Management of Head and Neck Cancer in Elderly Patients

Transcription

1 REVIEW ARTICLE Drugs Aging 2009; 26 (7): X/09/ /$49.95/0 ª 2009 Adis Data Information BV. All rights reserved. Management of Head and Neck Cancer in Elderly Patients Yassine Lalami, 1 Gilberto de Castro Jr, 2 Chantal Bernard-Marty 1 and Ahmad Awada 1 1 Medical Oncology Clinic, Institut Jules Bordet, Brussels, Belgium 2 Medical Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil Contents Abstract Head and Neck Cancer (HNC) Surgery in Older Patients Radiation Therapy in Older HNC Patients Chemotherapy in HNC Patients Cisplatin and Carboplatin Fluorouracil Methotrexate Taxanes Molecular-Targeted Therapies Multimodality Treatment of HNC in Older Patients Conclusions and Perspectives Abstract Head and neck cancer (HNC) represents a heterogeneous group of tumours requiring multimodality approaches. It is debatable whether HNC treatment in geriatric patients should be different to that delivered for younger patients. Furthermore, the risk of death seems to be higher in HNC patients with higher co-morbidity status. Despite the fact that there is no significant difference in outcome in younger versus older patients, older HNC patients are more likely to receive nonstandard, less aggressive therapies than younger patients. Age alone should not be the basis for selecting treatment options in older HNC patients. A thorough pretreatment evaluation of comorbidities should always be performed, and radical surgical options should not be excluded in older HNC patients treated with curative intent, as postoperative complications occur no more frequently in older patients than in younger patients. Locoregional control and disease-free survival in older patients treated with radiation therapy (either with curative intent or in the palliative setting) are comparable to the results seen in younger HNC patients, with the same acute toxicity profile. In patients receiving systemic therapies, special attention must be given to modification of chemotherapy dosages according to renal and hepatic function. Molecular-targeted therapies appear to be very useful in such patients because of their favourable tolerability. In conclusion, once all physiological and biological risk factors have been addressed, a large proportion of geriatric patients can and should be offered the same HNC treatment as is offered to younger patients.

2 572 Lalami et al. Head and neck cancer (HNC) represents a heterogeneous group of tumours requiring multimodality approaches to achieve the best therapeutic results. As with other malignancies, determining the optimal management of HNC in older patients is challenging. [1,2] It is debatable whether HNC treatment in geriatric patients should be different from that delivered to younger patients. Certainly, the risk of death seems to be higher in HNC patients with higher co-morbidity status and, as expected, a major background factor related to co-morbidity status is the patient s age. [3-5] Older HNC patients may experience a higher mortality rate because of advanced stages of cancer at diagnosis or decreased functional status, which precludes the use of more aggressive therapies. Moreover, inadequate access to the recommended or evidence-based standard of care because of lack of insurance or underinsurance may be linked to higher mortality in these patients. [6] Older HNC patients are more likely to receive nonstandard, less aggressive therapies than younger patients. [7-9] However, HNC in older patients seems not to have a significantly different outcome compared with the same disease in younger patients. [10,11] Interestingly, head and neck squamous cell carcinoma (HNSCC) diagnosed after the seventh decade of life seems to present less frequently with genetic alterations, namely p53 gene mutations, than the same disease in younger patients. [12] It is now clear that age alone should not be used to select the treatment options for older HNC patients. In this review, we aim to summarize the evidence regarding the multimodality treatment of HNC in older patients. Patients aged 65 years are underrepresented in clinical trials. [13] A review of National Cancer Institute trials by Lewis et al. [14] reported that 32% of patients entered in phase II and III trials were aged >65 years, despite the fact that an estimated 60% of cancer patients are in this age category. Indeed, there are few reports in the literature focusing on patients aged >65 years, and the data are especially sparse for individuals aged 75 years. This problem is becoming critical because of the rapid growth in the aging population. Data for this review were identified from the authors collections of publications, and by searching PubMed and references from relevant articles. The following search terms and their synonyms were used: head and neck cancer, elderly, surgery, radiotherapy, chemotherapy, epidermal growth factor receptor and comprehensive geriatric assessment. Papers published in English between 1990 and January 2009 were included. 