Treatment of small cell lung cancer in the elderly

Hematol Oncol Clin N Am 18 (2004) 433 – 443

Treatment of small cell lung cancer in the elderly Branislav Jeremic, MD, PhDa,*, Frank B. Zimmermann, MDa, Michael Bamberg, MDb, Michael Molls, MD, PhDa a

Department of Radiation Oncology, Klinikum rechts der Isar, Technical University Munich Ismaninger Strasse 22, D-81675 Munich, Germany b Department of Radiation Oncology, University Hospital, University of Tu¨bingen, Hoppe-Seyler-Str. 3, D-72076 Germany

Small cell lung cancer (SCLC) occurs in approximately 20% of all lung cancer cases. It has a specific histologic appearance and a different biologic behavior from all other types of lung cancer that are collectively termed non– small cell lung cancer (NSCLC). Its sensitivity to chemotherapy (CHT) and propensity for early metastatic spread made systemic CHT a major therapeutic intervention, but despite its use, only 5% of all patients receiving CHT achieve long-term survival (3 years). Without treatment, however, the median survival for patients is 2 to 4 months, obviating the need for a more active treatment approach regardless of its intention; this is also the case in the elderly. About 20% to 30% of patients are designated as having limited disease (LD; their tumor is confined to the hemithorax, the mediastinum, or the supraclavicular lymph nodes). This is the favorable group of patients because nearly all longterm survivors are derived from this group. All other patients (approximately two thirds) present with extended disease (ED), presenting with one or more extrathoracic sites of involvement. When a tumor in one hemithorax cannot be encompassed by a tolerable radiation portal, it has been designated as ED SCLC. For patients with ED, long-term survival is uncommon and the treatment is usually palliative. As with NSCLC, the disease itself is frequently accompanied by a coexisting morbidity, mostly cardiopulmonary, but paraneoplastic syndromes occur frequently. Elderly SCLC patients are less likely to be vigorously screened and

* Corresponding author. E-mail address: [email protected] (B. Jeremic). 0889-8588/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.hoc.2003.12.003

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staged, and as a consequence, frequently less aggressively treated and more likely to be offered no treatment at all than their younger counterparts.

Limited-disease small cell lung cancer The standard treatment approach in LD SCLC consists of CHT combined with thoracic radiation therapy (TRT), followed by prophylactic cranial irradiation in cases of complete response (CR). Currently, the most widely used CHT regimen in LD SCLC consists of cisplatin (P) and etoposide (E). The benefit of TRT has been confirmed by two meta-analyses published in 1992 [1,2]. Another meta-analysis demonstrated that additional prophylactic cranial irradiation further improves survival for LD SCLC patients in CR after combined radiation therapy (RT)/CHT [3]. One of the meta-analyses [1] showed that with increasing age, there was a continuous trend toward an increase in the relative risk of death with TRT/CHT versus CHT alone (1.07 in patients > 70 years compared with 0.72 in younger patients). Among the studies investigating the relationship between age, toxicity, and outcome among elderly SCLC patients treated with combined TRT/CHT, Findlay et al [4] observed significantly more toxicity in the intensively treated group (cyclophosphamide [C], doxorubicin [A], plus vincristine [V]) than in the less intensively treated group of SCLC patients (treatment with single agents, planned dose reductions, or RT alone). The LD SCLC intensive treatment led to a higher response rate in that group; however, it did not lead to an improvement in overall survival. Numerous retrospective studies investigated the influence of various prognostic factors in SCLC, including age [5 –9] (Table 1). In all of the studies, the elderly group tended to receive less intensive treatment, both CHT (dose reductions or reduced number of CHT cycles) [5– 7,9] and TRT (dose reductions, less intensive or less frequent use of TRT) [8]. Despite these differences sometimes being substantial, none of the studies demonstrated inferior response rates overall or event-free survivals for elderly patients. The situation remains the same today. In the retrospective analysis of 174 patients with LD SCLC, Ludbrok et al [10] reconfirmed that during the 1990s, elderly patients continued to be underdiagnosed and undertreated, resulting in lower median and overall survival rates, although toxicity and pattern of failure showed no difference compared with their nonelderly counterparts. When multivariate analysis was done, however, age was not shown to be an independent prognosticator of treatment outcome. Influence of age on treatment toxicity is rather unclear. Dajczman et al [6] observed fewer elderly patients with high-grade toxicity (P = 0.0001). The mean number of toxicities was also reduced in that group, with no difference in treatment-related deaths, which led the investigators to speculate about less intense treatment being one of the reasons for such a finding. Reports of Nou [7] and Jara et al [8] provided additional data on similar toxicities in both age groups, contrasting the findings of Yuen et al [9] who observed a higher rate of

Table 1 Retrospective studies in patients with limited-disease small cell lung cancer treated with radiation therapy/chemotherapy Year Age/n

RR(%)

Survival

Toxicity

Comments

Siu et al [5]

1996 <70: 580 70: 88

78%; n.s. 82%; n.s.

