22 Feasibility of Combined Chemo- and Radiation Treatment in Elderly/Comorbid Patients

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22 Feasibility of Combined Chemo- and

Radiation Treatment in Elderly/Comorbid Patients

Hans Geinitz

H. Geinitz, MD

Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675 Munich, Germany

22.1 Introduction

There is growing evidence from retrospective studies that radiation therapy in elderly patients is effective and well tolerated (Geinitz et al. 2005; Baumann 1998; Pignon et al. 1996, 1997, 1998). Most of the patients treated within these studies received radia- tion therapy either as the sole anti tumour agent or in conjunction with surgery in a neoadjuvant or adjuvant fashion. Only a few analyses deal with combined chemo- and radiation treatment in elderly patients. Large prospectively conducted studies assessing the safety and effectiveness of combined radio-chemotherapy in elderly patients are lacking.

On the other hand, the evidence for the superiority of radio-chemotherapy over radiation therapy alone in the elderly is limited since many study protocols either definitively exclude patients above the age of 70 years from participation or the contributing phy-

sicians are not willing to enter these patients on the trial. The underrepresentation of elderly patients in cancer-treatment trials is still an unsolved problem (Hutchins et al. 1999).

Older patients tend to be less often screened and subsequently more often present with advanced dis- ease (Clark et al. 2004; Berkman et al. 1994). Dis- ease staging is often carried out less accurately than in younger patients with malignant diseases (Wylie et al. 1998; Yancik and Ries 1994). Lastly, elderly patients are more often treated inadequately or not treated at all (Merchant et al. 1996; Berkman et al. 1994; Samet et al. 1986). The reasons for these age-related variations are not entirely clear.

Patient’s preferences and physician’s attitudes play a major role and are influenced by the fear of exces- sive treatment toxicity as well as the common belief that cancer in the aged is in general less aggressive than in their younger counterparts (Berkman et al.

1994). Recent advances in supportive cancer therapy may not have been acknowledged by elderly persons as well as their primary care physicians.

22.2 Demographics

In the next decades oncologists will be confronted more and more with cancer in the elderly. Life expectancy has steadily increased in industrial countries over the past 100 years. With advancing age, cancer incidence and cancer death arise in a near exponential fashion (Geinitz et al. 1999). In the United States the total number of newly diag- nosed cancer in persons aged 75 years or older is expected to increase nearly threefold from 389,000 in the year 2000 to 1,102,000 in the year 2050, a rise from 30 to 42% of the cancer population aged 75 years or older (Edwards et al. 2002). The further life expectancy of a 70-year-old woman in Germany is still 15.7 years, and that of a 70-year-old man is 12.8 years (Federal Statistical Office of Germany, life

CONTENTS

22.1 Introduction 333 22.2 Demographics 333

22.3 Comorbidity and Organ Function 334 22.4 Clinical Studies of Radio-chemotherapy

in the Elderly 334 22.4.1 Head and Neck Cancer 334 22.4.2 Oesophageal Cancer 335 22.4.3 Lung Cancer 335

22.4.4 Rectal and Anal Cancer 337 22.4.5 Bladder Cancer 338 22.4.6 Carcinoma of the Vulva 338 22.4.7 Glioblastoma Multiforme 338 22.5 Conclusion 339

References 339

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table 2002/2004; www.destatis.de). These time spans are too long to a priori choose a palliative therapy regime in patients whose malignant tumours are potentially curable with radio- or radio-chemother- apy. Most cancer recurrences occur within 25 years after treatment. Since there is no unequivocal data that malignant tumours are per se less aggressive with advanced age, recurrences will be experienced also by the elderly patient with all the negative con- sequences on the patient's quality of life.

22.3 Comorbidity and Organ Function

Comorbidity and organ function are important co- factors that must be taken into account when assess- ing the indication for radio-chemotherapy. The prev- alence of comorbid disease increases with age and organ capacity (renal, pulmonary and liver function) usually decreases with age (Ogle et al. 2000). The influence of concomitant disease on acute or late radiation toxicity has not yet been studied in great detail, but some investigators report that diabetes mellitus or hypertension have a negative impact on radiation side effects (Herold et al. 1999; Boehler et al. 1992). There is evidence that decreased pul- monary function limits the tolerated radiation dose to the lung (Mehta 2005). Concomitant disease as well as decreased organ capacity could impair the clearance of chemotherapeutic substances and con- sequently lead to toxic plasma- and/or tissue concen- trations. Furthermore, concomitant disease might be more important to the overall prognosis of the patient than the malignant disease itself. Comorbid- ity- and organ-functioning scores might further help assigning the indication to radio-chemotherapy in elderly patients (Charlson et al. 1987).

