Chemotherapy in small cell lung cancer

Chemotherapy is the keystone in the treatment of small cell lung cancer (SCLC). Objective remission and good palliation is achieved in ∼80% of the patients, but the remissions are in general short (mean <1 yr), and few are cured. As an example, 5- and 10-yr survival rates, in 1,714 SCLC patients treated in trials in Copenhagen during 1973–1987, were only 3.5 and 1.8%, respectively 1. Only 184 (11%) of these patients received chest irradiation. In those days the role of radiotherapy was still an issue of debate, but two meta-analyses, published in 1992 2, ended the discussion. Search for an optimal schedule and timing of the radiotherapy has prompted several randomized trials and the sum of the data from these trials suggests that radiotherapy should be given early, concurrently and twice daily 3. Irradiation of the adrenals has never proved worthwhile 4 while prophylactic cranial irradiation (PCI) in complete remission patients has a significant positive impact on the prognosis, proven in a meta-analysis 5. Trials aiming to find the optimal dose and indications for PCI are under way.

Sixty to 65% of patients with SCLC have extensive disease at the time of diagnosis. Spread of disease prevents appropriate limits for a chest radiation field, and the prognosis is significantly reduced. Many efforts have been undertaken to improve treatment outcome in extensive stage disease, especially trials on high dose or dose-accelerated regimes, but the outcome has been disappointing. High-dose chemotherapy plus haematological stem-cell support has found a place in haematology, such as in the treatment of recurrent lymphomas, and the strategy has also been investigated as a first-line treatment for good-prognosis patients with SCLC, mostly in phase II trials. High complete response rates are obtained, but there is considerable toxicity and the long-term survival rates are not improved.

Twenty-five per cent of patients with SCLC are aged >74 yrs and most of these patients may not tolerate combination chemotherapy. But elderly people are less fatalistic today, they expect treatment for conditions such as cancer, and although there have been some trials on older patients during the last 10–15 yrs, the treatment options are limited.

The fact that age has not proved to be an important prognostic factor in a large series 6 suggests that treatment for cure may be a reasonable policy in some elderly patients. The prognosis in SCLC is influenced by stage of disease plus other clinical characteristics such as performance status (PS) and plasma lactate dehydrogenase (LDH), followed by plasma sodium, anaemia, plasma albumin, alkaline phosphatase, and bicarbonate 6–9. Prognostic factors, especially PS and LDH, are important as in- and exclusion criteria in treatment trials, as stratification or balancing variables in randomized trials, and as potential end point confounders. In that context further standardization is warranted, a task which has recently been undertaken by a staging committee under the International Association for the Study of Lung Cancer (IASLC).

Surgery is seldom possible in SCLC 10 and explorative thoracotomies are rare today due to routine use of percutaneous lung biopsies and modern imaging techniques to guide invasive procedures if necessary. In addition mediastinoscopy has had a renaissance in the staging of lung cancer 11. More than 85% of SCLC patients have mediastinal lymph-node metastases 12 and in a time when better local control of the tumour seems possible, due to improved radiotherapy most will agree that surgery has had its role in the treatment of SCLC.

A number of new cytotoxic drugs have been investigated in the last decade including an antimetabolite (gemcitabine), taxanes and topoisomerase I inhibitors. Although the trials have resulted in reasonable developments, a complete understanding of the best way to use these agents is needed.

Treatment strategies in small cell lung cancer

Clinical research in to the treatment of SCLC is not driven by the same optimism as it was 20-yrs-ago but trials on new agents and new biological principles in conjunction with the classical regimes are always under way. With trials carried out by laboratories, who never lose interest, or initiated by drug companies, often in an international set up. Local trials on feasibility and practical, clinical characteristics of treatment regimes for SCLC also occur, often in certain categories such as elderly or poor-risk patients. Survival is still the major end point in trials on SCLC but outcome variables also include measures of palliation, reduced toxicity, days of hospitalization and cost-efficacy ratio. New strategies, based on a fast developing, molecular biological understanding of cancer, will certainly get an increasing impact on the clinical drive for a better treatment. Biological strategies have been tested in clinical practice since the introduction of chemotherapy three-decades ago. The classical example is the Goldie-Coldman hypothesis 13 from which a computer growth simulation model showed that alternating chemotherapy with noncrossresistant regimes would increase the chances of a successful outcome. The principle, however, turned out to have only a restricted impact in SCLC, detectable in extensive but not in limited stage disease 14–16.

Intensive and high-dose chemotherapy has found a place in the treatment of haematological neoplasms and achievements from this field plus development of the blood stem-cell rescue technology have stimulated trials on this strategy in solid tumours, including SCLC. Whether or not high-dose chemotherapy has a role in the treatment of SCLC is still an open question.

Radiotherapy is now a standard in the treatment of limited stage SCLC. Current investigations focus on the timing, fractionation and interaction with concurrent chemotherapy. PCI reduces the risk of brain metastases 17. The efficacy seems to be dose dependant and the balance point between maximal effect and minimal-late toxicity has to be found.

New cytotoxic drugs are steadily being investigated in various combination regimens, often in trials organized by the manufacturing drug company. The steering of this process is a big challenge to all clinical oncologists. Similar conditions are typical for clinical investigations on biological processes activated by the cancer to enable invasion, nourishment and spread, which include proteolysis, angiogenesis and interaction with the immune system.

Treatment of limited disease

Evidence for the usefulness of chest irradiation in limited-stage SCLC was established in two meta-analyses published in 1992 2, 18. The body of data for the two investigations was essentially the same, i.e. outcome of randomized trials from the period 1975–1989 including a total of some 2000 patients. One group retrieved the raw data 2 while the other skimmed the publications. The outcomes, however, were much alike, both proving a significant improvement in survival. As an example, the 3-yr survival rates in Pignon's study were 14.3% in 1,111 patients assigned to combined modality therapy compared to 8.9% in 992 patients treated with chemotherapy alone. The 3-yr survival rates in recent trials are ∼20% and rates >30% are reported. Several factors may contribute to higher rates. 1) Stage migration as a result of new imaging technologies in staging of lung cancer such as spiral computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scanners. 2) Chemotherapy in recent trials is based on the combination of cisplatin+etoposide (PE), which is more efficacious than some of the odd combinations used in the 1970–1980s 19 and less toxic than regimes including doxorubicine when delivered concurrently with the irradiation. 3) Most trials today include prophylactic brain irradiation to complete responders. 4) Timing, dosage, fractionation and computer-assisted CT based simulation of the chest irradiation may each contribute to the better long-term survival rates seen today.

Timing, dosage and fractionation of the chest irradiation are not new issues in SCLC. Early trials, however, were in general unable to give clear answers. The advantages anticipated were too optimistic so the trials were underdimensioned. Even the meta-analysis 2 was unable to prove significant differences in survival related to early versus late radiotherapy or to sequential versus nonsequential regimes.

Establishment of nationwide or international joint trials is the key to the recruitment of enough patients. The Canadian Lung Cancer Group is an example to follow and one of the questions investigated by the Canadian group is the role of timing of the chest irradiation in relation to the course of chemotherapy of limited-stage SCLC 20. A total of 308 patients were randomized to early (week 3) or late (week 15) irradiation concurrent with PE. The two agents were alternated with cyclophosphamide, doxorubicine and vincristine (CAV) for a total of six cycles of chemotherapy. The dose of radiotherapy was 40 Gy in 15 fractions over 3 weeks. Both progression-free and overall survival were significantly superior in the early radiotherapy arm. Thus, overall survival after 2 yrs was 40% versus 34% (tables 1⇓ and 2⇓), and after 3 yrs 30% versus 22%. The cumulative proportions of local recurrence did not differ, however, exceeding 50% in both arms. In a Danish trial 21 199 patients were randomized to early (weeks 1, 2, 4 and 5) or late (weeks 19, 20, 24, 25) radiotherapy. A course of PE was given in week 3 and week 22, respectively and altogether the chemotherapy comprised 3 cycles PE+6 cycles CAV. The first cycle of chemotherapy was delayed for 2 weeks in the “early” arm. There was no difference in survival between the arms. The 2-yr survival rates were 20 and 19%, respectively.

The Danish trial delayed chemotherapy in the “early” arm to avoid concurrent treatment. PE can, however, safely be given concurrently with radiotherapy, in contrast to the anthracyclines, which significantly increases the normal tissue radiotoxicity. This problem was clearly revealed in a North American multicentre trial 24 randomizing 386 patients to receive six-series CAV, given on day 1, every 3 weeks with or without concurrent chest irradiation: 30 Gy in 10 fractions weeks 1 and 2, plus 15 Gy in five fractions in week 7. Irradiation plus CAV increased the treatment toxicity, especially the haematological: 60% of the patients had grade 4 neutropenia compared to 39% in the other arm. There were six treatment-related deaths compared to three in the chemotherapy-alone arm. Only 57% of the patients received at least 80% of the intended dosage of the two myelotoxic agents (C and A) compared to 79% of the patients in the chemotherapy-alone arm. There was no significant difference in overall survival between the two arms but 2-yr survival in irradiated patients was 33% compared to 24% in nonirradiated patients.

The question of early versus late and of alternating versus sequential chest irradiation was addressed in a European multicentre trial (EORTC) randomizing 335 patients to early alternating or late sequential thoracic irradiation. The chemotherapy: five courses cyclophosphamide, doxorubicine, and etoposide (CAE) was not given concurrently. In the early arm, 50 Gy was given in weeks 6, 10, 14 and 18 alternating with CAE while patients in the late arm received 50 Gy at weeks 14–17, i.e. sequentially given between two courses of CAE. The dosage of chemotherapy was the same in the two arms, and >95% of the scheduled doses could be given in both, but with a cyclus time of 3 weeks in the sequential arm, and 4 weeks in the alternating arm, the dose rate (mg·m⁻²·week⁻¹) differed with as much as 31%. The relative risk of death was in favour of patients treated with the sequential regime (0.88) but the difference was not statistically significant. Grade 4 leukopenia occurred in 72% of patients in the alternating arm compared to 42% in the sequential arm.

Hyperfractionation may increase the efficacy of radiotherapy in SCLC. The theory is based on in vitro irradiation of SCLC cells, which do not exhibit the characteristic shoulder phenomenon reflecting repair of sublethal damage. Twice-daily radiotherapy (TDR) in weeks 2, 5 and 8 alternating with chemotherapy (PE) was investigated in an early pilot study 23 but the outcome did not differ remarkably from usual-treatment outcome at that centre neither in efficacy or toxicity. But a much larger, randomized intergroup trial 3 resulted in significantly higher survival rates in the TDR arm compared to the once-daily radiotherapy (ODR) arm. Chemotherapy: four series PE was given concurrently in both arms. The total dose of radiotherapy was 45 Gy in both regimes (tables 3 and 4⇓⇓). Kaplan-Meier curves of overall survival were superimposable the first year but then began to deviate, resulting in differences of 47% versus 41% after 2 yrs and 26% versus 16% after 5 yrs. The toxicity was similar in the two arms: grade 4 granulocytopenia in 60% and 59% of the patients, respectively, and grade 4 thrombocytopenia in 8% in both arms. Grade 3 oesophagitis was seen in 27 and 11%, respectively, reflecting that 45 Gy in TDR versus ODR are not biologically equivalent regimes. For comparison, in a trial 24 of CAV plus concurrent irradiation, 30 Gy in 10 fractions, the haematological toxicity was similar and grade 3 oesophagitis occurred in 13%, but rates of long-term survival were considerably lower.

The oesophageal mucosa is early reacting normal tissue and acute oesophagitis (≥grade 4) is a major clinical problem when chemo- and radiotherapy are given concurrently. The dose-limiting toxicity of TDR concurrent with cisplatin, cyclophosphamide and etoposide in conventional doses was investigated by Choi et al. 29 in a phase I study. The maximum-tolerated dose (MTD) of TDR was 45 Gy in 30 fractions over 3 weeks compared to at least 70 Gy in 35 fractions over 7 weeks for daily radiotherapy. Doses above this MTD seem to be applicable, however, if chemotherapy doses are reduced.

Other policies of TDR: early versus late and early concurrent versus late sequential, were investigated in two randomized trials, a Yugoslavian-Japanese 25 and a Japanese 28, respectively. In the first trial 54 Gy TDR in 36 fractions was given early: week 1–4; or late: week 6–9, concurrently with carboplatin (30 mg·day⁻¹) plus etoposide (30 mg·day⁻¹). Grade 3–4 acute oesophagitis was observed in 29% of 52 patients and in 25% of 51 patients, respectively. Subsequently, the patients received four-series PE in conventional doses. Median survival was >2 yrs in both arms, and the 5-yr survival rates were 30 and 15%, respectively, favouring the early radiotherapy regime. The other trial 28 included 231 patients between 1991–1995. Patients in both arms received TDR 45 Gy in 3 weeks, initiated on day 2, concurrent with PE in arm C and after four-series PE in the sequential arm S. A total of four-series PE was given, every 4 weeks in arm C but three-weekly in arm S. Dosage was the same. Median survival was 27 and 20 months, respectively, and 5-yr survival rates were 24 and 18% (p=0.057). Myelotoxicity was more severe in arm C but the nonhaematological toxicity, including oesophagitis, was not significantly different between the two arms. In contrast to these promising data experience in a French trial 27 on TDR was more sinister. The 27 patients received 45 Gy in 30 fractions concurrently with the second of six series PE (tables 3 and 4⇑⇑). The 2-yr survival rate was only 25% and the toxicity was problematic. Thus, 18 patients (67%) had grade 3–4 neutropenia, and two died whilst febrile and neutropenic and grade 3–4 oesophagitis was observed in 50% of the patients.

In a North-American randomized trial 26 TDR was given in split-course: 16 fractions on days 1–10 plus 16 fractions on day 29–38 to a total of 48 Gy was not superior to once-daily irradiation of 50.4 Gy in 28 fractions over 6 weeks. The 2- and 3-yr survival rates were 47 and 34% for patients in the ODR arm and 45 and 29% for patients in the TDR arm (p=0.44). The toxicity level was acceptable and similar in the two arms except that there were significantly more patients with oesophagitis in the twice-daily arm: 12 versus 5%.

It may be concluded that TDR plus concurrent chemotherapy seems to be the best treatment for limited-stage SCLC leading to 5-yr survival in one-quarter of the patients. The regimen is, however, quite toxic for some patients. Optional patients are patients in the good-risk group characterized by a median survival of 20 months and a 2-yr survival rate of 40%. Staging procedures and other inclusion criteria applied in North American trials seem more appropriate for selection of this patient category than those used in European trials. And selection is important in order to reduce overtreatment and toxic complications in patients who, it must be anticipated, basically have poor chances of long-term survival. Still, the strategy of early radiotherapy in a twice-daily fractionation, concurrent with PE, needs further documentation in confirmatory trials. At the same time clinical investigations are needed to find a good treatment for limited-stage patients in whom the concurrent chemo- plus TDR is too toxic. Seen in a broader clinical perspective that is also a challenge.

Prophylactic cranial irradiation

Brain metastases presenting at time of diagnosis can be brought into remission with systemic chemotherapy 30 but systemic chemotherapy cannot prevent occurrence of brain metastases. About 20–30% of the patients develop brain metastases during therapy 31. Patients in complete remission at conclusion of chemotherapy, proved with restaging procedures including a brain CT scan, have a cumulative risk of 50–60% of developing brain metastases over the subsequent 2 yrs. Survival after occurrence of brain metastases is short: median 3–6 months, although long-term survival can be seen in patients, who remain in systemic remission 32. The rate of brain metastases occurring in complete responders after conclusion of chemotherapy can be reduced significantly if cranial irradiation: 24–36 Gy is given prophylacticly 17, 22, 33 but an observed positive impact on overall survival was not statistically significant in these trials. This problem was solved with a meta-analysis published in 1999 5. Survival and relapse data on 987 patients from seven randomized trials were analysed. A total of 526 patients had PCI while 461 were controls. All were in complete remission at time of randomization. A minority of 140 patients (14%) had extensive disease when the systemic chemotherapy was initiated. The cumulative incidence of brain metastases 3-yrs after randomization was 33% in the PCI group compared to 59% in the control group. The risk of death was reduced 16% (p<0.01) in the PCI group corresponding to an increase in the 3-yr survival rate from 15.3 to 20.7%. The survival benefit appeared after 1 yr and the difference between the Kaplan-Meier curves persisted beyond 6 yrs. An editorial in the same issue of the New England Journal of Medicine concluded that “it is now resonable to include prophylactic irradiation as part of the treatment in patients with limited small-cell lung cancer … and of patients with extensive disease who have isolated metastases and are in complete remission” 34. The patient's age had no influence on the outcome. An irradiation dose of 30–40 Gy led to a significant lower risk of brain metastases compared to 24–25 Gy but the difference in overall survival (death hazard 0.81 versus 0.88) was not significant. A European multicentre randomized trial has now been initiated to investigate if 30–40 Gy is better than the lower dose. With a statistical power of 75% and α=0.05 a total of 374 patients must be included in each arm. The outcomes of the meta-analysis have been reproduced in two new meta-analyses 35, 36. Meert et al. 35 were concerned about the paucity of data on possible late neurological impairment following PCI. Currently, the worried patient can be reassured that late toxicity after PCI, such as impairment of cognitive function, is less frequent than suggested after observations made with an early generation CT scanner 37. Three investigations 17, 22, 38 found few additional patients with abnormal neurological or neuropsychological findings as well as CT-scan changes 2 yrs after PCI compared to baseline examinations performed after chemotherapy and before randomization to PCI. At baseline, however, impairments of cognitive functions could be detected in up to 50% of the patients while only a few had CT abnormalities, e.g. 17% of 183 patients in the French study 17. New CT abnormalities occurred in 10% of the patients after PCI versus 3% in the control group (p=0.6). For the individual patient, of course, loss of function may be a great problem, and possible risk factors should therefore be clarified, such as age and previous vascular incidents. PCI should not be given concurrently with the systemic chemotherapy.

Extensive disease

Treatment outcome in extensive-stage SCLC is a sinister story. Various strategies have been investigated but progress has been minimal. With the introduction of etoposide and cisplatin in the late 1970s a new, active combination was available, partly noncross resistant to the CAV regime. A computer model by Goldie and Coldman 58 predicting superiority of alternating compared to sequential treatment with noncross resistant regimes, could thus be tested in clinical practice. The model was corroborated by a Canadian trial on 289 patients 14; while others were unable to prove statistically significant differences in survival, including a 3-armed intergroup trial on 437 patients 59. The principle does not add to either cost nor toxicity and it is still frequently applied in extensive disease.

Chute et al. 60 have made an interesting retrospective analysis of survival characteristics in extensive SCLC in North America in the last 20 yrs as reflected in data from the control arms of phase III trials and from cases registered in the Surveillance, Epidemiology, and End Results (SEER) database. Both data sources reflected an improvement in median as well as 5-yr survival when data from 1972–1981 were compared with data from 1982–1990. Median survival in trials increased from 7.0 to 8.9 months and from 6.5 to 8.2 months in the SEER database. The 5-yr survival rate rose from 0.8% to 1.6%. Least square regression analysis of data from the trials showed that treatment with cisplatin and year of study initiation were both significantly related to median survival time. The influence of “year of study initiation” could be caused by stage migration 61 but the SEER data suggested a prolongation for all SCLC patients over the period. Prolongation of survival in SCLC with time could, in addition to better combinations of cytotoxic agents, be a result of improved means of general medical management including specific supportive care.

The retrospective analysis cannot, however, point out especially beneficial treatment strategies for extensive SCLC. The clinical characteristics of these patients vary much more than in patients with limited disease; some only have a minor lesion such as a lymph node high on the neck while others have multiple metastases in several organs. Aiming to find a main thread Aisner 62 reviewed trials on extensive-stage SCLC from the 1990s. It was found that it was useful to categorize treatment strategies into one of three groups: The aggressive therapeutic approach (29 series), the intermediate regimes (10 series) and the minimal approach (for poor-prognosis and for elderly patients) (10 series). Complete remission (CR) rates were higher and median survival times longer in the aggressive category compared to those in the intermediate category, while data on other important end-points such as rates of early death and long-term survival and, not least, on quality of life (QoL) were rarely available. The “minimal” approach resulted in response and survival rates considerably below the figures in the other two groups. How were patients selected to treatment in one or the other category? Aggressive treatment is not for poor-risk patients. But what about the poor-risk patients? Is it clinically meaningful and ethically correct to operate with a minimal approach? Many in this category die early, because treatment is insufficient or because they are too sick when treatment is initiated. “An early death from progressive disease is not likely to improve QoL.” Aisner states 62, thinking of those who were undertreated, and continue “Whether the toxicity-to-benefit ratio is appropriate to an individual patient is therefore a matter to be discussed between the patient and his or her care provider.” This is a point, but Aisner 62 does not refer to a toxicity-to-benefit model which could help the patient and the caretaker with this difficult choice. Simple algorithms can be established, however, predicting risk of early death from pretreatment characteristics such as performance status, serum LDH and age 63. If performance status (PS)>1 and LDH above the upper normal limit each contribute with one risk point patients can be categorized into one of three risk groups as shown in table 8⇓. The data were retrieved from the Copenhagen database, supplemented with a European series 64 to illustrate the consistency of the “system”. With these two simple clinical attributes it is possible to allocate extensive-stage patients into risk groups with clinically important differences in survival. It is likely that 23% of the patients, who are in the best category, should receive aggressive treatment (and that some may benefit from additional chest irradiation) and that an intermediate treatment approach is optimal for group 2 patients. A meta-analysis on available trial data might answer the question. As for group 3, which includes as many as 40% of the patients, the treatment approach should probably be designed according to physical deficit: one for older patients, and others for patients with compromised lung or liver function, as for patients with a heavily infiltrated bone marrow. Some, desperately ill patients should not be treated at all. Trials aiming to find an appropriate treatment for poor-risk patients are rare.

An example is a feasibility study on per oral etoposide and cyclophosphamide in treatment of poor-prognosis extensive SCLC 65. Patients who had a low serum albumin or a poor performance status for entry in the current SWOG trial received the two agents for 14 days every 28 days, either once daily (18 patients) or twice daily (39 patients). Age of the patients ranged between 46–94 yrs, 81% had PS=2 (None had PS>2) and 35% had a serum albumin <3.5 g·dL⁻¹. Grade 3–4 neutro- and leukopenia were observed in 58 and 53% of the patients, respectively. Early death or progression was observed in 37% of the patients, objective resonse was seen in 26% and unconfirmed response in further 16%. Median failure-free survival was 3–4 months. Serum etoposide on day 2 as well as pretreatment serum LDH were predicitive for the level of granulocyte nadir. Age was not included in the regression analysis. More appropriate regimes should be possible and further trials on this poorest category of the SCLC patients should be initiated.

Aggressive treatment approach for good-risk patients (patients aged <68 yrs and with a PS of 0–2) were investigated by Murray et al. 66. The regime: CODE, included weekly cisplatin and doxorubicine plus etoposide every second week. The control regime was CAV alternating with EP, three-times each. The response rate with CODE was higher (87 versus 69%) but progression-free and overall survival were not significantly better than in the control group. Death rates from neutropenic fever were 8% in the CODE arm versus 1% in the control arm. Ten per cent in both arms were progression free at 2 yrs. Thus, this trial did not support the idea that aggressive treatment is better than a conventional regime in good risk extensive SCLC.

Elderly patients

Elderly patients are, by convention, patients aged ≥70 yrs. In the 1970s many treatment trials did not include patients >70 yrs but most recent trials include patients aged 70–80 yrs. Compared to the incidence of lung cancer in this age group, however, these patients are underrepresented. This selection reflects a common clinical sense among lung physicians rather than in- and exclusion criteria for the individual trial. Elderly patients will often have cardiovascular disease, diabetes, reduced kidney function, locomotorical handicaps etc. making intensive chemo- and radiotherapy inappropriate. Gentle regimes for elderly patients have been investigated but simple guidelines and well-documented treatment options for making an easy choice are still a distant prospect. A retrospective clinical study of Dajczman et al. 67 from Quebec, Canada, gives a good impression of the clinical dilemma. Records were reviewed on 312 patients with a pathological diagnosis of SCLC at four McGill University Hospitals from a 7-yrs period: 1985–1991. Elderly patients (≥70 yrs) comprised 26% of the series, i.e. elderly patients were under-represented as there were 40% in this age group of SCLC patients notified in the British Columbia Cancer Registry in the same period 68). Staging and treatment of the elderly patients were compared to that of patients aged 60–69 yrs and <60 yrs, respectively. The treatment was regarded to have been “suboptimal” if neither chemo- or radiotherapy had been given to a patient with a performance status of ≤3. Suboptimal treatment was recorded in 23% of patients aged ≥70 yrs, compared to 9% of patients aged 60–69 yrs and 5% of patients aged <60 yrs. In limited stage patients chemo- plus radiotherapy was given to 43%, 65% and 69% of patients in the three age groups, respectively. There was no difference in proportions of limited stage disease: 43%, 40% and 45%, but elderly patients were less aggressively investigated compared to younger patients. Only one of 81 elderly patients was enrolled in an experimental protocol compared with 19 and 28% of the younger patient groups. Limited treatment of only 1–3 cycles of chemotherapy was quite frequent in elderly patients: 45% compared to 35% and 22% in the two younger age groups. Response and survival data in the treated patients reflected these differences in treatment intensity: CR or PR were seen in 25%, 49% and 41% in the three age categories; median survival figures were: 6, 9 and 8.5 months, respectively, but the 2-yr survival rates did not differ accordingly: being 8, 13 and 8%. Optimal versus suboptimal treatment was a significant and strong prognostic factor in a Cox analysis while survival was not affected by differences in patient age. These data on treatment outcome may support the view that choice and decisions made by the individual oncologist or lung physician seem to be reasonable. The larger proportions, however, of elderly patients who had few staging examinations, did not receive “optimal” therapy, did not receive chest radiation, only received “limited” chemotherapy, leaves the impression, that treatment outcome in these, selected, elderly patients could have been even better. In other words: a more active approach and uniform handling of elderly patients, including treatment regimens especially designed for this category of patients, are warranted. Ten-years-ago single-agent regimes with etoposide per orally were investigated as candidates for treatment of elderly SCLC patients 69–73. Given intraveneously in a dosage of 100 mg·m⁻² for 5 days every 3 weeks Bork et al. 71 obtained CR or PR in 65% of the patients, the median survival was 10.6 months and 2-yr survival 8%. Per oral etoposide 200 mg·m⁻² 5 days every 3 weeks resulted in a similar response rate (62%), but both response duration and median survival were three months shorter. The 2-yr survival was 7% 73. Two trials comparing p.o. etoposide with i.v. combination chemotherapy have definitively changed the view on the p.o. etoposide regime. The British Medical Research Council conducted a trial on SCLC patients with poor performance (2–4), at any age. Median age was 67 yrs, range: 35–83 yrs. Patients were randomized to receive four-cycles of etoposide 50 mg twice daily for 10 days every 3 weeks or four cycles of a control regimen of intravenous EV or CAV. The trial was closed after inclusion of 339 patients (planned 450 patients) because of inferior results in the etoposide arm. Thus, >30% of the patients in this group died before the 3-month assessment. Median survival was 130 days compared to 183 days in patients treated with intravenous chemotherapy. The palliative effects of the treatments were similar. Same experience was obtained in a trial conducted at four London hospitals 74. Patients with extensive SCLC, performance status 0–3, were randomized to treatment with six-cycles of either p.o. etoposide 100 mg·m⁻² for 5 days every 3 weeks or i.v. PE alternating with CAV. Median age of the patients was 66 yrs (50–86 yrs) and 67 yrs (49–80 yrs), respectively. The trial was stopped after inclusion of 155 patients from a projected intake of 365 patients because of inferior survival outcome in the etoposide arm. Median progression-free survival was only 3.6 months compared to 5.6 months in the control arm, 1-yr survival figures were 9.8% and 19.3%. Although the two trials did not specifically focus on the treatment of elderly patients, the outcome does not support continued use of the regimen in this group either.

A policy of combination chemotherapy regimes specifically designed for elderly patients has been investigated by the Canadian lung cancer group in Vancouver 68, 75. In the period 1982–1991 elderly or infirm patients with limited SCLC were offered a standard treatment of one-cycle CAV followed 3 weeks later by one-cycle EP plus concurrent thoracic radiotherapy, 20 Gy in 5 fractions or 30 Gy in 10 fractions. Prophylactic cranial irradiation was not routinely administered. The series included 55 patients, 67% of the patients were aged ≥70 yrs, 55% had PS 0–1, 71% had normal S-LDH, and 60% were females. Although the patients only received two-cycles of chemotherapy and a suboptimal radiotherapy, 28% of the patients survived 2 yrs and 18% 5 yrs.

