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.     

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.     

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.     

Docetaxel in the management of patients with head and neck squamous cell carcinoma

The taxanes play a significant role in the treatment of various solid tumors of epithelial origin. Docetaxel is the most extensively studied taxane in prospective head and neck cancer trials and has been investigated as induction chemotherapy or in combination with radiotherapy in locally advanced squamous cell carcinomas of the head and neck (HNSCC) and as palliation in recurrent or metastatic disease. The data in locally advanced disease are particularly compelling. Three recently reported randomized trials, carried out in patients with locally advanced disease who were receiving induction chemotherapy followed by radiotherapy or chemoradiotherapy, demonstrated that adding docetaxel to the standard induction regimen of cisplatin/5-fluorouracil (PF) significantly improved survival compared with PF alone, without significantly increasing toxicity. On the basis of these trials, docetaxel/PF (TPF) has become the current standard induction regimen and TPF-based sequential therapy can be considered a standard treatment alternative to chemoradiotherapy alone in patients with locally advanced HNSCC. This review article discusses the current developments of docetaxel-based chemotherapy and the optimal use of this agent in patients with HNSCC.     

Docetaxel in the management of patients with head and neck squamous cell carcinoma

The taxanes play a significant role in the treatment of various solid tumors of epithelial origin. Docetaxel is the most extensively studied taxane in prospective head and neck cancer trials and has been investigated as induction chemotherapy or in combination with radiotherapy in locally advanced squamous cell carcinomas of the head and neck (HNSCC) and as palliation in recurrent or metastatic disease. The data in locally advanced disease are particularly compelling. Three recently reported randomized trials, carried out in patients with locally advanced disease who were receiving induction chemotherapy followed by radiotherapy or chemoradiotherapy, demonstrated that adding docetaxel to the standard induction regimen of cisplatin/5-fluorouracil (PF) significantly improved survival compared with PF alone, without significantly increasing toxicity. On the basis of these trials, docetaxel/PF (TPF) has become the current standard induction regimen and TPF-based sequential therapy can be considered a standard treatment alternative to chemoradiotherapy alone in patients with locally advanced HNSCC. This review article discusses the current developments of docetaxel-based chemotherapy and the optimal use of this agent in patients with HNSCC.     

Recent advances in molecular-targeted drugs in head and neck cancer

Recently, the integration of radiotherapy and chemotherapy has advanced the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), allowing functional organ preservation while improving locoregional control and overall survival compared with radiotherapy alone. However, as recurrences remain inevitable, there is an absolute need for alternative modes of therapeutic intervention. Moreover, the use of chemotherapy and radiotherapy also increases the incidence of toxicities such as mucositis, myelosuppression, xerostomia, and dysphasia. More recently, the use of molecular-targeted drugs, which minimally adds to the existing toxicities, along with cytotoxic drugs and radiotherapy has been intensively investigated. Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. In a randomized trial of radiotherapy with or without cetuximab for locally advanced SCCHN, the addition of cetuximab significantly improved the locoregional control and overall survival without an increase in adverse events. Furthermore, a randomized trial of 5-FU and cisplatin with or without cetuximab for recurrent/metastatic SCCHN demonstrated a significant survival benefit for cetuximab combination arms compared with 5-FU and cisplatin arms alone. Based on these findings, many molecular-targeted drugs have been investigated in the treatment of the head and neck cancer to ensure better clinical outcomes in the near future.     

Expanding role of the medical oncologist in the management of head and neck cancer

The multidisciplinary approach to treating squamous cell carcinoma of the head and neck is complex and evolving. This article aims to review some recent developments in squamous cell carcinoma of the head and neck, in particular the expanding role of chemotherapy in its management. Surgery and radiotherapy have remained the mainstay of therapy. Chemotherapy is increasingly being incorporated into the treatment of squamous cell carcinoma of the head and neck. Previously, radiotherapy following surgery was the standard approach to the treatment of locoregionally advanced resectable disease. Data from randomized trials have confirmed the benefits of concurrent chemoradiotherapy in the adjuvant setting. Chemoradiotherapy is also the recommended approach for unresectable disease. Induction chemotherapy has been useful in resectable disease where organ preservation is desirable, but this approach was inferior for the goal of larynx preservation, while leading to similar survival when compared with concomitant chemoradiotherapy. There is recent evidence that taxanes added to induction chemotherapy with cisplatin and fluorouracil result in improved survival outcomes. Novel targeted agents, such as epidermal growth factor receptor antagonists, are showing promise in the treatment of patients with both locoregionally advanced and recurrent/metastatic squamous cell carcinoma of the head and neck.     

