6 Radiotherapy for Lung Cancer in Elderly Patient
Branislav Jeremi ´ c and Michael Molls
B. Jeremi´c, MD, PhD, Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 226, 81675 Munich, Germany
M. Molls, MD, Professor and Chairman, Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 226, 81675 Munich, Germany
Introduction
The Western world is rapidly ageing. The fastest-grow- ing segment of the population being that composed of individuals over the age of 65 years. By the year 2030, they will constitute approximately 20% of the total population of the United States. The number of persons of more than 75 years old will triple by 2030, while the number of those aged more than 85 years will double in the same period (Yancik 1997). There is, however, no widely accepted and exact defi nition of an elderly person. Cut-off age thresholds vary be- tween 60 and 80 years and many studies use cut-offs between 65 and 75 years of age. In contrast to fi xed thresholds to defi ne elderly persons, geriatric oncol- ogy has often been defi ned operationally as “when the health status of a patient population begins to interfere with the oncological decision making guide- lines” (Extermann 2000). Therefore, biological age should be defi ned individually by performance status and co-morbidities, which will infl uence the deci- sion-making, rather than an arbitrarily established age limit.
Among many consequences, increasing age has a particular one: it is directly associated with increas- ing cancer occurrence rates; there is an 11-fold in- crease in the cancer incidence in persons more than 65 years of age when compared with their younger counterparts, indicating that elderly population may well become one of the major targets in oncology in the future, requiring specifi c managements for vari- ous cancers (Yancik 1997).
Lung cancer is a typical disease of the elderly patient. It is the most lethal of the cancers in both sexes. Treatment approaches with curative intention are feasible in patients with localized disease, but the evidence is based on studies which are usually per- formed with selected patients, the elderly patients being underrepresented in clinical trials. A frequent observation in daily practice is that elderly patients are less likely to be vigorously screened and staged, and frequently their cancers receive less-aggressive treatment (Nugent et al. 1997).
However, when evaluated for specifi c features, they did not seem to have different characteristics at presentation, particularly related to stage of disease, performance status and histology, when compared with their non-elderly counterparts, although other characteristics such as type and number of co-mor- bidities and organ function differ in the two groups (Montela et al. 2002). Furthermore, although not clinically overt and therefore undetected in many
“healthy” elderly persons, there may be a reduction in functional organ capacity. With increasing age, not only the kidneys, but also the lungs and heart and even the immune system show a reduced function (Balducci and Extermann 2000).
A common practice in oncology is to base pa- tient selection on clinical judgement with perfor- mance status and organ function parameters. This, however, may not be adequate when one considers elderly patients, since it seems that there is a need for a more comprehensive tool of pre-treatment as- sessment which would take into account potential hazards in treating elderly patients the same way as their non-elderly counterparts. This may help in
CONTENTS
Introduction 309
6.2 Non-Small Cell Lung Cancer 310
6.2.1 Early Stage Non-Small Cell Lung Cancer 310 6.2.2 Locally Advanced Non-Small-Cell Lung Cancer 311 6.2.3 Metastatic Non-Small-Cell Lung Cancer 314 6.3 Small-Cell Lung Cancer 314
6.4 Conclusions 317 References 317
predicting and avoiding such hazards (Monfardini et al. 1995). To do so, a comprehensive geriatric as- sessment as an adjunct to general and cancer-spe- cifi c diagnostic procedures is developed and defi ned as a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological and functional capabilities of a frail elderly person in or- der to develop a coordinated and integrated plan for treatment and long-term follow-up (Rubenstein 1995; Osterweil et al. 2000; Bernabei et al. 2000).
Assessment is mandatory for adequate patient se- lection for radiation therapy, too. This assessment includes the medical assessment, assessment of functioning, psychological assessment, social assess- ment and environmental assessment (Balducci and Extermann 2000).
This chapter addresses important issues in radia- tion therapy of lung cancer in elderly patients. Widely accepted clinical designation of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) as two separate entities will here serve also to enable a suitable framework for addressing these issues in elderly patients.
6.2
Non-Small Cell Lung Cancer
Non-small cell lung cancer accounts for approxi- mately 80% of all lung cancer cases, with more than 50% of all patients with non-small cell lung cancer being older than 65 years and about one-third of all patients being more than 70 years old at the time of diagnosis. While curative approaches are feasible in patients with early stage (I/II) disease and in a proportion of patients with locally advanced disease (stage IIIA/IIIB), palliation is the goal for the remain- der of locally advanced and all metastatic (stage IV) non-small cell lung cancer patients. This general con- cept should also prove to be feasible in elderly with non-small cell lung cancer. Surgery is the treatment of choice for patients in early stage (I/II) non-small cell lung cancer, whereas the standard treatment for locally advanced non-small cell lung cancer is not well defi ned. Although stage IIIA non-small cell lung cancer patients can be treated with surgery alone if completely resectable or in combination with radio- therapy or chemotherapy, the majority of patients with locally advanced non-small cell lung cancer are unresectable, and, with increasing tumour stage, the outcome is inevitably limited by the distance spread.
6.2.1
Early Stage Non-Small Cell Lung Cancer
Besides their advanced age, elderly patients fre- quently are not undergoing surgery owing to exist- ing co-morbidity and, only occasionally, owing to refusal. In these cases, radiation therapy has been used and has been shown to be effective. It seems that Aristizabal and Caldwell (1976) were fi rst to show that elderly patients (70 years old or more) have signifi cantly better 2-year survival than non-elderly patients (49-69 years; 35.7% versus 13.1%, p=0.044).
This is explained by high local control (70%) and a lower incidence of distant metastasis. Coy and Kennelly (1980) and Newaishy and Kerr (1989) have observed a signifi cant trend towards better sur- vival in older patients with non-small cell lung cancer treated with radiation therapy alone. Noordijk et al.
(1988) have found no difference in the outcome of elderly patients treated with radiation therapy alone or surgery. Furthermore, when only patients treated with radiation therapy alone are considered, elderly patients have a similar outcome to non-elderly pa- tients. Also, Sandler et al. (1990) and Rosenthal et al. (1992) have found no signifi cant difference in overall survival, disease-specifi c survival or local, progression-free survival in elderly versus non-eld- erly patients. Wurschmidt et al. (1994) have used multivariate analyses also, as have Kaskowitz et al. (1993), to show no difference between elderly and non-elderly patients. The same observation has been made by Slotman et al. (1994), Gauden et al.
(1995) and Krol et al. (1996). In the two of studies of Jeremi´c et al. (1997, 1999), no difference has been observed between patients less than 60 years old and those 60 years old or more with stage I and II non- small cell lung cancer, respectively, treated with hy- perfractionated radiation therapy alone, with a total dose of 69.6 Gy using 1.2 Gy b.i.d. fractionation, in either survival or relapse-free survival. Multivariate analyses using both survival and relapse-free sur- vival confi rms that age plays no important role in this setting.
