Cancer Therapy Vol 3, page 85 Cancer Therapy Vol 3, 85-94, 2005

Head and neck cancer in elderly patients

Review Article

Daniele Bernardi1,2,*, Domenico Errante1, Luigi Barzan5, Giovanni Franchin3, Luigi Salvagno1, Antonio Bianco1, Luca Balestreri4, Umberto Tirelli2 and Emanuela Vaccher2
1 2

Division of Medical Oncology, Ospedale Civile, Vittorio Veneto (TV), Italy Division of Medical Oncology A, National Cancer Institute, Aviano (PN), Italy 3 Division of Radiotherapy, National Cancer Institute, Aviano (PN), Italy 4 Department of Radiology, National Cancer Institute, Aviano (PN), Italy 5 Division of Otolaryngology, Ospedale S. Maria degli Angeli, Pordenone, Italy

__________________________________________________________________________________
*Correspondence: Dr. Daniele Bernardi, U.O. Oncologia Medica, Ospedale Civile, Via Forlanini 71, 31021 Vittorio Veneto (TV), Italy; Tel. +39 0438 665371; Fax. +39 0438 665432; e-mail: daniele.bernardi@ulss7.it Key words: Head and neck, cancer, elderly, review Abbreviations: 5-fluorouracil, (5-FU); American Society of Anesthesiology, (ASA); complete remission, (CR); Comprehensive Geriatric Evaluation, (CGA); erythropoietin, (rhEpo); Geriatric Radiation Oncology Group, (GROG); Head and Neck, (H-N); local control, (LC); loco-regional control, (LRC); no evidence of disease, (NED); Performance status, (PS); quality of life, (QOL); Radiation Therapy and Oncology Group, (RTOG); Surveillance, Epidemiology and End Results data base, (SEER) Received: 21 February 2005; Accepted: 23 February 2005; electronically published: March 2005

Summary
Head and Neck cancers occur mostly in the fifth and sixth decade; their onset in patients older than 60 years is not a rare event, though. In almost all case series from the literature, radical treatments have a lower prevalence among elderly as compared to younger patients, in particular surgery and combined treatment. The advances in anesthesiology techniques, in peri-operative monitoring and in post-operative support allow now to deal with lower risks surgical procedures also in older patients. Elderly patients with N0 disease but at high risk of relapse or distant metastases should be offered appropriate surgical treatment and chronological age should not be considered a limit for neck dissection. Radiotherapy is a feasible treatment in elderly patients, and, in the era of organ preservation, the combination of chemotherapy and radiotherapy has a paramount importance, even if very few data exist on combined treatment in the elderly patients. Elderly patients who are functionally independent and do not show severe comorbidities must be treated in the same manner as younger patients, but during anti-cancer treatment, special attention should be paid to supportive treatment as well. Therapeutical planning must be based not only on tumor characteristics, but also on the physiological, rather than the chronological age of the patient. Therefore, in patients aged 70 or older, a selection of patients to be administered anticancer treatment has to be performed. A Complete Geriatric Assessment and a multidisciplinary approach are the crucial points.

I. Introduction
Approximately 60% of all tumors arise in patients older than 65 years and 70% of all deaths due to cancer occur in this age (Fentiman et al, 1990; Kennedy, 2000; Balducci and Beghe, 2001; Repetto et al, 2001). Although the majority of Head and Neck (H-N) cancers are seen between the fifth and sixth decade, their occurrence in elderly patients is not rare. In a retrospective survey conducted by the Italian Geriatric Radiation Oncology Group (GROG), H-N cancers were present in 12% of patients older than 70 years with different tumors, referred to 37 radiation therapy centers in Italy (Olmi and Ausili-

Cefaro 1997). Elderly patients aged 70 to 75 years represent 6 to 32% of all patients with H-N cancers in mono-institutional case series. The most frequent histologic type is squamous cell carcinoma and the most common sites of disease are larynx and oral cavity and, less frequently, oropharynx and hypopharynx. The distribution of stages does not differ from that of the younger patients, with the exception of some case series where a prevalence of stage N0 is present in elderly patients (Table 1). A peculiar characteristic of almost all case series from the literature is the lower prevalence of radical treatments among elderly patients as compared to younger patients (30-74% vs 67-91%, p<0.001), in 85

Bernardi et al: Head and neck cancer in elderly patients

Table 1. Clinical characteristics of H-N cancers in elderly patients in the main case series from literature Olmi (1997) % 365/1114 (32%) >70 1960-92 Hirano (1998) % 751/2508 (30%) >70 1971-95 Sarini (2001) % 273/4610 (6%) >75 1974-83 SEER (2001) % 9386 >65 1985-93 Vaccher (2002) % 181/2143 (8%) >75 1975-98

