotecan and 5-FU were 0.69 and 0.70, respectively. Of 51 patients, 48 were assessable for treatment response. Three patients were excluded from the response analysis. These three patients received two cycles of chemotherapy; two patients were lost to follow-up before tumour response evaluation, and the remaining patient withdrew consent and received further treatment at another hospital.

By intent-to-treat analysis, the overall RR was 18% [95% confidence interval (CI): 7∼29%], and 9 of 51 patients achieved PR. Fifteen patients (29%) had SD, and thus the DCR of FOLFIRI chemotherapy was 47% (95% CI: 33∼61%). Twenty-four patients (47%) had PD and, as mentioned earlier, three patients (6%) could not be evaluated. Based on univariate analysis using the χ²-test, patients whose disease had been controlled [complete remission (CR), PR or SD] by the first-line chemotherapy showed a higher DCR than patients who had been refractory to the first-line regimen (64% versus 35%, P < 0.05; Table2). The number of organs involved by metastases was counted at the initiation time of FOLFIRI chemotherapy and patients with fewer organs involved (1 or 2) by metastasis had a tendency toward a higher DCR than those with ≥3 involved organs (57% versus 27%, P = 0.086). ECOG PS, age and gender were not related to the achieved DCR by FOLFIRI chemotherapy. In multivariate analysis using a logistic regression model, both disease control (CR, PR or SD) after first-line chemotherapy (P = 0.024) and fewer organs involved (1 or 2) by metastasis (P = 0.047) were independently associated with higher DCR after second-line FOLFIRI chemotherapy. Other factors (PS, age and gender) had no effect on the DCR after FOLFIRI chemotherapy.

Toxicity

Fifty-one patients received a total of 282 treatment cycles, and the results are summarised in Table3. Toxicities were usually mild. The most common haematologic toxicity was anaemia, which occurred in 157 cycles (56%). However, grade 3/4 anaemia was noted in only 12 cycles (4%). Neutropenia developed in 80 cycles (28%) and grade 3/4 neutropenia was observed in 49 cycles (17%). Febrile neutropenia occurred in 4 cycles (1%). No grade 3/4 thrombocytopenia was observed. Non-haematologic toxicities consisted mainly of emesis and diarrhoea. Although nausea was noted in 14 patients (27%), grade 3/4 nausea developed in only 3 patients (6%). Vomiting was observed in 11 patients (22%), but grade 3/4 vomiting occurred in only 2 patients (4%). Although diarrhoea was noted in 11 patients (22%), grade 3/4 diarrhoea developed in only 3 patients (6%). No treatment-related deaths occurred.

Survival

The median follow-up duration was 7.4 months (range, 1.7∼33.6 months). The median PFS after initiation of FOLFIRI chemotherapy was 3.2 months (95% CI: 2.0∼4.4 months). After failure to respond to FOLFIRI, 34 patients received third-line chemotherapy; taxane-based therapy in 15 patients [pacl*taxel/cisplatin (eight patients), docetaxel-containing combination chemotherapy (four patients) and docetaxel alone (three patients)], oxaliplatin with infusional 5-FU/LV (FOLFOX) in 11 patients, capecitabine plus cisplatin in 2 patients and oral 5-FU analogue alone (capecitabine or TS-1) in 6 patients. As of the reference date of the final analysis (11 January 2008), 48 patients (92%) had died of their disease. The median OS of all patients was 9.1 months (95% CI: 5.9∼12.3 months; Fig.1A). The median PFS and OS in patients who had controlled diseases (CR, PR or SD) after FOLFIRI chemotherapy (disease-controlled group, N = 24) were 7.2 months (95% CI: 5.9∼8.5 months) and 11.9 months (8.4∼15.4 months), respectively. However, the median PFS and OS in patients who were resistant to FOLFIRI (resistant group, N = 24) were only 2.1 months (95% CI: 1.8∼2.4 months) and 6.4 months (95% CI: 3.6∼9.2 months), respectively (Fig.1B).

Univariate analysis showed that a longer PFS after FOLFIRI chemotherapy was associated with disease control after first-line chemotherapy [CR, PR and SD (4.8 months) versus PD (2.6 months), P = 0.075] and fewer organs involved by metastasis [1 or 2 (4.0 months) versus ≥3 (2.3 months), P = 0.076]. The ECOG PS [0 or 1 (3.2 months) versus 2 (2.9 months), P = 0.119], age (<60 versus ≥60 years) and gender had no effect on the PFS. In multivariate analysis using a Cox proportional hazards regression model, disease control after first-line chemotherapy, less organ involvement by metastasis, and good PS were independently associated with a longer PFS (Table4).

In univariate analysis, a longer OS was associated with a good ECOG PS [0 or 1 (11.8 months) versus 2 (5.3 months), P = 0.003]. Fewer organs involved by metastasis seemed to be related to a longer OS [1 or 2 (9.2 months) versus ≥3 (8.7 months), P = 0.098]. However, disease control after first-line chemotherapy [CR, PR and SD (8.7 months) versus PD (9.2 months), P = 0.749], age and gender had no effect on the OS. In multivariate analysis, a good PS and less organ involvement by metastasis were independently related to a longer OS (Table4).