5-y OS: 8%; n.s. 5-y OS: 11%; n.s.

Only cardiac grade 3/4 toxicity higher in age 70) Less high-grade toxicity and lower mean number of toxicities in elderly

All LD; CAV/PE + TRT + PCI (if CR) age not a prognostic factor in multivariate N = 123 LD, N = 89 ED; CAV or PE + TRT; No separate analysis for LD + ED for age >70: only 23% received optimal treatment (compared to 43% in the age <60 y and 50% in the age 60 – 69 y groups) 50% LD, 50% ED; (85% of LD and 15% of ED treated with CHT (various) + TRT Only LD evaluated; PE or cPE + TRT

Dajczman et al [6] 1996 < 60: LD 45, ED 55 49%; n.s. 60 – 69: LD 48, ED 73 52%; n.s. 70: LD 43, ED 57 51%; n.s.

2-y OS: 45 2-y OS: 48 2-y OS: 43

Nou [7]

1996 70: 243 >70: 110

All: 72% (n.s.) 5-y OS: 5%; n.s. 5-y OS: 1.3%; n.s.

Jara et al [8]

1999 <70: 25 70: 12 2000 <70: 271 70: 50

46%; 50%; 80%; 88%;

Yuen et al [9]

Ludbrok et al [10] 2003 <65: 55 65 – 74: 76 75: 43

91% 79% 74%

n.s. n.s. n.s. n.s.

MST: 12.3 mo MST: 14.9 mo 5-y EFS: 19%; n.s.* 5-y EFS: 16%; n.s.*

No difference between age 70 and >70

No difference between age 70 and >70 Grade III/IV hematologic toxicity higher in the elderly group, all other adverse effects: no difference MST: 17 mo 2-y OS: 37% No difference in the incidence MST: 12 mo 2-y OS: 22% of acute or late grade MST: 7 mo 2-y OS: 19% III/IV toxicity P = 0.003

All LD, except* (data for LD (N = 37) + ED (N = 57)

Age not significant prognosticator in multivariate analysis because elderly patients were less frequently treated with RT/CHT, intensive CHT and PCI

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Author [ref.]

Abbreviations: CAV, cyclophosphamide, doxorubicine, vincristin; CHT, chemotherapy; cPE, carboplatin, etopsoide; CR, complete response; ED, extensive disease; EFS, event free survival; LD, limited disease; MST, median survival time; n.s., not significant; OS, overall survival; PCI, prophylactic cranial irradiation; PE, cisplatin, etoposide; RR, response rate; RT, radiation therapy; TRT, thoracic irradiation. 435

