Abstract

Objective

Chemotherapy with irinotecan (CPT-11) or oxaliplatin (l-OHP) in combination with infusional 5-fluorouracil (5-FU) and their cross-over as second-line therapies are standard treatments for metastatic colorectal cancer (MCRC). Molecular target agents, which are used as third-line therapies in Western countries after failure of these three drugs, have not been available in Japan. Monotherapy with S-1 [Tegafur, Oteracil potassium and 5-chloro-2,4-dihydroxypyrimidine (CDHP)] showed activity against colorectal cancer with a response rate of 35% as a first-line therapy. It is not clear whether inhibition of dihydropyrimidine dehydrogenase by CDHP can modulate the activity of 5-FU even after patients initially fail with 5-FU. This retrospective study evaluated the efficacy and safety of monotherapy with S-1 for MCRC after the failure of standard chemotherapy.

Methods

The subjects of this study comprised two cohorts; the first was 27 patients with MCRC who had failed with 5-FU and CPT-11 before approval of l-OHP in Japan (cohort 1), and the second was 23 patients who had failed with 5-FU, CPT-11 and l-OHP (cohort 2). S-1 was given orally twice daily (80 mg m2/day) for 28 days followed by a 14-day rest.

Results

In cohorts 1 and 2, the response rates were 7% and 0%, and the median progression-free survivals were 2.8 and 2.7 months, and overall survivals after initiation of S-1 were 10.5 and 4.7 months, respectively. The common grade 3 and 4 adverse events in cohorts 1 and 2 were diarrhea 15% and 13%, anorexia 11% and 17% and anemia 26% and 30%, respectively.

Conclusions

S-1 monotherapy did not show promising activity against MCRC after the failures with 5-FU, CPT-11 and l-OHP.

INTRODUCTION

In Japan, colorectal cancer is the fourth most common malignancy and its incidence has been rising in recent years. Approximately 30–40% of patients with colorectal cancer have metastatic disease at the time of diagnosis. For patients with metastatic colorectal cancer (MCRC), treatment is generally palliative and mainly consists of systemic chemotherapy. Although palliative chemotherapy can relieve symptoms and prolong survival, the long-term prognosis remains poor (1,2).

In 2004, the results of a randomized trial (V308) comparing oxaliplatin (FOLFOX6) and irinotecan (FOLFIRI) in combination with short-term infusional 5-fluorouracil (5-FU) and leucovorin in 226 previously untreated patients were reported (3). Cross-over between FOLFOX6 and FOLFIRI was allowed as a second line of treatment after failure of the first drug due to progression or toxicities. The V308 trial demonstrated similar efficacies in response rates, progression-free survival (PFS) and median overall survival for FOLFOX6 and FOLFIRI. Therefore, either FOLFOX or FOLFIRI as the first-line therapy and subsequent cross-over to the other regime as the second-line therapy has been recognized as the standard treatment for MCRC all over the world. At present, the number of patients with MCRC who have failed to respond to 5-FU, irinotecan and oxaliplatin has been increasing remarkably. However, little is known about third-line treatments after the failure of these three drugs.

In Japan, neither infusional 5-FU regimens nor oxaliplatin was approved for MCRC until early 2005, so the regimen of irinotecan plus a bolus injection of 5-FU/LV (IFL) was the recognized standard treatment for MCRC instead of FOLFOX or FOLFIRI. Before early 2005, when oxaliplatin was approved in Japan, oxaliplatin had not been available for the subsequent treatment of patients after the failure with both 5-FU and irinotecan.

S-1 is an oral fluorinated pyrimidine developed by Taiho Pharmaceutical Co. Ltd (Tokyo, Japan). The agent contains tegafur (a masked 5-FU compound), 5-chloro-2,4-dihydroxypyrimidine (CDHP) and potassium oxonate in a molar ratio of 1:0.4:1, the last two components being biochemical modulators (4). S-1 showed promising activity against colorectal cancer in phase II studies (5,6), resulting in response rates of 35% and median overall survival of 12 months. These results suggest that S-1 may be more active than UFT (7) and 5-FU alone, and it is speculated that this difference may be brought about by inhibition of dihydropyrimidine dehydrogenase by CDHP. S-1 showed a response rate of 12% for advanced gastric cancer after failure of various first-line chemotherapies, including 5-FU (8).