22.4 Clinical Studies of Radio-chemotherapy in the Elderly

Clinical studies of radio-chemotherapy in the elderly are rare. Since the effects of radio-chemotherapy on the elderly are not very well known, study protocols often include lower radiation doses and/or less toxic chemotherapy protocols in this population than in younger patients (Jeremic et al. 1999a; Allal et al. 1999).

22.4.1 Head and Neck Cancer

Kodaira et al. (2005) carried out a phase-I trial in 15 elderly (>70 years) or medically unfit patients with head and neck cancer that were treated with com- bined radio-chemotherapy. Patients had to have an Eastern Cooperative Oncology Group (ECOG) per- formance status of 0–2 and adequate organ func- tion. In previously untreated patients radiation therapy was applied to a total dose of 60–66 Gy to the primary tumour and 66–70 Gy to involved cer- vical lymph nodes in 2-Gy fractions. Patients who had received radiation therapy to the neck before (n=5) were treated to doses of at least 39.4 Gy to the primary lesion in 1.8-Gy fractions with the cumula- tive dose of both radiation schedules not exceeding 100 Gy. Docetaxel was administered concomitantly once weekly over five consecutive weeks. The start- ing dose was 10 mg/m

²

which was escalated by 2 mg/

m

²

following the treatment of at least three consecu- tive patients until a grade-3 toxicity occurred (with the exception of side effects concerning mucosa, skin and nausea which had to be at least grade 4).

No patient experienced any grade-3 or higher hae- matological toxicity. Six patients developed grade-3 mucositis and 3 patients grade-4 mucositis, all of them in the 14-mg/m

²

dose group; thus, the recom- mended docetaxel dose was 12 mg/m

²

weekly over five consecutive weeks.

An Italian group prospectively evaluated postopera- tive radio-chemotherapy in 40 elderly patients with head and neck cancer and a high risk for loco-regional recurrence (Airoldi et al. 2004). Patients 70 years or older with an ECOG performance status of 0–2 who have had curative resection for squamous cell carci- noma of the oral cavity, oropharynx, hypopharynx or larynx were entered on this trial. A total dose of 54 Gy was applied to regions at risk of microscopic disease and a dose of 64.8 Gy was given for positive margins or extracapsular nodal extension. Carboplatin was administered 4560 min prior to irradiation at a dose of 30 mg/m

²

on days 1–5 of weeks 1, 3, and 5. Treat- ment was administered on an outpatient basis and 80% of the patients received all three cycles of che- motherapy. Grade-3 toxicity was observed for muco- sitis (25%), neutropaenia (15%), dermatitis (5%), and thrombocytopaenia (2.5%). No grade-4 toxicity occurred. One case of moderate osteoradionecrosis occurred as a late side effect. The 3-year local control rate was 79% and 3-year overall survival was 64%.

These data compared favourably to matched controls

70 years or older who received postoperative radio-

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therapy alone in the same institution (3-year local control 64%, 3-year overall survival 52%). Quality of life (Functional Assessment of Cancer Therapy) declined minimally during therapy (from 85.7 to 81.4) and fully recovered by 12 months (87.1).

Ampil et al. (2001) retrospectively analysed 10 patients aged 65 years or older who received com- bined radio-chemotherapy for advanced (stage III/

IV) head and neck cancer. Neoadjuvant chemo- therapy consisted of cisplatin (20 mg/m

²

day

^-1

on days 1–5), 5-FU 800 mg/m

²

24 h

^-1

continuously days 1–4) and etoposide (60 mg/m

²

day

^-1

on days 1–

3). This regimen was repeated every 21 days for three cycles. Conventionally fractionated radiation therapy began concomitant to the second cycle of chemotherapy. A total dose of 45–70 Gy was deliv- ered to the primary tumour and upper neck, the lower neck was treated to 45–50 Gy. Three of 10 patients experienced a grade-3 acute toxicity and 1 patient a grade 3 late side effect. The local failure rate was 30% with a 3-year survival of 30%.

