Chemotherapy for recurrent and metastatic head and neck cancer

At the present time, the treatment of recurrent and metastatic head and neck squamous and salivary gland cancers with chemotherapy is palliative. Pain relief, improvement in functional parameters, and improved survival are important goals. Although survival benefits are small, palliation can be significant. For squamous cancers, the median duration of response to chemotherapy is 2 to 4 months, and overall survival is about 6 months. Responses can be achieved with acceptable toxicity for good palliation in approximately 30% of patients treated with the standard regimens. Although more intensive chemotherapy regimens often result in higher response rates in pilot trials, they do not offer significant gains in effectiveness or survival. In salivary gland malignancies, results are substantially better, but this may only reflect the different natural history of this heterogeneous group of tumors. A small number of patients will have excellent and very durable responses to chemotherapy. Unfortunately, at this time we are unable to select these patients or determine which regimen will produce this desired result. The optimal use of currently available drugs is in the process of refinement. The timing of palliative chemotherapy represents a major challenge to oncologists and patients. Chemotherapy may in the future have a role in the cure of patients with recurrent disease, but innovative therapy, combined modality approaches, and new drug development will all need to be investigated. We look forward toward a new understanding of tumor biology and the development of agents that may substantially improve the control of these tumors.     

Chemotherapy for head and neck cancer relapsing after radiotherapy

Thirty-nine patients (28 men and 11 women, ages 43 to 83 years) with advanced head and neck epidermoid carcinoma (33 had relapsed from previous radiotherapy) were treated with a three-day bleomycin administration (30 by continuous intravenous infusion and nine by subcutaneous route) followed on the fifth day by intravenous administration of cyclophosphamide + methotrexate + 5-fluorouracil (Bleo-CMF). This drug schedule was based on the cell cycle synchrony principle. Twenty-one of 39 patients (54%) responded (seven complete, 14 partial remission) lasting from 4 to 20 months. The median duration of survival for complete remission, partial remission, and disease progression was 15, ten, and four months, respectively. The Bleo-CMF was well tolerated with minimal toxicity. The effectiveness of this regimen in previously irradiated patients compels us to pursue its application in a randomized study as an adjuvant for Stages III and IV head and neck cancer following maximum eradication of the local disease by surgery and/or radiotherapy.     

Chemotherapy in head and neck cancer.

The role of chemotherapy in the management of patients with head and neck cancer continues to evolve. Single-agent methotrexate or cisplatin, or the combination of cisplatin and infusional fluorouracil can be considered standard therapy for patients with recurrent disease. Neoadjuvant chemotherapy is being actively pursued. Although enhanced survival has not yet been demonstrated, the goal of organ preservation has been achieved for patients with laryngeal cancer. Because of the high incidence of locoregional failure, concomitant chemoradiotherapy is also under investigation. This treatment approach has already been suggested to result in prolonged survival in randomized studies and holds promise for the future.     

Role of Chemotherapy in head and neck cancer

For head and neck cancer, a recent meta-analysis of published randomized trial results showed that concurrent chemoradiotherapy, adjuvant chemotherapy and neoadjuvant chemotherapy may increase absolute survival by 12.1%, 6.5%, and 3.7%, respectively. Initial response rates to first line chemotherapy are high, but this responsiveness does not appear to translate into a survival benefit. Thus, chemotherapy can be indicated as the standard therapy for a very limited range of advanced head and neck cancers. With the aim of prolonging survival, N stage advanced nasopharyngeal cancer is a good candidate for neoadjuvant chemotherapy. Among a large number of randomized trials of neoadjuvant chemotherapy, organ function preservation studies showed the possibility of laryngeal preservation for locally resectable T2 and T3 laryngeal and hypopharyngeal cancer. Concurrent chemoradiotherapy may be indicated for advanced T stage head and neck cancers, especially those with locally unresectable lesions. For N stage advanced pharyngeal cancer patients, adjuvant chemotherapy with applied after the standard therapy has a role in the treatment. With palliative treatment in advanced and/or recurrent disease, there is less benefit from chemotherapy and indications for chemotherapy should be selected for individual patients.     

