Small Cell Lung Cancer

Reviews in Oncology 2 (1989) 2 (in Aclu 0ncoloKic.u Vol. 28, Fusc. 5 )

FROM THE DEPARTMENT O F CLINICAL RESEARCH, THE NETHERLANDS CANCER INSTITUTE, AMSTERDAM, HOLLAND.

SMALL CELL LUNG CANCER

Acta Oncol Downloaded from informahealthcare.com by 210.13.81.245 on 05/20/14 For personal use only.

J. G. MCVIE,0. B. DALESIO and H.

The treatment of this subtype of lung cancer provides a tantalizing challenge to the oncologist. Of all the adult solid tumors no other resembles leukemia more than this. Clinically the disease presents most frequently in a metastasized stage, its doubling time is clearly fast, it shrinks dramatically with chemotherapy (and radiotherapy) and yet the majority of patients die of recurrent, resistant disease. This chapter will point to good reviews covering different aspects of small cell lung cancer (SCLC), where they exist, and expand in areas where no recent compilation of data has been published. The ‘average’ patient investigated for respiratory complaints or for neuroendocrinological complaints will have a suspicious mass on the chest radiogram, supplemented by lung planigrams or CT scan, biopsy via bronchoscope or mediastinoscope or else needle aspiration to attain cytology. A variety of immunochemistry and electronmicroscopy techniques are available to substantiate the histological or cytological diagnosis of small cell lung cancer. The patient will then be staged by a minimum of CT scan of the abdomen, paying particular attention to liver and adrenals, CT or MRI scan of the brain with contrast, if indicated by existence of neurological symptoms or signs, and bone marrow biopsy and aspiration. New techniques are being described for less invasive techniques of staging. Patients with disease limited to the chest will be expected to be treated primarily with chemotherapy followed or accompanied by thoracic radiotherapy. Trials are ongoing of the value of surgical exploration at the end of such induction therapy. Most patients achieving clinical complete remission will then undergo prophylactic cranial irradiation and will not then receive any further maintenance therapy. The expected survival of such patients will be around 12 months with a 10% chance of long-term survival. A relapse is to be expected in areas of previous disease and in metastatic sites, such as brain, adrenal, liver, or bone. Such a relapse, should it

VAN

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occur after some months free of treatment, may again prove sensitive to the same therapeutic strategy as induced the first remission but the second remission will be considerably shorter than the first, again in parallel with the experience in the leukemia field. Patients progressing on induction therapy or relapsing shortly after discontinuation of induction therapy will rarely be expected to profit from further attempts at therapy and will have a life expectancy of less than 2 months. Patients with so called ‘extensive disease’, in other words disease spread outside the thorax will generally be treated solely with chemotherapy to a maximum of 5 or 6 cycles. Radiotherapy is reserved for palliative treatment of pain and in the form of prophylactic cranial irradiation for the occasional patient who achieves a complete remission. The survival of a group of uniformally treated extensive disease patients is from 6-10 months and the likelihood of survival longer than 3 years is almost zero. With this short sketch of the standard state of the art, each aspect of the diagnosis and therapy will be explored with emphasis on the recent data and new directions on which clinically research is focussing. Etiology

There is conclusive evidence that the vast majority of patients with small cell lung cancer have cigarette smoking to blame for their predicament. What exact steps are necessary in the carcinogenesis process is not yet clear, but the discovery of several oncogenes in small cell lung cancer cell lines has given an exciting lead to the molecular search for smoking related DNA damage. Oncogenes of the myc family, particularly c-myc, 1-myc and n-myc (1, 2) have been described in cell lines established from small cell lung cancer biopsies. There has been a claim that expression of c-myc, in particular, might have prognostic significance but as the study of fresh tissue samples

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J. G .