Hayakawa et al. (1999) treated 97 patients of 75
years old or more (elderly) and 206 patients less than
75 years old (non-elderly), with radiation therapy
doses of 60 Gy or more (up to 80 Gy) for inoperable
non-small cell lung cancer. Elderly patients were
classifi ed into two subgroups: A, 75–79 years; and B,
80 years or older. No difference was found between
the three age groups (5-year survival : 12% versus
13% versus 4% for non-elderly, elderly A and elderly
B, respectively), but a multivariate analysis disclosed
a detrimental effect of the oldest age, due to 14%
treatment-related deaths in patients receiving 80 Gy.
Unfortunately, no multivariate analysis has been done using disease-specifi c survival as endpoint to give better insight into this fi nding.
Most recently, Gauden and Tripcony (2001) have investigated the effect of age (less than 70 years ver- sus 70 years or older) on treatment outcome in pa- tients with stage I non-small cell lung cancer. The median survival times (22 versus 26 months) and a 5-year survival (22% and 34%), respectively, for non-elderly and elderly patients were observed. The same held true for recurrence-free survival. Finally, when the study group was divided into the 5-year subgroups, both overall survival and recurrence-free survival remained similar regarding the age groups.
The multivariate analysis excluded age as an impor- tant prognostic factor in predicting either of these two endpoints.
In contrast, Morita et al. (1997) have found a survival advantage for patients less than 80 years old when compared with those 80 years old or more (5-year survival rate: 25.2% versus 7.7%). Similarly, Sibley et al. (1998) have documented superior out- come in younger (less than 60 years) patients with stage I compared with older patients; this is uncon- fi rmed, however, when local progression is used as an endpoint (p = 0.10).
Although numerous studies have attempted evalu- ation of toxicity, in none of these series is it speci- fi ed that these toxic events happen in elderly patients.
When specifi cally addressing elderly patients with early stage non-small cell lung cancer, no signifi cant radiation therapy-related complications are found, and the incidence of both acute and late high-grade toxicity is similar among all age groups (Gauden and Tripcony 2001). When radiation therapy-related deaths occur, again, there is no difference between el- derly patients (5%) treated with the highest dose lev- els (80 Gy) and their non-elderly counterparts (4%) treated the same way (Hayakawa et al. 2001).
Taken together, the data from the literature show that conventionally planned, external beam radiation therapy is capable of producing the median survival times of 20–27 months and 5-year survivals of 15–
34% in patients of more than 70 years, and event bet- ter results are obtained when the cut-off of 60 years is used.
Recent years have also brought attempts to address prospectively the issue of the use of sophisticated treatment planning and delivery in this population.
Niibe et al. (2003) have treated 22 elderly patients who have tumours up to 5 cm with fraction size of
3–4 Gy, 5 fractions per week, to a mean total dose of 65.3 Gy. Local control rates at 1–3 years were 92%, 83% and 83%, respectively, while overall survival rates at 1–3 years were 100%, 83% and 56%, respectively.
No patients experienced grade 2 or greater toxicity.
These results show that this tool, now widely available worldwide, is feasible and effective in elderly patients.
The results hold promise for future studies in elderly patients with small-sized tumours.
Most recently, however, there has appeared an ini- tial study which compares surgery with continuous hyperfractionated accelerated radiation therapy in elderly patients with stage I non-small cell lung can- cer (Ghosh et al. 2003). One-hundred and forty-nine patients underwent lobectomy, 47 had wedge resec- tion, while 19 had radiation therapy alone. Non-lo- bectomy patients have signifi cantly lower pulmonary function. Survival at 1 and 5 years was 97% and 68%
versus 98% and 74% versus 80% and 39%, respec- tively (p = 0.0484), but this was associated with a 2.7%, 30–day operative mortality in the lobectomy group.. The frequency of loco-regional recurrence is similar between the groups. This study shows again that radiation therapy alone is a reasonable treatment option for those who are not suitable candidates for surgery.
6.2.2
Locally Advanced Non-Small-Cell Lung Cancer
Some of the studies discussed in the previous sec-
tion include also a proportion of patients with stage
III, while some do not specify outcome regarding
age. Nevertheless, due to poor results, early studies
prompted some to advocate prohibition of radiation
therapy in patients over 70 years of age (Aristizabal
et al. 1976; Patterson et al. 1998). Similarly, Nakano
et al. (1999) have undertaken a retrospective study
of elderly patients with stage III non-small cell lung
cancer who had been treated with radiation therapy
alone. It resulted in a median survival time (MST) of
11.5 months in the younger group and 6.3 months in
the elderly group (p = 0.0043). In multivariate analy-
sis, good performance status (age less than 75 years)
and good response are signifi cant, favourable inde-
pendent predictors of survival. In the elderly group
of patients, there were more frequent deaths from
respiratory infections and there were lower prog-
nostic nutritional indexes before and after radiation
therapy. Hayakawa et al. also reports an inferior sur-
vival for the subgroup of elderly patients with stage
III disease, but only in patients more than 80 years of
age (2001). Contrary to that, Kusumoto et al. (1986) have investigated this effect in stage III/IV non-small cell lung cancer. Patients less than 70 years old (n=64) and those 70 years and older (n = 36) achieve a MST of 7 and 6 months, respectively, the difference being insignifi cant.
Others, however, have provided data on the ef- fectiveness of radiation therapy in elderly patients.
Zachariah et al. (1997) have reported on radiation therapy in lung cancer in octogenarians treated with 59.40–66 Gy using standard fractionation. Response was observed in 43% patients, while only 24% had progressive disease. Evaluation of the data on 1,208 patients enrolled on several trials conducted by the European Organization for Research and Treatment of Cancer (Pignon et al. 1998) has given the oppor- tunity to investigate the infl uence of age on treatment outcome as well as acute and late toxicity of curative thoracic radiotherapy. Survival adjusted for the pri- mary location of the tumour is comparable in each group. The difference in distribution over age is not signifi cant for acute nausea, dyspnoea, oesophagi- tis, weakness and the World Health Organization performance status alteration. The minimal time to complication is similar in all age groups. There is no difference between age groups regarding the pa- tients experiencing no complications at post-treat- ment year 4. Among various toxicities, only grade 2 late oesophagitis demonstrates a signifi cant trend to be more frequent in older patients (p=0.01), but this difference disappears after adjustment to the study (p = 0.32). The Italian Geriatric Radiation Oncology Group (Gava 1999) has reported on outcome of ra- diation therapy alone in stage III non-small cell lung cancer in 38 elderly patients. The 1-year sur- vival rate approaches 44%. Another Italian study has confi rmed the effectiveness of radiation therapy in 48 patients of 75 years or older with locally advanced non-small cell lung cancer (Lonardi et al. 2000).