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grade IV neutropenia (P<0.01), grade III and IV thrombocytopenia (P = 0.03), and fatal toxicity (P = 0.01) in the elderly group, with all other toxicities being similar to those occurring in younger patients. Some prospective phase II or III studies investigated various aspects of combined RT/CHT optimization in this disease, including age. It is unfortunate that some of the studies did not provide subset analysis regarding the influence of age; most other studies excluded age >70 years. Nevertheless, Joss et al [11] and Jeremic et al [12] found no difference in outcome or toxicity when influence of age was considered. Jeremic et al [12] even observed a trend for better survival in patients >60 years. Three prospective studies specifically addressed the issue of optimizing the treatment approach in elderly patients with LD SCLC. In the study by Jeremic et al [13], only two courses of carboplatin (Cp; 400 mg/m2, days 1 and 29) and oral E (50 mg/m2, days 1– 21 and 29– 49) were administered concurrently with accelerated hyperfractionated RT (45 Gy in 30 fractions in 15 treatment days using 1.5-Gy twice-daily fractionation) in 75 patients 70 years with a Karnofsky performance status score of >60% and without major concomitant diseases. The median survival time (MST) was 15 months and the 5-year survival rate was 13%. Good pretreatment characteristics led to high compliance (83% received therapy on an outpatient basis) and low toxicity. Grade IV thrombocytopenia occurred in 1.4% of all patients, grade III thrombocytopenia in 11%, grade III leucopenia in 8.3%, grade III anemia 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 III esophagitis occurred in only 2.8% of the patients. An additional advantage of this approach was its short duration, resulting in more time spent at home and, therefore, better quality of life. A study done by Murray et al [14] also used only two cycles of CHT (CAV and PE) and RT (20 Gy in 5 fractions or 30 Gy in 10 fractions) that were specifically tailored for elderly, infirm, or noncompliant patients. Toxicity was low, except for three treatmentrelated deaths, two of which were cardiac toxicity, with likely ischemic cause. The median time to progression was 40 weeks and 2-year progression free survival (PFS) was 25%. The MST was 54 weeks and the 5-year survival rate was 18%. The MST and 5-year survival rate were similar for 18 patients <70 years and for 37 patients 70 years. The third report that addressed the issue of optimizing treatment approach in elderly patients was that of Matsui et al [15] who reported on 16 patients with LD SCLC >70 years for whom four cycles of Cp and oral E (40 mg/m2, days 1 – 14) were followed by chest RT (45 Gy). The MST was 15.1 months and the 2-year survival rate was 21.8%. For patients 75 years, the MST was 10.3 months and the 2-year survival rate was 11.3%. Grade III and IV leucopenia occurred in 36% and 14% of patients, respectively, and grade III and IV thrombocytopenia occurred in 39% and 14% of the patients, respectively. Grade III/IV anemia occurred in 50% of patients. Nonhematologic toxicity was rare. What these three prospective studies showed is that well-tailored treatment approaches, carefully balanced between administering the ‘‘optimal’’ TRT/CHT

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doses that elderly patients can tolerate and avoiding unnecessary toxicity, may lead to high treatment success and a toxicity profile not very different from that usually observed in younger patients. Retrospective studies also showed a similar outcome of elderly and nonelderly patients with LD SCLC despite elderly patients frequently receiving less intensive CHT or TRT. Furthermore, despite less compliance in elderly patients, no difference in either response rates or survival was detected between them and their nonelderly counterparts [5,6,9,16,17]. Although the reason for this phenomenon is still unclear, a possible explanation may lie in the different metabolism of drugs that may lead to a need for lower doses of various drugs in elderly patients [11,18,19]; different biologic behavior of tumors in the elderly is not very likely the cause [15]. As Yuen et al [9] pointed out, there may be a threshold above which a significant benefit can be realized. The modest dose reductions still may result in the delivery of ‘‘adequate’’ treatment to achieve a positive effect. This threshold will be hard to document/specify, but it seems that studies of Jeremic et al [13] and Murray et al [14] support this idea: although CHT was limited to only two cycles given concurrently with TRT, results were obtained that were not substantially inferior to those obtained with more intensive approaches. Every caution should be suggested in this patient population, however, particularly regarding hematologic toxicity.

Extensive-disease small cell lung cancer Standard treatment for patients with extensive-disease (ED) SCLC is CHT. The addition of TRT did not improve survival in the past, and TRT was applied only for palliation of local symptoms when CHT alone was not efficient [20]. A recent prospective randomized trial by Jeremic et al [21], however, showed an advantage of three cycles of platinum-E (PE) CHT followed by accelerated hyperfractionated TRT given concurrently with low-dose, daily CpE over CHT with PE (five cycles) alone. During this study, Jeremic et al [21] observed a survival advantage for patients >60 years old, a finding confirmed by the multivariate analysis identifying age as an independent prognosticator of survival in patients with ED SCLC (B. Jeremic et al, unpublished data, 1999). Multiagent CHT is more efficient than single-agent CHT. There are several active regimens in this disease such as PE, CpE, CAV alternating with CAV/PE, CAE, or PVAE . PE is the currently the most widely used schedule, but P is frequently substituted by the less toxic Cp. The duration of CHT administration is usually limited to six cycles. Dose intensifications [22,23] or maintenance therapy [24] proved to be of no additional benefit. It must be clearly emphasized, however, that elderly patients are usually under-represented in clinical trials and it is unknown whether the data from current practice (usually based on results from phase II and III trials) can also serve as guidelines for elderly patients. In the study by Tebbutt et al [16] in 81 patients with ED SCLC (<70 years, n = 55; 70 years, n = 26), elderly patients had similar baseline parameters and