For these reasons, before the approval of oxaliplatin, monotherapy with S-1 was one of the treatment options in clinical practice for patients with colorectal cancer who had failed with 5-FU and irinotecan. S-1 was also used in patients who had not responded to a combination of 5-FU, irinotecan and oxaliplatin after approval of oxaliplatin. Recently, it was reported that a phase II study of monotherapy with S-1 for colorectal cancer after the failure to respond to chemotherapy regimens containing 5-FU, irinotecan and oxaliplatin demonstrated a response rate of 14.3%, and a median time to progression of 91 days (9). However, its efficacy and safety profile, especially in clinical practice, remain controversial because of the small number of patients and the selection bias inherent in this phase II study.

In this retrospective study, the efficacy and safety of monotherapy with S-1 for MCRC after failure with both 5-FU and irinotecan, or failure of 5-FU, irinotecan and oxaliplatin, was assessed.

PATIENTS AND METHODS

Patients

In total, 57 patients with MCRC at the Shizuoka Cancer Center Hospital were treated by monotherapy with S-1 between December 2003 and October 2006, comprising 29 patients after the failure of both 5-FU and irinotecan and 28 patients after failing to respond to the three drugs, 5-FU, irinotecan and oxaliplatin. The subjects of this study were selected from these 57 patients according to the following criteria: (i) age 75 years or younger, (ii) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2, (iii) unresectable or recurrent colorectal cancer, (iv) histologically confirmed tubular adenocarcinoma, (v) the clinical course from initiation of S-1 was fully monitored in our hospital, (vi) absence of any other active malignant disease, and (vii) the absence of any central nervous system involvement.

From 29 patients in cohort 1, two patients were excluded because of the coexistence of hepatocellular carcinoma in one patient and incomplete information on the clinical course till progression in the other. From the 28 patients in cohort 2, five patients were excluded because of ages exceeding 75 years in three patients, central nervous system involvement in one and the coexistences of pancreas cancer in one. Thus, 27 patients (cohort 1) and 23 patients (cohort 2) were the subjects of this retrospective analysis.

Treatment Schedule

S-1 was orally administered twice daily after a meal at the following doses on the basis of body surface area: <1.25 m2, 40 mg; <1.50 m2, 50 mg; and >1.50 m2, 60 mg, for 28 days followed by a 2-week rest. This schedule was repeated every 6 weeks until disease progression, unacceptable toxicities or patient’s refusal.

Evaluation of Antitumor Effects and Adverse Events

All clinical data were obtained from the medical records retrospectively. Pretreatment evaluations included medical history, physical examination, laboratory tests and computed tomography (CT). Laboratory tests and toxicity were assessed at least biweekly during treatment cycle. The tumor was assessed every two cycles or when there were clinical signs suggesting tumor progression. Response was evaluated by CT or MRI according to the Response Evaluation Criteria in Solid Tumors (RECIST). Adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria (NCICTC version 2.0).

Statistical Analysis

PFS was calculated from the date of the first administration of S-1 to the earliest date when the treatment was discontinued for any reason including tumor progression or when the patient died from any cause. The overall survival time was calculated from the date of the first administration of S-1 to the date of death from any cause, or to the last date of confirmed survival. Survivals were analyzed by the Kaplan–Meier method.

RESULTS

Patient Characteristics

Patient characteristics for the 27 patients in cohort 1 and the 23 patients in cohort 2 are summarized in Table 1. Good performance status 1 or 0 was preserved in >90% of the patients in both cohorts. Major organs involved were liver, lung and lymph nodes in both cohorts, and the median numbers of organs involved were 2 (1–3) in cohort 1 and 1 (1–4) in cohort 2. The prior therapy is summarized in Table 2. In cohort 1, more than half of the patients had received the IFL regimen and 5-FU had been administered in a bolus injection in 21 patients (78%). Prior therapies in cohort 2 were mainly FOLFOX; 17 patients (74%) had received this treatment regimen, which contained both bolus and infusional injection of 5-FU.

Table 1.