Chemotherapy advances in locally advanced head and neck cancer

The management of locally advanced unresectable head and neck squamous cell cancer (HNSCC) continues to improve. One of the major advances in the treatment of HNSCC was the addition of chemotherapy to radiation in the treatment of non-surgical patients. The majority of the data regarding chemotherapy in HNSCC involve cisplatin chemotherapy with concurrent radiation. However, several new approaches have included targeted therapy against epidermal growth factor receptor and several recent studies have explored the role of induction chemotherapy in the treatment of HNSCC. The purpose of this article is to provide an overview of the role of chemotherapy in the treatment of locally advanced HNSCC.     

Chemotherapy and integrated treatment approaches in head and neck cancer

Chemotherapy continues to be studied intensively in head and neck cancer. Methotrexate and cisplatin remain standard agents for patients with recurrent disease. Neoadjuvant chemotherapy remains investigational with no firm evidence that it can prolong survival. It may, however, have a role in organ preservation. More recent and aggressive neoadjuvant chemotherapy regimens remain to be tested in randomized studies. Concomitant chemoradiotherapy is of high interest in this disease and is of proven benefit in randomized trials. Encouraging data from trials using protracted radiation schedules will require confirmation in randomized studies.     

Chemotherapy in the treatment of locally advanced head and neck cancer

Three decades of collaborative research have led to the integration of platinum-based chemotherapy into the curative management of squamous cell carcinoma of the head and neck and gains in local-regional control, organ preservation and survival endpoints. Concomitant cisplatin-based chemotherapy and radiotherapy is the strategy that has proven most effective for organ preservation for larynx and oropharynx cancers, the treatment of unresectable disease, nasopharyngeal cancer and the post-operative adjuvant treatment of patients at high risk of recurrence. The evolution of current indications for this multimodality approach is reviewed and current areas of investigation discussed. Nearly all patients with locally advanced head and neck cancer receive chemotherapy as part of initial curative treatment. The focus of future trials should be on survival improvement, toxicity reduction and risk stratification for treatment decision making.     

Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review

Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3–7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III–IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP–5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.     

Chemotherapy： Is it Warranted in Curable Head and Neck Cancer？

Since the last century, many physicians have been trying to utilize chemotherapy to replace conventional surgical treatment for cases of cancer of the oropharynx, larynx, and hypopharynx, which would otherwise be candidates for total laryngectomy. Some authors claim that the preservation rate of the larynx increases after treatment by chemotherapy, which even may take the place of routine surgical methods. However, when calculated in a more rigorous way following accepted statistical methods, what they claim is questionable. As a result, the routine application of chemotherapy in its present form is not advisable for curable squamous cell carcinoma of the head and neck region. Further research is required to justify its benefit.     

Chemotherapy in head and neck cancer. Overview of newer agents.

Several new chemotherapy agents show varying degrees of activity in head and neck cancer. The most extensively studied and most promising agents at this time are the taxanes, particularly paclitaxel. Its exact role in combination with other chemotherapeutic agents or with radiation is still being clarified in clinical testing, but it is certainly reasonable to use paclitaxel for palliation of metastatic or recurrent disease. Docetaxel is a more recently developed agent, and more information regarding its use in palliative therapy will be forthcoming as results from the international randomized trial become available. Gemcitabine has shown very modest activity when used as a single agent or in combination therapy, although further data from ongoing research have not yet been reported. It is an extraordinarily potent radiosensitizer in the head and neck, but unfortunately it appears to have a very narrow therapeutic ratio and should certainly not be used with radiation outside of a clinical trial with careful monitoring of toxicity. Topotecan does not appear to be a clinically useful single agent in treating head and neck cancer, and vinorelbine has shown minimal activity in the few clinical trials that have been conducted in head and neck cancer. Nedaplatin is a very new drug, and it is not possible to draw conclusions regarding its effectiveness until further evaluation has been completed. Continued investigation of new chemotherapeutic agents in head and neck cancer is needed.     