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were mostly treated with combination CHT. Despite these patients having dose reductions more often than younger patients, no significant difference in response rates and or survival was observed. Shepherd et al [25] treated 123 patients >70 years with LD and ED SCLC with CAV or PE. There were 74 patients between 70 and 74 years old, 35 patients between 75 and 80 years old, and 14 patients 80 years or older, with no difference in baseline patient characteristics including pre-existing comorbidity. The MST for ED SCLC was 5.2 months, with no influence of age (P = 0.4). Survival strongly correlated with the treatment received. Survival of patients who received CHT was significantly longer than that of untreated patients, even though frequent dose reductions for toxicity were required. Nou [7] reported on 171 patients with LD SCLC and 174 patients with ED SCLC treated with CHT using four-drug combinations, including C, A, V, methotrexate, lomustine, and E plus RT (40 Gy; given to 15% of the ED patients). Although a multivariate analysis showed a correlation between extent of disease and survival, the association between age and survival was less pronounced. There was, however, more toxicity in patients 70 to 75 years of age, including more lethal septic events in ED SCLC. In the study by Kelly et al [17] on 48 elderly (>65 years) and 70 nonelderly patients (65 years) with SCLC, 34 elderly and 62 nonelderly patients received CHT. The overall probability of survival with combination CHT was similar for both age groups (P = 0.374), leading the investigators to conclude that decisions about CHT in elderly patients with SCLC should be based on performance status, extent of disease, and clinical condition rather than age. Some studies that have investigated the impact of age on treatment outcome have mostly included patients with good performance status, such as the study by Raghavan et al [26]. This study assessed the efficacy and toxicity of two regimens based on CpE with or without CV in the management of patients with SCLC of whom 11 had ED SCLC. The two- and four-drug regimen yielded response rates of 58% and 79%, respectively. There was no significant difference in nonhematologic toxicity, response rate, or overall survival between the older and younger group, although severe hematologic toxicity was more frequent in the elderly patients. Ohnoshi et al [27] analyzed 218 patients, among whom were 101 patients 66 years and 117 patients <66 years. The CR rate was similar in elderly (33%) and nonelderly (23%) patients. Although survival also was similar between the two age groups, an improvement in survival was observed with the higher dose intensity in the elderly group. Although a significantly higher incidence of neutropenic fever was noted in the elderly group, nonhematologic toxicity was comparable for the two groups. Taken together, these retrospective data demonstrate that patients should not be excluded from standard treatments on the basis of age alone. It seems that elderly patients with ED SCLC may benefit from standard CHT regimens, providing that pre-existing comorbidities do not prohibit such treatment [4,28]. Although these data suggest that age itself should not prohibit the use of the standard multiagent CHT regimen in ED SCLC when a careful selection of patients is made, a substantial number of patients with severe comorbidities and

Table 2 Selected (20 patients) phase II studies of chemotherapy in extensive-disease small cell lung cancer in the elderly Year

Age

N

Regimen

Smit et al [31]

1989

>70

22

Westeel [40]

1998

>65

41

Matsui et al [15]

1998

>70

22

Okamoto et al [37]

1999

70

20

E: 800 mg/m2 over 5 consecutive d, every 4 wk P: 30 mg/m2, A: 40 mg/m2, V: 1 mg/m2 d 1; E: 100 mg/m2 d 1/3/5, every 3 wk/4 cycles; selected ED: TI E: (760 mg/m2 over 14 consecutive d), cP d 1 (Egorin’s carboplatin dosing formula – 20%) cP AUC of 5  (24-h creatinine clearance + 25), d 1, and E 100 mg/m2, d 1 – 3

Allan et al [38]

1984

>65

30

Byrne and Carney [34] Evans et al [35]

1994

>70

70

1995

>65

36

Quoix et al [29]

1992

>70

22

Vnd 3 mg/m2 d 1 + E 120 mg/m2 d 1, every 3 wk up to 6 cycles cP 300 mg/m2 d and oral E d 1 – 5 200 mg/d in a 4-wk schedule Oral E 700 mg/m2 over 7 d + cP 150 mg/m2 d 1, every 3 – 4 wk for 6 cycles epi 110 mg/m2 every 3 wk

MST (mo)

RR(%)