Baseline characteristics

 Cohort 1
 
Cohort 2
 
 No. of patients No. of patients 
No. of patients 27  23  
Baseline characteristics 
 Age, years, median (range) 57 (35–71) 57 (40–74) 
 Sex, female 11 41 12 52 
Performance status 
 0 16 59 39 
 1 10 37 12 52 
 2 
Primary disease site 
 Colon/rectum — — 
 Colon 13 48 17 74 
 Rectum 12 45 26 
Primary disease resection 22 81 20 87 
Pathologic histology 
 Well 26 39 
 Moderate 12 44 35 
 Others (por, muc) 
 Data missing 26 22 
Organs involveda 
 Any lung involvement 15 56 12 52 
 Any liver involvement 14 52 35 
 Any lymph node involvement 11 41 30 
 Cohort 1
 
Cohort 2
 
 No. of patients No. of patients 
No. of patients 27  23  
Baseline characteristics 
 Age, years, median (range) 57 (35–71) 57 (40–74) 
 Sex, female 11 41 12 52 
Performance status 
 0 16 59 39 
 1 10 37 12 52 
 2 
Primary disease site 
 Colon/rectum — — 
 Colon 13 48 17 74 
 Rectum 12 45 26 
Primary disease resection 22 81 20 87 
Pathologic histology 
 Well 26 39 
 Moderate 12 44 35 
 Others (por, muc) 
 Data missing 26 22 
Organs involveda 
 Any lung involvement 15 56 12 52 
 Any liver involvement 14 52 35 
 Any lymph node involvement 11 41 30 

aNo. of patients were overlapped.

Table 2.

Priory therapy

 Cohort 1
 
Cohort 2
 
 No. of patients No. of patients 
No. of priory regimens 
 1 33 — — 
 2 30 26 
 3 30 39 
 ≥4 35 
Priory therapya 
 IFL 14 52 10 43 
 CPT-11 (±MMC) 13 48 30 
 UFT (±LV) 26 
 5-FU+ LV 26 39 
 5-Fuci 22 
 New drugs 11 22 
 5-FUai (WHF) 11 22 
 FOLFIRI 30 
 FOLFOX — — 17 74 
 FLOX — — 30 
Type of previous 5-FU regimen 
 Infusion 11 
 Bolus 21 78 26 
 Bolus and infusion 11 17 74 
 Cohort 1
 
Cohort 2
 
 No. of patients No. of patients 
No. of priory regimens 
 1 33 — — 
 2 30 26 
 3 30 39 
 ≥4 35 
Priory therapya 
 IFL 14 52 10 43 
 CPT-11 (±MMC) 13 48 30 
 UFT (±LV) 26 
 5-FU+ LV 26 39 
 5-Fuci 22 
 New drugs 11 22 
 5-FUai (WHF) 11 22 
 FOLFIRI 30 
 FOLFOX — — 17 74 
 FLOX — — 30 
Type of previous 5-FU regimen 
 Infusion 11 
 Bolus 21 78 26 
 Bolus and infusion 11 17 74 

IFL, irinotecan plus a bolus injection of 5-fluorouracil/leucovorin; CPT-11, irinotecan; MMC, mitomycin C; UFT, uracil and tegafur; LV, leucovorin; 5-FU, 5-fluorouracil; WHF, weekly high-dose 5-fluorouracil (weekly hepatic arterial infusion therapy)

aNo. of patients were overlapped.

Adverse Events and Feasibility

The grade 3 and 4 toxicities in both cohorts are summarized in Table 3. The most frequent grade 3 or 4 non-hematological toxicities were diarrhea (15% and 13% in cohort 1 and 2, respectively) and anorexia (11% and 17% in cohort 1 and 2, respectively). Grade 3 or 4 nausea was more frequent in cohort 2 (22%) than in cohort 1 (7%). As for hematological toxicities, grade 3 or 4 anemia (hemoglobin) was observed in 26% (cohort 1) and 30% (cohort 2). S-1 treatment discontinuation due to toxicity occurred in one patient in cohort 1 and in four patients in cohort 2 during the first treatment course. The reason for discontinuation in cohort 1 was diarrhea, whereas in cohort 2, the reasons were nausea in three patients and anemia in one. In neither cohort, was there early death within 60 days of the initiation of S-1 treatment or treatment-related death.

Table 3.

Grade 3/4 toxicities

 Cohort 1
 
Cohort 1
 
 Grade 3
 
Grade 4
 
Grade ≥3
 
Grade 3
 
Grade 4
 
Grade ≥3
 
 No. No. No. No. No. No. 
Nausea — — 22 — — 22 
Vomiting — — 
Diarrhea 15 15 13 13 
Mucositis 
Anorexia 11 11 17 17 
Hand-foot skin reaction 
Febrile neutropenia 
Leukocytopenia 
Neutropenia 
Hemoglobin 15 11 26 22 30 
Thrombocytopenia 
 Cohort 1
 