Hyperfractionation for head and neck cancer

Between March 1978 and April 1984, 144 patients with 148 moderately advanced to advanced primary squamous cell carcinomas of the head and neck received treatment with curative intent with twice-a-day irradiation (120 cGy/fraction, 4-6 hour interfraction interval). Eighty-eight percent of the patients had AJCC Stage III-IV cancers. One hundred and thirty-two patients received irradiation alone to the primary site with or without radical neck dissection, with surgery reserved for salvage. The total doses administered were 7440-7920 cGy in the majority of instances. In 19 patients with oropharyngeal lesions, a 1000-1500 cGy radium needle boost was added after the basic dose. Twelve patients received preoperative irradiation (5040-6000 cGy) followed by primary resection and radical neck dissection. Local control results following irradiation alone to total doses of greater than 7000 cGy with minimum 2-year follow-up were 25/31 (81%), 38/50 (76%), and 5/25 (20%) for T2, T3, and T4 cancers, respectively. Local control rates did not correlate well with total dose. Local control following preoperative irradiation plus primary resection was obtained in 4 of 5 T3 and 2 of 3 T4 primary lesions. The 5-year actuarial rates of neck control were 100% for N0 (45 patients), 90% for N1 (25 patients), 77% for N2 (23 patients), 50% for N3A (9 patients), and 70% for N3B (42 patients). The 5-year actuarial rates of continuous disease control above the clavicles were 73% for Stage III, 64% for Stage IVA, and 32% for Stage IVB. The actuarial 4-year rate of continuous disease control above the clavicles was 78% for Stage II. For patients whose disease was controlled above the clavicles, distant metastases developed in 4% of patients with Stage II-III disease and in 18% of patients with Stage IV disease. Radiation complications following irradiation alone to the primary site correlated with total dose. Complications of planned neck dissection(s) were acceptable. Complications of salvage surgery at the primary site were similar to those seen in patients treated once a day. The actuarial 5-year survival rates, according to modified AJCC stage, were 59% for Stage III, 37% for Stage IVA, and 23% for Stage IVB. The actuarial 4-year survival rate for Stage II was 69%. Compared to historical control groups treated with once-a-day, continuous-course irradiation at our institution, twice-a-day treatment has produced local control results that are higher by 10-15 percentage points.     

Chemo-radiotherapy for head and neck cancer

Many randomized trials have investigated the effect on survival of induction chemotherapy; none however, has demonstrated improved survival. A study of the Department of Veterans Affairs Laryngeal Cancer Study Group demonstrated the feasibility of induction CDDP/5-FU plus surgical salvage as an alternative to initial laryngectomy, but it did not include a radiation-alone treatment arm. Thus, a three-arm trial (R 91-11) was needed to compare the regimen of induction chemotherapy plus surgical salvage treatment with radiation alone and with concurrent chemo-radiation, to determine whether the addition of chemotherapy led to better results than conventional radiation alone. R 91-11 data revealed that concurrent chemo-radiation significantly increased the time to laryngectomy and chemotherapy suppressed distant metastasis, but there was no difference in overall survival. Single-agent docetaxel is known to induce a response in 22-45% of patients with recurrent squamous cell cancer of the head and neck. When used in combination with CDDP, response rates of between 40 and 54% have been reported. Increased expression the epidermal growth factor receptor (EGFR) is reported in head and neck cancer. Anti-EGFR monoclonal antibody is associated with decreased cell proliferation, inhibition of metastasis and angiogenesis, and it has a synergistic effect with chemotherapy or radiotherapy. It is hoped that further advances will lead to greater realization of the therapeutic potential of these compounds as anticancer agents.     

