Five percent of all invasive cancers occur in the head and neck region with squamous cell being the predominant pathology. Less than 50% of individuals diagnosed with squamous cell carcinoma of the head and neck (SCCHN) will be cured. 1 Even though the prognosis of early-stage SCCHN is favorable, with survival at 5 years ranging from 70% to 90% following standard therapy, 66% of patients present with stage III and IV disease. The past twenty years of research have integrated chemotherapy into initial curative treatment, utilizing various strategies. Despite aggressive initial management of primary SCCHN, 60% of patients will develop loco-regional recurrence and 25% will develop distant metastases. The three-year survival in this subset of patients remains less than 30%. With a median survival of 6 months, patients who present with incurable or recurrent disease have a poor prognosis with conventional palliative care. 2
The combination of Platinol® and 5-FU is a standard regimen for initial combined modality therapy and also for recurrent and metastatic disease. Randomized trials have demonstrated improved response rate (RR) when utilizing combination Platinol® with 5-FU (30%) versus single agent Platinol®, 5-FU or methotrexate (10%-20%) in advanced SCCHN. Even with the improved RR in combination therapy versus monotherapy, overall survival (OS) still needs improvement. In addition, the Platinol®/5-FU regimen yields significant mucosal toxicity and prolonged administration times. This data warrants the need for new agents and more effective combination regimens. The newer agents demonstrating activity against SCCHN are the taxanes.
Knect, et al., conducted a study looking at the efficacy of three cycles of combined chemotherapy in patients with advanced SCCHN. 3 Taxotere® (75 mg/m 2 on day 1), Platinol® (100 mg/m 2 on day 1) and 5-FU (1000mg/m2 on days 1-5) were administered every 3 weeks. Thirty-six patients with stage III/IV were enrolled. Side effects are reported in Table 1.
Table 1. Incidence of Grade 3/4 Toxicity
Reported responses included 26 CR and 6 PR, with an overall response rate of 91%. The data suggests that this regimen may be more effective than standard Platinol®/5-FU (80%) as induction therapy for advanced SCCHN.
Arnedos, et al., initiated a phase I study to determine the safety and maximum tolerated dose (MTD) of capecitabine in combination with Platinol® in patients with previously untreated advanced and/or metastatic SCCHN. 4 Capecitabine is an oral tumor-selective fluoropyrimidine carbamate designed to mimic continuous infusion 5-FU. Patients were administered up to 6 cycles of the following: Platinol® 100 mg/m2 on day 1, combined with escalating doses (cohorts of 3 patients) of capecitabine (1650, 2000 or 2500 mg/m2 ) divided in 2 equal daily doses on days 1-14, every 3 weeks. Locally advanced SCCHN patients received a maximum of 2 cycles followed by standard chemo-radiation with Platinol® and 5-FU. MTD was defined as > 1/6 patients in any cohort experiencing a pre-defined dose limiting toxicity (DLT) in cycle 1. Twenty patients were enrolled, 15 with advanced disease and 5 with metastatic disease. Due to 3/5 patients experiencing DLT at 2500 mg/m2 (grade 3 diarrhea, grade 3 neurotoxicity and grade 3 stomatitis), six additional patients were treated at the 2000mg/m2 to confirm the recommended dose for the phase II study. None developed DLT. The response rates are reported in table 2.
Table 2. Response Rates
* 18 were evaluable
The study demonstrated that the combination of oral capecitabine with Platinol® has activity in advanced/metastatic SCCHN, with an acceptable side effect profile. This allows for an oral alternative therapy to intravenous 5-FU. A phase II study is ongoing.
Van den Brande, et al., reported on a phase II study, looking at the safety and efficacy of weekly Taxotere® in patients with recurrent and/or metastatic SCCHN. 5 The study included 27 pretreated (other than with prior taxanes) and untreated patients. Taxotere® (36mg/m 2 intravenously) was administered weekly x 6 following pretreatment with corticosteroids. Treatment was repeated every 8 weeks. Eight patients discontinued treatment prior to completion of the 6 cycles for the following reasons: 1 due to toxicity, 5 due to early progressive disease or death and 2 due to deterioration. Nineteen patients received a median of 6 weekly doses (range: 6-27). Five patients had dose reductions due to hematological toxicity (3) and mucositis (2). The following grade 3/4 hematological side effects occurred: leukopenia in 2, neutropenia in 3 and anemia in 10 cycles. Grade 3/4 non-hematological side effects were mucositis (1), infection (2), fatigue (4), nail changes (6) and dyspnea (2). Twenty-three patients were evaluable for response with 3 (13%) partial responses, 9 (39%) stable disease and 11 (48%) progressive disease. The data suggests that treatment with weekly Taxotere® in patients with recurrent and/or metastatic SCCHN is feasible and active with moderate toxicity.