Cohort 1
 
 Grade 3
 
Grade 4
 
Grade ≥3
 
Grade 3
 
Grade 4
 
Grade ≥3
 
 No. No. No. No. No. No. 
Nausea — — 22 — — 22 
Vomiting — — 
Diarrhea 15 15 13 13 
Mucositis 
Anorexia 11 11 17 17 
Hand-foot skin reaction 
Febrile neutropenia 
Leukocytopenia 
Neutropenia 
Hemoglobin 15 11 26 22 30 
Thrombocytopenia 

Response

The responses to monotherapy with S-1 are summarized in Table 4. Partial response was obtained in two patients (7%) in cohort 1, but there was no partial response in cohort 2. Stable disease was observed in 14 patients (52%) in cohort 1 and in 4 (17%) of cohort 2. The prior chemotherapy in the two patients with a partial response was based on the bolus injection of 5-FU. When categorized according to the type of 5-FU administration in the prior chemotherapy, 13 of 21 patients (62%) in cohort 1 who had received only a bolus injection of 5-FU and 3 of 6 patients (50%) who received infusional 5-FU showed partial response or stable disease. In cohort 2, 1 of 6 patients (17%) receiving a bolus injection of 5-FU and 3 of 17 patients (18%) receiving infusional 5-FU showed stable disease.

Table 4.

Response, survival and disease progression

 Cohort 1
 
Cohort 2
 
 No. of patients No. of patients 
Complete response (CR) 
Partial response (PR) 
CR + PR 
Stable disease 14 52 17 
Progressive disease 10 37 15 65 
Not evaluable — — 
Time to disease progression: median, months 2.8 (0.4–9.7)  2.7 (0.4–12.6)  
Overall survival: median, months 10.5 (1.7–25.3)  4.7 (1.0–28.9)  
Follow-up duration: median, months —  6.5 (1.1–10.5+)  
 Cohort 1
 
Cohort 2
 
 No. of patients No. of patients 
Complete response (CR) 
Partial response (PR) 
CR + PR 
Stable disease 14 52 17 
Progressive disease 10 37 15 65 
Not evaluable — — 
Time to disease progression: median, months 2.8 (0.4–9.7)  2.7 (0.4–12.6)  
Overall survival: median, months 10.5 (1.7–25.3)  4.7 (1.0–28.9)  
Follow-up duration: median, months —  6.5 (1.1–10.5+)  

Subsequent Therapy

The subsequent therapies in each cohort were summarized in Table 5. In cohort 1, 16 of 27 patients (60%) received subsequent therapy, which mainly comprised FOLFIRI and FOLFOX after infusional 5-FU combined with leucovorin and oxaliplatin was approved in Japan. In cohort 2, only 3 of 23 patients (13%) received any chemotherapy after failure to respond to S-1.

Table 5.

Subsequent therapies

 Cohort 1 (n = 27)
 
Cohort 2 (n = 23)
 
 No. of patients No. of patients 
No. of after regimens 
 0 (best supportive care) 11 40 20 87 
 1 30 
 2 26 
 3 — — 
Regimens after S-1a 
 FOLFOX 11 40 — — 
 FOLFIRI 26 — — 
 5-Fu/LV 19 
 UFT (±LV) — — 
 5-FUai (WHF) 
 MMC — — 
 Cohort 1 (n = 27)
 
Cohort 2 (n = 23)
 
 No. of patients No. of patients 
No. of after regimens 
 0 (best supportive care) 11 40 20 87 
 1 30 
 2 26 
 3 — — 
Regimens after S-1a 
 FOLFOX 11 40 — — 
 FOLFIRI 26 — — 
 5-Fu/LV 19 
 UFT (±LV) — — 
 5-FUai (WHF) 
 MMC — — 

aNo. of patients were overlapped.

Survival

At the time of analysis, all 27 patients in cohort 1 had died but 7 patients in cohort 2 were alive at our last contact, with a median follow-up time of 6.5 months (range: 1.1–10.5+). The PFS curves are shown in Fig. 1 with events confirmed in all patients. The median progression-free times were 2.8 months (range: 0.4–9.7) in cohort 1 and 2.7 months (range: 0.4–12.6) in cohort 2. Overall survival curves are shown in Fig. 2, and the median survival times were 10.5 months (range: 1.7–25.3) in cohort 1 and 4.7 months (range: 1.0–28.9) in cohort 2. One-year survival rates in cohorts 1 and 2 were 44% and 9%, respectively.

Figure 1.

Time to disease progression.

Figure 1.

Time to disease progression.

Figure 2.

Overall survival.

Figure 2.

Overall survival.

DISCUSSION

After oxaliplatin (l-OHP) appeared, two large trials of the patients pre-treated with 5-FU and irinotecan in the USA were reported by Rothenberg et al. (10) and by Kemeny et al. (11). Rothenberg’s trial was a phase III trial comparing three arms of FOLFOX4, l-OHP alone, infusional 5-FU and leucovorin (LV5FU2) in patients with colorectal cancer refractory to IFL therapy. Kemeny’s trial was a randomized phase II trial with LV5FU2 or FOLFOX4 and cross-over LV5FU2 to FOLFOX4 after failure to respond to 5-FU and irinotecan. The response rates, time to progression and overall survival of LV5FU2 were 0%, 2.7 and 8.7 months in the first group, and 2%, 2.4 and 11.4 months in the second group, whereas those of the patients in cohort 1 in the present study were 7%, 2.8 and 10.5 months. As for adverse events, the incidence of grade 3 or 4 diarrhea in monotherapy with S-1 was 15%, which was higher than that for LV5FU2 (3–6%), and the incidence of grade 3 or 4 neutropenia in monotherapy with S-1 was 4%, lower than that for LV5FU2 (5–13%). Overall, it was considered that the clinical outcomes of monotherapy with S-1 may be similar to those of LV5FU2 and, before approval of oxaliplatin in Japan, S-1 was an option after failure to respond to 5-FU and irinotecan.

However, the FOLFOX4 therapy in these two trials showed response rates of 10–13% and time to progression of 4.6–4.8 months, and these results were significantly better than those for LV5FU2. Monotherapy with S-1 seems to be inferior to FOLFOX4 in the second-line setting after 5-FU and irinotecan. Since oxaliplatin is a very potent drug and FOLFOX therapy is now available in Japan, FOLFOX therapy is now recommended instead of S-1 for MCRC after failure with irinotecan and 5-FU.

A phase II study of monotherapy with S-1 for MCRC after failure of chemotherapy regimens containing 5-FU, irinotecan and oxaliplatin demonstrated a response rate of 14.3%, and a median time to progression of 91 days. However, the response rate and PFS after monotherapy with S-1 were 0% and 2.7 months in our cohort 2. The incidence of grade 3 or 4 anemia was 29% associated with total grade 3 or 4 toxicities of 43%. The common S-1 monotherapy treatment schedule in Japan is 40 mg/m2 administered twice daily for 28 days followed by a 2-week rest. But, in this phase II study, the treatment schedule was 35 mg/m2 administered twice daily for 14 days followed by a week's rest. Our patients in 74% patients of cohort 2 were pretreated with the above three regimens (25% patients of this phase II study). Capecitabine, which is another oral fluoropyrimidine with biological modulation, has recently been tried in patients after failure to respond to the three drugs. It showed no objective response in 5-FU-resistant cancer in a phase II trial (12). Its combination with MMC resulted in a response rate of 15% for irinotecan-resistant cancer, but the response rate fell to 5% for cancer resistant to both irinotecan and oxaliplatin. Its combinations with other drugs such as trimetrexate or irinotecan did not show any additional benefit either (13–15). From these results, treatment with oral fluoropyrimidines with biological modulation, such as S-1 and capecitabine, does not appear to provide a satisfactory outcome.

Recently, several studies with molecular targeted agents have been conducted for colorectal cancer refractory to the three drugs. Lenz et al. (16) reported that monotherapy with cetuximab in colorectal cancer patients refractory to irinotecan, oxaliplatin and 5-FU resulted in a response rate of 12% and PFS of 1.4 months. And Jonker et al. (17) reported that in comparison with best supportive care alone, cetuximab treatment in patients refractory to the three anti-tumor agents was associated with a significant improvement in overall survival and in PFS. Chen et al. (18) reported that treatment with bevacizumab in addition to 5-FU and leucovorin brought a response rate of 4% and PFS of 3.5 months in patients with colorectal cancers refractory to both irinotecan and oxaliplatin. Malik et al. (19) reported the efficacy of panitumumab in patients who failed to respond to the three drugs (response rate 8%, PFS 4.2 months) and the phase III trial of panitumumab showed a survival benefit compared to best supportive care (20). The PFS time in phase III trial was 8.5 weeks (2.2 months) for best supportive care. There is no difference between best supportive care and S-1 monotherapy in cohort 1 and 2. Recently, cetuximab therapy has now become available in Japan.

In conclusion, S-1 monotherapy cannot be recommended and new treatments based on molecular target agents should be developed and introduced for use after failure with the three anti-tumor agents.

Conflict of interest statement

None declared.

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