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DALESIO AND


failed to reveal a significant percentage of c-myc positive tumors, this is going to have little practical relevance as a prognostic factor. In contrast, the finding of K-ras expression in fresh samples of adenocarcinoma of the lung, rather than in cell lines, may be more useful for prognostication in that cell type (3). More recently c-myb, fos, ras and fes oncogenes (4) have been discovered in SCLC cell lines, but they are rarely overexpressed in fresh tissue. Oncogene expression could be useful, not only for prognostication but also for assisting in diagnosis of small tissue samples now that the technique polymerase chain reaction (PCR) has been developed, whereby DNA from small numbers of cells may be amplified to achieve concentrations, which are necessary for oncogene detection. There are several possibilities for detecting oncogenes with monoclonal antibodies at present in the development stages. Staging In contrast to non small cell lung cancer (NSCLC) SCLC does not lend itself completely to the classical TNM classification. The original division into limited and extensive disease derives from use by radiotherapy groups, who defined limited disease as a disease which could be encompassed in a conventional radiation field. Since then it has been shown that the presence of contralateral hilar nodes, and supraclavicular nodes have little or no impact on prognosis, provided the patient is treated as limited disease namely with chemotherapy or radiotherapy; thus such patients have been included in the definition of limited disease. It is less clear whether the finding of SCLC cells in pleural effusion or bone marrow have a major prognostic significance and there are also some series where liver metastases as the sole site of metastases outside the chest have not been associated with major deterioration in survival curves. There is no dissension about the negative effect on survival of multiple sites of metastases outside the chest nor the finding of bulky disease in any one organ. One might legitimately ask what the relevance is, or cost-effectiveness of, wide-spread invasive staging procedures, such as biopsies of liver or bone, peritoneoscopy, brain scans with contrast, etc. As chemotherapy regimens have become more aggressive it is clear that the difference between extensive and limited disease is becoming less pronounced and the major influence on therapy would be the decision on thoracic irradiation. Most centers agree that prophylactic cranial irradiation should be offered to patients who have achieved a complete remission, irrespective of stage as it has been shown that this cuts down the incidence of later relapse, although not impacting on survival (see later). It is, however, unlikely that irradiation of the thoracic tumor would have much relevance to a patient, who has got metastases in liver and bone, even though they have gone into complete remission with chemotherapy, as experience has taught us that

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the time to relapse is short in such patients and the recurrence of tumor in the original site in the chest is frequently merely a herald of relapse in metastatic sites (often within a month or two). There has been considerable labor expended to establish simple prognostic factors for categorization of patients into poor and good prognosis groups, so that those with poor prognosis may be given a minimum amount of palliative therapy, to improve quality of life without raising expectations of prolongation of life. On the other hand the small group of patients who may have a chance of cure will be in the good prognosis group by definition, and doctor and patient are usually willing to pursue a more aggressive multi-modality therapeutic plan accompanied by greater cost, in terms of dollars and toxicity, in order to achieve that goal. The finding of brain metastases at the time of presentation of disease has an effect on therapeutic choice. Radiotherapy used to be immediately instituted in such patients, followed or accompanied by chemotherapy. Recently, however, there has been more realization that remission, even in brain metastases, can be achieved with conventional intravenous therapy. Staging of the patient with small cell lung cancer includes bone scanning and bone marrow biopsy. Recently magnetic resonance imaging (MRI) has been successfully used to detect bone marrow involvement in patients with SCLC (5). Coronal images of the femoral and pelvic marrow were obtained using a 1.5 tesla super conducting magnet system and results were compared with conventional staging procedures (CT-scan and isotope bone scan, unilateral bone marrow aspirate and biopsy). Of 24 patients considered to have limited disease by the usual procedures 10 (41 %) were moved into the extensive disease category thanks to MRI. In a group of 48 patients, bone marrow invasion was detected in 19 with MRI compared to 2 using bone scan and bone marrow histology. It would appear from the preliminary data that this technique may also be useful in monitoring therapy as the MRI scans reverted to normal in several patients who achieved a response to chemotherapy. Several monoclonal antibodies have been claimed to be more or less specific for detection of small cell carcinoma (6). Until recently these have only been used to assist the pathologist in achieving a diagnosis. In such an antibody (NR/LU/IO) the FAB portion of an IGG2b antibody has in fact been labelled with 9 9 T ~and m used to scan patients by gammacamera imaging (7). No toxicity was observed from injection of this FAB formulation and 95 out of 116 known metastases were imaged successfully. A further 19 previously unsuspected lesions were discovered and in a total of 20 patients, 19 were correctly staged as limited or extensive by the use of this single technique. Clearly both of these approaches have considerable promise for cutting down time and expense required in staging SCLC patients.

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Prognostic factors Prognostic factors can generally be split into two categories, namely factors which relate to the patient such as age, sex, performance status, etc. and those which relate to the tumor or effect of the tumor on the patient. These last include stage of disease, sites of disease, number of organs involved, tumor markers (8) and biochemical or hematological abnormalities. At Leeds Castle recently a consensus meeting, involving the major cooperative groups who have conducted trials in small cell lung cancer over the last 15 years, addressed the question of prognostic factors in SCLC (9). They came to the conclusion that there was no single or combination of tumor markers (including oncogenes, polypeptides secreted by the tumor, such as gastrin releasing peptide, or antigens, such as carcinoembryonic antigen) which reliably predicted for achievement of remission, median, or Iong term survival. Several biochemical parameters, however, were found to be of prognostic value for survival, both median and at two years, using univariate and multivariate analyses. These include serum LDH and alkaline phosphatase as the most powerful with albumin and sodium less so. Gamma GT and liver enzymes such as SGOT have prognostic effects but of considerably less power than the above. Whereas a white blood count greater than 10. 109h and a drop in hemoglobin showed an effect in univariate analyses they were not important when combined in the multivariate models. These factors added prognostic information to the usual categorisation of limited and extensive disease, and it was felt that few other prognostic factors were required to divide patients into good and poor risk groups for further therapy trials. Such factors do not replace anatomical staging methods if these are needed for planning local treatment but they do provide a reproducible and inexpensive way of allowing comparisons of results of multicenter trials carried out by different groups. The importance of multiple sites of involvement with SCLC was mentioned above and this consensus meeting underlined the importance of pleural effusion particularly taking into account the large databases provided by the South West Oncology Group (SWOG) (10) and the European Organization for Research and Treatment of Cancer (EORTC) (1 1) as a poor prognostic factor. Both these large studies and those of the Copenhagen group (12) and Cancer and Leukemia Group B (CALGB) (13) found that females survived better than males, particularly those with limited disease and there was a tendency in all trials for younger patients to do better than older patients. A study from France (Lebeau, personal communication) showed that there was no difference in response rate to chemotherapy between patients older than or younger than 70 years of age, but that the older group tended to have poor prognostic factors and a high drug-induced myelotoxicity rate leading to a 3-fold higher incidence of early death due to complications of therapy. More aggres-

sive supportive care in such patients might be expected to improve their outcome in the future. 'keatment Surgery

In all the old series of surgically treated stage I or I1 lung cancer, patients can be found whose histology was SCLC and they generally had a poorer prognosis compared to NSCLC patients. There are occasional patients who must have been truly stage I and who were cured by surgery but this is a tiny minority ( < l o % of the largest series). With improvement of diagnostic techniques, particularly needle biopsy and aspiration, there are very few patients who are now subjected to a thoracotomy without a preoperative diagnosis. The majority of centers do not submit patients known to have SCLC to operation, but should this occur then the standard procedure is to follow surgical resection by chemotherapy. A recent report from Austria detailed the outcome of 135 patients who were surgically resected for very limited SCLC and then received one of three postoperative combination chemotherapy regimens (14). None of these regimens was any better than the other. Each included at least two active cytotoxic drugs and the projected 3-year survival f x patients with NO disease was 64% and N2 disease 33%. Another approach has been taken by three of the major cooperative groups (Lung Cancer Study Group (LCSG), Eastern Cooperative Oncology Group (ECOG), and EORTC). They have instituted a trial of primary chemotherapy for such patients followed by local irradiation of the tumor site in lung, prophylactic cranial irradiation and then randomization to surgery or not. The rationale for such an approach is that there are patients with truly limited disease who relapse in the chest despite optimal chemotherapy and radiotherapy and frequently when the patients have been explored surgically the histology has been shown to be NSCLC (15). Presumably such patients had mixed tumor histologies and the small cell element had been removed by cytotoxic drugs and radiotherapy leaving the more resistant NSCLC elements. The therapy plan was based on experiences from a pilot study of ECOG (16), in which 2 courses of chemotherapy, cyclophosphamide, doxorubicin and etoposide, achieved 1 CR and 19 partial remissions in 37 patients with SCLC. Thirteen patients then underwent a pneumonectomy and 7 a lobectomy. No operative morbidity could be attributed to the chemotherapy and of 7 patients who had mixed histologies, 5 are alive free of disease after a median follow-up of 36 months. Twelve patients still had SCLC histology and 7 are alive free of disease. Only 2 of the 16 unresected patients were alive at 15 and 31 months. A study with similar outcome was reported recently by Williams et al. (17). They gave 3 cycles of chemotherapy and achieved an 84% response rate. Thereafter 25 patients were operated, 4 were inoperable, 9 had a lobecto-

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J . G . MCVIE. 0. B. DALES10 AND H . VAN TINTEREN

my and 12 a pneumonectomy. Only one of their patients had a mixed histology, and only 4 had pathologically confirmed complete remissions. These last mentioned were the only ones who achieved long-term survival. The results of the ongoing randomized study are therefore awaited with great interest.