1. Head and Neck Cancer (HNC) Surgery in Older Patients Surgery is considered an essential step in the multidisciplinary management of HNC patients, irrespective of age. As noted by Sanabria et al., [15] because the risk of postoperative complications is higher in older patients, surgeons must make therapeutic decisions based on the expected oncological results and their subjective assessment of the possible development of complications. The main predictive factor for postoperative complications in older patients is co-morbidity. [16,17] Given the natural history of HNSCC, which is the most common histological type of HNC, and the specific anatomical sites of these tumours, locoregional involvement usually leads to malnutrition, anaemia, pain, swallowing difficulties, respiratory discomfort and disfigurement, among other symptoms. Indeed, given the effects that tobacco and alcohol-related co-morbidities (e.g. pulmonary obstructive diseases, cirrhosis and cardiac problems) can also have, many HNSCC patients present to the multidisciplinary oncology team with low performance status, sometimes potentially irreversible from the medical point of view. Moreover, the frequency of second neoplasia (around 7%) in these patients is not negligible. [18] Their management, therefore, represents a truly difficult challenge. Experts of the International Society of Geriatric Oncology have recently published recommendations on the surgical management of elderly patients with cancer. [19] In general, the postoperative complication rate after HNC radical surgery seems to be comparable for all ages. A review of 162 HNSCC

3 Head and Neck Cancer in the Elderly 573 patients aged >70 years treated with surgery from suggested that aggressive surgical therapies is advisable. [20] Barzan et al. [21] reported that HNC in older patients seems to present with different clinical features compared with younger patients (e.g. lower staging, lower frequency of hypopharyngeal cancer), although postoperative complications, local control and overall survival did not differ between older and younger groups. [21] In another study, cardiovascular and pulmonary complications appeared to be more frequent among older patients. [22] Microvascular free tissue transfers for head and neck reconstruction can be safely performed in elderly patients, and the rate of surgical complications does not appear to be higher in this group than in younger patients. [23] One practical question is how best to assess co-morbidity status in older HNC patients. Radical surgical procedures can be performed safely in HNC patients who have no severe co-morbidities; indeed, it is likely that the severity rather than the number of co-morbidities is of greatest relevance in the decision-making process. [5] Co-morbidity as measured by the Adult Comorbidity Evaluation-27 (ACE-27) index was a prognostic factor for overall survival in 310 HNC patients aged >70 years and findings on this instrument should be used in longitudinal studies as an adjustment factor when assessing long-term prognosis. [24] The Karnofsky Performance Scale Index score was associated with survival to a greater degree than ACE-27 index score in this study and must also be viewed as an essential variable that should be considered for clinical and research purposes in older populations. The ACE-27 index score also appears to be a prognostic factor in salivary gland cancer patients. [25] Sanabria et al. [15] recently described a predictive index of postoperative complications in older patients undergoing HNC surgery based on five variables: bilateral neck dissection, two or more co-morbidities, reconstruction, male sex and clinical stage IV. The index has a sensitivity of 84%, a specificity of 41% and a rate of correct classified data of 67%. A total of 118 older (aged 70 years) and 148 younger (45 60 years) HNC patients were followed up for 3 6 years in a study by van der Schroeff et al. [26] During follow-up, 33 younger and 24 older patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and QLQ-Head & Neck Module (QLQ-H&N35) questionnaires. The survival rate for younger patients was 36%, compared with 31% in older patients. Higher tumour stage, more co-morbidities and nonstandard treatment were shown to be independent prognostic factors for mortality. No independent prognostic value of age was detected. The global quality-of-life score