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 G₁ 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.     

西妥昔单抗治疗头颈部鳞状细胞癌研究进展

常规放化疗治疗进展期头颈部鳞状细胞癌（HNSCC）的不良反应大,疗效有限。近期临床研究表明表皮生长因子受体（EGFR）抑制剂西妥昔单抗联合放疗治疗局部晚期HNSCC显示高效低毒的优越性,单药对铂类耐药病例仍有一定疗效。西妥昔单抗在HNSCC的综合治疗中有广阔的应用前景。     

Cetuximab in the treatment of squamous cell carcinoma of the head and neck

The majority of the head and neck cancers are squamous cell carcinomas, which commonly overexpress the EGF receptor (EGFR). Cetuximab is a chimeric monoclonal antibody that binds with high affinity to the extracellular domain of EGFR, and in addition induces antibody-dependent cellular cytoxicity. In a randomized Phase III trial in patients with locoregionally advanced squamous cell carcinoma of the head and neck, the addition of cetuximab to radiotherapy prolonged the median time of locoregional control from 14.9 to 24.4 months and increased the median overall survival from 29.3 to 49.0 months. In patients with platinum-refractory recurrent and/or metastatic disease, the objective response and disease-control rates in various studies ranged from 10 to 13% and from 46 to 56%, respectively. In the EXTREME trial, the addition of cetuximab to platinum/5-fluorouracil as first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck not only led to significant improvements in survival, response rate and disease control, but also induced a better symptom control in comparison with that observed with platinum/5-fluorouracil alone.     

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.     

Surgical treatment in head and neck cancer

Three topics currently important in head and neck surgery are voice-conserving surgical treatment of laryngeal cancer, the role of modified radical neck dissection in the treatment of cervical metastases, and reconstruction and rehabilitation of the head and neck cancer patient. The laser has become an accepted modality for the treatment of early vocal cord cancer and has local control rates comparable to other treatment methods. Partial laryngectomy can conserve voice and yield excellent local control rates. The modified radical neck dissection has been shown to yield rates of local recurrence no greater than radical neck dissection for N0 and N1 neck disease associated with laryngeal cancer. Vocal rehabilitation following total laryngectomy has been revolutionized by the tracheoesophageal puncture procedure. Most patients can be expected to acquire voice using tracheoesophageal puncture following total laryngectomy. Free flaps have improved the functional results of many major head and neck surgical procedures and offer the possibility of better results in the future. However, more conventional reconstructive techniques, including local flaps, continue to have a role in head and neck surgery.     

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.     

Brachytherapy in the treatment of head and neck cancer

Brachytherapy is a therapeutic modality that may provide a significant improvement in the therapeutic ratio when appropriately applied, and hence, is an appealing treatment strategy for the head and neck. For several tumor sites in the head and neck, the use of a brachytherapy implant has been demonstrated to be effective and is optimally provided within a multidisciplinary team setting. This enables meticulous attention to technical and treatment-related factors that have been demonstrated to influence the therapeutic ratio for low-dose-rate implants. Recent technologic advances have enabled the study of promising high-dose-rate and pulsed-dose-rate afterloading brachytherapy techniques, in an attempt to expand the role of brachytherapy in the head and neck. These techniques minimize radiation exposure hazards while offering the physical and biologic advantages of brachytherapy. Issues pertinent to members of the brachytherapy team providing multidisciplinary care of the implanted head and neck patient are discussed.     

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.     

Cetuximab as treatment for head and neck cancer patients with a previous liver transplant: report of two cases

Cetuximab is a monoclonal antibody against epidermal growth factor receptor useful in the treatment of patients with Head and Neck Squamous Cell Carcinoma combined with radiotherapy or chemotherapy. Its pharmacokinetics are not influenced by hepatic status and there are no specific warnings concerning its indication in patients with impaired hepatic function. Patients with a previous liver transplant are at risk for hepatic toxicity and use immunosupressants to avoid rejection that can interact with other drugs. We present two cases of patients with a previous liver transplant in which cetuximab was administered to treat head and neck cancer.     