Tot Age, years Year of diagnosis Site of disease: Oral cavity Oropharynx Larynx Hypopharynx TNM Stage - T1-T2 T3-T4 - N0 N1 N2-N3 - M1 UICCb Stage I-II III-IV
a b

32 28 40 -62 38 81a 19 --

12 17 22 25

40 29 25 9 40 60 60 --1 31 69

39 20 42 --

23 17 49 10 61 39 72 13 14 2 52 48

N0+N1; UICC = Union Internationale Contre le Cancer.

particular surgery and combined treatment of surgery plus radiation therapy or chemotherapy and radiation therapy. Overall, survival is significantly lower in elderly patients, with an actuarial rate at 5 years of 17-31% vs 30-44% (p<0.001) in younger patients in the same case series (Olmi et al, 1997; Hirano and Mori 1998; Barzan et al, 1999; Sarini et al, 2001; Reid et al, 2001; Vaccher et al 2002). In the analysis of the case-control study from the Surveillance, Epidemiology and End Results data base (SEER), on 2508 case of carcinoma of the larynx, tongue and tonsil in patients older than 50 years, cancer specific survival of patients older than 70 years has been shown to be similar to that of patients of 50-69 years, with the exception of stage I and IV glottic carcinoma and stage III tonsil carcinoma, whose cancer-specific prognosis has been demonstrated to be worse and better in elderly patients, respectively (Bhattacharyya et al, 2003). Both groups were homogeneous according to sex, year of diagnosis, tumor characteristics and type of treatment. According to the same study, the overall medical morbidity and mortality rates were 5.65% and 2.98%, respectively. Postoperative pneumonia was the most common medical complication (3.26%) and was associated with a mortality rate of 10.94% (odd ratio for mortality, 4.4). Acute myocardial infarction and stroke were rare and were not statistically associated with increased mortality. Procedures that involved the esophagus carried the highest mortality rate (8.38%). Nevertheless, in the analysis of the prognostic factors for overall survival performed on the whole case-series in the SEER elderly patients, constituted by 9386 patients older than 65 years with the same type of H-N tumor but not

selected by stage and/or therapy, the main prognostic factor has been shown to be comorbidity according to the Charlson score. The presence of one comorbidity whatsoever is prognostically more important in patients with an age between 65 and 74 years as compared to those older than 85 years, probably due to the lower life expectancy of the latter group (HR 1.53, 95% CI 1.38-1.69 vs 1.32, 95% CI 1.09-1.84) (Reid et al, 2001). Ageing is always associated with a multiorgan functional decline, an increase in comorbidity and a decline of cognitive functions (Kennedy 2000; Balducci and Beghe 2001; Repetto et al, 2001). The presence of these failures is very heterogeneous in the population of elderly patients and anagraphic age by itself cannot be the only criterion for the therapeutic planning. In a quality of life (QOL) analysis carried out by a Dutch group, treatment does not affect QOL differently in older (70 years) and younger (45-60 years) patients affected by H-N cancer (Derks et al 2004).

II. Surgery
In general, solid tumors, including H-N cancer, are still most frequently treated with surgery. Elderly patients, though, have a higher potential operative risk of morbidity and mortality due to the presence of comorbidity and physiologic reduction of functional reserve connected to ageing. Elderly patients are more sensitive than younger patients to the volume depletions that are often associated to wide resections and/or longer surgical procedures typical of surgical oncology, and less resistant to postoperative infections due to the progressive impairment of the immune system (Kemeny et al 2000; Kennedy 2000; Balducci and Beghe 2001; Repetto et al, 2001). The first 86