22.4.2 Oesophageal Cancer

The Roswell Park Cancer Institute reviewed their experience with combined radio-chemotherapy in patients aged 70 years or older with oesopha- geal cancer (Nallapareddy et al. 2005). Data on 30 patients were available. Radiation doses ranged from 45 to 64.8 Gy in 1.8-Gy daily fractions. Various chemotherapy regimens were applied on an outpa- tient basis. 5-FU continuous infusion was used in 26 patients at a median dose of 1220 mg/m

²

per week. In 13 patients it was combined with cisplatin (27–36 mg/

m

²

per week) and in 8 patients with oxaliplatin (31–

46 mg/m

²

per week). Four patients received pacli- taxel (50–80 mg/m

²

per week). The following grade-3 or grade-4 toxicities were observed: haematologi- cal 17%; febrile neutropaenia 13%; mucositis 40%;

dehydration/diarrhoea that required hospitalisation 50%; pulmonary 20%; cardiac 7%; and neuropathy 7%. Median survival was 10 months; 6 patients died of local recurrence and 7 of metastatic disease.

A Japanese group analysed the efficacy and toxic- ity of concurrent radio-chemotherapy in 22 patients with oesophageal cancer aged 75 years or older (Uno et al. 2004). Patients had to have a Karnofsky perfor- mance status of at least 70 and no serious comorbid- ity. Total radiation doses ranged from 50 to 65 Gy conventionally fractionated. Different chemother- apy protocols were applied concurrently with radia-

tion therapy, the most common (n=12) was a com- bination of cisplatin (15 mg/m

²

, five consecutive days) and 5-FU (500 mg/m

²

as continuous infusion 5 days/week). Four patients received lower doses of cisplatin and/or 5-FU, 1 patient received a combina- tion of carboplatin and 5-FU and 5 patients received 5-FU alone. Two patients experienced grade-3 neu- tropaenia, and no grade-4 toxicity was observed.

The median survival was 9 months; 13 patients died of local recurrence and 4 of distant metastasis.

A study by Rice et al. (2005) analysed retrospec- tively the outcome and operative mortality in 74 patients aged 70 years or older with cancer of the oesophagus. Patients received either preoperative radio-chemotherapy (group I; n=35) or no neoad- juvant treatment (group II; n=39). The elderly were compared with patients younger than 70 years who received radio-chemotherapy before oesophagec- tomy (group III; n=165). Neoadjuvant treatment was not reported on in detail. Patients received total doses of 4550 Gy in 1.8-Gy daily fractions along with chemotherapy which was mostly administered concomitantly. Chemotherapy typically included 5-FU plus a platinum agent but taxanes were also frequently incorporated into the treatment regi- men. Perioperative mortality was not significantly increased in elderly patients with neoadjuvant treatment as compared with the other groups (3%).

Except for the use of more perioperative blood transfusions and a higher rate in atrial arrhythmias in pre-treated elderly patients, postoperative com- plications were similar between groups. The authors did not report on toxicity during neoadjuvant treat- ment. Overall survival of elderly patients with pre- operative radio-chemotherapy did not differ signifi- cantly from that of younger pre-treated patients.

22.4.3 Lung Cancer

Approximately 67% of all new lung cancer cases in the United States are diagnosed in persons 65 years and older, and about 31% of the cases in persons

>75 years (Edwards et al. 2002).

Schild et al. (2003) retrospectively analysed tox-

icity and outcome data for 63 patients >70 years

who were treated within a North Central Treatment

Group phase-III trial. The trial compared bid radio-

chemotherapy (60 Gy, 1.5 Gy bid, 2-week break after

30 Gy) with once daily radio-chemotherapy (60 Gy,

2 Gy) for the treatment of stage IIIA-B non-small-

cell lung cancer. In both treatment arms etoposide

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100 mg/m

²

and cisplatin 30 mg/m

²

were applied on days 1–3 and days 28–30. Study participants had to have an ECOG performance status of 0 or 1 and ade- quate haematological, renal and pulmonary func- tion. Elderly patients experienced significantly more grade-4 or grade-5 haematological side effects (78 vs 56%) and more grade-4 or grade-5 pneumonitis (6 vs 1%). No difference in grade-4 or grade-5 oesophagi- tis was observed. Survival did not differ between age groups. The 2- and 5-year survival rates were 36 and 13%, respectively, in elderly patients and 39 and 18%, respectively, in patients younger than 70 years.