Despite recent advances in multimodality management for SCCHN, prognosis for stages III- IV M0 patients remains dismal.Recurrence often occurs following local therapy with the 3-5 year survival less than 30%. 6 It is becoming clear that the use of chemo-radiation therapy contributes to the improved loco-regional control and overall survival. In order to improve upon the current survival rates, other agents are being studied in combination with radiation therapy. 7
Tishler, et al., assessed the safety and efficacy of a combined modality approach for poor prognosis SCCHN in a phase I trial. 8 Patients received concurrent Taxotere® (D) and concomitant boost radiation therapy (D/XRT) following induction chemotherapy with 3 cycles of a platinum/5-FU based regimen. Poor prognosis was based on initial stage, partial response (PR), non-response (NR) at the primary or nodal site, or a positive post-induction biopsy. Four weekly doses of Taxotere® were administered at 20 mg/m2or 25 mg/m2 with concurrent daily radiation therapy at 1.8 Gy/day followed by bid radiation at 1.8/1.5 Gy for a total dose of 69-72.3 Gy. Seventeen patients have entered the study with 14 having completed D/XRT. All patients developed grade 3 mucositis and pain. There was no acute DLT in either dose of Taxotere®. Thus, Taxotere® at 25 mg/m2 was chosen for the phase II portion of the trial. Six patients were not evaluable for primary site response, but nine CRs, 2 stable/progressive disease were reported. Of the 10 patients with nodal disease following induction chemotherapy, eight achieved a CR after D/XRT. Following completion of D/XRT, 11 patients were disease free, 1 patient experienced a local recurrence at 6 months and 1 patient developed distant metastases at 12 months. This study demonstrated a trend toward PEG-tube dependence and other late toxicity at the 25mg/m 2 dose. Additional patients are being added at the 20mg/m 2 dose and long-term side effects will continue to be monitored. In conclusion, D/XRT has tolerable side effects and promising activity following induction chemotherapy in this subset of patients.
Rapidis, et al., initiated a trial with the primary intent being to demonstrate efficacy in an aggressive chemo-radiation regimen for inoperable stage III/IV SCCHN patients. The regimen in this trial was based on prior results demonstrating activity, utilizing taxanes. 9 Treatment included 2-30 day courses of induction chemotherapy with Taxotere® (40 mg/m2 on days 1 and 15), Platinol® (40 mg/m 2 on days 2 and 16) and 5-FU (325 mg/m 2 on days 2, 3, 4, 16, 17, 18). The regimen was repeated along with concurrent radiation therapy at 200 cGy daily x 5 weeks for a total dose of 66 to 68 Gy in 7 weeks. Two patients died during therapy (1 from cardiotoxicity and 1 hemorrhage from the primary site). Results comparing completion of induction chemotherapy and completion of chemo-radiation are listed in table 3.
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Table 3. RR Comparison between Induction Chemotherapy and Chemo-radiation
Although the follow-up time was limited, early results demonstrate therapeutic efficacy with aggressive chemo-radiation for those who have completed therapy.
Van Den Weyngaert, et al., conducted a phase II safety and efficacy study looking at weekly Gemzar® administered concurrently with XRT in locally advanced SCCHN patients with primary or recurrent disease. 10 Gemzar® has demonstrated excellent radiosensitizing properties in pre-clinical and clinical data. Prior radiation therapy or chemotherapy was allowed as long as therapy had been discontinued > 4 weeks. Twenty-eight patients were enrolled in the study. Gemzar® was administered weekly at 100mg/m 2 IV over 30 minutes (median number of Gemzar® cycles administered was 7) (range 2-8). Radiation was delivered concomitantly with the median dose of 70 Gy (range 50-84.75). No grade 3/4 hematological side effects were reported. Grade 3 non-hematological side effects were as follows: 18/23 mucositis, 14/23 dermatitis, 17/21 dysphasias and 2/23 pain. Six patients were not evaluable for response. One patient achieved a CR and 18/19 (95%) primary disease patients achieved a PR (5CR). The researchers concluded that radiation plus Gemzar® is highly active with tolerable side effects.
Huerta, et al., analyzed a study looking at concomitant chemo-radiation utilizing weekly Paraplatin® and tegafur-uracil for locally advanced SCCHN. 11 Fifty-eight patients were entered into the study. The regimen consisted of weekly Paraplatin® (100mg/m2 IV) and daily, oral tegafur-uracil (400mg/m2 ). Radiation therapy was delivered at 60+ – 10 Gy. Grade 3/4 side effects were as follows: mucositis 47%, emesis 5%, leukopoenia 17%, anemia 9%, thrombocytopenia 10% and diarrhea 7%. Response rates were reported as follows: OS 74%, CRs 41%, PRs 33%, SD 7% and PD 5%. At the time of analysis 19% of patients were alive and disease-free, 12% were alive with disease and 40 patients had died (60% secondary to disease, 5% by other causes and 3% due to toxicity). Median time to progression was 10 months and median survival was 18.4 months. This regimen demonstrated responses, with long-term survival higher than radiation therapy alone. Although the response was good, the side effects warrant that treatment be administered in experienced centers.
Aggressive combined modality therapy with new agents for the treatment of SCCHN and appropriate supportive care conducted in experienced centers has demonstrated improved overall survival results. Van den Brande demonstrated efficacy with moderate toxicity in weekly monotherapy with Taxotere® for recurrent and metastatic disease. Knect’s analysis of 3 cycles of combined Taxotere®/Platinol® and 5-FU showed improved overall response rates compared to the standard Platinol®/5-FU (91% vs 80%). The Arnedos phase I trial of oral capecitabine and Platinol® demonstrated an OS of 94.4% with an acceptable side effect profile. Data regarding chemo-radiation has shown improved loco-regional control and OS as demonstrated by the trials reviewed in this summary. These complex treatments can have an effect on patient compliance. Future research needs to focus attention on toxicity modification without compromising treatment results.
1.Forastiere A, Leong T, Rowinsky E, et al. Phase III Comparison of High-Dose Paclitaxel + Cispltain + Granulocyte Colony-Stimulating Factor Versus Low-Dose Paclitaxel + Cispltain in Advanced Head and Neck Cancer:Eastern Cooperative Oncology Group Study E1393. J Clin Oncol. 2001; 19: 1088-1095.
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