Cancer Therapy Vol 3, page 87 studies on demolitive surgery in H-N cancers in elderly patients date back to the 1970s and 1980s and show a significant increase in mortality in patients older than 6570 years with a rate ranging from 3.5-7.4% vs 0.8-1.4% in younger patients (Morgan et al, 1982; McGuirt et al, 1997). The first study of the 1990s was published by Barzan and co-workers and focused on the impact of demolitive surgery on a group of 107 patients older than 70 years, compared with 135 patients aged 60-69 years and 196 patients younger than 59 years. As predictable, systemic contraindications to surgery and/or refusal of surgery were more frequent in elderly patients as compared to other patients. The number of patients undergoing en-bloc surgery was higher in the group of younger patients, but post-operative local or systemic complications were similar in all age groups (Table 2). Moreover, no difference was shown in loco-regional control (LRC) and in cancer specific survival among the age groups. Performance status (PS) and stage of disease, but not age, were the main prognostic factors for survival (Barzan et al, 1990). In a group of 43 patients older than 80 years, compared with 79 patients younger than 65 years, Clayman and co-workers demonstrated the feasibility of demolitive surgery even in very old patients. Although 93% of elderly patients fit in the high anesthesiologic risk category (Group 3-4 according the American Society of Anesthesiology [ASA]) classification) vs 63% of other patients (p<0.001), the complications were similar in the two groups, with a rate of major complication of 23% in elderly patients vs 20% in younger patients and of minor complications respectively in 28% and 23% of cases. The type of complications was different among the groups, with a higher prevalence of systemic complications, in particular cardiovascular and pulmonary, in the older patients and a higher prevalence of local complications in the younger patients. Post-operative mortality was 2% in the elderly and absent in the younger patients. LRC at 2 and 5 years in patients stratified by stage of disease was similar in the two groups, whereas overall survival was lower in elderly patients as compared to the control group (at 5-years 33% vs 63%, p<0.001), but similar to that of the population of the same age group (Clayman et al, 1998). Patients older than 75 years with locally advanced stage of disease have a higher operative morbidity and mortality risk as compared to the other age groups (McGuirt and Davis 1995). Conservation surgery, such as supraglottic laryngectomy, reconstructive subtotal laryngectomy, conservation surgery of base of tongue and of hypopharynx, showed a moderate mortality rate in elderly patients (0-7%). The low compliance to rehabilitation in elderly patient, due to refusal and/or the lack of an adequate familial and social support, seriously affects the functional outcome of surgery and is frequently associated with an increased risk of aspiration pneumonia (Barzan et al 1999). Supracricoid partial laryngectomy, one of the surgical treatments with a higher risk of inhalation of food in the airways, is feasible in cooperative elderly patients. In fact, in a series of 69 patients older than 65 years (median age 71 years), with a carcinoma of the glottic and supraglottic larynx (stage I-II 61%), mortality was shown to be absent and the rates of surgical complications (13%) and medical complications (10%) during the operative procedure and in the immediate post-operative period were similar to that reported in younger patients. Twenty-two percent of patients showed an inhalation pneumonia in the first 6 months of follow-up and 1% died after 3 years, due to pulmonary complications. Therefore, nutritional rehabilitation after this surgical procedure must be continued for a long period of time (Lacourreye et al, 1998). Age does not affect the outcome of reconstructive surgery with free flaps, where engraftment occurs overall in 95-100% of elderly patients (Shestak et al, 1992, Bridger et al, 1994, Malata et al 1996, Shaari et al, 1998, Pompei et al, 1999, Blackwell et al, 2002). Nevertheless, patients older than 70 years, with important comorbidities, show a rate of local complications, such as ischemic necrosis, significantly higher as compared to younger patients without comorbidities (12% vs 8% in the case series of Pompei). Patients older than 80 years, 92 % with high ASA anesthesiologic risk, have a rate of medical intra- and post-surgical complications higher than that of younger patients (62% vs 15%, p=0.02), after reconstructive surgery with free flaps. Considering the same ASA class, the incidence of complications is still higher in patients older than 80 years and correlates with the duration of the surgical procedure (Blackwell et al, 2002).

Table 2. Surgical treatment and post-operative complications in a case series of 438 patients with H-N cancers, stratified by age. AGE (years) <59 % 48 a 47 a 25 25

Surgery Resection En bloc Complications Local Systemic

a

60-69 % 33a 35a 25 25

>70 % 19 a 20 a 40 27

p<0.001 From Barzan et al, 1990, modified.