Yuen et al. (2000) performed a retrospective analy- sis for 50 patients >70 years who participated in the phase-III Intergroup trial 00096 for limited-stage small cell lung cancer. Patients received cisplatin 60 mg/m

²

, day 1, and etoposide 120 mg/m

²

, days 1–

3, for four cycles and either once or twice daily con- current thoracic radiotherapy to 45 Gy. Grade-4 to grade-5 haematological toxicity (84 vs 61%; p<0.001) and fatal toxicity (10 vs 1%; p=0.01) occurred more often in patients >70 years despite the fact that they received all four cycles of chemotherapy less frequently than younger patients. Fatal toxicity in the elderly was related to infection (2 patients), pul- monary toxicity (1 patient), hemorrhage (1 patient), and coagulation (1 patient). There was no difference in the frequencies of grade-3 or grade-4 oesophagitis between age groups. Response rate, time to local fail- ure and duration of response did not differ between groups. Overall survival at 5 years was significantly lower for elderly patients (16 vs 22%).

A group from Osaka conducted a multicenter phase- II study of 38 patients 76 years or older with medically inoperable or unresectable stage-I to stage-III non- small-cell lung cancer (Atagi et al. 2000). Patients with ECOG performance status 0–2 and adequate organ function received conventionally fractionated thoracic radiotherapy (mediastinum, hilar region, primary tumour with or without supraclavicular fossa) to a dose of 40 Gy and a subsequent boost to the primary tumour and involved lymph nodes of 10–20 Gy. Carboplatin 30 mg/m

²

on days 1–5 was given concurrently during weeks 1–4. The follow- ing grade-3 or grade-4 haematological toxicity was observed: leucopenia (71%); thrombocytopaenia (29%); and anaemia (34%). No grade-3 or grade- 4 oesophagitis was observed but 2 patients died because of pneumonitis (5%). For stage-III patients 2-year survival was 21% and for stage-I/II patients 3-year survival was 69%.

Jeremic et al. (1999a) studied a hyperfractionated accelerated radiation therapy regimen with concur-

rent carboplatin/oral etoposide in 58 elderly patients

>70 years with stage-III non-small-cell lung cancer and a Karnofsky performance status of >70. In this phase-II trial radiation therapy was given to a total dose of 51 Gy in 34 fractions over 3.5 weeks. Carbo- platin (400 mg/m

²

) was administered intravenously on days 1 and 29, and etoposide (50 mg/m

²

) was given orally on days 1–21 and 29–42. The haemato- logical, oesophageal and bronchopulmonary acute grade-3 or grade-4 toxicities amounted to 22, 7 and 4%, respectively. No grade-3 or grade-4 late toxicity was observed. In 55 evaluable patients the median survival time was 10 months and the 2- and 5-year survival rate was 24 and 9%, respectively. The 5-year local control rate was 13%. The authors state that the observed toxicity was lower than anticipated, but that on the other hand, the efficacy was inferior to (more aggressive) combined radio-chemotherapy in younger patients.

Another phase-II study by the same investigators evaluated a palliative radio-chemotherapy protocol in 50 patients >70 years with stage-IV non-small- cell lung cancer (Jeremic et al. 1999b). Study entry criteria required a Karnofsky performance status of at least 70. Low-dose hypofractionated radiation therapy was given to the mediastinum and primary tumour to a total dose of 14 Gy in two 7-Gy frac- tions on days 1 and 8. Chemotherapy consisted of carboplatin (300 mg/m

²

) on days 1 and 29 and oral etoposide (50 mg/m

²

) days 1–21 and 29–42. Com- bined modality treatment was administered totally on an outpatient basis. Grade-3 haematological side effects were observed in 19% of the patients. Non- haematological grade-3 toxicity comprised oesoph- agitis (19%) and bronchopulmonary side effects (9%). No grade-4 or grade-5 toxicity occurred. The median overall survival was 7 months. Cough, hae- moptysis and chest pain improved in 60, 75 and 68% of cases, respectively. The authors state that symptom improvement in their study was similar to that observed in various chemotherapy studies using more aggressive protocols.