DISCUSSION

As salvage treatment for MRGC patients, only two phase II studies have been published that strictly restricted the use of the FOLFIRI regimen as second-line therapy (15,16). In a Korean phase II study, which included 64 MRGC patients who were previously treated with taxane and cisplatin, biweekly FOLFIRI [irinotecan (150 mg/m² on day 1) and LV (100 mg/m² on day 1), followed by a 5-FU continuous infusion (1000 mg/m² on days 1 and 2)] showed an RR of 21%, a median time to progression of 2.5 months and a median OS of 7.6 months (16). In a British trial, which included 38 patients who had failed previous 5-FU-based chemotherapy, a biweekly FOLFIRI regimen [irinotecan (180 mg/m² on day 1), along with 5-FU (400 mg/m² bolus) and LV (125 mg/m²), followed by a 5-FU infusion (2400 mg/m² over 48 h)] showed an RR of 29%, a failure-free survival of 3.7 months and an OS of 6.4 months. However, this study included patients with advanced oesophageal and gastric cancer. Because metastatic oesophageal cancer and MRGC are different disease entities and have different disease courses, and only 14 MRGC patients (37%) were enrolled, application of the results of this study to Asian MRGC patients is impertinent (15). Another Korean phase II study (17) reported the efficacy of the FOLFIRI regimen as salvage treatment. In this study, 36 MRGC patients were enrolled and FOLFIRI [irinotecan (150 mg/m² on day 1) and LV (20 mg/m² on days 1 and 2), followed by 5-FU (a 400-mg/m² bolus and a 600-mg/m² 22-h continuous infusion on days 1 and 2)] was administered every 14 days. However, in the study, heterogeneous MRGC patients were included; enrolled patients received FOLFIRI chemotherapy as second, or more, line of therapy and only 18 patients (50%) received FOLFIRI as second-line treatment. The overall RR, median PFS and OS of all 36 patients were 10%, 3.3 and 10.9 months, respectively. Treatment outcome of 18 patients who had received FOLFIRI as second-line therapy was not separately reported (17). Therefore, there is still need for more data about the salvage effects of the FOLFIRI regimen on MRGC as second-line therapy. In addition, few data exist about the selection of MRGC patients who might benefit most from second-line treatment. Our study was performed based on this background.

Although our study was not designed prospectively and was performed in a clinical practice setting, our results showed similar treatment outcomes to previously reported phase II studies (15,16). FOLFIRI was tolerable, but the administered relative DI’s of irinotecan and 5-FU in our study were 0.69 and 0.70, respectively, which were relatively less than the relative DIs of those agents reported in previous reports (15,16). The most common cause of treatment delay or dose reduction in our study was haematologic toxicity, and this may be brought about by higher bolus doses of 5-FU used in our study compared with the doses in other studies. However, as our study was not prospectively designed, its dose modification was not so strict as in other phase II studies. In addition, some factors unrelated to adverse events of FOLFIRI treatment also had influences on treatment delivery. For example, as admission was required for FOLFIRI therapy, an every 2-week schedule of FOLFIRI could not be strictly kept in some cases because of the admission delay associated with insufficient wards in our institutes. All these complicated factors along with toxicities of FOLFIRI treatment is thought to contribute to relatively low DI in our study compared with other reports. However, our observation on the efficacy of the FOLFIRI regimen as a second-line treatment of MRGC in the clinical practice setting was comparable to previous phase II studies; the overall RR was 18% and the median PFS and OS for all patients were 3.2 and 9.1 months, respectively.

Palliative chemotherapy is well known to prolong OS in MRGC compared with BSC, and various chemotherapeutic agents are being tried to improve treatment outcomes (3–6,18). However, for MRGC patients who relapsed from, or failed, first-line therapy, there is considerable controversy about whether second-line therapy for MRGC has any advantages over BSC. Therefore, it is an important issue to select the criteria for choosing the patients who may benefit most from second-line chemotherapy. In our study, patients with disease control (CR, PR or SD) after second-line FOLFIRI treatment had longer PFS and OS than those who were refractory to FOLFIRI (Fig.1B). Multivariate analysis showed that disease control after first-line chemotherapy and less organ involvement by metastasis were independently related to higher DCR from second-line FOLFIRI therapy. Patients with disease control after first-line chemotherapy, less organ involvement by metastasis and good PS were independently associated with a longer PFS. However, only a good PS and less organ involvement by metastasis were independently related to a longer OS, and disease control after first-line chemotherapy had no effect on OS in our study (Table4). In contrast, longer PFS after first-line chemotherapy was reported to be a predictor for patients who may benefit from second-line therapy in MRGC in a small retrospective study (19). Non-association of disease control after first-line chemotherapy with OS after second-line chemotherapy in our study may be caused by a small sample size of patients or by the possible effects of third-line chemotherapy that was performed on 34 patients (67%) enrolled in this study.

In our study, thirty-eight patients (75%) had previously received 5-FU-containing chemotherapy. It is questionable whether 5-FU in FOLFIRI is necessary in these patients who were refractory to 5-FU. In vitro studies have shown that irinotecan down-regulates TS expression in tumour cells, leading to synergy between irinotecan and 5-FU (20,21). However, regarding the reintroduction of a previous failed drug in combination with another newly administered agent, data on metastatic colorectal cancer have shown controversial results. FOLFOX regimen showed superior RR (9.9% versus 1.3%) and time to progression (4.6 versus 1.6 months) compared with oxaliplatin alone after front-line irinotecan plus bolus 5-FU/LV therapy (P values of <0.05) (22). On the contrary, FOLFIRI did not demonstrate better RR, PFS or OS than irinotecan alone as second-line therapy after failure to respond to first-line infusional 5-FU/LV (23). There are few reports about benefits of reintroduction of a prior failed drug in combination with a newly introduced drug in MRGC patients. Considering more toxicities related with combination treatment, further studies about the reintroduction of a previous failed drug combined with another agent to MRGC patients are necessary.

In conclusion, administration of FOLFIRI chemotherapy as a second-line therapy in MRGC showed modest activity, and toxicities were favourable. Based on our data, less organ involvement in metastasis or good PS may be optimal selection criteria for patients suitable for second-line chemotherapy.

Conflict of interest statement

None declared.

References

© The Author (2008). Published by Oxford University Press. All rights reserved

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