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Bernardi et al: Head and neck cancer in elderly patients The advances in anesthesiology techniques, in perioperative monitoring and in post-operative support allow now to face with lower risks surgical procedures in older patients as well. In general, in tumors of the oral cavity, surgical procedures including wide reconstructions (skinbone-mucosa) and revascularized flaps are more difficult to perform. In the carcinoma of the oropharynx, wide resections of base of tongue or of the lateral wall more easily can lead to chronic inhalation and therefore should not be performed. In the carcinoma of the larynx and hypopharynx, conservation surgical procedures must be weighted in relation to the entity of the predictable resection, the patients respiratory function and his/her possibility to cooperate in a post-operative rehabilitation program. Chronological age should not be considered a limit for neck dissection. Appropriate surgery treatment should be offered to elderly patients with N0 disease but at high risk of relapse or distant metastases. The deterioration of the general conditions and the diagnostic delay following the impossibility of an adequate follow-up, can often render non-feasible the salvage surgery in elderly patients (Barzan et al, 1999) In this setting, despite advances in conservative laryngeal surgery and radiotherapy, total laryngectomy remains a valuable and reliable treatment for advanced pharyngo-laryngeal cancers in elderly patients The classification of the operative risk according to the ASA score does not seem to have a predictive value in elderly patients. Transoral laser surgery, most commonly with CO2 laser, has achieved a key position in minimally invasive treatment concepts in the ears, nose and throat area, especially for the treatment of malignancies of the upper aerodigestive tract. In the hands of experienced surgeons it remains a valuable option for elderly patients since it is a minimally invasive, functional and rapidly performed treatment (Werner et al, 2002). of Florence, Italy, published the biggest case series on 446 cases of carcinoma of the larynx, oropharynx and oral cavity in patients older than 70 years, treated exclusively with RT with curative intent, whose outcome was compared to that of patients <70 years with the same type and stage of tumor. In this case series, laryngeal cancers were mostly at early stage (T1-T2), while in both groups the other neoplasias were mostly in advanced locoregional stage. No differences in 5-year actuarial local control (LC) or survival with no evidence of disease (NED) were seen between the two age groups for laryngeal and oropharyngeal cancer. For patients with cancer of the oral cavity, LC was better in the younger patients than in those aged 70 years and older (50% vs 28%, p=0.04). There was no statistically significant difference in the NED survival between the two groups. Acute or late reactions from RT in older patients were not different from those observed in younger patients (Olmi et al, 1997). The Gustave Roussy Institute reported the experience on 331 elderly patients with an age >70 years affected by carcinoma of the larynx (28%), oropharynx (27%) and oral cavity (16%) treated with radical RT (65-70 Gy) in 84% of cases and with palliative RT (30 Gy) in the remaining 16% in poor general conditions. Overall, the treatment was well tolerated with a grade 3-4 toxicity according to the Radiation Therapy and Oncology Group (RTOG) score as follows: cutaneous 1%, mucositis only in 17%, but nasoenteral feeding was required in 54% of cases. A reduced psychological tolerance due to depression, confusion or inability to cooperate, affected the feasibility of RT in 6% of patients, with a heterogeneous distribution in the age groups (5% in patients 70-75 years old, 9% and 21%, respectively, in patients 75-80 years and 80-85 years). Overall, the LC at 3-years was 71% for patients treated with radical dose and 19% for those treated with a palliative dose. The analysis of the LC by stage of disease showed similar data to those of historical control groups with an age lower than 70 years (Table 3). Five-year survival rates of 30%, 27%, 21% and 0% were observed for the 70-75, 75-79, 80-85 and over 84 age groups, respectively. In patients treated with palliative dose, the survival rate at 5-years was only 5% (Lusinchi et al, 1990).

III. Radiotherapy
A. Conventional fractionation
The most widely used treatment in H-N tumors in elderly patients is represented by external beam radiotherapy with conventional fractionation (180-200 cGy/day for 5 days/week) (standard-RT). The University

Table 3. Loco-regional control (LRC) in 331 patients >70 years with H-N tumorsa treated with radiotherapy and stratified by stage (TNM) STAGE Primary tumor T1-T2 T3-T4 Nodal disease N0 N1-N2 N3
a

LRC at 3 years % 89-66 47-41 88 71 46

oropharynx 30%, larynx 28% From Lusinchi et al, 1990, modified.

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Cancer Therapy Vol 3, page 89 Thompson and co-workers reported 2 case series in patients older than 75 years, 68 of whom had laryngeal carcinoma, treated with radical RT in 59% of cases and 33 patients with carcinoma of the hypopharynx, treated with curative intent in 52% of cases. The 3-year actuarial survival was 57% in the group of patients with laryngeal carcinoma and 22% in the group of patients with carcinoma of the hypopharynx (Thompson et al, 1996). The GROG evaluated prospectively the feasibility of radical radiotherapy in 91 elderly patients (age 70-88 years) with laryngeal carcinoma, mainly (56%) in stage III. Overall, the treatment was well tolerated, with a mild cutaneous and mucosal toxicity, respectively in 11% and 38%, and severe (G3-G4) in 1% and 5% (Olmi et al, 1997). The impact of age on the development of an acute or chronic toxicity was evaluated by Pignon and coworkers on 589 patient with H-N carcinoma treated with radical RT in 5 protocols of the EORTC, activated between 1980 and 1995. The acute normal tissue reactions (mucositis and weight loss) in elderly patients (>70 years) was not different from that of younger patients, but, considering the same objective damage, the severe subjective intolerance, defined as G3-4 functional acute toxicity, was significantly more frequent in elderly patients (Table 4). No difference was shown in the analysis of the late toxicity. In these studies, where usually patients in very good general conditions and without important comorbidities were enrolled, LRC and cancerspecific survival were similar in all age groups (Pignon et al, 1996). Data on the use of RT in very old patients (>80-90 years) are limited to few case series and have mostly been reported together with other tumors. In the case-series of Zachariah, on 203 patients older than 80 years, 50 patients (25%) had H-N cancer in different sites and stage of disease. Thirty-five of them (70%) were treated with radical RT and 15 (30%) with palliative RT. In the group treated with higher dose, 51% of patients developed a mild mucositis (G1-G2 according to RTOG), 29% a moderatesevere mucositis (G3) and only 3% a severe hemorrhagic mucositis (G4). With supportive therapy, mucositis disappeared in 4-6 weeks. In the group treated with palliative RT, G1-G2 mucositis was demonstrated in only 13% of patients. The objective response rate was 86%, with 66% complete remission (CR) in the radically treated group, while a palliation of the symptoms of the disease was obtained in 67% of patients treated with low dose RT. Overall, patients achieving a CR presented a longer median survival of 25 months (Zachariah et al, 1997). Mitsuhashi reported on 32 patients older than 90 years, 14 of whom (44%) affected by H-N tumors, 11 (79%) treated with radical RT (median dose 61.2 Gy) and 3 (21%) with palliative RT (40 Gy). The treatment had to be discontinued for 2-3 weeks in 4 (36%) patients of the first group due to G2-G3 mucositis. The median survival in the radically treated patients was 8 months (range 3-55) while that of patients treated with palliative intent was 6 months (Mitsuhashi et al, 1999).