remained roughly comparable between the two age groups. [26] Comprehensive geriatric assessment (CGA) describes a multidisciplinary evaluation of an older individual s functional status, co-morbid medical conditions, cognition, psychological state, social support, nutritional status and medications. [27] In addition to evaluating performance status, the geriatrician assesses functional status in terms of the patient s ability to complete activities of daily living and instrumental activities of daily living, as well as objective performancebased measures of functional status, such as the Timed Up and Go test, the 6-minute walk and grip strength. A longitudinal incorporation of CGA into daily clinical practice as well as into clinical trials can provide important information. Recent studies have demonstrated that the domains evaluated in a CGA can predict morbidity and mortality in older patients with cancer. [28-30] These data should prompt integration of CGA into studies that include older patients and evaluation of the impact of CGA in guiding interventions to improve the outcome of these patients. Followup geriatric assessments at scheduled timepoints after initiation of cancer therapy can quantify the longitudinal impact of the therapy on the older adult s functional status and other geriatric assessment parameters. Use of a CGA can also stimulate the development of novel endpoints for clinical trials in geriatric oncology. Barriers to CGA include time, familiarity, cost and lack of a well defined procedure to interpret and apply the information. Practical algorithms to aid in

4 574 Lalami et al. Table I. Pretreatment evaluations for incorporation in the daily care of older patients with head and neck cancer Adult Comorbidity Evaluation 27 (ACE-27) index [24] Comprehensive geriatric assessment [28,30] Nutritional evaluation Ultrasound screening of carotid arteries (if cervical radiation therapy is planned) [39] Detection (and treatment of) depression Identification (and treatment) of tobacco smoking and excessive alcohol consumption Renal function measured by isotopic clearance method [40] the selection of patients whose treatment decisions can be changed by CGA have been suggested. [31] Conservative surgical techniques appear to be attractive to those treating elderly patients with HNC. One potential limitation is the lack of compliance with feeding and phonatory rehabilitation observed in older patients. [32] Aspiration pneumonitis is also a major risk. [32] A comparative analysis in patients undergoing reconstructive surgery with flaps showed that there was a major complication rate of 12% in flaps used in older (aged >70 years) patients, as compared with 8% for those used in younger (aged 70 years) patients. [33] Transoral carbon dioxide laser laryngectomy followed by radiation therapy (RT) for early supraglottic laryngeal carcinomas is a very attractive option in older patients, and early results are promising. [34,35] Among 24 patients aged >75 years diagnosed with laryngeal squamous cell carcinoma (SCC) treated with carbon dioxide laser in one series, the major postoperative complications were related to dysphagia and aspiration pneumonia. [36] There is scarce information about HNC surgery in patients aged 80 years. [37] However, the authors of a recent retrospective review of 316 HNC patients aged 80 years treated with surgery and/or RT concluded that outcomes were similar in this group to those of younger patients. [38] The outcome in patients with stage III and IV disease was poor because of the unselected nature of this group of patients, the adverse prognostic effect of advanced age and suboptimal treatment. In summary, a thorough presurgical evaluation of co-morbidities must always be performed in older HNC patients. Adequate surgical treatment options should not be excluded when treatment with curative intent is undertaken in these patients, in whom postoperative complications, long-term results and quality of life do not seem to be different from those in younger patients. Some pretreatment evaluations that can be incorporated in the daily care of older HNC patients are suggested in table I. 2. Radiation Therapy in Older HNC Patients Case series of older HNC patients treated with conventionally delivered RT, either with curative intent or in the palliative setting, have shown that locoregional control and disease-free survival are comparable to the results seen in younger patients. [41,42] The same acute and late toxicity profile was also observed. Severe acute toxicity was reported as significantly more frequent in older patients (aged 65 years), that is, 67% versus 49% in younger patients (aged <65 years) for grade 3 4 toxicity. [43] As