Radiation therapy alone was used to give a median dose of 50 Gy. Overall survival was 10% at 24 months.
Elderly patients treated with 50 Gy or more achieved signifi cantly better survival than those treated with less than 50 Gy (the MST, 8 versus 4 months; 2-year survival, 20% versus 4%, respectively; p = 0.03).
Tombolini et al. (2000) have also analysed patients 70 years and older in stage III treated by radiation therapy alone with 50–60 Gy (and a 10-Gy boost to the gross tumour volume) in 1.8- to 2-Gy fractions.
Two-year overall and disease-free survival was 27%
and 14.6%, respectively. Most recently, Pergolizzi et al. (2002) have reported on curative radiation therapy alone in 40 elderly patients with stage IIIA. Radiation
therapy was directed towards gross tumour burden with a median of 60 Gy, conventionally fractionated.
No treatment-related mortality was observed and no clinically signifi cant acute morbidity was scored. The MST was 19 months and 5-year survival was 12%.
Since radiochemotherapy is a widely used ap- proach for non-small cell lung cancer patients with locally advanced, non-resectable non-small cell lung cancer and good performance status, one may won- der whether this is also true for elderly patients with locally advanced non-small cell lung cancer. Some studies provide retrospective subgroup (age) analy- ses of patients enrolled into radiochemotherapy tri- als but do not identify age as negative prognostic factor in multivariate analyses (Schaake-Koning et al. 1992; Jeremi´c et al. 1998; Clamon et al. 1999;
Furuse et al. 1999). However, the Radiation Therapy Oncology Group has reported on a study which in- cluded 1,999 patients treated with radiation therapy with or without chemotherapy in several prospective studies. Using a recursive partitioning and amalga- mation analysis they have found a negative infl uence of older age on survival (Werner-Wasik et al. 2000).
These results confi rm earlier results from another
analysis by the Radiation Therapy Oncology Group
(Movsas et al. 1999), where a quality-adjusted sur-
vival was used to examine six prospective Radiation
Therapy Oncology Group trials, including 979 pa-
tients with inoperable stage II/IIIB non-small cell
lung cancer patients treated with radiation therapy
with or without chemotherapy. Elderly patients had
the best quality-adjusted survival with radiation
therapy alone, which was in sharp contrast to their
younger counterparts, who benefi ted mostly from
more aggressive, combined approaches. Although
these two large analyses stand unifi ed against the
more intensive treatment approach in elderly pa-
tients, it must, however, be clearly emphasized that
they are diffi cult to interpret, because the compila-
tion of patients treated on separate study protocols
implies a comparison between patients with a variety
of entry criteria used to defi ne eligibility and differ-
ent treatment regimens administered, including a
single-modality radiation therapy in many of these
studies. Contrasting these, Rocha Lima et al. (2002)
have analysed older patients from a randomized can-
cer and leukaemia Group B trial of induction chemo-
therapy followed by either radiation therapy alone or
concurrent radiochemotherapy for locally advanced
non-small cell lung cancer. They have shown that
patients older than 70 years complete treatment to
the same extent as younger patients and attain simi-
lar response and survival, but at the expense of in-
creased toxicity, especially high-grade (greater than 3) nephrotoxicity and neutropenia. Furthermore, in a retrospective analysis of the data from the Radiation Therapy Oncology Group 94-10 study, Langer et al.
(2001) have investigated the infl uence of age on treat- ment outcome. Patients older than 70 years (n = 104) were compared with those younger than 70 years (n = 491) and it was shown that elderly patients ben- efi t from concurrent as compared to sequential ra- diochemotherapy in a similar way to their younger counterparts. As with the study of Rocha Lima et al.
(2002), they suffer from an increase in toxicity, espe- cially severe oesophagitis. Most recently, Schild et al. (2003) have performed a secondary analysis of the North Central Cancer Treatment Group study, which evaluated split-course versus standard fraction radio- therapy and cisplatin/etoposide in stage III non-small cell lung cancer. When restricted to age, the 2- and 5- year survival rates are similar between the two age groups(less than 70 versus 70 years and older), but grade 4+ toxicity occurred in 62% patients less than 70 years of age compared with 81% in those 70 years and older (p=0.007). Both grade 4+ haematological toxicity and grade 4+ pneumonitis are signifi cantly more frequent in the elderly group.
Besides these, some studies have provided data on prospective approaches addressing this issue.
Between January 1988 and June 1993, Jeremi´c et al. (1999) enrolled a total of 58 patients, who en- tered a phase II study. Carboplatin (400 mg/m
2) was given intravenously on days 1 and 29, and etoposide (50 mg/m
2) was given orally on days 1–21 and 29–42.
Accelerated hyperfractionated radiotherapy was administered starting on day 1, with a total dose of 51 Gy in 34 fractions over 3.5 weeks. In 55 evaluable patients, the complete response rate was 27% and the overall response rate was 65%. For the 55 patients, the MST was 10 months, and the 1-, 2-, and 5-year sur- vival rates were 45%, 24% and 9.1%, respectively. The median time until relapse was 8 months, and the 1-, 2- and 5-year relapse-free survival rates were 45%, 20% and 9.1%, respectively. The median time to lo- cal recurrence was 14 months and the 5-year local control rate was 13%; while the median time to dis- tant metastasis was 18 months and the 5-year distant metastasis-free rate was 15%. Haematological, oe- sophageal and bronchopulmonary acute grade 3 or 4 toxicities were observed in 22%, 7% and 4% of the patients, respectively. There was no grade-5 toxicity or late grade-3 toxicity. Jeremi´c et al. have concluded that concurrent accelerated hyperfractionated ra- diotherapy and carboplatin/oral etoposide produce relatively low and acceptable toxicity. The survival
results appear to be comparable with those obtained in non-elderly patients with stage III non-small cell lung cancer treated by full-dose radiation.
During a phase II study, Atagi et al. (2000) used standard fraction radiation therapy with 50–60 Gy and concurrent, low-dose daily carboplatin (30 mg/
m
2) in 38 patients with locally advanced non-small cell lung cancer, 26 of whom were stage III. The MST was 15.1 months and 2-year survival was 20.5%.
Finally, Nakano et al. (2003) have reported on a pilot study in which low-dose cisplatin (6 mg/m
2; days 1–5, 8–12, 29–33 and 36–40) was added to conventionally fractionated radical radiation therapy (60 Gy in 20- Gy daily fractions) in elderly patients with locally advanced, unresectable non-small cell lung cancer.