B. Unconventional fractionation
A promising method to improve the treatment outcome in patients with H-N carcinoma is constituted by accelerated RT (fraction size of daily dose >200 cGy) and hyperfractionated RT (more than one fraction per day), often used in combination. Nonetheless, in general, elderly patients are excluded from protocols with unconventional fractionated RT, due to the fear of an increased toxicity, sometimes relevant also in younger patients. A Swiss group recently published the first study with an unconventional RT regimen (accelerated concomitant boost RT schedule), in a group of 39 patients older than 70 years with carcinoma of the hypopharynx-larynx (49%) and of the oral cavity-oropharynx (46%), compared with 81 patients < 70 years. Elderly patients were in 79% of cases in good general conditions (PS 0-1) and, in comparison with younger patients, had a more advanced T stage (T3-T4 54% vs 30%, p=0.01) but a less advanced N stage (N0 46% vs 72%, p=0.01). The primary tumor area and both sides of the neck down to the clavicles received a dose of 50.4 Gy over 5.5 weeks given daily fractions of 1.8 Gy, 5 times a week. The boost to the initial involved sites comprised 13 fractions of 1.5 Gy (total 19.5 Gy) given as a second daily fraction beginning the last day of the second week. Withdrawal of treatment due to toxicity occurred in only 8% of elderly patients and in none of the younger patients. The median dose administered and the

Table 4. EORTC Radiation Trials in H-N cancers (1589 patients): evaluation ad the impact of age on acute toxicity AGE ACUTE TOXICITY <70 years % Objectivec G0 G1-G2 G3 Functionald G0 G1-G2 G3-G4
a

>70 years % 2 41 58 0 34 67

pa

1 48 51 2 49 49

NS

<0.001

X2 test; c1307 evaluable patients; d868 evaluable patients. From Pignon et al, 1996, modified.

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Bernardi et al: Head and neck cancer in elderly patients median treatment time were similar in the two groups. Acute and late toxicities were similar in the two age groups, as well as LRC and overall survival (Allal et al, 2000). drugs and reduce the capacity of healthy tissues to recuperate. Moreover, polypharmacy, typical of the older age, can be responsible for pharmacokinetic and pharmacodynamic interactions between the different types of drugs. Table 5 shows data on potential toxicity of cisplatin and 5-FU in elderly patients in solid tumors (Kennedy 2000, Balducci and Beghe 2001, Repetto et al, 2001, Balducci and Corcoran 2000, Zagonel et al, 1998). Cisplatin is associated with an increase in peripheral neuropathy, anemia, and nephropathy. Generally, sensorymotor peripheral neuropathy initially arises with paresthesia, loss of deep tendinous reflex and tactile sensitivity and then with muscular weakness that sometimes severely affects patients autonomy (Rudd et al, 1995; Zagonel et al, 1998; Balducci and Corcoran, 2000). In vitro studies have clearly demonstrated that elderly patients have a reduced capacity to repair cisplatininduced DNA damages. Treatment with 5-FU, mostly administered in continuous infusion at high dose, determines in elderly patients a potential increase in cardiotoxicity, mucositis and leukopenia. Cardiotoxicity has its main cause in the frequent co-existence of a cardiomyopathy and/or alterations in electrolytes that occur during treatment. Mucositis is in general more severe than in younger patients and requires significantly longer time to recuperate. Leukopenia is mostly determined by a reduction in the bone marrow functional reserve and its severity is strictly related to the age of the patient (Stein et al, 1995; Zagonel et al, 1998; Balducci and Corcoran, 2000). An interesting study was performed on 71 patients aged 70 or older treated with cisplatin and 5-FU, with an age-adjusted dose regimen. Patients aged 70-79 years were treated with standard-dosage of cisplatin 100 mg/m2 day 1 and 5-FU 1000 mg/ m 2/day continuous infusion for 5 days, while those aged 80-84 years with a reduction of the dosage by 20% and those older than 85 years with a reduction of the dosage by 30%. The objective response rate was 79% (CR 52%) among the 54 patients aged 70-79 years and only 31% (CR 6%) among the 17 patients aged 80 or older. In the group of patient older than 80 years, patients responsive to chemotherapy were in better general conditions as compared to the non-responsive patients.