Concomitant cisplatin and radical radiation in locally advanced head & neck carcinoma

Effective treatment modalities for locally advanced squamous cell carcinoma of the head and neck are limited and seldom result in long term survival. The improved results with cisplatin chemotherapy are encouraging and represent an additional therapeutic modality for head and neck cancer. To estimate the effectiveness, safety and tolerance of simultaneous cisplatin and radiotherapy in advanced carcinoma of the head and neck this phase II study was undertaken. 40 eligible patients with advanced squamous cell carcinoma of the head and neck were entered into the study. Group I (20 patients) received conventional radical radiation 64 Gy/32 F/6.5 weeks and Group II (20 patients) received in addition to above radiotherapy, concomitant cisplantin 100 mg/m² every 3 weeks for three doses with forced diuresis and antiemetic schedule, on day 1, 22 and 43rd of rediation treatment. The complete response with RT alone was 40% and with combined treatment 70%. The treatment tolerance was approximately equal in both groups and all patients completed treatment in scheduled time.     

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.     

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...     

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.     

Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck

Induction chemotherapy, followed by surgery and/or radiotherapy was utilized in patients with advanced squamous cell carcinoma of the head and neck. During these trials, the authors observed that response to chemotherapy predicts further response to subsequent radiotherapy. This study was comprised of 57 patients with 60 separate neoplasms who demonstrated less than complete response (partial or no response) to initial treatment with a combination chemotherapy containing cisplatin. Subsequently radiotherapy, either 5000 rad preoperatively or 6600 rad as definitive therapy, was employed. Forty-one of the 42 tumors with initial partial response to chemotherapy also responded to radiotherapy (97.6%). Only one of the 18 tumors that initially failed to respond to chemotherapy subsequently responded to radiotherapy (5.5%). This observation suggests that patients with head and neck cancer sensitive to initial chemotherapy share parameters that are also radiation sensitive.     

Radiation Therapy With 5-fluorouracil in Head and Neck Cancer

5-Fluorouracil (5-FU) alone or combined with other drugs, most frequently cisplatin, has been used concurrently or as induction or adjuvant therapy with radiotherapy with or without surgery in the treatment of head and neck cancer. Improved local-regional control and disease-free survival or overall survival have been shown in several randomized trials using a concurrent approach. However, acute mucositis is usually increased with simultaneous 5-FU and radiation administration, especially when other drugs are used in addition to 5-FU. Alternating radiotherapy with 5-FU and cisplatin was shown to improve the local-regional relapse-free, progression-free, and overall survival of unresectable squamous cell carcinoma of the head and neck compared with radiotherapy alone in one randomized trial. Further evaluation of the alternating chemotherapy and radiotherapy approach is needed, however, before one can accept this as a standard of practice. Induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in the chemotherapy responders in an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hypopharynx who wish to preserve organ function. Induction or adjuvant chemotherapy with 5-FU infusion and cisplatin may also decrease or delay the occurrence of distant metastasis. Induction chemotherapy, however, has not been shown to improve local-regional control or overall survival. Further clinical trials combining 5-FU and its biochemical modulators using innovative radiation and drug dose schedules and other treatment modifiers are needed to improve the therapeutic ratio.     

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。     

Attempts to improve organ preservation in patients with squamous cell carcinoma of the head and neck

When surgical resections are performed for patients with locally advanced head and neck cancer, a critical consideration is which organs and functions of patients are sacrificed. In attempts to improve the organ preservation rate in patients with advanced squamous cell carcinoma of the head and neck (SCCHN), chemotherapy has been used either before(neoadjuvant or induction), with (concurrent or concomitant), after (adjuvant) radiotherapy, or as alternating treatment with radiotherapy. A recent systematic review using meta-analysis has revealed that concurrent chemotherapy with radiotherapy shows a significant benefit for the survival rate of patients with SCCHN when compared with radiotherapy alone, and is superior to neoadjuvant chemotherapy. However, no standard concurrent chemoradiotherapy regimen has been defined,although concurrent chemotherapy together with regimens including cisplatin has been considered to be most effective for SCCHN. We combined radiotherapy concurrently with chemotherapy including cisplatin, 5-fluorouracil, methotrexate, and leucovorin in patients with advanced resectable SCC of the hypopharynx to minimize the necessity of radical surgery and preserve the functional larynx. In conclusion, previous reports and our data show that an organ preservation treatment approach using concurrent chemoradiotherapy is feasible.     

