Abstract
Background: This retrospective study evaluates the efficacy and safety of S-1 chemotherapy or S-1 followed by low-dose docetaxel chemotherapy for recurrent head and neck cancer. Patients and Methods: S-1 was administered to 21 patients with recurrent head and neck cancer, in outpatient settings. Of these 21 patients, 8 were additionally administered a low dose of docetaxel fortnightly. Results: The survival rate of patients with squamous cell carcinoma of the head and neck was 59.1% for 12 months and 17.5% for 24 months, with a median survival time of 18 months. Time to progression of more than 12 months was shown by 4 patients (22.2%). Most adverse events were mild (up to grade 2). Conclusion: S-1 therapy is considered a safe and effective treatment option. From the viewpoint of tumour dormancy, S-1 therapy is a useful vigorous anticancer treatment that can be provided while maintaining patients' quality of life in recurrent cases.
Salvage surgery and/or chemo-radiation therapy is usually the first choice for the treatment of recurrent head and neck cancer, after definitive therapy. However, chemotherapy plays an important role in the treatment of recurrent post-irradiated, unresectable and/or distant metastatic head and neck cancer (PUMHNC).
S-1 is an oral anticancer agent containing a combination of 2 modulators and tegafur, which is a pro-drug of 5-fluorouracil (5-FU). One of the modulators is 5-chloro-2,4-dihydroxypyridine, which causes prolonged retention of 5-FU in the blood. Furthermore, it enhances the pharmacological actions of 5-FU by competitively inhibiting its degradation. The other modulator is potassium oxonate, which is localized in the mucosa of the gastrointestinal tract after oral administration and alleviates gastrointestinal toxicities induced by 5-FU (1, 2). S-1 alone has been reported to produce a good response rate (46.2% in an early phase II study and 28.3% in a late phase II study for advanced head and neck cancer) (3, 4) and can be administered long-term in outpatient settings, even to patients who have undergone definitive therapy (5).
Because PUMHNC is usually incurable, the goal of treatment is to achieve prolonged survival while maintaining quality of life of patients. Therefore, the study focused on a good response rate and the possibility of long-term administration of S-1 in outpatient settings and indicated S-1 chemotherapy for PUMHNC with the aim of achieving prolonged survival without interrupting daily life. Here, both the therapeutic and adverse effects of outpatient chemotherapy with S-1 and S-1 followed by a low dose of docetaxel (DOC) are reported.
Patients and Methods
The participants in this study were 21 patients with recurrent PUMHNC to whom S-1 administration was initiated during the period from September 2003 to July 2007. In this study, unresectable cases were defined as those involving the cervical vertebrae, brachial plexus, deep neck muscles or carotid artery. Clinical characteristics of the patients are shown in Table I. All the patients were initially administered S-1 orally at a dosage based on the patient's body surface area (BSA) as follows: BSA <1.25 m2, 80 mg/d; 1.25 m2 ≤BSA <1.5 m2, 100 mg/d; and BSA ≥1.5 m2, 120 mg/d. S-1 was given for 14 consecutive days, followed by a 7-day rest period. In some cases, the dosage was adjusted between 80 mg/day and 120 mg/day, depending on renal function, bone marrow function, or other side-effects. After S-1 therapy, 8 patients were additionally administered DOC at a dose of 20 mg/m2 of BSA fortnightly. DOC was administered as an alternative for S-1 therapy, since it became very difficult to continue with S-1 therapy because of the development of uncomfortable side-effects such as anorexia and hyperpigmentation. Both the chemotherapies were performed in outpatient settings for all the patients and continued until severe side-effects developed, or the patients refused to continue with the therapies because of the development of uncomfortable side-effects. The survival period was calculated from the initiation of S-1 administration to death or 1 January 2008, by using the Kaplan-Meier method. The time to progression (TTP) was defined as the period from the initiation of S-1 therapy to the first day when progression was noted.
Results
S-1 administration period, excluding periods of rest, ranged from 2 to 74 weeks (mean, 18.2 weeks). Total dose of S-1 ranged from 1,400 mg to 62,160 mg (mean, 13,887 mg). DOC administration ranged from 2 to 20 times (mean, 8.4 times). Total dose of DOC ranged from 64 mg to 680 mg (mean, 277 mg). Of the 21 patients, 8 patients, 7 with tumours and 1 without any tumour, survived until 1 January 2008; the survival duration of these 8 patients after the initiation of S-1 administration ranged from 1 to 36 months. The response rate was only 9.5% (only 2 out of the 21 cases: one case of complete response [CR] and another of partial response [PR]). The cumulative survival rates of all the patients (n=21) were 65.3% and 22.4% for 12 months and 24 months, respectively, with a median survival time (MST) of 18 months. The cumulative survival rates of the squamous cell carcinoma (SCC) patients (n=18) were 59.1% and 17.5% for 12 months and 24 months, respectively, with an MST of 18 months (Figure 1). Six patients (28.6%), including 4 SCC patients (22.2%), showed TTP of more than 12 months. Among them, 3 SCC patients (16.7%) were observed to have stable disease (SD) for more than 14, 24 and 32 months (Table II). Most adverse events were mild, i.e. up to grade 2 according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) (Table III). Only 1 patient, with a performance status (PS) of 2, had grade 3 leukocytopenia and thrombocytopenia; however, the patient recovered quickly after the withdrawal of medication.