C. Conclusions
In conclusion, RT is a feasible treatment in elderly patients, also in very advanced age groups and even with innovative schedules with unconventional fractionation. When radical doses are employed, the LRC is almost superimposable to that obtained in younger patients with the same type of neoplasia. Acute and chronic toxicities are similar to those showed in younger patients, but subjective tolerance and sometimes compliance are significantly lower as compared to the other age groups. Therefore, this data show the need to increase supportive medical and psychological therapy always during and after treatment. Frail patients seem to tolerate well palliative radiation treatment, but the data from the literature are at the moment too unclear to provide treatment guidelines in this subset of patients. Finally, the fact that in certain stages or sites of disease, in patients treated with radical therapy, the outcome in elderly patients is more unfavorable as compared to the younger ones prompts the activation of studies aimed at evaluating the impact of age on the tumor biology.

IV. Chemotherapy
A background exists for an increased toxicity from chemotherapy in elderly patients, but clinical studies, aimed at evaluating the relationship between toxicity from chemotherapy and age, are very few (Balducci and Corcoran, 2000; Argiris et al, 2004). Nonetheless, elderly patients are often excluded from chemotherapy clinical trials (Fentiman et al, 1990). Standard chemotherapy for H-N carcinomas is the Al-Sarraf regimen, a sequential combination of cisplatin and infusional 5-fluorouracil (5FU) that, in the treatment of locoregional recurrences and/or distant metastases achieves a response rate of 4050% (CR 5-10%) and in neoadjuvant setting (CT-RT) for organ preservation of 70-88% (CR 40-60%) (Posner et al, 2000). The reduced functional reserve of elderly patients can potentially alter the pharmacokinetics of cytotoxic

Table 5. Possible causes of increased acute toxicity from Cisplatin and 5-Fluorouracil in elderly patients TOXICITY CISPLATIN Peripheral neuropathy Anemia Nefrotoxicity 5-FLUOROURACIL Cardiotoxicity Mucositis CAUSE Reduced capacity of DNA-damage reparation. Pharmacokinetic alterations. Multiorgan functional reduction. Reduced glomerular filtration rate. Cardiomiopathy. Pharmacokinetic alterations. Reduced intracellular concentration of dihydropirimidine carboxilase. Reduced bone marrow reserve.