Of 12 registered patients, 11 were eligible for this analysis, 91% of whom were stage III. The overall re- sponse rate was 82% and the median overall survival was 23 months. The 2-year survival rate was 53%.
The most common grade 3 toxicities included grade 3 leucopenia and thrombocytopenia, occurring in 20% and 9%, respectively. No other high-grade toxic- ity was observed during this study.
In an interesting attempt to selectively target tu- mour cells with cisplatin and to decrease the toxic- ity that concurrent radiochemotherapy can bring, Karasawa et al. (2002) have used bronchial arte- rial infusion of cisplatin and concurrent radiation therapy (dose, 50.4–73.2 Gy; median, 60.8 Gy) in 31 elderly, stage III non-small-cell lung cancer pa- tients. The results were compared with those ob- tained in 30 elderly patients receiving no cisplatin.
Response rate was 90% in the cisplatin group and 83% in the non-cisplatin group. Two-year, local con- trol MST and 5-year survival were all improved in the cisplatin group (81.0%, 33.4 months and 38.3%
versus 38.1%, 9.8 months and 4.2%, respectively; lo- cal control, p<0.01; survival, p <0.00). Multivariate analysis shows that addition of bronchial infusion cisplatin is the strongest predictor of improved sur- vival achieved with no increase in life-threatening toxicity.
In most of these studies, the toxicity of the com- bined treatment is tolerable (Jeremi´c et al. 1999;
Lonardi et al. 2000), with both acute and late high- grade toxicity not different from that observed with similar approaches in non-elderly patients. Contrary to that, Atagi et al. (2000) have observed high-grade haematological toxicity in 34.2%–71.1% of patients.
Non-haematological toxicity was mild, with no pa-
tient developing grade 3 oesophagitis or higher, al-
though two (5%) grade 4 pulmonary toxicities oc-
curred.
6.2.3
Metastatic Non-Small-Cell Lung Cancer
Although radiation therapy is frequently used to treat intrathoracic or distant spread in stage IV (meta- static) non-small cell lung cancer, there are virtu- ally no data on the feasibility and effectiveness of radiation therapy in this setting. In order to defi ne the “optimal” treatment approach in these patients, Jeremi ´ c et al. (1999) have designed and performed a phase II study evaluating concurrent short-term chemotherapy and palliative radiotherapy. Between January 1988 and June 1993, a total of 502 patients entered into a study that used 2 cycles of carbopla- tin, 300 mg/m
2, on days 1 and 29, and oral etopo- side, 50 mg/m
2, on days 1–21 and 29–42. Radiation therapy was administered with a dose of 14 Gy, in two fractions, given with a 1-week split, days 1 and 8. From 47 patients evaluable for the response, there were 3 (6%) complete responses and 10 (21%) par- tial responses, making an overall response rate of 13 (28%). Response duration was 2–8 months (median, 5 months; mean, 5 months). MST for all 50 patients was 7 months, and 1- to 3-year survival rates were 31%, 4.1% and 2%, respectively. Only 9 (19%) pa- tients experienced haematological grade 3 toxicity, all other chemotherapy-induced toxicity being grade 1 or 2. Of radiation therapy-induced high-grade toxic- ity (according to the Radiation Therapy Oncology Group), grade 3 oesophageal toxicity was observed in 9 (19%) patients, while only 4 (9%) patients experi- enced grade 3 bronchopulmonary toxicity. No grade 4 or 5 toxicity occurred during this study. Short-course chemotherapy and palliative radiation therapy in el- derly patients with stage IV non-small cell lung can- cer was well tolerated, with mild to moderate toxicity.
Together with other results obtained this way, these fi ndings warrant further studies evaluating the effec- tiveness of this approach and possible chemotherapy and/or radiation therapy dose escalation in elderly patients with stage IV (metastatic) non-small cell lung cancer.
6.3
Small-Cell Lung Cancer
Small-cell lung cancer represents 20–25% of all lung cancers cases. Its chemosensitivity and great meta- static potential make it a good candidate for che- motherapy. However, with chemotherapy alone, the outcome of small cell lung cancer is poor. Although
the initial response rates are high, only 5% of patients achieve long-term survival at 3 years. Of all small cell lung cancer cases, only approximately 20–30%
of all patients present with a tumour confi ned to the hemithorax of origin, the mediastinum or the supraclavicular lymph nodes, designated as having limited-disease small cell lung cancer. All other pa- tients present with disseminated, extended disease.
Since they have a dismal prognosis and are, therefore treated mostly with palliative intention, this section focuses on limited-disease small cell lung cancer in elderly.
Standard treatment for limited-disease small cell lung cancer is combined radiation therapy and che- motherapy, a practice widely accepted after the sur- vival benefi t of thoracic radiation therapy has been confi rmed by two meta-analyses published in 1992 (Pignon et al. 1992; Warde and Payne 1992). The most widely used approach in limited-disease small cell lung cancer consists of 4 cycles of cisplatin/etopo- side and thoracic radiation therapy. This is nowadays routinely followed by prophylactic cranial irradiation in cases of complete remission, owing to fi ndings of a meta-analysis demonstrated that prophylactic cra- nial irradiation improves survival for limited-disease small cell lung cancer patients in complete remission after radiochemotherapy (Auperin et al. 1999).
For the vast majority of elderly patients with lim- ited-disease small cell lung cancer, the evidence for the standard treatment must be derived from phase III trials in which elderly patients are largely under- represented. It remains unclear to what extent these results are biased by eligibility criteria of the trials, which restrict the entry of elderly patients, since one of meta-analyses shows that the survival benefi t from thoracic radiation therapy is restricted to younger patients (Warde and Payne 1992), possibly because of toxicity. Therefore careful selection of elderly pa- tients suitable for a full dose of radiation therapy and chemotherapy is an important issue.
Randomised phase III studies investigating vari- ous issues of radiation therapy and chemotherapy in elderly patients with limited-disease small cell lung cancer are lacking, and the prognostic signifi cance of age in small cell lung cancer is not well defi ned.
While Southwest Oncology Group and Cancer and
Leukaemia Group B have demonstrated an infl u-
ence of age in limited-disease small cell lung cancer
(Spiegelman et al. 1989; Albain et al. 1990), others
do not confi rm this observation (Osterlind and
Anderson 1986; Sagman et al. 1991). Among the
studies investigating the relationship between the
age and toxicity and outcome among elderly patients
treated with combined thoracic radiation therapy and chemotherapy in small cell lung cancer, Findlay et al. (1991) have observed signifi cantly more toxicity in the intensively treated group (cyclophosphamide, doxorubicin, vincristine) than in the less-intensive group of small cell lung cancer patients (single agents, planned dose reductions, or radiation therapy alone), which was accompanied by a higher response rate in that group. However, in the limited-disease small cell lung cancer patients, intensive treatment did not lead to an improvement in overall survival.
The 1990s also brought a number of studies inves- tigating the infl uence of various prognostic factors in small cell lung cancer, including age (Table 6.1) (Siu et al. 1996; Dajczman et al. 1996; Nou 1996;
Jara et al. 1999; Yuen et al. 2000). Confl icting results were observed, probably owing to various cut-off values used with regard to age as prognostic factor.
Regardless, in all of the studies frequent dose emis- sions/reduced number of chemotherapy cycles (Siu et al. 1996; Dajczman et al. 1996; Nou 1996; Yuen et al. 2000) or dose reductions/less intensive (Jara et al.
1999) or less frequent use of radiation therapy made the elderly patients the group not only receiving less- intensive treatment, but also less likely to be included in clinical trials as well. The situation remains the same. In a retrospective analysis of 174 patients with limited-disease small cell lung cancer, Ludbrok et al. (2003) have recently reconfi rmed that, during the 1990s, elderly patients continued to be underdiag- nosed and undertreated, resulting in lower median and overall survival rates; although toxicity and pat- tern of failure show no difference when compared with their non-elderly counterparts. When, however, multivariate analysis was done, age was not shown to be an independent prognosticator of treatment out- come. It is more than interesting, however, to observe that none of the studies observed a signifi cantly infe- rior response rate, overall survival or event-free sur- vival for elderly. If therapy is administered, therefore, the outcome in elderly patients is the same as that in younger patients. For example, Siu et al. (1996) have observed that age infl uences survival in the univari- ate analysis, but not in a multivariate analysis. It may well be that factors frequently associated with age, such as co-morbidity, performance status or less-in- tensive treatment seem to infl uence prognosis, rather than age itself.
Numerous studies have investigated the infl uence of age on toxicity. Some have observed fewer elderly patients with high-grade toxicity (p=0.0001), and a similar incidence of treatment-related deaths due to less-intensive treatment (Dajczman et al. 1996).
Others have reported on similar toxicities in both age groups. When a higher rate of haematological toxicity and fatal toxicities occur in the elderly group, other toxicities are similar compared with younger patients (Nou 1996; Jara et al. 1999; Yuen et al. 2000).
In addition to retrospective studies, there are also prospective studies specifi cally addressing the is- sue of optimising the treatment approach in elderly patients with limited-disease small cell lung cancer.
Jeremi ´ c et al. (1998) have tailored the combined treatment in elderly with limited-disease small cell lung cancer by administering concurrently only two courses of carboplatin (400 mg/m
2, days 1 and 29) and oral etoposide (50 mg/m
2, days 1–21 and 29–49) with accelerated hyperfractionated radiation therapy (45 Gy in 30 fractions in 15 treatment days, using 1.5 Gy b.i.d. fractionation) in 75 patients of 70 years or older with a Karnofsky performance status score of greater than 60% and without major concomitant diseases. The MST was 15 months and 5-year sur- vival was 13%. Good pre-treatment characteristics led to high compliance (83% received therapy on an outpatient basis) and low toxicity. Grade 4 thrombo- cytopenia occurred in 1.4% of all patients, throm- bocytopenia grade 3 in 11%, grade 3 leucopenia in 8.3%, grade 3 anaemia in 2.8%, infection in 4.2%, and nausea and vomiting in 4.2% of all patients. No high- grade bronchopulmonary toxicity was observed and grade 3 oesophagitis occurred in only 2.8% of the pa- tients. An additional advantage of this approach was its short duration, resulting in more time spent at home and, therefore, a good quality of life. Murray et al. (1998) have also used only 2 cycles of chemo- therapy (cyclophosphamide/doxorubicin/vincris- tine and platinum/etoposide) and radiation therapy (20 Gy in 5 fractions or 30 Gy in 10 fractions) spe- cifi cally tailored for elderly, infi rm or non-compliant patients. Toxicity was low, except in the cases of three treatment-related deaths, two of which were caused by cardiac toxicity, with likely ischemic cause. The median time to progression was 40 weeks and 2-year PFS was 25%. The MST was 54 weeks and 5-year sur- vival rate was 18%. The MST and 5-year survival were similar for 18 patients younger than 70 years and for the 37 patients 70 years or older.
Most recently, Matsui et al. (1998) have reported on 16 patients of more than 70 years of age with lim- ited-disease small cell lung cancer for whom 4 cycles of carboplatin and oral etoposide (40 mg/m
2, days 1–
14) were followed by chest radiation therapy (45 Gy).
The MST was 15.1 months and a 2-year survival rate
was 21.8%. For patients 75 years or older, the MST
was 10.3 months and 2-year survival rate was 11.3%.
Grade 3 and 4 leucopenia occurred in 36% and 14%
of patients, respectively, and grade 3 and 4 thrombo- cytopenia occurred in 39% and 14% of the patients, respectively. Grade 3/4 anaemia occurred in 50% of patients. Non-haematological toxicity was rare. What these three prospective studies have shown is that well-tailored treatment approaches, carefully bal- anced between “optimal” thoracic radiation therapy and chemotherapy elderly patients can tolerate and avoid unnecessary toxicity, may lead to high treat- ment success and a toxicity profi le not very different to that usually observed in younger patients.
Retrospective and prospective studies have also shown, despite elderly patients frequently receiving less-intensive chemotherapy and/or thoracic radia- tion therapy, a similar outcome of elderly and non- elderly patients with limited-disease small cell lung
cancer. Furthermore, despite less compliance in eld- erly patients, no difference in either response rates or survival has been detected between them and their non-elderly counterparts (Kelly et al. 1991; Siu et al. 1996; Dajczman et al. 1996; Tebbutt et al. 1997;
Yuen et al. 2000). While the reason for this phenom- enon is still unclear, a possible explanation may lie in a different metabolism of drugs, which may lead to a need for lower doses of various drugs in elderly pa- tients (Montamat et al. 1989; McKenna 1994; Joss et al. 1995), since different biological behaviours of tumours in elderly patients is not a very likely cause of this observation (Matsui et al. 1998). As Yuen et al. (2000) point out; there may be a threshold above which a signifi cant benefi t can be realized. The mod- est dose reductions still may result in the delivery of “adequate enough” treatment to achieve a posi-
Table 6.1. Retrospective studies in patients with limited-disease small cell lung cancer treated with radiation therapy and chemotherapy
Author Year Age (years)/n RR (%) Survival Toxicity Comments
Siu et al. 1996 <70 (n=580)
*70 (n=88)
78%; n.s.
82%; n.s.
5-year OS: 8%; n.s.
5-year OS: 11%; n.s.
Only cardiac grade 3/4 toxicity increase in *70)
All LD; CAV/PE + TI + PCI (if CR)
Age not a prognostic factor in multivariate analysis
Dajczman et al.
1996 <60 (LD n=45, ED n=55) 60-60 (n=LD n=48, ED n=73)
*70 (LD n=43, ED n=57)
49%; n.s.
52%; n.s.
51%: n.s.
2 year OS: 45 2-year OS: 48 2-year OS: 43
Fewer high-grade toxicity and the mean number of toxicities in elderly patients
n=123 LD, n=89 ED; CAV or PE + TI;
No separate analysis for LD + ED
>70: only 23% received optimal treatment (com- pared with 43%/50% in the younger groups)
Nou 1996 )70 (n=243)
>70 (n=110)
All: 72%
(n.s.)
5-yearOS: 5%; n.s.
5-yearOS: 1.3%; n.s.
No difference between )70 and >70
50% LD 50% ED; (85%
of LD and 15% of ED treated with CHT (vari- ous) + TI
Jara et al. 1999 <70 (n=25)
*70 (n=12)
46%; n.s.*
50%; n.s.*
MST: 12.3 months MST: 14.9 months
No difference between )70 and >70
only LD evaluated; PE or cPE +TI
Yuen et al. 2000 <70 (n=271)
*70 (n=50)
80%; n.s.
88%; n.s.
5-year EFS: 19%;
n.s.*
5-year EFS: 16%;
n.s.*
Grade III/IV haemato- logical toxicity higher in the elderly group;
all other adverse effects: no difference
All LD, except* (data for LD; n=37) + ED (n=57)
Ludbrok et al.
2003 <65 (n=55) 65-74 (n=76)
> 75 (n=43)
91%
79%
74%
MST: 17 months 2-year OS: 37%
MST: 12 months 2-year OS: 22%
MST: 7 months 2-year OS: 19%
P=0.003
No difference in the incidence of acute or late grade 3/4 toxicity
Age not signifi cant prog- nosticator in multivariate analysis since elderly patients less frequently treated with RT/CHT, intensive CHT and PCI
RR, response rates; n.s., not signifi cant; LD, limited disease; CAV, cyclophosphamide, doxorubicin, vincristine; PE, cisplatin, etoposide; TI, thoracic irradiation; PCI, prophylactic cranial irradiation; CR, complete response; OS, overall survival; ED,
tive effect. This threshold will be hard to document and/or specify, but it seems that studies of Jeremi´c et al. (1998) and Murray et al. (1998) support this statement: Although chemotherapy was limited to only 2 cycles given concurrently with thoracic radia- tion therapy, it was possible to obtain results which are not substantially inferior to those obtained with more intensive approaches. However, every caution should be taken with this patient population, particu- larly regarding haematological toxicity.
In extensive-disease small cell lung cancer, stan- dard treatment for patients with extensive-disease small cell lung cancer is chemotherapy. The addition of thoracic radiation therapy has not improved sur- vival in the past, and thoracic radiation therapy was applied only for palliation of local symptoms when chemotherapy alone was not effi cient (Livingston et al. 1984). However, a recent prospective random- ized trial by Jeremi´c et al. (1999) has shown an ad- vantage for 3 cycles of platinum-etoposide chemo- therapy followed by accelerated hyperfractionated thoracic radiation therapy given concurrently with low-dose, daily carboplatin/etoposide over chemo- therapy with platinum/etoposide (5 cycles) alone.
During that study, survival advantage was observed for patients more than 60 years old, a fi nding con- fi rmed by the multivariate analysis, identifying the age as an independent prognosticator of survival in patients with extensive-disease small cell lung cancer (unpublished observations; drawn from Jeremi´c et al. 1999).
6.4
Conclusions
Accumulated evidence identifi es radiation therapy as an important treatment modality in elderly patients with lung cancer. This is so irrespective of the con- sideration of cut-off age, histology or stage, as this applies to combined radiation therapy and chemo- therapy. Encouraging results have been obtained in both non-small cell lung cancer and small cell lung cancer, although prospective studies are lacking.
Current evidence, unfortunately, also points out that age alone is an uncertain prognostic criterion when outcome is considered together with toxicity.
More important than chronological age seems to be the biological age of each individual elderly patient, which therefore requires a specifi c geriatric assess- ment of each individual patient, including detection of co-morbidities and the functional capacity for
performing activities of daily living, and the cogni- tive and nutritional status of the patient. The deci- sion-making of radiation therapy alone or in com- bination with chemotherapy in elderly patients with lung cancer should be based on both disease- and patient-specifi c criteria. Age itself is not a contrain- dication for applying the standard treatment, but the individualized management of the elderly patient must refl ect the results of a comprehensive geriatric assessment.
However, a major issue in this fi eld is the lack of prospective clinical studies investigating “optimal”
treatments in this setting. This is especially so since accumulated evidence clearly shows that “fi t” elderly patients may tolerate the treatments, regardless of its intensity, considerably well. They could serve as the starting point for inclusion of more elderly patients in clinical studies. However, every caution should be undertaken in order not to overemphasize the results of recent studies, which are, unfortunately, mostly retrospective. That said, inherent biases and under- lying problems, unsolved so far, may hamper future endeavours having the same goal: enabling elderly patients with lung cancer equal diagnostic and treat- ment approaches to their younger counterparts, on or off the protocol. While this should be a continuous reminder to all working in this fi eld, we need more clinical studies in elderly patients with lung cancer and we need them now.
References
Albain KS, Crowley JJ, LeBlanc M, Livingston RB (1990) Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580-patient Southwest Oncol- ogy Group data base. J Clin Oncol 8:1563-1574.
Aristizabal SA, Caldwell WL (1976) Radical irradiation with the split-course technique in carcinoma of the lung.
Cancer 37:2630-2635.
Aristizabal SA, Meyerson M, Caldwell WL, Mayer EG (1976) Age as a prognostic indicator in carcinoma of the lung.
Radiology 121:721-723.
Atagi S, Kawahara M, Ogawara M, et al (2000) Phase II trial of daily low-dose carboplatin and thoracic radiotherapy in elderly patients with locally advanced non-small cell lung cancer. Jpn J Clin Oncol 30:59-64.
Auperin A, Arriagada R, Pignon JP, et al (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476- 484.
Balducci L, Extermann M (2000a) Cancer and aging. An evolv- ing panorama. Hematol Oncol Clin North Am 14:1-16.
Balducci L, Extermann M (2000b) Management of cancer in
the older person: a practical approach. Oncologist 5:224- 237.
Bernabei R, Venturiero R, Tarsitani P, Gambassi G (2000) The comprehensive geriatric assessment: when, where, how.
Crit Rev Oncol Hematol 33:45-56.
Clamon G, Herndon J, Cooper R, et al (1999) Radiosensi- tization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukaemia Group B and the Eastern Coopera- tive Oncology Group. J Clin Oncol 17:4-11.
Coy P, Kennelly GM (1980) The role of curative radiotherapy in the treatment of lung cancer. Cancer 45:698-702.
Dajczman E, Fu LY, Small D, Wolkove N, Kreisman H((1996) Treatment of small cell lung carcinoma in the elderly.
Cancer 77:2032-2038.
Extermann M (2000) Measurung co-morbidity in older cancer patients. Eur J Cancer 36:453-471.
Findlay MP, Griffi n AM, Raghavan D, et al (1991) Retrospec- tive review of chemotherapy for small cell lung cancer in the elderly: does the end justify the means? Eur J Cancer 27:1597-1601.
Furuse K, Fukuoka M, Kawahara M, et al (1999) Phase III study of concurrent versus sequential thoracic radiother- apy in combination with mitomycin, vindesine, and cis- platin in unresectable stage III non-small-cell lung cancer.
J Clin Oncol 17:2692-2699.
Gauden S, Ramsay J, Tripcony L (1995) The curative treat- ment by radiotherapy alone of stage I non-small cell car- cinoma of the lung. Chest 108:1278-1282.
Gauden SJ, Tripcony L (2001) The curative treatment by radi- ation therapy alone of Stage I non-small cell lung cancer in a geriatric population. Lung Cancer 32:71-79.
Gava A (1999) Lung cancer radiation treatment in the elderly.
Crit Rev Oncol Hematol 32:45-48.
Ghosh S, Sujendran V, Alexiou C, Beggs L, Beggs D (2003) Long term results of surgery versus continuous hyperfraction- ated accelerated radiotherapy (CHART) in patients aged
>70 years with stage 1 non-small cell lung cancer. Eur J Cardiothorac Surg 24:1002-1007.
Hayakawa K, Mitsuhashi N, Saito Y, et al (1999) Limited fi eld irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer. Lung Cancer 26:137-142.
Hayakawa K, Mitsuhashi N, Katano S, et al (2001) High-dose radiation therapy for elderly patients with inoperable or unresectable non-small cell lung cancer. Lung Cancer 32:81-88.
Jara C, Gomez-Aldaravi JL, Tirado R, et al (1999) Small-cell lung cancer in the elderly – is age of patient a relevant factor? Acta-Oncol 38:781-786.
Jeremi´c B, Shibamoto Y, Acimovic L, Milisavljevic S((1997) Hyperfractionated radiotherapy alone for clinical stage I nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 38:521-525.
Jeremi´c B, Shibamoto Y, Milicic B, et al (1998a) Concurrent radiochemotherapy for patients with stage III non-small- cell lung cancer (NSCLC): long-term results of a phase II study. Int J Radiat Oncol Biol Phys 42:1091-1096.
Jeremi´c B, Shibamoto Y, Acimovic L, Milisavljevic S (1998b) Carboplatin, etoposide, and accelerated hyperfraction- ated radiotherapy for elderly patients with limited small cell lung carcinoma: a phase II study. Cancer 82:836-841.
Jeremi´c B, Shibamoto Y, Acimovic L, Milisavljevic S (1999a)
Hyperfractionated radiotherapy for clinical stage II non- small cell lung cancer. Radiother Oncol 51:141-145.
Jeremi´c B, Shibamoto Y, Milicic B, et al (1999b) A phase II study of concurrent accelerated hyperfractionated radiotherapy and carboplatin/oral etoposide for elderly patients with stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 44:343-348.
Jeremi´c B, Shibamoto Y, Milicic B, et al (1999c) Short-term chemotherapy and palliative radiotherapy for elderly patients with stage IV non-small cell lung cancer. A phase II study. Lung Cancer 24: 1-9.
Jeremi´c B, Shibamoto Y, Nikolic N, et al (1999d) Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer:
a randomized study. J Clin Oncol 17: 2092-2099.
Joss RA, Bacchi M, Hurny C, et al (1995) Early versus late alternating chemotherapy in small-cell lung cancer. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 6: 157-166.
Karasawa K, Niibe Y, Igaki H, Ieki R, Tanaka Y (2002) Radio- therapy combined with bronchial arterial infusion of CDDP in the treatment of stage III non-small cell lung cancer for aged patients. Int J Radiat Oncol Biol (Suppl.) 54:104 (Abstract 175).
Kaskowitz L, Graham MV, Emami B, Halverson KJ, Rush C (1993) Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 27:517-523.
Kelly P, O’Brien AA, Daly P, Clancy L (1991) Small-cell lung cancer in elderly patients: the case for chemotherapy. Age Ageing 20: 19-22.
Krol AD, Aussems P, Noordijk EM, Hermans J, Leer JW (1996) Local irradiation alone for peripheral stage I lung cancer:
could we omit the elective regional nodal irradiation? Int J Radiat Oncol Biol Phys 34:297-302.
Kusumoto S, Koga K, Tsukino H, et al (1986) Comparison of survival of patients with lung cancer between elderly (greater than or equal to 70) and younger (70 greater than) age groups. Jpn J Clin Oncol 16:319-323.
Langer CJ, Hsu C, Curran WJ Jr, et al. (2001) Do elderly patients with locally advanced non-small-cell lung cancer benefi t from combined modality therapy? A secondary analysis of RTOG 94-10. Int J Radiat Oncol Biol Phys (Suppl. 23) 51:31.
Livingston RB, Mira JG, Chen TT, et al (1984) Combined modality treatment of extensive small cell lung cancer:
a Southwest Oncology Group study. J Clin Oncol 2: 585- 590.
Lonardi F, Coeli M, Pavanato G, et al (2000) Radiotherapy for non-small cell lung cancer in patients aged 75 and over:
safety, effectiveness and possible impact on survival. Lung Cancer 28:43-50.
Ludbrok JJ, Truong PT, MacNeil MV, et al (2003) Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer ? A community- based population analysis. Int J Radiat Oncol Biol Phys 55:1321-1330.
Matsui K, Masuda N, Fukuoka M, et al (1998) Phase II trial of carboplatin plus oral etoposide for elderly patients with small-cell lung cancer. Br J Cancer 77:1961-1965.
McKenna RJ Sr((1994) Clinical aspects of cancer in the eld- erly. Treatment decisions, treatment choices, and follow- up. Cancer 74:2107-2117.
Monfardini S, Sorio R, Boes G, Kaye S, Serraino D (1995) Entry
and evaluation of elderly patients in European Organiza- tion for research and Treatment of Cancer (EORTC) new- drug-development studies. Cancer 76:333-338.