Gemcitabine in the treatment of advanced head and neck cancer

AimsSeveral new chemotherapy agents show varying degrees of activity in head and neck cancer. One of them is gemcitabine, which is a new nucleoside analogue with an innovative cytostatic mode of action. Gemcitabine has demonstrated a broad spectrum anti-tumoural effect and a favourable toxicity profile. These attributes prompted us to introduce gemcitabine into the treatment of head-and-neck tumours.Materials and methodsTen heavily pre-treated patients with recurrent and incurable squamous-cell carcinoma of the head and neck (SCCHN) were treated with Gem. The initial cycle consisted of six administrations of the drug (1250 mg/m² once weekly intravenously over 30 min) followed by a week without cytotoxic treatment. All following cycles were composed of two infusions once weekly (d1, 8), followed by a week of rest.ResultsToxic effects, length of survival and tumour response was assessable in eight patients owing to one suicide and loss of one patient for follow-up. One complete remission, two partial remissions and three ‘no change’ situations (stable disease) were observed, yielding a response rate of 37.5%. Median survival was 8 months (range 3–12). The incidence of haematological toxicity was low, with grade 3–4 neutropenia in less than 10%. Flu-like symptoms were reported by one-third of patients.ConclusionsIn this small phase-II study, gemcitabine demonstrated a high anti-tumoural activity in SCCHN, with a favourable toxicity profile. Gemcitabine seems to be a promising new drug without severe burden even for patients who are refractory to other cytostatic drugs. Within recent years, the activity and tolerability of gemcitabine was documented in several phase I and phase II trials, especially in combination with cisplatin, and paclitaxel resp, carboplatin/paclitaxel, cisplatin/ifosfamide, and 5-fluorouracil/paclitaxel. The results of these trials will be outlined in the discussion.     

Altered fractionation in the treatment of head and neck cancer

Several altered fractionation schemes have evolved to exploit different aspects of head and neck cancer growth kinetics and normal tissue repair. Hyperfractionation schedules exploit the differential repair abilities of tumor and normal tissue, whereas accelerated fractionation regimens minimize the time of tumor repopulation. Significant clinical data have accumulated that indicate an improvement between 15% and 20% in locoregional control from altered fractionation. Preliminary analysis of a randomized Radiation Therapy Oncology Group trial testing four fractionation schemes confirms the benefit of one altered fractionation approach. Several promising concurrent chemoradiation treatments involving altered fractionation have been reported. Future trials will determine whether the addition of chemotherapy to altered fractionation schemes is warranted in light of the factor of added toxicity.     

Cetuximab in the treatment of colorectal cancer

The role of epidermal growth factor receptor (EGFR)-driven signaling in different stages of colorectal carcinogenesis, as well in the acquisition of therapy resistance, has been established. Multiple strategies have been developed for the therapeutic targeting of EGFR. Cetuximab is a chimeric monoclonal antibody selective for EGFR with efficacy alone or in combination with irinotecan in the treatment of metastatic colorectal cancer patients, who have progressed to using irinotecan-containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Based on this data, the combination of cetuximab with standard chemotherapy regimens such as irinotecan/ 5-FU/folinic acid (FA) or oxaliplatin/5-FU/FA are currently being investigated in Phase III trials for chemotherapy-naive patients with metastatic colorectal cancer.     

Salivary gland sparing in the treatment of head and neck cancer

Radiotherapy is an important component of the multimodality treatment of head and neck cancer. Although an effective treatment for many patients, it can have significant long-term sequelae. In particular, xerostomia - or dry mouth - caused by salivary gland injury is a serious problem suffered by most patients and leads to problems with oral comfort, dental health, speech and swallowing. This article explores the mechanisms behind radiation injury to the major salivary glands, as well as different strategies to minimize and alleviate xerostomia. This includes technical approaches to minimize radiation dose to salivary tissue, such as intensity-modulated radiotherapy and surgical transfer of salivary glands, as well as pharmacologic approaches to stimulate or protect the salivary tissue. The scientific literature will be critically examined to see what works and what strategies have been less effective in attempting to minimize xerostomia in head and neck cancer patients.     

Salivary gland sparing in the treatment of head and neck cancer

Radiotherapy is an important component of the multimodality treatment of head and neck cancer. Although an effective treatment for many patients, it can have significant long-term sequelae. In particular, xerostomia – or dry mouth – caused by salivary gland injury is a serious problem suffered by most patients and leads to problems with oral comfort, dental health, speech and swallowing. This article explores the mechanisms behind radiation injury to the major salivary glands, as well as different strategies to minimize and alleviate xerostomia. This includes technical approaches to minimize radiation dose to salivary tissue, such as intensity-modulated radiotherapy and surgical transfer of salivary glands, as well as pharmacologic approaches to stimulate or protect the salivary tissue. The scientific literature will be critically examined to see what works and what strategies have been less effective in attempting to minimize xerostomia in head and neck cancer patients.     

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.