Effect of cetuximab in recurrent and refractory squamous cell carcinoma of the head and neck (SCCHN): a case report

The epidermal growth factor receptor (EGFR) is frequently overexpressed in squamous cell carcinoma of head and neck (SCCHN). Different strategies to target the activated EGFR have reached the clinic. Cetuximab is a monoclonal antibody that selectively binds to the extracellular domain of the EGFR on the tumor cell, thereby inhibiting receptor-associated tyrosine kinase activation. Two randomized phase III clinical trials have recently demonstrated that cetuximab increases the activity of radiotherapy in the treatment of locally advanced SCCHN and of platinum-based chemotherapy in the treatment of metastatic SCCHN. Here we report the clinical case of a long-lasting complete response in a 57-year-old male, who was a current smoker and had a history of alcohol abuse, affected by recurrent locally advanced SCCHN after failure of radiotherapy and of platinum-based chemotherapy.     

Ifosfamide in the treatment of head and neck cancer

Ifosfamide (IFO) has demonstrated activity in recurrent/metastatic squamous cell head and neck carcinoma with an overall response rate of 24-26%. Better results are reported for chemotherapy-naive patients; in heavily pretreated cases results are poor and toxicity unacceptable. Cisplatin-IFO combination in stage III-IV is probably more active than IFO alone (ORR = 60-72 vs. 50%) but is indicated in patients who desire aggressive treatment and are physically able to tolerate the drugs. The carboplatin-IFO scheme is better tolerated than the cisplatin-IFO regimen with superimposable clinical results (ORR = 69%; CR = 15%). Carboplatin-taxol-IFO is one of the most active regimens in recurrent (ORR = 59%; CR = 17%) and in locally advanced (ORR = 81%; CR = 31%) head and neck cancer. Its role in the multidisciplinary treatment of advanced head and neck cancer is under investigation. In recurrent/metastatic undifferentiated nasopharygeal carcinoma, IFO combinations have proven to be effective as first- and second-line treatment.     

Cetuximab in the treatment of head and neck cancer

Approaches to the treatment of locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have been limited by their toxicity. Effective, better tolerated approaches are urgently required. Cetuximab is an immunoglobulin G(1) monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR), which is commonly expressed in a number of solid tumors, including SCCHN, where it is associated with poor prognosis. Cetuximab is approved in 56 countries for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy and has recently received approval in Europe and the USA for use in the treatment of SCCHN. A randomized Phase III study has demonstrated that cetuximab plus radiotherapy can significantly improve locoregional control and prolong overall survival compared with radiotherapy alone. Cetuximab has also been confirmed to be effective as monotherapy in recurrent and/or metastatic SCCHN that has progressed on platinum-containing therapy. Clinical studies have demonstrated that cetuximab is well tolerated and does not significantly increase the side effects associated with radiotherapy or chemotherapy. This article presents the rationale for EGFR inhibition in the management of head and neck cancers, and the preclinical and clinical evidence for the use of cetuximab in the treatment of SCCHN.     

Feasibility and tolerance of sequential chemoradiotherapy in squamous cell carcinoma of the head and neck

LOO S.W., GEROPANTAS K., TASIGIANNOPOULOS Z., MARTIN C. & ROQUES T.W. (2013) European Journal of Cancer Care 22 , 32–40 Feasibility and tolerance of sequential chemoradiotherapy in squamous cell carcinoma of the head and neck This paper evaluates the feasibility and tolerance of sequential chemoradiotherapy in patients with squamous cell carcinoma of the head and neck and ascertains whether the use of induction chemotherapy compromises delivery of subsequent radiotherapy with or without concurrent chemotherapy. We also compared sequential chemoradiotherapy treatment adherence between the elderly and younger patients with squamous cell carcinoma of the head and neck. One hundred and ninety-four patients with head and neck squamous cell carcinoma who received induction chemotherapy with cisplatin and 5-fluorouracil were included in this study. Treatment-related death rate from induction chemotherapy was 1.5%. One hundred and ninety-one patients (98.5%) proceeded to radical radiotherapy, with 90.1% also receiving planned concomitant chemotherapy. One hundred and seventy-eight patients (93.2%) completed radiotherapy with no prolongation of the treatment duration. There were no statistical differences in sequential chemoradiotherapy treatment adherence and tolerance between the elderly and younger patients apart from the proportion who required hospitalisation during radiotherapy. Induction chemotherapy in head and neck squamous cell carcinoma does not compromise delivery of definitive radiotherapy with or without concurrent chemotherapy. Elderly patients with head and neck squamous cell carcinoma are able to tolerate aggressive treatments such as sequential chemoradiotherapy. Treatment ‘deintensification’ based solely on chronological age is not recommended.     

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.