expected, depression and confusion as adverse events of RT are common (up to 21%) in patients aged years. [44] Only a few cases of patients aged 80 years are reported, but results are relatively encouraging in terms of response rate, symptom palliation, tolerance and survival. [45] The EORTC recommendation to delete age limits from RT protocols has been followed in more than half (57%) of the protocols developed since [46] No impact of age on outcome after RT for HNC has been reported other than more severe functional acute reactions in older patients. [46] As reviewed by Horiot, [46] only 15% of the 574 patients included in nine studies conducted by the EORTC were aged 65 years and only one patient was aged >75 years. The proposed reasons for such low recruitment of older patients included lack of knowledge and resistance on the part of both the investigators and patients. Another reason probably related to the protocols for concurrent chemoradiation, which is considered more toxic than RT alone. [46] Older patients are usually excluded from studies of alternative fractionation schedules (accelerated and/or hyperfractionated RT) because of safety reasons. One study published in

5 Head and Neck Cancer in the Elderly evaluated the feasibility and efficacy of accelerated RT in older HNC patients, and similar median administered RT doses and treatment times were observed between patients aged >70 years and younger patients, as well as in terms of locoregional control (73% vs 68%, respectively) and overall survival. [47] Older age is a strong independent risk factor for severe late toxicity after concurrent chemoradiation, including feeding tube dependence more than 2 years after RT, pharyngeal and/or laryngeal dysfunction and fistula, among others. [48] There needs to be a major effort to improve the quality of supportive care before, during and after RT in elderly patients with HNC. Nutritional support, early identification and aggressive treatment of mucositis, infections and xerostomia, and access to new technologies such as intensitymodulated RT are very important issues. Some initiatives to incorporate CGA in the initial management of HNC patients who are candidates for RT have been recently published. [49] Carotid artery stenosis is a cause of stroke and one of the leading causes of mortality in older patients. As carotid artery stenosis and HNSCC share tobacco use as a risk factor, when treating HNSCC patients, steps must be taken to control and avoid this type of atherosclerotic disease, including stopping smoking, achieving the best possible control of hypertension and dyslipidaemia, and early detection of carotid artery stenosis before deliveryofrttotheneck.therateofcarotidartery stenosis in HNSCC treated with neck dissection and RT can reach 30 40%. [50,51] RT alone for HNC, but not postoperative RT, is associated with excess cerebrovascular disease risk in older patients. [39] Therefore, ultrasound screening of the carotid arteries should be considered in HNSCC patients if RT is planned and also during follow-up evaluation of long-term survivors, particularly in those patients who have had neck dissection or are symptomatic. [50-52] Other CT-based screening techniques are under development. [53] Treating co-morbid smoking, alcohol consumption and depression are relevant components of a more holistic approach to HNC patients. Reports of some successful tailored interventions have been published. [54] Taking all these data concerning RT in older HNC patients into account, either in the curative or palliative setting, locoregional control and disease-free survival are comparable to those seen in younger patients, with the same overall acute toxicity profile. Late toxicities deserve special attention in older patients. 3. Chemotherapy in HNC Patients Age-related changes in physiology, such as decreased renal function and changes in splanchnic blood flow, can affect the pharmacokinetics and pharmacodynamics of systemic cancer therapy. [55,56] However, while older patients are considered to be more vulnerable to myelosuppression, mucositis and other gastrointestinal adverse effects of cancer therapy, the available data indicate that overall morbidities and mortality associated with experimental systemic therapies do not differ significantly from those associated with standard treatments in trials in which more than 40% of those enrolled were elderly. [57] The pharmacokinetics and pharmacodynamics of some chemotherapeutic agents used in geriatric patients are reviewed elsewhere. [58] Despite the fact that HNSCC is considered a chemosensitive disease, older patients are excluded from studies of chemotherapy because of safety reasons. [58,59] The