Salvage therapy with oral etoposide in recurrent and/or metastatic squamous cell carcinoma of the head and neck

Background: The purpose of this retrospective evaluation was to assess the palliative effect of oral etoposide in heavily pretreated patients with squamous cell carcinoma of the head and neck. Patients and Methods: Between October 1995 and February 2003, a total of 26 patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with oral etoposide. Therapy consisted of etoposide at a total dose of 100 mg daily for 7 days and was repeated every 4 weeks until progression of disease or for a maximum of 8 courses. Eighteen patients underwent primary surgery of the tumour followed by adjuvant irradiation or surgery after neoadjuvant radiochemotherapy. Eight patients had primary irradiation with or without concomitant chemotherapy. All patients previously received at least one palliative chemotherapy with cisplatin/5-floururacil (5-FU) or cisplatin/taxotere. Patients did not routinely receive anti-emetic medication. Results: All patients were eligible for toxicity and survival assessment, and 24 of 26 patients for response evaluation according to an intention-to-treat principle. Two patients had a partial response (8 percent); disease was stable in 9 patients (35 percent) and progressed in 13 patients (50 percent). The median time to progression for all patients was 3 months (range, 2-54), and median overall survival was 10 months (range, 2-52). Toxicity was in general mild and moderate (Grade 1 and 2), except three patients, who experienced Grade 3 anaemia, and one patient who had Grade 3 thrombocytopenia without bleeding complications. Severe nonhematologic adverse reactions were not seen, except for alopecia. Conclusion: Our data suggest that oral etoposid is markedly effective, in regard to stabilization of disease and survival, and an excellent tolerated therapy for pretreated patients with recurrent and/or metastatic head and neck carcinomas. Its advantage over other commonly used and more intensive regimens such as 5-fluorouracil (5-FU) + cisplatin or taxane-containing combinations is its superior tolerance, in particular the incidence of nausea and vomiting, complete alopecia, and/or hematologic complications.     

Clinical phase II evaluation of paclitaxel in combination with cisplatin in metastatic or recurrent squamous cell carcinoma of the head and neck

Background: Paclitaxel as single agent has shown marked activity in several malignancies. The aim of the present phase II trial was to determine the activity of paclitaxel/cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.Patients and methods: 200 mg/m² paclitaxel was administered over three hours followed by cisplatin (100 mg/m²), repeated every 22 days. Twenty-eight patients were entered and received a total of 99 cycles (median 2, range 1–6). All patients were evaluable for toxicity, and 25 for response.Results: Hematologic toxicities included leukopenia CTC grade 3 in 13 patients, and grade 4 in five patients, neutropenia grade 3 in nine patients, and grade 4 in eigth patients, grade 3 anemia and grade 2 thrombocytopenia in one patient each. Non-hematologic toxicities included hypotension grade 2 (six patients), grade 3 (four patients), and grade 4 (two patients). A decline in renal function was observed in 15 courses and 10 patients, leading to a median delay of 2.5 days. Neurosensory and neuromotor toxicity grade 1 were observed in 13 patients (grade 2: 12 patients; grade 3: one patient), myalgia grade 3 in one patient, asthenia grade 3 in two and grade 4 in one patient. Partial responses were observed in 12 patients for an overall response rate of 48% (95% CI: 28%–68%) with a median response duration of 6.5 months (range 1-10 months). Stable disease was observed in seven patients, of who two also had clinical benefit.Conclusions: Paclitaxel 200 mg/m² administered over three hours combined with cisplatin 100 mg/m² is an active regimen warranting further evaluation.     

An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

Background: Vinorelbine is an active drug in the treatment of lung and breast cancers and has a favorable toxicity profile. Many clinical trials have demonstrated its antitumor activity in other tumor types including squamous cell carcinoma of the head and neck (SCCHN). We investigated the efficacy and tolerability of vinorelbine in patients with recurrent and/or metastatic SCCHN, previously untreated by chemotherapy.Patients and methods: Seventy-one patients with locoregional recurrent and/or metastatic SCCHN were treated with vinorelbine at a dose of 30 mg/m2/week i.v. by short-duration infusion on an out-patient basis. Doses were adjusted according to tolerance.Results: Two complete and seven partial responses were observed among 56 evaluable patients, yielding a response rate of 16% (95% confidence interval (CI): 8%–28%). The overall response rate of all eligible patients (63) was 14%. The responses were seen in recurrent tumors, lymph nodes and in lung metastases, and their median duration was 19 weeks (12–63). The main toxicity, severe and reversible neutropenia (grade 3–4) occurred in 53% of the 69 evaluable (for toxicity) patients. Twelve patients developed severe bronchopulmonary infections, which caused two early deaths. Constipation was observed in 31 patients (45%). Other gastrointestinal toxicities, asthenia, acute pain syndrome and peripheral sensory neuropathy, were mild to moderate. The median number of treatments was seven cycles and the median relative dose intensity of vinorelbine was 85% (25.5 mg/m2/week).Conclusions: Vinorelbine is an active drug, with acceptable toxicity, in recurrent and/or metastatic SCCHN, at the dose and schedule administered in the present study. Further evaluation in association with other agents and/or radiotherapy is warranted.     