Radiotherapy for head and neck cancer

The length and quality of head and neck cancer survivorship continues to improve. Radiotherapy has been central to this process through advances in treatment technology, fractionation schemas, radiosensitizing chemotherapy, and surgical technique. The future of head and neck radiotherapy looks brighter still with progress in radiosensitizing biologic therapy, molecular characterization, functional imaging, and rehabilitative strategies fast approaching. Head and neck cancer, a disease once fraught with nihilism and failure, is evolving into a major success story of multidisciplinary solid tumor management. Continued dedication and work on the part of provider and patient alike will be required to make this promise a reality.     

Immunotherapy for head and neck cancer

Overall survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has not improved appreciably over the past few decades. Novel therapeutic approaches, such as immunotherapy, are under clinical investigation since the standard treatments are toxic and have not successfully controlled this disease with sufficiently high success rates. Cancer immunotherapy describes various techniques to expand and activate the immune system to control tumor growth in vivo, and clinical evaluation has so far demonstrated low toxicity. Immunotherapy appears to have the most applicability in settings of minimal residual disease and to reduce distant metastases after other therapeutic interventions, and its potential clinical value is now receiving intensive evaluation. Emerging forms of SCCHN immunotherapy involve both the use of monoclonal antibodies (mAb) that target growth factor receptors where immune activation appears to contribute to tumor cell lysis, as well as various forms of active vaccination strategies which activate and direct the patient’s cellular immunity against the tumor. This article reviews immunotherapeutic strategies currently in clinical trials or under development for patients with SCCHN.     

Chemotherapy following surgery for head and neck cancer. A Radiation Therapy Oncology Group Study

The feasibility of chemotherapy of three courses of cis-platin and 120-h 5-fluorouracil (5-FU) infusion after definitive surgery, followed by standard radiotherapy, in patients with resectable locally advanced head and neck cancer was carried out in Radiation Therapy Oncology Group (RTOG). Seventy-nine percent of the patients had stage IV cancer, 65% of the tumors were moderately differentiated, and primary sites were 38% oropharynx and 28% larynx. Toxicity to chemotherapy was acceptable, with no life-threatening side effects. Nausea and vomiting were the most common side effects (78%) and were severe in 26%; 30% of patients experienced had leukopenia, 22% had anemia, 13% had thrombocytopenia, and 9% had renal impairment--all of which were mild and reversible. In six patients, chemotherapy was not given for medical conditions or because of patient refusal. Of 23 patients started on cis-platin and 5-FU postsurgery, 18 (78%) completed all three courses. Ninety-six percent of the patients finished adequate radiotherapy according to the protocol. With minimum follow-up of 24 months, 62% of the patients were alive. Of the expired patients, 5 died from other causes, without evidence of recurrence at the time of their death. It is our conclusion that chemotherapy with cis-platin and 5-FU infusion following definitive surgery is feasible on the group level, and a Phase III trial comparing this combined modality therapy to standard treatment of surgery and post-operative radiotherapy is underway by the Head and Neck Cancer Intergroup.     

Chemotherapy for head and neck cancer. Comparison of cisplatin + vinblastine + bleomycin versus methotrexate

One hundred ninety-one patients with recurrent or metastatic squamous cell carcinoma of head and neck origin were allocated at random to chemotherapy with conventional-dose weekly intravenous methotrexate or the combination of cisplatin, vinblastine, and bleomycin. Methotrexate induced responses in 16 of 98 patients (16%), whereas 22 of 92 (24%) responded to the combination regimen (P = not significant). Remission duration (20.2 weeks methotrexate; 15.1 weeks combination) was similar on both arms, as was survival (31.4 weeks methotrexate; 29.0 weeks combination). Therapy was relatively well-tolerated on both treatment arms, although methotrexate produced more mucositis and the combination more gastrointestinal and renal toxicity. Response to chemotherapy and disease confined to the locoregional area were associated with somewhat longer survival. Combination chemotherapy as given in this study did not improve any observed parameter, and the results of treatment were poor in both arms.