following sections provide a summary of some of the relevant pharmacological considerations relating to use of cytotoxic agents in the treatment of older patients with HNC. 3.1 Cisplatin and Carboplatin Cisplatin is a cornerstone in the treatment of HNSCC and has been studied using a variety of doses, combinations and schedules. The classic combination of cisplatin and infusional fluorouracil is still considered the standard systemic therapy not only in the neoadjuvant setting, with overall response rates of 70 88% and complete response rates of 40 60%, but also in cases of locoregional or distant recurrent disease, where overall response rates of 40 50% and complete response rates of 5 10% have been described. [60,61]

6 576 Lalami et al. A review of two mature phase III trials using cisplatin-based chemotherapy (cisplatin/fluorouracil or cisplatin/paclitaxel) for recurrent and/or metastatic HNSCC identified 53 elderly patients (13%) that were aged 70 years. [62] Both response rates (28% vs 33%) and median time to progression (5.3 vs 4.8 months) were comparable between older and younger patients, respectively. However, older patients experienced higher rates of severe nephrotoxicity, diarrhoea and thrombocytopenia. Toxic deaths were also more common in older patients (13% vs 8%). Cisplatin-based chemotherapy combinations may cause severe toxicities, including renal impairment with magnesium and potassium loss, nausea, vomiting, myelosuppression, auditory impairment and peripheral neuropathies. These toxicities may impact severely on patients quality of life. Given that vigorous hydration before cisplatin administration is not always possible in older patients, most clinicians are rather reluctant to prescribe cisplatin in this population. Carboplatin appears to be an alternative with a better toxicity profile, especially taking into account that its dose is calculated based on the area under the plasma concentration-time curve (AUC) of the drug and renal creatinine clearance. However, its antitumour activity appears to be less impressive than that of cisplatin in HNSCC patients. 3.2 Fluorouracil Published data yield conflicting results as to whether fluorouracil is more toxic in older patients. [58] Cardiotoxicity worsened by electrolyte imbalances during chemotherapy is a possible toxicity of infusional fluorouracil. Mucositis induced by fluorouracil may seriously interfere with the nutritional status of older patients. Prevention of mucositis with the use of a low energy level laser may be considered in this setting, but access to this technique is limited. Despite all the above mentioned physiological limitations, cisplatin/ fluorouracil chemotherapy can be safely delivered to fit patients aged >70 years. [59] 3.3 Methotrexate Methotrexate is considered an alternative for palliative treatment of platinum-resistant HNSCC. The response rate in HNSCC patients treated with the standard dose (usually 40 mg/m 2 weekly) varies from 12% to 35%. [63] Since the drug is eliminated mainly (44 100%) by renal excretion, older patients with impaired renal function are more susceptible to increased toxicity, primarily mucositis, myelotoxicity and transaminitis. Dose modifications based on renal function are encouraged in elderly patients. 3.4 Taxanes Taxanes (paclitaxel and docetaxel) are among the most active single agents for HNSCC. Their metabolism can be affected by alterations in liver function as well as by other drugs acting as substrates of cytochrome P450 isoenzymes. Although there are somewhat conflicting data regarding the impact of age on paclitaxel clearance, a Cancer And Leukemia Group B study (CALGB 9762) revealed a significant decrease in total paclitaxel clearance with increasing age without severe sequelae. [64] Weekly regimens of paclitaxel are well tolerated but repeated administration of dexamethasone (given as a premedication to avoid allergy when paclitaxel is prescribed) must be monitored in older patients. Peripheral neuropathy as an adverse effect of paclitaxel can interfere with patients autonomy, especially those previously treated with cisplatin. Because their metabolism is dependent on liver function, administration of taxanes can be problematic in patients with severe hepatic dysfunction (e.g. alcohol-induced). Docetaxel is being widely used in combination with cisplatin and fluorouracil as induction chemotherapy for locally advanced HNSCC. [65] Its clearance is a strong independent predictor of grade 4 neutropenia and febrile neutropenia. Myelotoxicity, neutropenic sepsis and severe stomatitis can be increased in patients with hepatic dysfunction. Age and gender do not appear to modify the pharmacokinetic behaviour of docetaxel. [66] In addition to controversies about the actual impact of induction chemotherapy, there is a genuine concern about the toxicities of a triplet schedule of this nature in older and frail patients. A recent phase II trial evaluated the efficacy of

