Squamous cell carcinoma of the head and neck (SCCHN) is an increasingly common cause of morbidity and mortality throughout the world1; it occurs particularly in an elderly patient population with heavy exposure to alcohol and tobacco. Approximately 10% of the patients show distant metastases at the time of initial presentation, and chemotherapy represents the only therapeutic option for this subset of patients. Nearly three-quarters of the patients are diagnosed with locoregionally advanced disease (Stage III–IV, M0). In the multidisciplinary treatment of this subset of patients, Phase III studies have established a role for chemotherapy when it is alternated with radiotherapy.2–4 The role of induction chemotherapy prior to local therapy is defined less clearly. In fact, an Italian study5 demonstrated that treatment with induction chemotherapy followed by radiotherapy resulted in improved survival compared with radiotherapy alone in patients with inoperable tumors. Furthermore, three randomized Phase III trials6–8 demonstrated that, in patients with advanced but resectable carcinoma of the larynx or hypopharynx, induction chemotherapy followed by radiotherapy provided organ preservation without reduction in survival compared with conventional surgery and postoperative radiation therapy. However, other randomized studies have failed to demonstrate an improvement in survival for induction chemotherapy followed by radiotherapy over radiotherapy alone.9, 10
There remains an unresolved issue with regard to the specific regimen of induction chemotherapy. Currently, the combination of cisplatin (CDDP) and a continuous infusion of 5-fluorouracil (5-FU)11, 12 is still considered the reference regimen. However, the combination of CDDP and bolus 5-FU may result in response rates comparable to the combination of CDDP and prolonged infusion of 5-FU.13
Clinical trials conducted throughout the world have focused on the modulation of 5-FU in the induction chemotherapy setting with the aim of increasing complete remission (CR) rates, because a significant correlation between CR and survival has been observed.14
A great deal of in vitro and in vivo evidence exists that the cytotoxicity of 5-FU is increased by folinic acid, which significantly improves the response rate to 5-FU in colorectal carcinoma15 and in carcinoma of the head and neck.16 Folinic acid is a precursor of a reduced folate, 5,10-methylene-tetrahydrofolate (5,10-CH2-THF), which enhances the inhibition of thymidilate synthase (TS) induced by the 5-FU anabolite, 5-fluoro-2-deoxyuridine-5′-monophosphate (FdUMP), through the formation of a ternary complex (consisting of FdUMP, 5,10-CH2-THF, and TS), leading to the covalent binding of FdUMP to the enzyme.
In the past, methotrexate (MTX) has probably been the most commonly used drug for the palliation of patients with recurrent SCCHN; response rates were reported to average approximately 30%17 with acceptable toxicity. Also, MTX has been studied extensively as a means of achieving adequate biochemical modulation of 5-FU, and MTX inhibits purine synthesis, leading to intracellular accumulation of 5-phosphoribosyl-1-pyrophosphate (PRPP), which leads to an increased formation and subsequent incorporation into RNA of 5-FU-triphosphate (5-FUTP), the final 5-FU metabolite that inhibits RNA synthesis. Furthermore, the polyglutammated form of MTX is a strong TS inhibitor itself.
Cisplatin on its own does not have a very high or reproducible activity against carcinoma of the head and neck: In fact, although response rates average approximately 30% and vary between 0% and 41%, responses are often short lasting, and recurrent disease is often resistant to second-line chemotherapy18; however, both in vitro and in vivo studies suggest a 5-FU/CDDP synergism that can be explained mainly by the CDDP-induced increase in intracellular levels of reduced folates.19
In a previous Phase I study,20 we treated patients with locoregionally advanced and metastatic SCCHN with alternately escalating doses of bolus 5-FU plus CDDP, MTX, and L-folinic acid (LFA) every 2 weeks. The regimen was well tolerated, and a significant antitumor activity was observed at the dose level, which was selected for the present Phase II study.
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- PATIENTS AND METHODS
The vast majority of patients with newly diagnosed SCCHN present with locoregionally advanced disease. This subset of patients represents a therapeutic challenge; in fact, conventional radiotherapy, which has been considered thus far as standard treatment for unresectable SCCHN, is highly palliative because of the risk of local and distant recurrences.18 Recently, a role for chemotherapy as induction therapy before surgery or radiotherapy or alternated with radiotherapy2–4 has been demonstrated in Phase III studies. In particular, a large Phase III trial5 demonstrated an improved survival for patients with inoperable or unresectable disease treated with chemotherapy and radiotherapy compared with those treated with radiotherapy alone. However, other randomized trials have failed to achieve similar results.9, 10 The role of induction chemotherapy in patients with operable lesions is better established; in fact, in these patients, trials of induction chemotherapy with strategies for primary tumor site preservation have demonstrated that organ preservation is possible for tumors of the hypopharynx or larynx, with clear functional and cosmetic advantage, without a different survival outcome with respect to conventional treatment, including surgery and radiotherapy.6–8 The rationale for application of neoadjuvant chemotherapy includes better delivery of drugs to tumors with an intact vascular supply, better utilization of local therapy in a debulked tumor, and better tolerance of higher doses of chemotherapy by previously untreated patients. Also, in tumors characterized by rapid development of drug resistance, such as SCCHN, early application of combination chemotherapy at optimal dose intensity may prevent the development of resistant cell clones in the primary tumor or in clinically latent micrometastases.