Toxicity

9

63

10.8

87

8.6

71

10.1

85

9

66

8

60

10.8

67

‘‘Mild’’ hematoxicity, alopecia; no treatmentrelated deaths Grade III/IV nausea: 9%; 15% treatmentassociated hospitalization; neutropenic fever 6% (all CHT-only group) Grade III+IV neutropenia: 53%; grade III+IV thrombocytopenia: 53%; grade III+IV anemia: 50%, other infrequent Grade III/IV leukopenia: 57%/3%; grade III/IV thrombocytopenia: 40%/11%; other toxicities mild; one treatment-related death due to hemoptysis Mild reversible neurotoxicity, two neutropenic deaths in patients with bone marrow involvement Neutropenia as the dose-imiting toxicity; other toxicities mild Grade III+IV neutropenia: 84%; grade III+IV thrombocytopenia: 21%; grade III+IV anemia: other infrequent Grade III+IV neutropenia: 50%; grade III+IV thrombocytopenia: 8%; grade III+IV anemia: 3%; grade 2 cardiac toxicity: 10%

6.05a

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Author [ref.]

Abbreviations: A, doxorubicin; AVC, area under the curve; cP, carboplatin; E, etoposide; ED, extended disease; epi, epirubicine; LD, limited disease; MST, Median survival time; P, cisplatin; RR, response rate; TI, thoracic irradiation; V, vincristine; Vnd, Vindesine. a Includes 18 patients with LD. 439

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poor performance status are not suitable for such treatment [25]. Therefore, less toxic but still active regimens are needed. Several single agents and combination regimens have been evaluated in that respect (Table 2). Single-agent epirubicin was administered in elderly or unfit patients with SCLC in the study by Quoix et al [29]. The main toxicity was leucopenia and, less frequently, thrombocytopenia and anemia accompanied by three toxic deaths (7.3%) due to infections occurring during leucopenia. Nonhematologic side effects were alopecia, nausea, stomatitis, and diarrhea. With known activity against SCLC, a defined toxicity profile, and the availability of an oral form, E seems a suitable candidate for patients with ED SCLC and contraindications to platinum-based combination regimens. In a phase II trial by Carney et al [30], oral E was given to 53 patients 70 years of age with SCLC to achieve an overall response rate in ED SCLC of 65%. Alopecia developed in all patients, whereas significant neutropenia (8%) and thrombocytopenia (6%) were rare. No treatment-related deaths or hospital admissions were observed. Smith et al [31] reported on a similar study in 35 patients >70 years with SCLC treated at presentation with the same treatment schedule. The MST for patients with ED SCLC was 9 months, accompanied by moderate hematologic toxicity. Although phase II data have shown the feasibility of single-agent E, combination regimens appear superior, even in patients with poor performance status. The Medical Research Council Lung Cancer Working Party in Great Britain compared four cycles of oral E (50 mg twice daily for 10 days; N = 171) with EV or CAV (N = 168) [32]. Fifty-eight percent of patients in the oral E arm and 55% in the control arm had ED SCLC. The trial was prematurely stopped because of the inferior response rate (51% versus 45%) and overall survival (hazard ratio, 1.35; P = 0.03) of the oral E group, although the palliative effects of treatment were similar in the E and control groups (41% versus 46%) and grade 2 hematologic toxicity was similar (29% in the E arm versus 21% in the control arms). The MST was 130 days in the E group and 183 days in the controls; survival rates were 11% and 13% at 12 months, respectively. No information for ED SCLC or for the elderly subgroup, however, is provided in that study. Souhami et al [33] reported similar results after comparing oral E (100 mg given twice daily for 5 days) with alternating cycles of PE and CAV in patients with mostly ED SCLC (90%). An inferior 1-year survival rate in the oral E group compared with the intravenous combination therapy and a trend toward an inferior overall survival was observed in an interim analysis. The MST was 4.8 months for oral treatment and 5.9 months for intravenous therapy. Progression-free survival was also worse in the oral E arm (median, 3.6 months versus 5.6 months; P<0.001), as was the overall response rate (32.9% versus 46.3%; P<0.01). Palliation of symptoms and quality of life were either the same or worse in the oral E group, which led investigators to prematurely close this trial also. In the study by Byrne and Carney [34], CpE (Cp, 300 mg/m2/day, and oral E, 200 mg/day, days 1 – 5) was administered every 4 weeks in 70 elderly patients with ED SCLC or poor performance status. Similar response rates as obtained in their previous phase II trail with E alone were reported. Evans et al [35] used a