Discussion
Many reports have indicated intensive combination chemotherapy to be effective in treating recurrent head and neck cancer with improvement in response rate. However, thus far, it has not been proved whether the high response rates translate into improved survival rates in recurrent head and neck cancer (6). In addition, it is doubtful whether intensive chemotherapies improve a patient's quality of life in recurrent cases because such chemotherapies generally require hospitalization as well as inducing high-grade toxicity (6). Unfortunately, despite many trials conducted using platinum drugs, taxanes, methotrexate, bleomycin, fluorouracil, etc., no specific agent or regimen alone is known to significantly increase survival in advanced/metastatic head and neck carcinoma (7-14). However, a meta-analysis revealed that median survival trends slightly favoured single agents over combinations (15). In the light of these facts, S-1 and DOC were used in single-agent chemotherapies for PUMHNC. Moreover, these chemotherapies are advantageous since they can be performed in outpatient settings because of their relatively mild side-effects. Most of the cases (20 out of the 21 cases, 95.2%) had adverse effects of less than grade 2, which were mainly myelosuppression and gastrointestinal tract discomfort. Consequently, all the patients could be treated in the outpatient settings with comparatively long-term drug administration. Thus, the patients could undergo anticancer therapy while maintaining their quality of life.
Here, the concept of tumour dormancy needs to be addressed. Browder et al. revealed that frequent administration of a low dose of cyclophosphamide suppressed the growth of drug-resistant Lewis lung carcinoma 3 times more effectively than the conventional administration in a mouse model (16). Furthermore, Takahashi et al. mentioned that tumour shrinkage is not essential for improving survival time (17). Thus, according to this concept, prolonged survival may be achieved with fewer side-effects and quality of life can be maintained. The single-agent chemotherapies reported here, which were performed using S-1 and a low dose of DOC, were continuity-conscious therapies based on the concept of tumour dormancy. In other words, the aim was to achieve prolonged survival without tumour shrinkage by continuing the chemotherapies for as long as possible. In the presented cases, long-term administration and sufficient total dosage were ensured; as a result, a favourable MST was obtained despite the patients' response rate of only 9.5% . MST of 1.8-12.1 months has been reported in many trials involving intensive chemotherapy for recurrent head and neck cancer (6). For the SCC patients in this case, MST was 18 months. Because of the differences in patients' backgrounds such as their PS, treatment history or their clinical status at the time of the diagnosis, the results could obviously not be compared with those of the previous studies. However, with regard to only recurrent PUMHNC cases, the results are satisfactory. The usefulness of S-1 chemotherapy and S-1 followed by low-dose DOC chemotherapy for treating recurrent and/or metastatic cases has been suggested by using MST or TTP as the end point and not the reduction rate of tumour size. As shown by this study, continuation of chemotherapy considering no change (NC) in tumour size is important because of the possibility of achieving a favourable MST despite an unfavourable response rate. Prospective randomized trials based on approaches aimed at cancer stability as the end point of factors such as MST or TTP are required for identifying treatment options for incurable cases like those of PUMHNC.
Although 12 out of 21 patients had undergone previous chemotherapy, there was no association between the effect of outpatient chemotherapy and the presence/absence/kinds of previous chemotherapy. Among the 12 patients, 2 patients (patients number 12 and 14; Table II) who showed TTP of more than 24 months after therapy despite the effect of DOC + cisplatin + fluorouracil (TCF) chemotherapy, which was administered just before S-1 therapy, had progressive disease (PD). By using a mouse model, Browder et al. and Klement et al. reported that continuous low-dose chemotherapy can cause long-term suppression of tumour proliferation, even in the case of drug-resistant tumours. Furthermore, they indicated that one of the action mechanisms of continuous low-dose chemotherapy involves its anti-angiogenic effect (16, 18). They also reported that such an effect of continuous low-dose chemotherapy may delay or prevent the acquisition of drug resistance by cancer cells, unlike conventional dose chemotherapy (16, 18). It is possible that the same effects are exerted in the case of these patients. These facts suggest that continuous low-dose chemotherapy may be effective for the treatment of patients with recurrent cancer, even for those who have acquired drug resistance by previous chemotherapy.
S-1 chemotherapy and S-1 followed by low-dose DOC chemotherapy for recurrent and/or metastatic head and neck cancer could safely be performed in the outpatient settings. From the viewpoint of tumour dormancy, S-1 chemotherapy and S-1 followed by low-dose DOC chemotherapy were useful vigorous anticancer treatments for incurable recurrent and/or metastatic head and neck cancer, maintaining the quality of life of the patients.
Footnotes
- Received October 27, 2008.
- Revision received December 1, 2008.
- Accepted December 11, 2008.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved