Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck

This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m(2)administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9-20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7-28.1 months; 95% CI: 3.9-7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B(12)supplementation.     

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.     

Sequential chemo-radiotherapy in locally advanced squamous cell carcinoma of the head and neck

Between 1982 and 1983, 32 patients were treated for locally advanced inoperable squamous cell carcinoma (SCC) of the head and neck in a prospective pilot study. Patients received two to five courses of chemotherapy consisting of methotrexate, bleomycin and cis-dichlorodiammine-platinum (II). Radical radiotherapy was performed two weeks after administration of chemotherapy. Despite the high initial response rate to chemotherapy of 62.5%, long-term results remained poor. After a median follow-up of 10.5 months (3-39 months), 15 patients were still alive, but only 4 were clinically free of disease. Aggressive chemotherapy does not prevent delivery of full-dose radiotherapy for SCC of the head and neck. Furthermore, our study does not suggest that chemotherapy has a great influence on long-term results.     

Chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck

Recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) are difficult problems and likely to become more challenging as concurrent chemotherapy and radiation are more widely used. Randomized studies reported in 1992 established the combination of cisplatin and infusional 5-fluorouracil (5-FU) as the reference regimen for chemotherapy-naive, good-performance status patients. Subsequently, a randomized study of 194 patients comparing cisplatin and 5-FU to cisplatin and paclitaxel found better tolerance, better pain relief, and improved quality of life with the newer regimen, but no survival differences (medians of 9 months) were detected. Phase II studies of a platinum/taxane combination with a third drug have reported response rates of greater than 50%, including 15% complete responses. A number of non-platinum-containing regimens are active in pretreated patients. Gefitinib has shown median survival times comparable to those achieved with cisplatin and paclitaxel, and appears especially promising for patients who recur after cytotoxic chemotherapy. Newer antifolates, agents that target or restore deficient p53, and other signal transduction inhibitors are under study.     

Simultaneous cis-platinum and radiotherapy in inoperable or locally advanced squamous cell carcinoma of the head and neck

A synergism between cis-platinum (CDDP) and radiotherapy (RT) has been demonstrated both in culture systems and in clinical studies. On the above basis, we planned, in patients with locally advanced or unresectable squamous cell carcinoma of the head and neck, a concomitant treatment with CDDP 80 mg/m2 i.v. every 3 weeks for three doses (days 1, 21 and 42) and RT in the primary and in the neck nodes bilaterally, for a total dose of 60-70 Gy. Thirty-five untreated patients with poor prognosis unresectable stage II and stages III-IV disease were entered in the study and 32 were evaluable. Complete response (CR) rate was 75% (24/32) with 95% confidence limits from 60 to 90% (+/- 15%): 8 cases (25%) achieved a partial response, for an overall response rate of 100%. A significantly higher CR rate and a longer survival rate was observed in patients with good performance status (PS = 90-100) and stages II-III. The overall estimated 2-year survival is 46%; 59% for patients who obtained a CR versus 0% for those who achieved only a partial response. Overall the treatment was well tolerated and gastrointestinal and hematologic toxicities were the most common side effects. In conclusion, the combination of CDDP plus RT is a very effective and safe treatment and we recommend such an approach in head and neck squamous cell carcinoma, particularly in those patients with good PS and with unresectable stage II or stage III disease.     

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.     

局部晚期头颈部鳞癌术后辅助治疗的进展

局部晚期头颈部鳞癌的术后辅助治疗在整个治疗中占有重要地位,方案的选择日益注重个体化.调强技术使放疗更精确和适形.术后应尽早开始放疗,超过6周降低局部控制率.综合治疗在11周内完成较好.PET指导勾画靶区的作用仍有待进一步研究和形成共识.术后同步放化疗可以提高高危患者的疗效,但未能明显减少远处转移的发生.分子靶向治疗(西妥昔单抗)的疗效已经在非术后临床试验中被证实.人乳头瘤病毒、表皮生长因子受体和抑癌基因p53是目前分子生物学研究的热点,有望成为寻找个体化治疗新途径的突破口.     

The role of chemotherapy in locally advanced head and neck squamous cell carcinoma

The role of chemotherapy in multimodality treatment for locally advanced head and neck squamous cell carcinoma, although firmly established, presents several unresolved issues. Concomitant platinum-based chemoradiation (CRT) is a standard treatment for unresectable, resectable but nonsurgically treated, and postoperative high-risk patients with locally advanced head and neck squamous cell carcinoma. However, no clear conclusion can be drawn regarding the optimal platinum compound or combinations to use, the type of schedule, and number of cycles (ie, platinum total dose) to be delivered. Cetuximab administered concomitantly with radiotherapy has not been directly compared with CRT but offers a potential different approach using a noncytotoxic systemic agent. In the organ preservation setting, CRT, although yielding a superior 5-year larynx preservation rate, showed similar outcomes to induction chemotherapy (IC) followed by radiation in terms of 5-year laryngectomy-free survival and overall survival, with a higher incidence of grade 3-4 mucositis. The role of IC in nonorgan preservation programs has not yet been established. Phase III trials comparing concomitant CRT versus IC followed by CRT are ongoing with results anticipated in the near future.     

Docetaxel induction therapy in locally advanced squamous cell carcinoma of the head and neck

Patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) are often treated with induction chemotherapy or chemoradiotherapy, but to date without major impact on survival. The combination of cisplatin-5-fluorouracil (5-FU) (PF) has been used as standard induction therapy; however, poor patient survival has stimulated investigation into new agents with potential activity in SCCHN. Docetaxel has significant single-agent activity in SCCHN and has been investigated in combination with PF regimens as induction therapy. The results of six phase II studies of docetaxel-PF regimens (TPF) as induction in locally advanced SCCHN patients are reviewed and reported. Consistently, high 2-year survival rates and overall response rates were demonstrated across the phase II trials in the range 42-82 and 71-100%, respectively. The toxicity profile seen with TPF-based regimens was acceptable. The primary toxicity was neutropenia, which together with gastrointestinal complaints accounted for the majority of adverse events. Given the encouraging phase II experience with TPF-based regimens, two large-scale phase III studies comparing TPF-based regimens with standard PF regimens are underway. The results have significant potential for validating the findings of the phase II studies, demonstrating improved survival and overall response of patients treated with docetaxel-based induction chemotherapy.     

Genetic aberrations in squamous cell carcinoma of the head and neck (SCCHN), with reference to oral carcinoma (review)

Squamous cell carcinoma of the head and neck (SCCHN) arises as a consequence of multiple molecular events induced by the effects of various habits such as tobacco and use of alcoholic beverages, influenced by environmental factors, possibly viruses in some instances, against a background of heritable resistance or susceptibility. Oral squamous cell cancers have a similar aetiology. Genetic damage affects many chromosomes and genes, including oncogenes and tumour suppressor genes, and it is the accumulation of such genetic damage, possibly along with an impaired ability to repair this damage - an inherited trait in some cases - that appears to lead to carcinoma in some instances, sometimes via a clinically evident pre-malignant, or potentially malignant, lesion. This communication reviews the advances in the understanding of this complex and rapidly developing area of research over the past decade. Cytogenetic and molecular analyses have shown changes in several chromosomes in oral cancer, particularly in chromosomes 3, 9, 11, 13 and 17. Analyses of allelic losses has allowed for the identification of chromosomal regions harbouring tumour suppressor genes (TSGs). Impaired function of such genes or their products, or activation of oncogenes, or both, may be involved in carcinogenesis. Probably the most significant findings thus far have been in relation to TSGs with the discovery of p53 mutations on chromosome 17 as in many other tumours, indicating disturbed function of this TSG and some on chromosomes 3 and 9 (MTS-1) which may be of comparable or greater significance. Over-expression of oncogenes, especially those on chromosome 11 (PRAD-1, Int-2, hst-l, and bcl-1 in particular) has also been implicated in carcino-genesis. The analysis of microsatellite instability (MI or RER, replication error repair) in tumour specimens, which are associated with defects in DNA repair genes has provided a further method of assessing genetic damage in the genome of sporadic cancers. Microsatellite instability (MI) has been demonstrated in several carcinomas as well as SCCHN. These research findings have now reached the stage where it is becoming possible to begin to introduce them into clinical practice for the more sensitive detection of potentially malignant lesions, better diagnosis and prognostication, and hopefully, to start to develop novel therapies such as gene therapy.     

Cetuximab: a standard approach to the first-line treatment of recurrent and/or metastatic and locally advanced squamous cell carcinoma of the head and neck

The burden of squamous cell carcinoma of the head and neck (SCCHN) on healthcare systems is expected to rise in line with projected increases in population sizes in general, and the relative proportion of elderly individuals in particular, underlining the need for effective, well tolerated treatment strategies. The epidermal growth factor receptor (EGFR)-targeted IgG1 monoclonal antibody, cetuximab, is the only EGFR-targeted agent currently approved for use in the treatment of SCCHN. Adding cetuximab to standard first-line platinum-based chemotherapy in the treatment of recurrent and/or metastatic SCCHN significantly improved overall survival (hazard ratio [HR] 0.80; P = 0.04), progression-free survival (HR 0.54; P < 0.001) and response rates (odds ratio 2.33; P < 0.001), compared to platinum-based chemotherapy alone. This was the first time in 30 years that a significant increase in overall survival had been achieved over platinum-based therapy alone and established cetuximab plus platinum-based chemotherapy as the new standard first-line treatment approach for recurrent and/or metastatic disease. In locally advanced SCCHN, cetuximab plus radiotherapy significantly improved locoregional control (HR 0.68, P = 0.005) and overall survival (HR 0.74; P = 0.03) compared to radiotherapy alone. In both recurrent and/or metastatic disease and locally advanced disease, adding cetuximab to standard therapy was generally well tolerated and did not affect patients’ quality of life. The clinical benefits seen with the addition of cetuximab to standard chemotherapy or radiotherapy make it one of the most significant advances made in SCCHN treatment in recent years.     

局部晚期头颈部鳞癌同步放化疗研究进展

同步放化疗(CCRT)是治疗局部晚期头颈部鳞癌的新热点。对以手术治疗为主的局部晚期头颈部鳞癌而言,CCRT的疗效与以手术为主的综合治疗的疗效相似,同时保全了器官及功能;对传统采用非手术治疗的局部晚期头颈部鳞癌而言,CCRT取得了更理想的局部控制率、无远处转移率和生存率。因此,CCRT为局部晚期肿瘤的临床治疗提供了新的模式。     

局部晚期头颈部鳞癌同步放化疗研究进展

同步放化疗（CCRT）是治疗局部晚期头颈部鳞癌的新热点。对以手术治疗为主的局部晚期头颈部鳞癌而言，CCRT的疗效与以手术为主的综合治疗的疗效相似，同时保全了器官及功能；对传统采用非手术治疗的局部晚期头颈部鳞癌而言，CCRT取得了更理想的局部控制率、无远处转移率和生存率。因此．CCRT为局部晚期肿瘤的临床治疗提供了新的模式。