The combination of CDDP and continuous infusion 5-FU represents a widely used regimen for induction chemotherapy in locally advanced SCCHN,11, 12 although no survival benefit has been observed in randomized trials comparing this combination with either MTX alone22 or other combinations of active drugs.23 The PF regimen was reported initially as having a clinical CR rate of 54% in 61 patients with advanced but operable and resectable SCCHN.24 However, subsequent evaluation indicated that the true CR rate after three courses was lower, i.e., between 20% and 35%.8 Because the achievement of a CR to the induction chemotherapy has been demonstrated to have a favorable impact on survival,14 the identification of regimens that may result in higher CR rates has achieved a high priority. Among the treatment strategies that have been experimented with to accomplish this goal (multiple courses of therapy, high CDDP and/or 5-FU dosages, increased dose delivery intensification through weekly CDDP administration, combination with other agents25–28), the adequate biochemical modulation of 5-FU with agents like MTX, hydroxyurea, α-interferon, and folinic acid seems to be the most promising.16, 29–31 Four studies have now been completed with the combined use of CDDP, 5-FU, and leucovorin (PFL) as induction chemotherapy in locally advanced SCCHN,16, 32–34 with objective response rates ranging between 45% and 90% and with CR rates ranging between 23% and 54%. In all of these trials, 5-FU has been administered by continuous infusion at doses between 500 mg/m2 and 1000 mg/m2 for 5 days. The 54% CR obtained by Clark et al.34 in 102 patients looks particularly favorable, because it is associated with excellent FFS and overall survival after subsequent locoregional treatment (51% and 52% 5 years after the study onset, respectively).
In the present trial, we tried to combine three active drugs in carcinoma of the head and neck while exploiting the biochemical modulation of 5-FU by the double pretreatment with MTX and LFA, in agreement with our wide experience in advanced gastrointestinal carcinoma.35, 36 Patients with distant metastases were included in our trial as well. The schedule of drug administration was chosen in keeping with experimental and clinical data, which suggest that an adequate interval should elapse between MTX and 5-FU administration,37 whereas a relatively high dose of folate is indicated immediately before the administration of 5-FU. We preferred to use a regimen that included intravenous bolus 5-FU administration, because it could be administered entirely on an outpatient basis, thus substantially lowering cost and improving patient compliance. Previous data confirming the activity of the drug when it is administered as intravenous bolus in this setting13 encouraged us in the choice of this treatment schedule.
The treatment used in the current study was generally well tolerated. The biweekly schedule allowed the concurrent administration of three active drugs with a high dose intensity at the expense of a toxicity that is significantly lower than that reported in similar studies.
In fact, only one death occurred during the treatment, and its correlation to the treatment itself is at least questionable. Neutropenia represented the most frequent toxic effect, occurring in nearly all patients and reaching Grade 3–4 in 50% of them; however, febrile complications were unusual and never required hospitalization, because they were always managed at home with appropriate intravenous antibiotics. Patients were never admitted to the hospital before their planned time for chemotherapy recycling because of overwhelming toxicities of any kind. Nausea and vomiting were very well managed with 5HT3 blocking agents. The incidence of both mucositis and diarrhea was much lower than that reported in other studies with PFL combination34 in which frequent dose reductions of fluorouracil and leucovorin were required to avoid these toxicities. Alterations of renal function were always minor, and peripheral neuropathy never represented a major problem.
The response rate of our combination was 80%, which is in keeping with data reported in studies with PFL regimen, although the CR rate is substantially lower than that reported by Clark et al.34 Patients who achieved an objective response to chemotherapy obtained a CR to subsequent radiotherapy in 100% of cases; on the other hand, only 3 of 6 patients who did not have a response to chemotherapy obtained a CR to subsequent radiotherapy. This observation, although it is devoid of statistical significance due to the low number of patients, lends support to the idea that response to induction chemotherapy might be a predictive factor for response to subsequent radiotherapy. In the current trial, the percentage of patients who were rendered disease free after systemic plus locoregional treatment was considerable and was even higher than that reported by Clark et al.34; this is in keeping with our survival data, which look quite encouraging; in fact, after a median follow-up of 20 months, the median overall survival was 21 months. These survival data compare favorably with the generally accepted figures for these patients,38 even though they look less impressive than those reported by Clark et al.34 However, in their study, 5-FU was administered by continuous infusion at a dose of 800 mg/m2 for 5 days, and frequent dose reductions were required to improve control of toxic effects; furthermore, the incidence of oral stomatitis, diarrhea, and unanticipated hospitalization added significantly to the treatment-related morbidity experienced by these patients. Our schedule is associated with significantly lower toxicity and is far less costly, because it does not require pumps or other expensive devices for drug administration, it can be administered entirely on an outpatient basis, and it is accepted better by patients. We think that the cost effectiveness of our regimen is well worth emphasizing, not only compared with different schedules of similar regimens but also compared with regimens that include new active drugs, such as taxanes.
We conclude that our combination chemotherapy regimen definitely deserves further evaluation; in particular, our next plan is to integrate our regimen within a program of alternating radio/chemotherapy, which has previously provided a survival advantage when compared with neoadjuvant chemotherapy followed by definitive radiotherapy2. In this trial, adequate dose intensity will be maintained by concurrent cytoprotection with amifostine.