Phase II study of rubitecan in recurrent or metastatic head and neck cancer

PURPOSE: Rubitecan is an oral camptothecin analogue that has shown activity against a broad spectrum of human tumor xenografts and has been tested in several diseases. PATIENTS AND METHODS: In the present study, 19 patients with incurable, recurrent or metastatic head and neck cancer were treated with rubitecan at the initial dose of 1.5 mg/m(2) x 5 days per week. An appropriate dose modification program was set up according to the observed toxicities. RESULTS: Thirteen out of the 19 treated patients were formally evaluable for tumor response. Ten patients had a disease progression and three patients had a stabilization of disease as their best response. The mean duration of stable disease was 141 days. Median survival was 16 weeks (range 2-22 weeks). Three patients died during the study or less than a month after their last dose of study medication. Hematologic toxicity was serious in this study since four patients discontinued their participation because of severe anemia. The drug was also associated with grade 1-4 neutropenia, and with 1-3 thrombocytopenia. CONCLUSION: We conclude that rubitecan is not effective as a single-agent in recurrent or metastatic head and neck cancer with the doses and schedule used in this study.     

Docetaxel and cisplatin: An active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck

Background: Docetaxel and cisplatin are among the most active antitumor agents in head and neck cancer, and phase I studies found the combination of the two drugs to be feasible. The EORTC ECSG performed a multicenter phase II study in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck to evaluate the antitumor efficacy and toxicity of this combination.Patients and methods: Eligibility criteria included written informed consent, a WHO performance status <2, life expectancy of >12 weeks, and adequate bone marrow, liver and renal function. Neoadjuvant pretreatment with cisplatin-based chemotherapy or prior radiotherapy were allowed. Patients were ineligible if pretreated with taxoids, had CNS involvement, concurrent malignancy, peripheral neuropathy, or no measurable disease. Treatment consisted of docetaxel 100 mg/m2 (one-hour i.v. infusion), followed by cisplatin 75 mg/m2 (three-hour i.v. infusion), repeated every three weeks. Supportive care included hydration, 5HT3- antagonists, and corticosteroids.Results: Forty-four patients (median age 55 years, range 35–76) entered the trial; 41 patients were eligible, 164 cycles of treatment were evaluable for toxicity, and 31 patients for response. Fourteen patients had undergone prior surgery, 15 had received radiotherapy, and five had had chemotherapy. A median number of four treatment cycles (range 1–6) was given. Hematologic and non-hematologic toxicities were common, but hypersensitivity reactions and fluid retention were very infrequent due to corticosteroid prophylaxis. Four patients were taken off the study due to toxicity, and one toxic death occurred due to pneumonia. Among 41 eligible patients, objective responses as confirmed by independent review included six complete remissions and 16 partial remissions, resulting in an overall response rate of 53.7% (95% confidence interval: 37.4%–69.3%). Responses occurred in locally advanced, recurrent and metastatic disease, both in pre- and non-pretreated patients. Of 22 evaluable, non-pretreated patients with locally advanced or metastatic disease, five achieved complete responses, and 14 partial responses. Observed among nine evaluable pretreated patients with locally advanced or metastatic head and neck cancer were one complete response and two partial responses.Conclusion: The combination of docetaxel and cisplatin is feasible and active in locally advanced, recurrent, and metastatic squamous cell carcinoma of the head and neck.     

Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma

Introduction: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M HNSCC) is rapidly evolving.

Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC.

Expert commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel.

Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.     

Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck

PurposePlatinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN.MethodsPatients received cetuximab 250 mg/m² (loading dose: 400 mg/m²) days 1, 8 and 15; pemetrexed 500 mg/m² + cisplatin 75 mg/m² on day 1, q3w up to six cycles and folic acid, vitamin B₁₂ and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated.ResultsSixty-six patients received ?1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred.ConclusionsEfficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.     

Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial.

BACKGROUND: The aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: Seventy patients with previously untreated stage III-IV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m(2) as a 3-h infusion on day 1, cisplatin 100 mg/m(2) on day 2, and 5-fluorouracil (5-FU) 500-750 mg/m(2)/day as a 24-h continuous infusion on days 2-6, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m(2)/day to 500 mg/m(2)/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery. RESULTS: Two-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 2-3, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 40-63 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively. CONCLUSIONS: The PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.     

Paclitaxel, cisplatin, leucovorin, and continuous infusion fluorouracil followed by concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck

The primary objective of this phase II study was to access the complete response (CR) rate to a new innovative induction regimen in patients with locally advanced head and neck cancer (LA-HNC). From October 2000 until October 2003 a total of 38 eligible patients (33 men and 5 women) entered the study. The large majority of them presented with a performance status of 0–1 and with clinical stage IV disease. Treatment consisted of three cycles of induction chemotherapy (IC) with paclitaxel 175 mg/m² in a 3-h infusion on d 1, leucovorin (LV) 200 mg/m² over 20 min immediately followed by FU 400 mg/m² bolus and then 600 mg/m² as a 24-h continuous infusion on d 1 and 2 and a cisplatin 75 mg/m² over 1-h infusion on d 2 every 3 wk. This was then followed by radiation (70 Gy) and weekly cisplatin 40 mg/m². After the completion of IC, 6/38 (16%) patients had CR. The CR rate was increased to 66% post-concomitant chemoradiotherapy (CCRT). Neutropenia (37.5%), pain (62%), nausea/vomiting (21%), and alopecia (79%) were the most frequent side effects during IC. The most pronounced toxicities during chemoradiotherapy were stomatitis (62.5%) and xerostomia (53%). Median time to progression was 11.0 mo and median survival 16.7 mo. One- and 2-yr survival rates were 73% and 38%, respectively. In conclusion, this novel induction regimen is active, is well tolerated, and can be successfully followed by CCRT with weekly cisplatin. CCRT should remain standard treatment for patients with LA-HNC. Novel induction combinations, such as that reported in the present study, should be evaluated in combination with CCRT only in the context of clinical trials.     

Management and palliative chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck with distant metastases or locoregional relapse not amenable to radical surgery or radiation therapy are incurable. Median overall survival is approximately 10 months and the site of relapse, frequently in the head and neck area, is responsible for important local and regional complications that significantly impact quality of life. This article will focus on the general management and treatment of these recurrent and/or metastatic patients. We will discuss the challenges faced by the clinician when diagnosing tumor recurrence, as well as the indications and the limitations of the locoregional and systemic treatments available to treat this population.     

A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck.

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m(-2) by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1-9) per patient. The median cumulative dose was 449 mg m(-2). Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1-50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4-52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h(-1) m(-2) and an area under the curve of 6.00 microg ml(-1) h(-1) was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.     

Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study

Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with Zubrod performance status 0-2. Docetaxel 65 mg/m² and carboplatin (AUC of 6) were given IV in a 21-day cycle to 68 patients. Response probability was 25 percent (95%CI: 15-38). The major toxicity observed was neutropenia, with 36 patients (61 percent) experiencing Grade 3 or worse. Median progression-free survival was 3.8 months (95%CI, 3.1-4.8) Median overall survival was 7.4 months (95%CI, 6.2-8.9). The results of this study suggest this regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status.     

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

Purpose

To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials.

Patients and methods

Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m²/day: 4 patients; 15 mg/m²/day: 4, 20 mg/m²/day: 5 and 25 mg/m²/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level.

Results

The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m² level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m² level (grade 3 GI disorders), one at 10 mg/m² level (grade 4 mucositis). PK analysis showed no significant difference of C_max values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum).

Conclusion

Due to 3 DLTs experienced at 25 mg/m²/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m²/day.     

Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck

Background A phase I/II trial of concurrent docetaxel and radiation for head and neck cancer was conducted to estimate the recommended dose schedule of docetaxel, and then to evaluate the therapeutic benefit.Methods Patients received radiation in 2.0-Gy single daily fractions to a total dose of 60Gy. Docetaxel was administered weekly for 6 consecutive weeks.Results Docetaxel 15mg/m² was considered the maximum tolerated dose (MTD). The recommended dose was decided as 10mg/m². The phase II study was conducted using docetaxel at 10mg/m². Thirty-nine patients were enrolled. The overall response rate was 96.9%. The prognosis of the complete response (CR) patients was significantly better than that of the partial response (PR) patients. Grade 3 or 4 adverse events consisted of lymphopenia, stomatitis, and anorexia. Thirty-two of the 35 eligible patients showed high compliance, of over 90%, and their toxicities were manageable.Conclusion Even low-dose docetaxel shows a strong effect in combination with radiation, with a high survival rate in CR patients. The effect on survival will be assessed by further follow-up.Yukio Inuyama for the Japan Cooperative Head and Neck Oncology Group (JCHNOG)     

Outpatient chemotherapy for recurrent and/or advanced squamous cell carcinoma of the head and neck

Background. The efficacy of the treatment of cancer has been traditionally judged by outcome measures such as disease-free survival, overall survival, and tumor response rate. Our goal of salvage and/or adjuvant chemotherapy is to improve not only the survival period but also the quality of life (QOL). The conventional regimens containing cisplatin (CDDP) require hospitalization of patients, which has been responsible for disappointingly low QOL. Thus, we developed a new outpatient regimen that has same magnitude of activity and less toxicity compared with conventional CDDP-containing regimens. Methods. Sixteen patients with recurrent or advanced head and neck cancer were treated by the outpatient setting Long-CF regimen. The Long-CF regimen consisted of cisplatin (CDDP) (CDDP, 5 mg/m²/2 h infusion on days 1–5, 8–12, 15–19, 22–26) and 5-fluorouracil (5-FU) [oral administration of tegaful-uracil (UFT-E), 400 mg/body on days 1–28]. Results. Among 16 patients entered in this trial, 1 patient was disqualified from analysis for reasons of protocol violation. Of 15 patients evaluable for response, 2 complete responses (13%) and 4 partial responses (27%) were achieved, with an overall response rate of 40%. Myelosuppression was the major side effect. Leukopenia and anemia (13% greater than WHO grade III) were dose-limiting toxicities. Other adverse reactions including mucositis were all mild and transient. Conclusion. As this regimen is given in an outpatient setting, we concluded that this regimen produced a beneficial effect in patients with recurrent and/or advanced head and neck cancer. Moreover, the toxicity of this regimen was limited; thus, attempts to increase the complete response rate by dose escalation or intensive scheduling appear warranted. Received: May 18, 1998 / Accepted: May 27, 1999     

Single-agent docetaxel in patients with platinum-refractory metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN)

BACKGROUND: The objective of this retrospective study was to investigate the efficacy and tolerability of single-agent docetaxel in patients with platinum-refractory squamous cell carcinoma of the head and neck (SCCHN). METHODS: Platinum-refractory disease was defined as cancer with documented tumor progression during platinum-based treatment or recurrence within 6 months after platinum-based chemoradiotherapy. Patients fulfilling the following criteria were enrolled: histologically confirmed SCCHN, excluding nasopharyngeal cancer; measurable metastatic lesions as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST); and platinum-refractory disease. Docetaxel (60 mg/m2) was administered every 3-4 weeks and continued unless there was evidence of disease progression or unacceptable toxicity. RESULTS: Twenty patients were recruited. Overall response rate was 10% (2/20) and tumor control rate was 25% (5/20). Median progression-free and median overall survival times were 1.7 and 4.6 months, respectively. The most common hematological toxicities were leucopenia (grade 4: 35%) and neutropenia (grade 4: 30%). Grade 3 febrile neutropenia and grade 3 mucositis (functional/symptomatic) each occurred in two patients (10%). One fatal bleeding occurred during this treatment, however, the relation between this event and docetaxel was unlikely. Median inpatient period during treatment was 5.4 days (range, 0-50 days). CONCLUSION: A single-agent docetaxel regimen appeared to offer an acceptable clinical profile in patients with platinum-refractory SCCHN.     

Effectiveness of pharmacokinetic modulating chemotherapy combined with cisplatin as induction chemotherapy in resectable locally advanced head and neck cancer: phase II study

Purpose

To test the efficacy and safety of pharmacokinetic modulating chemotherapy combined with cisplatin (PMC-cisplatin) as induction chemotherapy (ICT) before definitive treatment in patients with respectable locally advanced head and neck squamous cell carcinoma (HNSCC).