In the following period: 1991–1994 the Vancouver group replaced the two series CAV with four series PAVE (cisplatin 30 mg·m⁻² day 1, adriamycin 40 mg·m⁻² day 1, vincristine 1 mg·m⁻² day 1, etoposide 100 mg·m⁻² days 1, 3, 5) plus the same simple irradiation programme for treatment of limited disease and in selected patients with extensive disease. The chest irradiation was given concomitantly with the second cycle of chemotherapy which was then reduced to only PE. A total of 66 patients were treated: 25 patients with limited disease, with a median age of 72 yrs (66–79 yrs), and 41 patients with extensive disease, median age 69 yrs (66–81 yrs). The 2-yr survival rates for limited and extensive stage patients were 38% and 18%, respectively, and the 5-yr survival rates were 24% and 5%. Prognostic attributes such as PS, LDH and metastatic sites did not suggest that these patients were especially selected. It is difficult to explain these favourable results on the basis of the general model of SCLC as a tumour with a high incidence of clonal heterogeneity but from a practical point of view the outcome is very stimulating for further development of specific treatment regimes for elderly patients. Two to four cycles of chemotherapy seem to be appropriate and chest irradiation can be given in less fractions, suggesting, that late lung toxicity does not seem to be a major problem in these patients.

A Japanese phase II trial 76 conducted in 1995–1996, also supports the supposition that a reasonably high initial dose level is important for the outcome. Thus, 36 patients, aged 73 yrs (70–80 yrs), received up to 4 cycles of carboplatin (AUC 5) plus etoposide 100 mg·m⁻² i.v. days 1–3 every 4 weeks. The 44% of patients with limited disease had additional chest irradiation after chemotherapy. Sixty-one per cent of the patients received the scheduled 4 cycles and dose reductions were only necessary in 10% of the patients. Median survival was 10.8 months and 1 and 2-yr survival rates were 47.2% and 15.4%, respectively. Serum LDH, stage and anaemia were significant prognostic factors in a Cox analysis but age was not.

The high rates of long-term survival in these patients could hardly have been obtained without chest irradiation. A subgroup analysis in the meta analysis on thoracic radiotherapy for SCLC 2 proved no benefit of chest irradiation in patients aged ≥70 yrs, but these data derived from trials using other agents and other radiation schedules such as split course and greater doses on fewer fractions, resulting in greater toxicity than seen today. In current regimes elderly people seem to both tolerate and to benefit from chest irradiation. As an example, the intergroup trial comparing twice-daily with once-daily thoracic radiotherapy 3 patients aged 82 yrs were included. Outcome was independent of age 77 and age was not a risk factor in a multivariable Cox analysis 3. Treatment in these series also included prophylactic-cranial irradiation to patients in CR and no extraordinary neurotoxicity was observed. Systematic assessments, however, in larger series would be useful. Finally, the populations are changing and the increasing number of elderly people in good general health represents both a stimulus and a demand for development of specific regimes for elderly patients. Many elderly will tolerate combination chemotherapy and all will expect to be offered an individualized, documented and efficacious treatment.

New chemotherapeutic agents

The activity of six new agents have been investigated in phase I, II and III trials during the past 9 yrs but the definitive roles of each agent have not yet been defined 78, 79. The agents are two taxanes: paclitaxel and docetaxel, two topoisomerase I inhibitors: topotecan and irinotecan, an antimetabolite: gemcitabine and a spindle inhibitor: vinorelbine 80–86 (table 9⇓) (a seventh agent: oxaliplatin, has not yet been tested in SCLC). The phase II trials include previously untreated patients with extensive disease or patients with relapse after >3 months in remission after first-line treatment. A few trials include patients with refractory tumours on first-line treatment. Some trials use G-CSF as rescue or as an integrated part of the treatment. The addition of G-CSF has an influence on the observed haematological toxicity and may have an impact on the response rates. The strategy thus makes it more difficult to compare the outcome with that from other trials.

Comparison of haematological toxiciy data is furthermore difficult because of various ways to describe the observations: nadirs in first cycle or global nadir from all cycles; per cent of patients or per cent of series with grade 3 or grade 4 toxicity. Survival data should be interpreted cautiously because similar pretreatment characteristics of the patients do not prove the same degree of selection.