7 Head and Neck Cancer in the Elderly 577 induction chemotherapy based on docetaxel and cisplatin in 44 elderly stage III and IV HNSCC patients treated according to a very convenient 3-week course. [67] The overall response rate was 88% (partial response 52% and complete response 36%). Such results are similar to those reported in patients treated with the cisplatin/ fluorouracil combination. Grade 3 4 neutropenia occurred in 75% of patients and 9% experienced febrile neutropenia. No treatment-related deaths andnograde3 4 renal toxicity occurred. Standard chemotherapy regimens can be safely administered to fit older patients without severe co-morbidity, so long as special attention is paid to the modification of dosages according to renal and hepatic function. During chemotherapy, the best possible supportive care is essential in order to maintain chemotherapy dose intensity. Dose reductions based only on patients age must be avoided, particularly if treatment is administered with a curative intent. If possible, a CGA should be performed to evaluate not only functional status and co-morbidity, but also socioeconomic conditions, nutrition, polypharmacy and geriatric syndromes. It must be emphasized that the Cockroft-Gault method for calculating creatinine clearance appears to underestimate renal function in older patients. [40] Toxicities must be diagnosed early and promptly treated. If indicated, administration of haematopoietic growth factors and cytoprotectants can be considered. [68-70] 4. Molecular-Targeted Therapies When treating older patients with HNC in the multidisciplinary care context, it is essential to weigh efficacy (response rate, progression-free survival and overall survival) against toxicity and tolerance. Randomized trials have shown that molecular-targeted therapies, either as monotherapy or in combination with cytotoxic chemotherapy or RT, can increase the efficacy of combination therapies at the cost of an acceptable added toxicity, making them attractive for use in older patients. However, the proportion of older patients included in trials evaluating molecular-targeted therapies, when mentioned, is usually below 20%. [71] The high expression of the epidermal growth factor receptor (EGFR) in HNSCC cells (>90%), [72-75] and its relationship to the malignant phenotype in terms of diminished apoptosis, higher proliferation rate, increased invasiveness, metastatic potential and angiogenesis, led to the development of therapies directed at this receptor and to the signal transduction pathway downstream of activated EGFR. Theoretically, therapies directed at biologically relevant targets such as EGFR could help to block the malignant phenotype described above and also present a better toxicity profile than traditional cytotoxic agents, making these agents very attractive for use in older patients. Cetuximab is a chimeric monoclonal antibody directed at the extracellular domain of the EGFR. The response rates to cetuximab in HNSCC patients refractory to cisplatin-based chemotherapy vary from 13% as monotherapy to 6 26% in combination with cisplatin. [72-75] Stable disease is the most commonly observed response, with a median overall survival of around 5 6 months. In patients with locoregional disease, better locoregional control (24 vs 15 months, hazard ratio [HR] 0.68, p = 0.005), median progression-free survival (17 vs 12 months, HR 0.70, p = 0.006) and median overall survival (49 vs 29 months, HR 0.74, p = 0.03) were observed in patients treated with cetuximab and RT compared with those treated with RT alone (control), respectively, with a favourable toxicity profile. [76] The control arm was heterogeneous in that investigators could choose from hyperfractionated, accelerated or daily RT. However, RT alone might not have been a good comparator because chemoradiation has already been demonstrated to be superior to RT alone. Addition of cetuximab to concurrent accelerated RT and cisplatin 100 mg/m 2 on days 1 and 22 in stage III and IV laryngeal, hypopharyngeal and oropharyngeal SCC patients is being tested in the RTOG-0522 randomized trial (ClinicalTrials. gov identifier: NCT ). For those patients who are not candidates for cisplatin-based chemotherapy, cetuximab is a reasonable choice. However, special attention must be given to cutaneous toxicity when adding cetuximab to RT. Cetuximab has also been evaluated in combination with fluorouracil and cisplatin in HNSCC