Montamat SC, Cusack BJ, Vestal RE (1989) Management of drug therapy in the elderly. N Engl J Med 321:303-309.
Montella M, Gridelli C, Crispo A, et al (2002) Has lung cancer in the elderly different characteristics at presentation?
Oncol Rep 9:1093-1096.
Morita K, Fuwa N, Suzuki Y, et al (1997) Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I: a retrospective analysis of 149 patients.
Radiother Oncol 42:31-36.
Movsas B, Scott C, Sause W, et al (1999) The benefit of treatment intensification is age and histology-depend- ent in patients with locally advanced non-small cell lung cancer (NSCLC): a quality-adjusted survival anal- ysis of Radiation Therapy Oncology Group (RTOG) chemoradiation studies. Int J Radiat Oncol Biol Phys 45:1143-1149.
Murray N, Grafton C, Shah A, et al (1998) Abbreviated treat- ment for elderly, infi rm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16:3323- 3328.
Nakano K, Hiramoto T, Kanehara M, et al (1999) Radiother- apy alone for elderly patients with stage III non-small cell lung cancer. Nihon Kokyki Gakkai Zasshi 37:276- 281.
Nakano K, Yamamoto M, Iwamoto H, Hiramoto T (2003) Daily low-dose cisplatin plus concurrent high-dose thoracic radiotherapy in elderly patients with locally advanced unresectable non-small-cell lung cancer. Gan To Kagaku Ryoho 30:1283-1287.
Newaishy GA, Kerr GR (1989) Radical radiotherapy for bron- chogenic carcinoma: fi ve year survival rates. Clin Oncol (R Coll Radiol) 1:80-85.
Niibe Y, Karasawa K, Shibuya M, Ieki R, Tanaka Y (2003) Prospective study of three-dimensional radiation therapy (3D-CRT) using a middle fraction size for small-sized lung tumor in elderly patients (abstract). Proc Am Soc Clin Oncol 2702.
Noordijk EM, Poest Clement E, Hermans J, Wever AM, Leer JW (1988) Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13:83-89.
Nou E (1996) Full chemotherapy in elderly patients with small cell bronchial carcinoma. Acta-Oncol 35:399-406.
Nugent WC, Edney MT, Hammerness PG, et al (1997) Non- small cell lung cancer at the extremes of age: impact on diagnosis and treatment. Ann Thorac Surg 63:193-197.
Osterlind K, Andersen PK (1986) Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation.
Cancer Res 46:4189-4194.
Osterweil D, Brummel-Smith K, Beck JC, eds (2000) Compre- hensive geriatric assessment. McGraw Hill, New York.
Patterson CJ, Hocking M, Bond M, Teale C (1998) Retrospec- tive study of radiotherapy for lung cancer in patients aged 75 years and over. Age Ageing 27:515-518.
Pergolizzi S, Santacaterina A, De Renzis C, et al (2002) Older people with non small cell lung cancer in clinical stage IIIA and co-morbid conditions. Is curative irradiation feasible? Final results of a prospective study. Lung Cancer 37: 201-206.
Pignon JP, Arriagada R, Ihde DC, et al (1992) A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624.
Pignon T, Gregor A, Schaake-Koning C, et al (1998) Age has no impact on acute and late toxicity of curative thoracic radiotherapy. Radiother Oncol 46 ; 239-248.
Rocha Lima CM, Herndon JE, Kosty M, Clamon G, Green MR (2002) Therapy choices among older patients with lung carcinoma: an evaluation of two trials of the Cancer and Leukaemia Group B. Cancer 94:181-187.
Rubenstein LZ (1995) An overview of comprehensive geriat- ric assessment: rationale, history, program models, basic components. In: Rubinstein LZ, Wieland D, Bernabei R (eds) Geriatric assessment technology: the state of the art.
Springer, New York.
Sagman U, Feld R, Evans WK, et al (1991) The prognostic signifi cance of pretreatment serum lactate dehydroge- nase in patients with small-cell lung cancer. J Clin Oncol 9:954-961.
Sandler HM, Curran WJ, Jr., Turrisi AT 3rd (1990) The influence of tumor size and pre-treatment staging on outcome following radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 19:9-13.
Schaake-Koning C, Bogaert W van den, Dalesio O, et al (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-530.
Schild SE, Stella PJ, Geyer SM, et al (2003) The outcome of combined-modality therapy for stage III non-small-cell lung cancer in elderly. J Clin Oncol 3201-3206.
Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR (1998) Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 40:149-154.
Siu LL, Shepherd FA, Murray N, et al (1996) Infl uence of age on the treatment of limited-stage small-cell lung cancer.
J Clin Oncol 14:821-828.
Slotman BJ, Njo KH, Karim AB((1994) Curative radiotherapy for technically operable stage I nonsmall cell lung cancer.
Int J Radiat Oncol Biol Phys 29:33-37.
Spiegelman D, Maurer LH, Ware JH, et al (1989) Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients. J Clin Oncol 7:344-354.
Tebbutt NC, Snyder RD, Burns WI (1997) An analysis of the outcomes of treatment of small cell lung cancer in the elderly. Aust NZ J Med 27:160-164.
Tombolini V, Bonanni A, Donato V, et al (2000) Radiotherapy alone in elderly patients with medically inoperable stage IIIA and IIIB non-small cell lung cancer. Anticancer Res 20:4829-4833.
Warde P, Payne D((1992) Does thoracic irradiation improve survival and local control in limited-stage small-cell car- cinoma of the lung? A meta-analysis. J Clin Oncol 10:890- 895.
Werner-Wasik M, Scott C, Cox JD, et al (2000) Recursive partitioning analysis of 1999 Radiation Therapy Oncol- ogy Group (RTOG) patients with locally-advanced non- small-cell lung cancer (LA-NSCLC): identifi cation of fi ve groups with different survival. Int J Radiat Oncol Biol Phys 48:1475-1482.
Wurschmidt F, Bunemann H, Bunemann C, Beck-Bornholdt HP, Heilmann HP (1994) Inoperable non-small cell lung
cancer: a retrospective analysis of 427 patients treated with high-dose radiotherapy. Int J Radiat Oncol Biol Phys 28:583-588.
Yanick R (1997) Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 80:1273-1283.
Yuen AR, Zou G, Turrisi AT, et al (2000) Similar outcome of elderly patients in intergroup trial 0096: Cisplatin,
etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma.
Cancer 89:1953-1960.
Zachariah B, Balducci L, Venkattaramanabalaji GV, et al (1997) Radiotherapy for cancer patients aged 80 and older: a study of effectiveness and side effects. Int J Radiat Oncol Biol Phys 39:1125-1129.
