Treatment of squamous cell carcinoma of the head and neck with multi-drug chemotherapy and radiotherapy

Multi-drug chemotherapy containing cisplatin has been reported to be one of the most active chemotherapy regimens in advanced or recurrent head and neck squamous cell carcinoma. In this study, the current status of clinical investigation of combination chemotherapies is reviewed. And our data are presented in head and neck cancer with multi-drug chemotherapy containing cisplatin. Thirty-five patients of stage 3-4 and 70 patients with recurrent and/or metastatic head and neck squamous cell carcinoma were treated by multi-drug chemotherapy containing cisplatin, and radiotherapy and/or operation. The overall response rate was 71.4%, with 17.1% complete remission in previously untreated, locally advanced patients and 31.4% in recurrent or metastatic patients. Problems of chemotherapy combined with radiotherapy and future direction of clinical study in locally advanced or recurrent head and neck cancer are discussed.     

尼妥珠单抗联合多西他赛和顺铂一线治疗复发或转移性头颈部鳞癌疗效观察

目的 观察尼妥珠单抗联合多西他赛和顺铂一线治疗复发或转移性头颈部鳞癌的疗效及安全性.方法 回顾性分析28例尼妥珠单抗联合多西他赛+顺铂(观察组)及30例多西他赛+顺铂(对照组)一线治疗复发或转移性头颈部鳞癌患者的临床资料,比较两种方案的客观缓解率(ORR)、疾病控制率(DCR)、无进展生存时间(PFS)及总生存时间(O...     

静脉持续滴注氟尿嘧啶联合顺铂治疗晚期头颈部鳞癌30例的临床分析

目的探讨持续静脉滴注氟尿嘧啶联合顺铂,治疗复发和远处转移头颈部鳞癌的疗效和安全性。方法30例复发和转移头颈部癌予5-Fu750mg/（m^2.d）持续静脉滴注120h,每天DDP25mg/m^2,第1～3天,3W为1个周期,2个周期后评价疗效。结果CR1例,PR12例,近期客观有效率为44.8%（13/29）。中位TTP7.8个月。初治与复治有效率分别为76.9%（10/13）、18.7%（3/16）,差异有统计学意义（χ^2=9.814,P=0.02〈0.05）。主要不良反应为骨髓抑制,胃肠道反应和黏膜炎。结论持续静脉滴注氟尿嘧啶联合顺铂治疗晚期头颈部癌安全有效。     

Ifosfamide, cisplatin, and 13-Cis retinoic acid for patients with advanced or recurrent squamous cell carcinoma of the head and neck: a phase I-II study

BACKGROUND: Ifosfamide (IFO) and cisplatin (CDDP) are active drugs in the treatment of patients with squamous cell carcinoma (SCC) of the head and neck. 13-Cis retinoic acid (RA), along with its antiproliferative and differentiating activity on SCC cell lines, has immunomodulatory and chemopreventive effects. The objective of the current Phase I-II study was to evaluate the combination of CDDP, IFO, and RA in patients with advanced or recurrent SCC of the head and neck. METHODS: Patients with measurable recurrent, metastatic, or locally advanced SCC of the head and neck were eligible. Patients received a fixed dose of 20 mg/m(2) CDDP, and IFO was administered with sodium mercaptoethanesolfonate in three-dose increments (1000 mg/m(2), 1200 mg/m(2), and 1500 mg/m(2)) up to dose limiting toxicity. Both drugs were given for 5 consecutive days every 3 weeks. RA (0.5 mg/kg) was given orally for 5 days per week. RESULTS: Fifty-two patients either with locoregional recurrence or distant metastases (50%) or with locally advanced SCC of the head and neck beyond surgery or radiation therapy (50%) were entered into the trial. Fifteen patients were enrolled in the Phase I study, during which the maximum tolerated dose of IFO was 1500 mg/m(2). In the Phase II study (CDDP 20 mg/m(2) and IFO 1200 mg/m(2)), the response rate was 72% (95% confidence interval, 57-83%). After a median follow-up of 23 months, the median time to disease progression was 10.4 months (range, 2.9-47.2+ months), and the median overall survival was 12.95 months (range, 1.7-47.2+ months). Two patients were converted from a partial response to a complete response with RA. Toxicity was relatively well tolerated and caused no deaths. Grade 3-4 neutropenia was observed in 16 patients, and Grade 2-3 diarrhea toxicity occurred in 9 patients. CONCLUSIONS: The dose and schedule for the combination of CDDP, IFO, and RA that were used in this study are feasible and active in the treatment of patients with SCC of the head and neck, with durable responses and a relatively well tolerated toxicity.     

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.     

头颈部鳞状细胞癌靶向治疗进展

每年全世界大约有65万例新的头颈癌病例出现,其中绝大多数是头颈部鳞状细胞癌。晚期头颈部鳞状细胞癌的治疗需要综合治疗,尽管放化疗及手术治疗手段在不断发展,但是预后仍不理想且具有一定的毒副反应。靶向治疗是目前治疗研究头颈部鳞癌的热点,其在针对头颈部鳞癌的治疗特别是对局部晚期或复发/转移性头颈部鳞癌治疗中展现出了希望。本文综述了靶向治疗的最新进展。     

Recent multidisciplinary approach with molecular targeted drugs for advanced head and neck cancer

The multidisciplinary approach is becoming the standard for treatment of advanced head and neck cancer. Combined modality treatment preserves quality of life as well as improving the length of survival time. Molecular targeted drugs have become very important in the multidisciplinary approach for the treatment of advanced head and neck cancer. Cetuximab has been shown to have locoregional control and additional survival benefits in locally advanced squamous cell carcinoma of the head and neck as well as additional survival benefits in distant metastatic/recurrent squamous cell carcinoma of the head and neck. Recently, many clinical studies of the multidisciplinary approach including cetuximab have been carried out in Europe and the US. It has been shown that cetuximab in combination with radiotherapy (RT) is significantly superior to the RT alone in median locoregional control duration and median overall survival (OS). For recurrent or metastatic disease, the results of a phase III randomized control study of CDDP + 5-fluorouracil combination therapy with or without cetuximab reported that OS was significantly longer with than without cetuximab, demonstrating an additional survival benefit of cetuximab. Many trials including induction chemotherapy are being conducted. Clinical trials with cetuximab have also been conducted in Japan. Though combination with cetuximab shows some benefit, further studies are necessary to obtain the standard treatments for a multidisciplinary approach for advanced head and neck cancer.     

Cetuximab in squamous cell carcinoma of the head and neck

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemotherapy and chemoradiotherapy are new alternatives for locally advanced disease, particularly induction chemotherapy for patients with unresectable tumors. In recurrent/metastatic disease and after progression to platin-based regimens, no treatments other than best supportive care are currently available. Most SCCHN tumors overexpress the epidermal growth factor receptor (EGFR). This is a tyrosine kinase membrane receptor and has a clear implication in angiogenesis, tumor progression and resistance to different cancer treatments. Cetuximab is a monoclonal antibody that binds to EGFR and alters the tyrosine kinase-mediated signal transduction pathway. The drug is active in colon cancer and is currently being tested in SCCHN patients. For locally advanced disease, cetuximab/radiotherapy combination has demonstrated a benefit in survival when compared with radiotherapy alone as radical treatment. Cetuximab is an active treatment in platin-refractory patients with recurrent/metastatic disease.     

A phase II study of cisplatin and continuous infusion of vindesine in metastatic head and neck squamous cell cancer

The chemotherapeutic treatment of recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck (H & N) has a very dismal prognosis, with survival usually not exceeding 1 year. Reported objective response rates vary between 3% and 70%. This difference appears largely attributable to the heterogeneity of the patient populations included in most published Phase II studies in H & N cancer. They usually include together initially metastatic, recurrent, and post primary treatment metastatic disease patients. These patients respond differently to chemotherapy. Because of this situation, we decided to study a more homogeneous patient population consisting of metastatic patients only. Cisplatin (CDDP) and vindesine (VDS) are active agents in H & N SCC. As VDS has a cycle-specific activity, the therapeutic index may be increased if it is administered in a continuous infusion (CI) schedule. Thirty-three patients with metastatic H & N (69% biopsy proven) were treated with a combination regimen including CDDP (100 mg/m2) day 1 and VDS 0.6 to 1 mg/m2 for 96 hours of CI. Thirty-one patients were evaluable for response: five had a complete response (CR; 16%) and 11 had a partial response (PR; 36%) with an overall rate response of 52% (95% confidence limit: 33% to 70%). Median duration of CR was 6.4 months (3 to 19 months) and 4.4 months for PR (3 to 6 months). A decrease in the leukocytes was the main toxicity encountered with this regimen. This combination regimen containing CDDP and CI VDS was well tolerated and active in H & N SCC. The incorporation of an active vinca-alkaloid in neoadjuvant regimens should be considered.     

Taxanes in the treatment of head and neck cancer

PURPOSE OF REVIEW: This review presents new data on the role of paclitaxel and docetaxel in the management of squamous cell carcinoma of the head and neck. Recently both agents have been tested in squamous cell carcinoma of the head and neck in combination with other chemotherapeutic agents, targeted drugs, and radiotherapy in in-vitro experiments and in the clinic as first-line treatment of patients with metastatic/recurrent and locally advanced squamous cell carcinoma of the head and neck. RECENT FINDINGS: The combination of taxanes with standard or accelerated radiotherapy is feasible and induction chemotherapy followed by chemoradiation is active and feasible without excessive toxicity in patients with locally advanced squamous cell carcinoma of the head and neck. The use of low-dose fractionated radiotherapy shows promising in-vitro and clinical results and is further explored. SUMMARY: Both docetaxel and paclitaxel can be combined with chemotherapeutic agents and radiotherapy, but phase III studies are needed to prove the superiority of these approaches compared to standard treatment. The final results of the combination study of cisplatin and 5-fluorouracil with or without docetaxel may change the standard chemotherapeutic regimen for induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.     

Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.     

Phase II study of docetaxel and topotecan combination chemotherapy in patients with advanced head and neck cancer

Purpose To evaluate the activity of combination chemotherapy with docetaxel and topotecan in patients with advanced head and neck cancer.Methods Docetaxel was given at 60 mg/m² as a 60-min intravenous infusion on day 1. Topotecan at 0.75 mg/m² per day was infused over 30 min on days 1, 2 and 3. Cycles were repeated every 21 days.Results There were no responses (CR+PR) seen in the ten patients. Only one patient had stable disease and was able to receive six cycles of chemotherapy. Median survival was 81 days (range 67–161 days).Conclusions The combination of docetaxel and topotecan at these doses and in this schedule is not recommended for patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Other investigational approaches are needed.     

Chemotherapy for recurrent or metastatic carcinoma of the nasopharynx. A review of the Princess Margaret Hospital experience

There is little information about the ability of chemotherapy to achieve palliation for patients with recurrent or metastatic carcinoma of the nasopharynx. Therefore, the authors reviewed the records of all patients who had received chemotherapy for this disease at the Princess Margaret Hospital between 1970 and 1989. Seventy patients were identified who had measurable disease and had not received prior systemic therapy. Forty patients received single agents or nonaggressive drug combinations, most of them before 1980. There were three complete responses (CR) and seven partial responses (PR) among this group for a response rate of 25% (95% confidence limits, 13% to 41%). Thirty patients received either drug combinations that were active in aggressive lymphomas or cisplatin-based combinations. There were 7 CR and 14 PR among this group for a response rate of 70% (95% confidence limits, 51% to 85%). Two patients who were treated aggressively are still alive and in complete remission at 3 and 12 years. This type of retrospective review cannot exclude bias caused by patient selection. However, in the absence of randomized trials, the authors suggest the following: (1) carcinoma of the nasopharynx should be considered a malignant neoplasm that is distinct from squamous cell cancer in other sites of the head and neck; and (2) selected patients with recurrent or metastatic carcinoma of the nasopharynx should receive aggressive combination chemotherapy.     

Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck

Background: To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck.Patients and methods: Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks.Results: Twenty-four patients with a median age of 59 years (range 42–74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%–42%). The main toxicity was hematological: neutropenia grade 3–4 in 28% of the cycles and thrombocytopenia grade 3–4 in 16%. The most significant non-hematological toxicity was asthenia grade 2–3 in 24% of the cycles.Conclusions: This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.     

Weekly docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

BACKGROUND: The objective of this study was to assess the antitumor activity and toxicity profile of weekly docetaxel in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Patients with recurrent, metastatic, incurable squamous cell carcinoma of the head and neck were enrolled. Weekly docetaxel (30 mg/m2) was administered for 4 weeks every 5 weeks for a maximum of 6 cycles. RESULTS: The activity and toxicity of docetaxel were assessed in all 38 patients who were entered on the study. No Grade 3-4 toxicities were recorded. No treatment delays were required because of toxicity or dose reductions. Responses were observed in 42% of patients (95% confidence interval, 26-58%). The median duration of response was 8.39 months, the estimated median overall survival was 11.3 months, and the 1-year survival rate was 39%. CONCLUSIONS: The results of this study suggested that weekly docetaxel was an active agent for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.     

5-fluorouracil + folinic acid with cisplatinum and bleomycin in the treatment of advanced head and neck squamous cell carcinoma.

Thirty-six patients with advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with a regimen including cisplatinum (CP) 30 mg/m2 i.v., 5-fluorouracil (5-FU) 500 mg/m2 i.v. bolus, folinic acid (FA) 200 mg/m2 i.v. in a continuous one-hour infusion, and bleomycin (B) 15 mg i.m. on the first and second days and repeated every 28 days. Thirty-three patients (25 with recurrent disease and 8 untreated) are evaluable for objective response. Of these, 4 (12%) achieved CR and 15 (45%) PR. All of the untreated patients responded. The mean duration of response in the patients with recurrent or metastatic disease was 5.5 months (range 2-10+). Remission of symptoms, such as pain and dysphagia, was obtained in 58% and in 44%, respectively. Subjective remission occurred almost exclusively in objectively responsive patients. The major side effects were leukopenia (55%) and nausea/vomiting (58%). This regimen is active in the treatment of advanced SCCHN. The quality of life may be improved in responsive patients.     

Recombinant interferon alpha-2 (Sch 30500) in patients with head and neck cancer

Fifteen patients with advanced recurrent or metastatic carcinoma of the head and neck were treated with recombinant interferon alpha-2. Cumulative doses for evaluation of at least 1.2 X 10(8) IU were given over a period of 4 weeks. No significant regression was shown in 14 evaluable patients, 6 of which showed no change and 8 progression. Toxicities were minimum and acceptable. All patients had an episode of elevated body temperature. One patient showed transient effects on the central nervous system, which may be a dose-limiting factor. Recombinant interferon alpha-2 was therefore not recommended as a modality for the treatment of recurrent head and neck cancer.     

Standard, and novel cytotoxic and molecular-targeted, therapies for HNSCC: an evidence-based review

(1) Head and neck squamous cell carcinoma is the sixth most frequently occurring cancer worldwide.(2) Chemotherapy has shown some success as part of multimodal treatment schedules for locally advanced, nonmetastatic head and neck squamous cell carcinoma, and too a much lesser extent for metastatic head and neck squamous cell carcinoma.(3) A recent meta-analysis of 32 studies involving >10,000 patients concluded that chemotherapy added to radiotherapy produces a large survival advantage relative to radiotherapy alone.(4) Concurrent or alternate chemoradiotherapy, with a schedule based on cisplatin, has an established place in the management of locally advanced nonmetastatic head and neck squamous cell carcinoma.     

Role of epirubicin in advanced breast cancer

Anthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease. Unfortunately, their clinical value is limited by late-onset ventricular dysfunction. Epirubicin, an anthracycline analogue, does not eliminate the risk of cardiotoxicity but is less cardiotoxic and myelotoxic than doxorubicin at equimolar doses, thereby allowing the safe administration of cumulative doses between 950 and 1000 mg/m2. The inclusion of epirubicin in combination regimens, such as fluorouracil/epirubicin/cyclophosphamide (FEC), has been shown to be safe and active as first-line treatment for metastatic breast cancer. In the past few years, new drugs, including taxanes, have shown a high level of activity as single agents in the treatment of advanced breast cancer. Doxorubicin/paclitaxel combinations have shown high overall response rates (90%) as first-line chemotherapy of advanced breast cancer; however, congestive heart failure has been reported in up to 20% of patients. Epirubicin/paclitaxel combinations have been associated with grade 3 cardiotoxicity (6%) in only one study. We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84% and a complete response (CR) rate of 19%. Achieving a CR to first-line chemotherapy for advanced breast cancer appears to predict survival, and adding an active drug with a different mechanism of action and nonoverlapping toxicity might increase the percentage of CRs. We therefore tested the feasibility and activity of 6 to 8 courses of first-line treatment with a three-drug combination (gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, and paclitaxel 175 mg/ m2 over 3 hours on day 1) in a phase II study of 36 metastatic breast cancer patients. Treatment was well tolerated, with an ORR of 92% (95% confidence interval: 77.53%-98.25%) and a CR of 31%. In considering retreating patients who progress or relapse after receiving an anthracycline-/taxane-containing regimen with the same active drugs, epirubicin appears ideal in both the adjuvant and metastatic breast cancer settings.     

Long-term results of the combined modality therapy for advanced cervical metastatic head and neck squamous cell carcinoma.

AIM: A consensus treatment strategy for advanced cervical metastatic head and neck squamous cell carcinoma has not been established. The aim of this retrospective study was to investigate the outcome of these patients uniformely using a strategy which consists of surgery for the primary tumor and the neck metastases followed by postoperative radio(chemo)therapy. METHODS: We included a selected series of 518 patients with previously untreated head and neck squamous cell carcinoma. The overall survival (OS), the disease specific survival (DSS), the disease free survival (DFS), the local control (LC) and regional control (RC) estimates were calculated. The statistical relationship of various clinical and histopathological variables on the above mentioned estimates were analyzed. RESULTS: The overall survival probability was 73.2% for pN0 stage, 43% for pN>1 stages and 31% for pN2c/pN3 stages. The pN stage significantly influenced the survival probabilities in oropharyngeal (p=0.0001) and laryngeal tumors (p<0.0001) in univariate analyses. In multivariate analysis, age, pT stage, pN stage, M stage, and extranodal spreading were independent risk factors for decreased disease-specific survival. CONCLUSIONS: We could show that pN stage is an important independent prognostic factor in head and neck cancer. The presented multimodal treatment protocol provides excellent oncological outcomes and should therefore be standard of care for patients with operable advanced cervical metastatic head and neck squamous cell carcinoma.