8 578 Lalami et al. patients with recurrent/metastatic disease in the EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer) trial. [71] This trial showed that the triple combination was superior to the fluorouracil/cisplatin combination in terms of response rate (36% vs 20%, p = 0.001), median progression-free survival (5.6 vs 3.3 months, HR 0.54, p < 0.001) and median overall survival (10.1 vs 7.4 months, HR 0.80, p = 0.04). Therefore we could speculate that a targeted therapy (anti-egfr or antiangiogenic) delivered as adjuvant treatment (e.g. for 4 6 months after the endofchemoradiation)wouldbeusefulindiminishing the risk of distant failures. However, a major obstacle to the adjuvant strategy would be poor compliance in this setting. The high cost of cetuximab is also a barrier to its widespread use. Another strategy for targeting EGFR involves a tyrosine kinase inhibitor. The most studied molecules of this type are gefitinib and erlotinib. In HNSCC patients presenting with platinumrefractory disease, the IMEX (Iressa versus Methotrexate) trial showed that neither the low dose of gefitinib (250 mg/day) nor the high dose (500 mg/day) were superior to methotrexate in terms of overall survival. [77] In fact, it was found that more patients treated with gefitinib, compared with methotrexate, had tumour bleeding: 9% (14/158) of patients taking gefitinib 250 mg/day and 11% (19/166) of patients taking gefitinib 500 mg/day, compared with 2% (3/159) of patients taking methotrexate. A phase II study evaluated erlotinib as a single agent in patients with metastatic/advanced platinum-refractory HNSCC. [78] The response rate was 4% and disease stabilization occurred in 38% of patients. Median overall survival was 6 months. Grade 2 rash was associated with better overall survival. Another phase II study that evaluated the erlotinib/cisplatin combination in recurrent or metastatic HNSCC reported nine objective responses among 51 patients. [79] Preliminary results for gefitinib in combination with docetaxel are encouraging. [80] Research into and development of new cytotoxic compounds and molecular-targeted drugs in HNSCC are eagerly awaited, given the limited activity of current platinum-, fluorouracil- and/or taxane-based chemotherapy regimens and their toxicity profiles. Results for ixabepilone, an epothilone B analogue with anti-microtubule activity and non-cross resistance with taxanes, in metastatic or recurrent HNSCC have recently been reported. [81] Pemetrexed, a multi-target anti-folate agent, is also under investigation for the treatment of HNSCC. In terms of moleculartargeted therapies, small molecule tyrosinekinase inhibitors such as ZD6474 and lapatinib (both with anti-egfr activity), desatinib (a Bcl- Abl and Src-inhibitor) and cediranib (formally AZD2171, with antiangiogenic activity) are also being studied in phase II trials. A push in translational research in this field is essential. Exploratory and translation outcomes must be part of HNSCC clinical studies, especially as it is relatively easy to obtain biological samples in newly diagnosed patients. 5. Multimodality Treatment of HNC in Older Patients Combined modality treatment is considered the standard curative therapeutic approach for stage III and IV HNSCC, as well as in the adjuvant setting. [82] Such intensive treatment can be of benefit in well selected and fit older patients. A retrospective analysis has demonstrated that multimodality therapies, either curative surgery with postoperative RT or neoadjuvant threedrug chemotherapy followed by RT, can achieve long disease-free survival with an acceptable toxicity profile in selected older patients with advanced HNSCC (3-year survival rate of 27 30%). [83] Little is known about the toxicity of concurrent chemoradiation in older HNSCC patients because they are often excluded from these clinical trials. A recent prospective trial demonstrated that adjuvant chemoradiation could be performed safely in 40 patients aged >70 years. [84] Postoperative chemoradiation consisted of carboplatin (30 mg/m 2 on days 1 5 of weeks 1, 3 and 5) concurrent with RT (64 Gy, 5 daily fractions of 1.8 Gy per week). No grade 4 toxicity was observed. Grade 3 toxicity included mucositis (10 patients), neutropenia (6 patients), dermatitis (2 patients) and