A randomized multicenter study of the Japan Clini-

cal Oncology Group (JCOG9812) in elderly patients

with locally advanced non-small-cell lung cancer

was prematurely closed because of a high rate of

treatment related deaths (Atagi et al. 2005). Patients

aged 71 years or older with stage-III non-small-cell

lung cancer were randomised either to convention-

ally fractionated radiation therapy of 60 Gy to the pri-

mary tumour (RT) or to the same radiation treatment

with concomitant carboplatin 30 mg/m

²

per fraction

up to the first 20 fractions (CRT). Treatment tech-

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niques were simple and consisted of anterior/poste- rior opposed fields up to 40 Gy and bilateral oblique fields thereafter. No lung heterogeneity corrections were used. Forty-six patients were randomised. No patient in the RT arm had grade-4 haematologi- cal toxicity and 2 (9%) and 4 (17%) patients in the CRT arm experienced grade-4 leucocytopaenia and neutropaenia, respectively. Grade-3/4 subacute lung toxicity was observed in two patients in the RT arm and 4 patients in the CRT arm. Four patients died as a result of radiation pneumonitis, one in the RT arm and 3 in the CRT arm. Post-hoc quality assurance revealed a major protocol violation in 60% of the cases, and in 7% the dose constraints to the lung were violated. In the latter group were two of the patients who died from radiation pneumonitis. A new trial (JCOG0301) with prospective quality assurance was activated in September 2003.

22.4.4 Rectal and Anal Cancer

Although the 1990 NIH consensus recommended adjuvant radio-chemotherapy for stage-II and stage- III rectal cancer without an upper age limit, this recommendation was far from being accepted for the wide majority of elderly patients treated in the 1990s (Neugut et al. 2002; Schrag et al. 2001).

Neugut et al. (2002) carried out a population- based study on the use of adjuvant chemotherapy and radiation therapy for rectal cancer among patients 65 years or older who were diagnosed between 1992 and 1995. A total of 983 patients with stage-II and 824 patients with stage-III disease who had received surgery were identified in the Surveil- lance, Epidemiology, and End-Results (SEER) Medi- care data base. Of the total population 28% received surgery alone, 11% received surgery plus radiation therapy, 14% received surgery plus adjuvant 5-FU and 37% received surgery with radiation plus adju- vant 5-FU chemotherapy. Of the patients with com- bined radio-chemotherapy 89% received treatment postsurgically, 10% presurgically and 1% pre- and postsurgically. Age was inversely associated with receiving combined adjuvant therapy as were high comorbidity scores. The number of involved lymph nodes increased the odds of radio-chemotherapy.

The cumulative mortality was lower among patients receiving radiation plus 5-FU than among patients treated with surgery alone (47 vs 54%, respec- tively; p<0.01). This was confirmed in multivariate analysis. When stratified by age a significant sur-

vival benefit was found for stage-III patients only:

patients receiving radio-chemotherapy had a 29%

risk reduction in overall mortality at 5 years.

Another SEER study by Schrag et al. (2001) on 1411 patients aged 65 years or older with resected stage-II or stage-III rectal cancer disclosed simi- lar results concerning the under-usage of adjuvant radio-chemotherapy: only 42% of the entire cohort received chemotherapy and radiation. Age was the strongest determinant of treatment: 60% of patients aged 65–69 years; 52% aged 70–75 years; 36% aged 75–79 years; 23% aged 80–84 years; and 12% aged 85 years or older received radio-chemotherapy.

During the 5 years of diagnosis (1992–1996) the pro- portion of patients that received combined adjuvant treatment merely increased by 1% (from 42 to 43%).

A study group from Leeds evaluated a low-dose radio- chemotherapy protocol in 16 elderly (77–91 years) frail patients with anal carcinoma (Charnley et al.

2005). Patients not suitable for full-dose radio-che- motherapy due to low performance status or comor- bidity were treated with 30 Gy in 15 fractions to the gross tumour volume plus a 3-cm margin. Concur- rent chemotherapy comprised 5-FU 600 mg/m

²

24 h

^-1

continuous infusion on days 1–4. All 16 patients com- pleted treatment as planned. Only 1 patient experi- enced grade-3 skin toxicity. The local control at a median follow-up of 16 months was 73%. Overall sur- vival was 69% and disease-specific survival 86%.

Allal et al. (1999) et al. reported on 42 patients aged 75 years or older that received either radiotherapy alone (RT; n=21) or radio-chemotherapy (RT-CT;

n=21) for anal carcinoma. Radiation therapy was administered in two sequential courses, the first with a median dose of 39.6 Gy in 22 fractions to the pelvis, the second with a median dose of 20 Gy in 10 fractions as a boost to the tumour region. Median interval between the two courses was 43 days. Che- motherapy consisted of mitomycin C 9.5 mg/m

²

on day 1 and 5-FU 600 mg/m

²

24 h

^-1

continuously on days 1–4. Because of toxicity 11 patients required an unplanned treatment break (4 in the RT and 7 in the RTCT group). Acute grade-3 toxicity was 54%

(53% in the RT group and 55% in the RTCT group).

No grade-4 or grade-5 acute toxicity occurred in

either group. Five of 35 patients available for long

term follow-up experienced grade-3 to grade-4 late

complications all observed in female patients in

the RTCT group. The 5-year local control rate was

78.5% (73 and 83% for the RT and RTCT groups,

respectively; p=0.36). The 5- and 8-year overall

survival rates were 54 and 36% without differences

between treatment groups.

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A research group from Rome analysed 17 patients aged 75 years or older who received radio-chemo- therapy for anorectal cancer (Valentini et al. 1997).

Patients had to have an ECOG performance status

<2 and adequate bone marrow, renal, liver, cardio- vascular and pulmonary function. Ten patients had rectal cancer and 7 patients anal cancer. Radiation therapy was applied according to treatment indica- tion and site of disease: patients with rectal carci- noma who were treated in curative intent received preoperatively 38 Gy to the pelvis in 1.8-Gy frac- tions, patients with rectal carcinoma treated in pal- liative intent received two courses of 24 Gy to the pelvis with a 4- to 5-week interval and patients with anal carcinoma received two courses of 24 Gy to the pelvis with a 4- to 5-week split, followed by a boost of 15 Gy in 3 patients. Concomitant chemotherapy consisted of mitomycin C 10 mg/m

²

on day 1 and 5- FU 1000 mg/m

²

continuous infusion an days 1–4.

Acute grade-3 toxicity occurred in 3 patients. No severe late toxicity developed during 26 months of follow-up. None of the resected patients with rectal cancer (n=4) and none of the patients with anal car- cinoma treated in curative intent developed local or distant failure during follow-up.

22.4.5 Bladder Cancer

Goffin et al. (2004) reviewed their data on patients aged 70 years or older who received radio-chemo- therapy for T2–T4 bladder cancer. Three different protocols were applied: Seven patients received radi- ation therapy to a total dose of 44 Gy with 3 Gy bid on days 1, 3, 15, 17, then 2.5 Gy bid on days 63, 65, 77, 79 with concurrent cisplatin (15 mg/m

²

) and 5-FU (400 mg/m

²

) on days 1–3, 15–17, 63–65 and 77–79.

Six patients were treated with conventionally frac- tionated radiation therapy to doses of 52–60 Gy with concurrent cisplatin (20–30 mg/m

²

weekly during radiation). One patient received 40.8 Gy in a bid regi- men with concurrent cisplatin, metothrexate and vinblastine. Six of 14 patients experienced grade-3 or grade-4 toxicity including 1 patient with cispla- tin/hydration-induced heart failure. The median survival was 19 months; 5 patients had local recur- rences and 7 patients developed distant metastasis.

A study by Patel et al. (2005) analysed toxicity and outcome of concurrent radio-chemotherapy in a cohort of 14 patients with urothelial carcinoma that were not considered candidates for cystectomy or platin-based therapy because of low perfor-

mance and/or advanced comorbidity. Median age was 80 years (46–88 years); 9 patients had local- ized disease and 5 patients advanced disease. The 3D target volume encompassed the primary and draining lymph nodes with a subsequent boost to the primary tumour. Median radiotherapy dose was 63 Gy (40–68.4 Gy) at 1.8–2.5 Gy per fraction.

Chemotherapy consisted of capecitabine 1200 mg/

m

²

day

^-1

to 1800 mg/m

²

day

^-1

Monday through Friday throughout radiation therapy. All patients underwent transurethral resection before radio- chemotherapy. Grade-3 toxicity comprised predom- inately diarrhoea (3 patients; 29%) and dehydration (3 patients). One patient experienced grade-3 infec- tion. No grade-4 or grade-5 toxicity was observed.

The overall response rate was 85%. Follow-up was too short to draw conclusions on local control and survival.

22.4.6 Carcinoma of the Vulva

Cunningham et al. (1997) reported on 14 patients with advanced vulvar carcinoma who were not candidates for standard radical vulvectomy that were submitted to combined radio-chemotherapy.

Median age was 68 years. Patients were treated with a dose of 45–50 Gy to the pelvis and the total doses to the vulva with or without groins ranged from 50 to 65 Gy. Chemotherapy was administered in the first and last weeks of radiotherapy and consisted of 5-FU 1000 mg/m

²

24 h

^-1

continuous infusion over 96 h and cisplatin 50 mg/m

²

on day 1. Two patients experienced grade-3 toxicity and radiation therapy had to be stopped prematurely. One patient died during therapy due to congestive heart failure and aspiration pneumonia. No significant myelosup- pression, sepsis, renal, or gastrointestinal toxicity was observed. One grade-4 delayed complication occurred (small bowel obstruction). After a median follow-up of 26 months 4 patients with partial response died (three of them due to progressive dis- ease), and of the 9 patients with complete response, 5 died (only one of them due to vulvar cancer).

22.4.7 Glioblastoma Multiforme

Treatment of glioblastoma multiforme in the elderly

is a matter of debate. Age is a critical and inde-

pendent prognostic factor in patients with malig-

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nant glioma (DeAngelis 2000). In elderly patients in good clinical condition standard fractionated or short course hypofractionated radiation ther- apy are offered in some institutions, depending on the extent of prior tumour resection; however, those elderly patients with extensive tumours that cannot be resected, who are in poor clinical con- dition, may not be treated with radiation therapy at all. The limiting factor in these patients is their extremely poor outcome and short survival from tumour progression (DeAngelis 2000). A prospec- tive study analysed the outcome of sequential radia- tion and chemotherapy in 79 patients aged 65 years or older (Brandes et al. 2003). Patients had to have a Karnofsky performance status >60 to enter the study and their residual disease after surgery had to measure <2 cm. All patients received radiation therapy to the gross tumour volume and oedema plus a 2-cm margin to a total dose of 59.4 Gy in 1.8- Gy daily fractions. Patients treated between 1993 and 1995 received no further treatment. Patients who were enrolled between 1995 and 1997 received adjuvant chemotherapy with lomustine 110 mg/m

²

on day 1, procarbazine 60 mg/m

²

on days 8–21, and vincristine 1.4 mg/m

²

on days 8 and 29 (PCV) every 8 weeks. Patients enrolled between 1997 and 2000 were treated with adjuvant temozolomide 150 mg/

m

²

for 5 days every 28 days. Chemotherapy was car- ried out until disease progression or occurrence of grade-3 to grade-4 non-haematological toxicity. The incidence of grade-3 thrombopaenia and leukopenia was 10 and 4.4%, respectively, for PCV therapy and 1.7 and 6%, respectively, for temozolomide. Median time to disease progression and median overall survival for all patients was 7.2 and 12.5 months, respectively. Patients with adjuvant temozolomide therapy had a significantly better time to disease progression as compared with the other groups and a better overall survival as compared with patients who received radiation therapy alone.

22.5 Conclusion

The amount of clinical data for combined radio-che- motherapy in elderly patients is limited. Specially designed treatment protocols that used reduced radiation doses or low-intensity chemotherapy were feasible in selected patients beyond 70 years with acceptable toxicity; however, the superiority of these protocols over radiation therapy as sole modality

has yet to be determined. Before submitting elderly patients to radio-chemotherapy organ function- ing and comorbid disease should be assessed thor- oughly. During therapy the nutritional and hydra- tion status, blood cell counts and signs of infection should be monitored closely with supportive mea- sures being applied early in the course of combined modality treatment.

In two prospective studies cisplatin-based radio- chemotherapy was applied to elderly patients with lung cancer in comparable dosage as in their younger counterparts (Schild et al. 2003; Yuen et al. 2000).

Retrospective analyses of these studies disclosed more grade-4, and in one study more grade-5, tox- icity in patients 70 years or older, although study entry criteria selected only those patients who had a good performance status and adequate organ func- tioning. In a randomised prospective Japanese trial on elderly patients with lung cancer an unacceptably high rate of treatment-related deaths was found in the combined radio-chemotherapy arm, although poor treatment quality might have contributed to this outcome (Atagi et al. 2005). Until further data accumulates, the indication to aggressive combined radio-chemotherapy in elderly patients, especially those with lung cancer, should be given with cau- tion and treatment should be carried out under close surveillance.

With regard to the steady aging of the population in industrial countries, the paucity of studies analys- ing the feasibility and effectiveness of radio-chemo- therapy in elderly patients is hardly understandable.

Combined efforts of medical oncology and radiation oncology should be made to enter elderly patients with cancer into specially designed clinical trials.

These trials should also include quality of life as a major outcome parameter.

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