Leukopenia

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Cancer Therapy Vol 3, page 91 Myocardial ischemia, the only form of cardiotoxicity that was examined in this study, was very low and similar in the two age groups, with a rate of 2% in the first group and 3% in the second (Schneider et al, 1994). Chemotherapy seems to be feasible also in patients aged 80 years or older, but a reduction in the dosage dependent only on the chronological age can seriously affect the efficacy of the treatment. The Eastern Cooperative Oncology Group (ECOG) has recently analyzed data from two randomized studies employing intensive cisplatin-based regimen for the treatment of patients with recurrent/metastatic H-N carcinoma, to evaluate the outcome of elderly patients. Fifty-three patients aged 70-80 years had comparable response rates (28% vs 33%) and survival outcomes (1year survival 26% vs 33%) compared with 346 younger patients. However, severe nephrotoxicity, thrombocytopenia and diarrhea were more common in the elderly than in the younger patients, occurring in 8% vs 2% (p=0.04), 26% vs 12% (p=0.009) and 17% vs 3% (p=0.0002), respectively (Argiris et al, 2004). Strategies to ameliorate toxicity should be pursued in the elderly. In the era of organ preservation, chemotherapy combined with RT has a paramount importance in the treatment of H-N tumors (Posner et al, 2000). Elderly patients, an emerging problem for public health in the industrialized countries, cannot be excluded a priori from organ preservation programs. Older patients who are functionally independent and do not show severe comorbidities must be treated in the same exact manner as younger patients, but during the treatment, supportive treatment must be increased. In particular, the administration of bone marrow growth factors, such as GCSF and erythropoietin (rhEpo) must be always evaluated. Data concerning the use of rhEpo in the prevention of chemotherapy-related anemia in early or advanced H-N cancer are not extensive (Tsukuda et al, 1993; Dunphy et al, 1997; Oettle et al, 2001). The role of recombinant rhEpo in preventing or correcting chemotherapy-related anemia in elderly patients with H-N cancer has been recently described (Gebbia et al, 2003). Acoording to this study, recombinant rhEpo is able to prevent anemia, to reduce transfusion requirements and to improve quality of life parameters in patients treated with carboplatin and 5FU as compared to untreated controls. The use of amifostine in the prevention of mucositis from CT is still controversial and should be eventually considered only when RT is administered (Schuchter et al, 2002). On the other hand, topical use of GM-CSF, administered as oral gargles, might accelerate the resolution of mucositis, even if an improvement of the quality of life has never been clearly demonstrated. In all patients particular attention should be paid to maintaining an adequate nutritional status, since malnutrition can affect both efficacy of chemotherapy and patients survival (Zagonel et al, 1998; Balducci and Corcoran 2000; Kennedy 2000; Balducci and Beghe 2001; Repetto et al, 2001). In fact, nutrition is often deficient in elderly patients in general, due to several reasons, such as depression, poor dentition, functional impairment, cognitive impairment, lack of appetite due to chronic comorbid disease, and lack of caregiver. Elderly patients with cancer may also face additional problems brought on by chemotherapy, such as nausea, vomiting, diarrhea, and painful oral ulcerations. Correcting malnutrition and establishing a suitable dietary plan are simple measures that can substantially improve the patients clinical outcome and quality of life. The main concern with respect to emotional conditions in these patients is depression, which is common in both geriatric and oncology populations, and is therefore especially common in elderly patients with cancer. Depression and cognitive disorders can be mistaken for each other and either type of condition could adversely affect the patients functional status and the outcome of cancer treatment. Patients older than 80 years, patients not functionally independent and/or with severe associated comorbidities, must be treated in the setting of new treatment protocols, in which the choice of the regimen employed and the dose of the drugs must be adjusted according to a Comprehensive Geriatric Evaluation (CGA). CGA is an instrument aimed at evaluating the overall status of the patient and its efficacy has been documented by several randomized studies (Monfardini et al, 1996; Zagonel et al, 1998; Balducci and Corcoran 2000; Kennedy 2000; Balducci and Beghe 2001; Repetto et al, 2001). The preliminary results have been published of an ongoing trial using CGA to tailor the treatment of patients affected by aggressive non-Hodgkins lymphoma; to date, 23 patients have been treated with reasonable efficacy and toxicity (Bernardi et al, 2003). Noteworthy is the fact that in none of the studies concerning treatment in H-N cancers that have been published so far in the literature, a CGA has been used in the evaluation of the clinical status of the elderly patient.

V. Combined treatment
A number of important factors should be considered in deciding the best therapy for the patient when chemoradiotherapy is used in a combined modality plan for the curative treatment of locally advanced H-N cancer (Vokes et al, 2000). No data exists in the literature on combined chemo-radiotherapy in the elderly, and there are very few experiences on retrospective subgroup analysis. It is essential to identify appropriate patients for combination therapy. Patients with underlying severe comorbidities, age-related frailty, or underlying severe psychosocial problems are not good candidates for highly intensive treatment plans. These patients may benefit less complicated or less potentially toxic treatment plans. The biology of the patients disease also must be considered in selecting or planning a combined modality approach. Patients with rapidly growing tumors or with advanced nodal presentation are less likely to be cured with surgery or radiation therapy alone and are most likely to benefit from the addition of chemotherapy. The location of the primary tumor is also an important factor in selecting therapy. Small lesions in the larynx, base of tongue and hypopharynx may benefit from an organ preservation approach, while similarly sized lesions in the anterior oral cavity might be better treated with direct surgical and 91

Bernardi et al: Head and neck cancer in elderly patients radiotherapy approaches. The goals of the addition of chemotherapy in a treatment plan must be considered in determining the best therapy: appropriate goals in the curative treatment of locally advanced H-N cancer include organ preservation, improved survival, optimization of quality of life and reduction in metastases (Posner et al, 2000). A recent study (Airoldi et al, 2004) assessed treatment toxicity, patient compliance, and clinical results in 40 patients >70 years who were treated with concomitant adjuvant chemoradiotherapy. The results of this study confirm previously established beliefs that adjuvant chemioradiotherapy can be successfully applied in older patients who are fit to receive such treatment. The role of the combination therapy in the postoperative setting can only be validated by phase III trials. A comparison of the results of the study by Airoldi with those of the group 70 years or older treated with radiotherapy alone suggests that superior results can be obtained with chemoradiotherapy compared with radiotherapy alone in this age group.
and neck cancer treated with cisplatin-based chemotherapy. J Clin Oncol 22, 262-268. Balducci L, Beghe C (2001) Cancer and age in the USA. Crit Rev Oncol Hematol 37, 137-45. Balducci L, Corcoran MB (2000) Antineoplstic chemotherapy of the older cancer patient. Hematol Oncol Clin North Am 14, 193-12. Barzan L, Olmi P, Franchin G, Vaccher E, Politi D, Loreggian L, Grando G, Tirelli U (1999) Carcinomi del distretto ORL. Argomenti di Oncologia 20,149-54. Barzan L, Veronesi A, Caruso G, Serraino D, Magri D, Zagonel V, Tirelli U, Comoretto R, Monfardini S (1990) Head and neck cancer and ageing: a retrospective study in 438 patients. J Laryngol Otol 104, 634-40. Bernardi D, Milan I, Balzarotti M, Spina M, Santoro A, Tirelli U (2003) Comprehensive Geriatic Evaluation in elderly patients with lymphoma: feasibility of a patient-tailored treatment plan. J Clin Oncol 21,754. Bhattacharyya N (2003) A matched survival analysis for squamous cell carcinoma of the head and neck in the elderly. Laryngoscope 113, 368-72. Blackwell KE, Azizzadeh B, Ayala C, Rawnsley JD (2002) Octogenarian free flap reconstruction: complications and cost of therapy. Otolaryngol Head Neck Surg 126, 301-06. Bridger AG, OBrien CJ, Lee KK (1994) Advanced patient age should not preclude the use of free-flap reconstruction for head and neck cancer. Am J Surg 168, 425-28. Clayman G, Eicher SA, Sicard MW, Razmpa E, Goepfert H (1998) Surgical outcomes in head and neck cancer patients 80 years of age and older. Head Neck 20, 216-23. Derks W, de Leeuw RJ, Hordijk GJ, Winnubst JA (2004) Quality of life in elderly patients with head and neck cancer one year after diagnosis. Head Neck 26, 1045-1052. Dunphy FR, Dunleavy TL, Harrison BR, Boyd JH, Varvares MA, Dunphy CH, Rodriguez JJ, McDonough EM, Minster JR, McGrady MD (1997) Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. Cancer 79, 1623-1628. Fentiman IS, Tirelli U, Monfardini S, Schneider M, Festen J, Cognetti F, Aapro MS (1990) Cancer in the elderly: why so badly treated? Lancet 335, 1020-1022. Gebbia V, Di Marco P, Citarella P (2003) Systemic chemotherapy in elderly patients with locally advanced and/or inoperable squamous cell carcinoma of the head and neck: impact of anemia and role of recombinant human erythropoietin. Crit Rev Oncol Hematol 48 (suppl.), S4955. Hirano M, Mori K (1998) Management of cancer in the elderly: therapeutic dilemmas. Otolaryngol Head Neck Surg 118, 110-14. Kemeny MM, Busch-Deverauz E, Merriam LT, OHea BJ (2000) Cancer surgery in the elderly. Hematol Oncol Clin North Am 14, 169-92. Kennedy BJ. Aging and cancer. Oncology (Huntingt) 2000, 14, 1731-33. Laccourreye O, Brasnu D, Pri S, Muscatello L, Mnard M, Weinstein G (1998) Supracricoid partial laryngectomies in the elderly: mortality, complications, and functional outcome. Laryngoscope 108, 237-42. Lusinchi A, Bourhis J, Wibault P, Le Ridant AM, Eschwege F (1990) Radiation therapy for head and neck cancers in the elderly. Int J Radiation Oncology Biol Phys 18, 819-23. Malata CM, Cooter RD, Batchelor AG, Simpson KH, Browning FS, Kay SP (1996) Microvascular free-tissue transfers in elderly patients: the Leeds experience. Plast Reconstr Surg 98, 1234-41.

VI. Closing remarks

The physiological, rather than the chronological age of the patient, together with tumor characteristics, should be considered when planning the treatment of H-N cancers in older patients. Elderly patients who are functionally independent and do not show severe comorbidities must be treated in the same manner as younger patients, but during anti-cancer treatment, special attention should also be paid to supportive treatment. Patients with underlying severe comorbidities, age-related frailty, or severe psychosocial problems are not good candidates for highly intensive treatment plans. The key issue is, therefore, the selection of patients to be administered anticancer treatment. In patients aged 70 or older, CGA and a multidisciplinary approach are the crucial points for an adequate therapeutical planning. A determinant factor in the prognosis of the patient with H-N tumors of any age is the multidisciplinary management of the disease. Surgeons, radiation-therapy specialists, medical oncologists and geriatricians must actively cooperate in a multidisciplinary setting.

Acknowledgements
The skillful and patient assistance of Mrs. Paola Favetta in the preparation of the manuscript is gratefully acknowledged.

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Daniele Bernardi

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