9 Head and Neck Cancer in the Elderly 579 thrombocytopenia (1 patient). The median RT dose administered was 62 Gy. Thirty-two patients (80%) received three cycles, six (15%) received two cycles and two (5%) received one cycle. Three-year disease-free and overall survival rates were 58% and 64%, respectively. The MACH-NC (Meta-Analyses of Chemotherapy in Head and Neck Cancer) meta-analysis revealed that concurrent chemoradiation offered an absolute 8% 5-year survival benefit in comparison with RT alone (35% vs 27%, p < ). [85] The interaction between age and treatment effect was evaluated in this metaanalysis. The effect of concurrent chemotherapy on overall survival was found to decrease with increased age: patients aged 71 years had a lower performance status, less advanced stage and laryngeal cancer more frequently than younger patients. The proportion of deaths not due to HNC increased with age from 15% to 39% in MACH- NC. The authors concluded that patients aged 71 years did not benefit from concurrent chemotherapy. The increasing risk of death from other causes (co-morbidities, increased toxicity) with age may be a possible explanation for this fact. However, this meta-analysis included patients who were treated in the late 1960s and 1970s. Since then, huge medical progress has been achieved in the supportive care setting. Clinicians should also be aware that salvage surgery after chemoradiation may be extremely difficult and poorly tolerated by older patients. [86] There is a great need for direct comparisons between cisplatin-based chemoradiotherapy and a combination of RT with targeted therapies, radiosensitizers, antiangiogenic and hypoxiatargeting agents in older patients. Our personal experience of weekly carboplatin (AUC 1.5 2) with RT in 20 stage III and IV HNSCC patients with a median age of 61 years shows a response rate of 81% (Lalami Y., unpublished data). Furthermore, after a median follow up of 22 months, 70% of the patients were alive, including 13 patients who were disease-free. One potentially useful drug to be tested with concurrent chemoradiation is docetaxel. As this drug acts by stabilizing microtubules and inhibiting their disassembly, there is an accumulation of cells at G2/M cell cycle phases, which are considered to be the most radiosensitive. A phase I study of concurrent RT and weekly docetaxel (10 14 mg/m 2 ) in 15 older unfit HNSCC patients (median age 74 years) revealed encouraging data: no grade 3 4 haematological toxicity occurred and the most common observed toxicity was stomatitis within the RT field. [87] Another potentially useful strategy is to deliver high drug concentrations to the tumour through intraarterial cisplatin administration, followed by systemic neutralization by intravenous sodium thiosulfate. [88] These types of different approaches must be compared in future prospective clinical studies with the standard cisplatin-based concurrent chemoradiation. 6. Conclusions and Perspectives As HNC is a heterogeneous disease and given the treatment modalities mentioned previously, patient selection is essential, especially in the geriatric population. The most ideal approach would have to take into account the clinical presentation, the primary tumour site, risk factors, human papillomavirus (HPV) tumour positivity and biological markers. Assuming a thorough presurgical evaluation of co-morbidities has been completed, surgical treatment options should not be excluded in elderly patients treated with curative intent as part of the multidisciplinary care of HNC. Surgery can also be considered when planning RT. If surgically accessible, radical procedures can also be considered, even for relapsed disease. Markers such as xeroderma pigmentosum, complementation group F (XPF) and excision repair cross-complementation group 1 (ERCC1), which are related to DNA repair pathways, are emerging as predictors of response to systemic therapies in patients with HNC. [89] Their value must be adequately tested in well designed prospective studies. It is now clear that HNSCC patients included in prospective clinical trials must also be stratified according to HPV-positivity, since HPV-positive tumours usually have better treatment responses and are associated with a more favourable prognosis. [90] In addition, CGA

10 580 Lalami et al. appears to be a useful tool for selecting patients for different treatment modalities in the geriatric population. Phase II and III studies of cancer therapies in HNSCC older adults are desperately needed, as the usual study endpoints of efficacy and toxicity do not fully address the risks and benefits of therapy for an older patient. Such studies must investigate treatment regimens with different grades of aggressiveness and optimize these. In the very old and frail, minimal treatments must be compared with observation in terms of their effects on survival, cancer control and quality of life. After correction of physiological and biological risk factors, a large proportion of geriatric patients can and should be offered the same cancer treatment as that offered to younger patients. 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