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similar schedule with lower doses of CpE in 47 elderly or medically unfit patients with SCLC. Although the treatment was well tolerated, neutropenia was the doselimiting toxicity, and 4 patients (8.5%) presented with sepsis. Matsui et al [15] also reported on similar results with a modified CpE combination in 38 elderly patients with SCLC of whom 22 had ED SCLC. Grade IV thrombocytopenia was observed in 10% of patients, grade IV leucopenia in 9%, and there were two toxic deaths. Attempts to tailor the dose according to the renal function were made in the study by Larive et al [36] who reported on 59% grade III to IV hematologic toxicity, with toxic deaths in 9% of all elderly patients with ED SCLC treated with CpE. The study by Okamoto et al [37] attempted to determine the toxicity and efficacy of Cp based on Calvert’s formula plus the standard dose of intravenous E for elderly patients (70 years of age) with SCLC. Only one toxic death was observed, with a response rate of 75%. E has also been combined with another vinca alkaloid, vindesine, in the study by Allen et al [38] in which 43 previously untreated patients had poor-prognosis SCLC or were >65 years old. The time to relapse was short in responders (4– 4.5 months), and most responders required additional treatment. The overall toxicity was minimal, although two deaths occurred during pronounced neutropenia. In contrast to these somewhat poorer results, a randomized trial with 310 patients demonstrated the equivalence of E/vindesine to a more aggressive regimen including E, C, methotrexate, and V in the treatment of patients with either LD SCLC with poor performance status (N = 89) or ED SCLC (N = 221); 48% of these patients were <65 and 52% between 65 and 80 years [39]. Although the palliative effect was high and similar in the two treatment groups, the E/vindesine regimen caused less toxicity. There was no difference in overall response or survival for the two- and four-drug regimens (MST, 131 versus 141 days; 1-year survival, 10% versus 12%). It is unfortunate that no further information regarding age was provided to give better insight into the influence of age in this setting. Additional evidence comes from a recent phase II study reporting on 66 patients >65 years of whom 41 were ED SCLC [40]. The regimen consisted of P, 30 mg/m2, intravenously (IV) day 1; A, 40 mg/m2, IV day 1; V, 1.0 mg/m2, IV day 1; and E, 100 mg/m2, IV day 1 and orally days 3 and 5; repeated every 3 weeks for four cycles. Selected patients with ED SCLC received RT delivered concurrently with PE at the time of the second CHT cycle. For ED SCLC, MST was 46 weeks and the 5-year survival rate was 5%. One treatment-related death occurred, but severe toxicity was infrequent. The treatment outcome achieved in this phase II study compares favorably with results of standard regimens in this patient population and in those with more favorable characteristics, speculating on its verification in selected patients in a randomized fashion.

Summary For fit LD SCLC patients, standard combination regimens of RT and four cycles of CHT should be recommended. In cases of infirm patients, abbreviated regimens

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should be encouraged. Otherwise, single- or multiagent CHT should be attempted, taking into account toxicity profiles of prospective drugs/regimens. In ED SCLC, combination CHT is preferred but its effectiveness and toxicity depends on the choice of drugs. RT can be attempted in the best prognostic subgroup. In a palliative setting, single- or two-drug regimens are preferred, as in LD SCLC.