Patients and methods

Patients with stage III–IV resectable locally advanced HNSCC were enrolled. All eligible patients received PMC-cisplatin regimen as ICT containing intravenous leucovorin 250 mg/m² and 5-FU 600 mg/m² on day 1, oral tegafur–uracil (UFUR^®) 250 mg/m²/day on days 1–5, repeated every week for six courses. Cisplatin 100 mg/m² was given during the first and fourth courses of PMC. For ICT responders, concurrent chemoradiotherapy (CRT) with cisplatin/tegafur–uracil/70 Gy radiotherapy was performed. Salvage surgery plus postoperative CRT was given to ICT non-responders.

Results

The overall response rate of PMC-cisplatin as ICT was 76%, including a complete remission rate of 23%. The overall organ preservation rate of the multimodality treatment was 75%, with 97% in ICT responders. At a median follow-up of 25 months, 47% of the patients were still alive and disease-free. The superiority of disease-free survival was demonstrated in ICT responders. The 3-year overall survival rate was 67%. The toxicity of treatment was acceptable.

Conclusions

Application of PMC-cisplatin as the induction chemotherapy before definitive treatment provides a promising result in treatment response and survival of advanced HNSCC. This regimen is effective and safe, and further studies considering the combination of PMC with other chemotherapeutics such as taxanes to improve the clinical outcome of advanced HNSCC is warranted.     

A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck

Purpose SU5416 is a novel small organic molecule that non-competitively inhibits the phosphorylation of the VEGF tyrosine kinase receptor, Flk-1. This phase IB study was performed to determine the safety, pharmacokinetics, and preliminary efficacy of the combination of SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck.Methods Enrolled in the study were 12 patients with biopsy-proven recurrent or metastatic carcinoma of the head and neck. Six patients received intravenous SU5416 110 mg/m² on days 1, 15, 18, 22 and 25, and paclitaxel 70 mg/m² on days 8, 15 and 22. Since two patients experienced a dose-limiting toxicity (DLT) in cohort 1, the next six patients received identical treatment as above except the paclitaxel dose was reduced to 55 mg/m² per week.Results A total of 42 cycles at two different dose levels were given. In cohort 1 there were two deep venous thromboses that were DLTs. In the second cohort there was a DLT consisting of a transient ischemic attack after receiving SU5416. Most of the other toxicities seen were grade 1 or 2 in nature and consisted of headache, facial flushing, and fatigue. Two patients developed extensive ulcerative cavities at sites of prior radiation. There were no significant changes in the pharmacokinetic parameters of SU5416 given with paclitaxel. Four patients had prolonged freedom from progression of 18, 28, 42, and 60 weeks duration.Conclusions The combination of SU5416 with paclitaxel had a higher than expected incidence of thromboembolic events and prophylactic anticoagulation should be considered for future trials that combine an angiogenesis inhibitor with cytotoxic chemotherapy. Although the future development of SU5416 as a chemotherapeutic agent is unclear, there was a clinical benefit seen with this combination in 36% of the patients. This trial supports the use of developing antiangiogenic combinations, using molecular targeted agents, in head and neck carcinoma.     

Estimating the risks and benefits before salvage surgery for recurrent head and neck squamous cell carcinoma

IntroductionThe risks associated with salvage surgery of head and neck squamous cell carcinoma (SCC) in a previously irradiated field needs to be balanced against the expected survival benefits. We want to identify preoperative predictive factors for overall and disease-specific survival (OS/DSS) and for the development of serious (Clavien-Dindo, CD≥III) complications following salvage surgery for radiorecurrent SCC to help surgeons, patients, and caregivers in the decision-making process in this setting.Materials and methodsThe records of 234 patients presenting to the Lorraine Cancer Institute with locoregional radiorecurrent SCC were reviewed. The primary endpoint was OS, secondary endpoints were DSS, OS without tracheostomy/gastrostomy, and the risk of CD≥III complications. Multivariate analyses were carried out to explore preoperative factors associated with survival and the risk of postoperative complications.ResultsWith a median follow-up time of 19 months, 5-year OS since the first salvage surgery was 28.3%, 5-year DSS was 38.9%. 2- and 5-year functional OS were 45.6% and 27.2%. rcT-rcN, and WUNHCI ≥4 were both independent significant preoperative predictors of OS and DSS. 30-days postoperative complications occurred in 44.4% of patients (28 CD I, 24 CD II, 34 CD III, 11 CD IV, 7 CD V). A salvage procedure involving T+N plus the presence of a WUHNCI ≥4 was the only independent predictor of CD≥III complications.ConclusionWhen discussing with the patients and the caregivers salvage surgery for recurrent head and neck SCC, a careful evaluation of the preoperative comorbidities by the WUHNCI tool can reliably predict the expected risks and benefits from the procedure.