References [1] Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for smallcell lung cancer. N Engl J Med 1992;327:1618 – 24. [2] Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10:890 – 5. [3] Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476 – 84. [4] Findlay MP, Griffin AM, Raghavan D, et al. Retrospective review of chemotherapy for small cell lung cancer in the elderly: does the end justify the means? Eur J Cancer 1991;27: 1597 – 601. [5] Siu L, Shepherd FA, Murray N, et al. Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 1996;14:821 – 8. [6] Dajczman E, Fu LY, Small D, et al. Treatment of small cell lung carcinoma in the elderly. Cancer 1996;77:2032 – 8. [7] Nou E. Full chemotherapy in elderly patients with small cell bronchial carcinoma. Acta Oncol 1996;35:399 – 406. [8] Jara C, Gomez-Aldaravi JL, Tirado R, et al. Small-cell lung cancer in the elderly—is age of patient a relevant factor? Acta Oncol 1999;38:781 – 6. [9] Yuen AR, Zou G, Turrisi AT, et al. 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 2000;89:1953 – 60. [10] Ludbrok JJS, Truong PT, MacNeil MV, et al. 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 2003;55:1321 – 30. [11] Joss RA, Bacchi M, Hurny C, et al. Early versus late alternating chemotherapy in small-cell lung cancer. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 1995;6:157 – 66. [12] Jeremic B, Shibamoto Y, Acimovic L, et al. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997;15:893 – 900. [13] Jeremic B, Shibamoto Y, Acimovic L, et al. Carboplatin, etoposide, and accelerated hyperfractionated radiotherapy for elderly patients with limited small cell lung carcinoma: a phase II study. Cancer 1998;82:836 – 41. [14] Murray N, Grafton C, Shah A, et al. Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 1998;16:3323 – 8. [15] Matsui K, Masuda N, Fukuoka M, et al. Phase II trial of carboplatin plus oral etoposide for elderly patients with small-cell lung cancer. Br J Cancer 1998;77:1961 – 5. [16] Tebbutt NC, Snyder RD, Burns WI. An analysis of the outcomes of treatment of small cell lung cancer in the elderly. Aust N Z J Med 1997;27:160 – 4. [17] Kelly P, O’Brien AA, Daly P, et al. Small-cell lung cancer in elderly patients: the case for chemotherapy. Age Ageing 1991;20:19 – 22. [18] McKenna Sr RJ. Clinical aspects of cancer in the elderly. Treatment decisions, treatment choices, and follow-up. Cancer 1994;74:2107 – 17.

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[19] Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med 1989;321:303 – 9. [20] Livingston RB, Mira JG, Chen TT, et al. Combined modality treatment of extensive small cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1984;2:585 – 90. [21] Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17:2092 – 9. [22] Murray N. Importance of dose and dose intensity in the treatment of small-cell lung cancer. Cancer Chemother Pharmacol 1997;40:S58 – 63. [23] Murray N, Livingston RB, Shepherd FA, et al. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an intergroup study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999;17:2300 – 8. [24] Beith JM, Clarke SJ, Woods RL, et al. Long-term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung. Eur J Cancer 1996;32A:438 – 43. [25] Shepherd FA, Amdemichael E, Evans WK, et al. Treatment of small cell lung cancer in the elderly. J Am Geriatr Soc 1994;42:64 – 70. [26] Raghavan D, Bishop JF, Stuart-Harris R, et al. Carboplatin-containing regimens for small cell lung cancer: implications for management in the elderly. Semin Oncol 1992;19:12 – 6. [27] Ohnoshi T, Ueoka H, Hino N, et al. Treatment of small cell lung cancer in the elderly: the progress and limitation of chemotherapy. Nihon Kyobu Shikkan Gakkai Zasshi 1992;30: 216 – 23. [28] Bishop JF. Carboplatin/etoposide in small cell lung cancer. Oncology 1992;49:111 – 7. [29] Quoix EA, Giaccone G, Jassem J, et al. Epirubicin in previously untreated patients with small cell lung cancer: a phase II study by the EORTC Lung Cancer Cooperative Group. Eur J Cancer 1992;28A:1667 – 70. [30] Carney DN, Grogan L, Smit EF, et al. Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 1990;17:49 – 53. [31] Smit EF, Carney DN, Harford P, et al. A phase II study of oral etoposide in elderly patients with small cell lung cancer. Thorax 1989;44:631 – 3. [32] Medical Research Council Lung Cancer Working Party. Comparison of oral etoposide and standard intravenous multi-drug chemotherapy for small-cell lung cancer: a stopped multicentre trial. Lancet 1996;348:563 – 6. [33] Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced smallcell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577 – 80. [34] Byrne A, Carney DN. Small cell lung cancer in the elderly. Semin Oncol 1994;21:43 – 8. [35] Evans WK, Radwi A, Tomiak E, et al. Oral etoposide and carboplatin. Effective therapy for elderly patients with small cell lung cancer. Am J Clin Oncol 1995;18:149 – 55. [36] Larive S, Bombaron P, Riou R, et al. Carboplatin-etoposide combination in small cell lung cancer patients older than 70 years: a phase II trial. Lung Cancer 2002;35:1 – 7. [37] Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol 1999;17:3540 – 5. [38] Allen SG, Gregor A, Cornbleet MA, et al. Phase II trial of vindesine and VP16 – 213 in the palliation of poor-prognosis patients and elderly patients with small cell lung cancer. Cancer Chemother Pharmacol 1984;13:106 – 8. [39] Medical Research Council Lung Cancer Working Party. Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Br J Cancer 1996;73:406 – 13. [40] Westeel V. New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 1998;16:1940 – 7.