Chemotherapy

Chemotherapy is the cornerstone of treatment of SCLC due to the above mentioned chemosensitivity, which is in sharp contrast to the relative resistance of NSCLC (18, 19). Most cytostatic agents are active singly (20), but a study of today's combination schedules in common use shows regular inclusion of cyclophosphamide, doxorubicin, vincristine, etoposide, methotrexate, cisplatin, and CCNU (semustine). Malik (21) reviewed all the randomized trials of single agent chemotherapy and combination regimens in 1986. The more recent data have not altered the conclusions of that review substantially, although the use of several new drugs, namely teniposide (22, 23), carboplatin (24), 4-epidoxorubicin (25), and ifosfamide (26) are to be found in the latest combination. Unfortunately all four drugs are analogs of drugs mentioned in the first list and tend to have a similar spectrum of activity. There is an urgent need for a new class of compounds, which is active in SCLC and not cross-resistant to conpounds in current use. There are two problems with chemosensitivity in this disease; One is that complete remissions as assessed routinely with plain radiograms and scans, in reality turn out not to be complete; in other words the incidence of partial remissions due to pre-existing chemoresistant clones of cells is substantial. The second problem is that SCLC cells seem to have a tendency to develop resistance to the drugs used in first-line therapy and the change in these cells confers resistance to a wide range of other compounds, by analogy with the laboratory model of multidrug resistance (MDR). Mention has already been made of the overexpression of certain oncogenes when SCLC cells are cultured and it would be valuable to know if expression of the MDR genes can be exaggerated between the time of presentation of SCLC and the time of relapse or progression after conventional first-line chemotherapy. The MDR gene is responsible for the overproduction of p-glycoprotein in cell membranes which accelerates the extrusion of naturally occumng substances including anthracyclines, Vinca alkaloids and podophyllotoxins (etoposide and teniposide). Cells overexpressing the MDR gene and overproducing p-glycoprotein in vitro tend to remain sensitive to some agents, such as cisplatin and carboplatin and indeed clinical evidence is now emerging to support the fact that the platinum compounds may not be truly cross-resistant with other agents commonly used in SCLC, such as cyclophosphamide, doxorubicin and vincristine (27, 28). Einhorn et al. (29) used these three

drugs to induce remission and then consolidated with cisplatin and etoposide in half of the patients. The additional therapy increased median survival from 68 to 98 weeks (p=0.0094). Adding cisplatin to the combination etoposide and vindesine failed to make such an impact, but did cause substantially increased toxicity (30). A randomized trial (31) of a platinum combination versus a combination of cyclophosphamide, doxorubicin and vincristine versus the two combinations alternating with each other, resulted in the same response rates (95%, 85% and 85% respectively) (32). When patients failed, however, on one of the first two regimens, they were crossed over to the other, and 1 of 11 platinum failures responded to the cyclophosphamide combination, whereas 5 out of 18 non-responders to the cyclophosphamide regimen responded to the platinum regimen. This is of some interest academically, but these responses did not contribute enough to the survival curves, as they were identical for all three groups of patients. The studies by Qsterlind et al. (33), Pedersen et al. (34) and Aisner et al. (35) showed no differences in median survival or response rates between alternating chemotherapy regimens and sequential use of chemotherapy regimens, but these trials comprised around 100 patients in total, whereas the negative trial alluded to above had over 100 patients in each arm and is largely similar to a recent Japanese trial (36). A recent Canadian study with 150 patients per arm showed that a cyclophosphamide standard regimen, identical to that of Roth was inferior in response rate and survival to the same regimen alternated with etoposide and cisplatin (37). The conclusion of these various studies is that there may be a small effect of addition of cisplatin to conventional regimens, but this is counterbalanced by increased toxicity due to that drug, and the overall effect on survival is unimpressive (26, 38). A major criticism of the majority of studies reported, not only on chemotherapy regimens but also chemotherapy/radiotherapy regimens, is that there is too much concentration on comparison of median survivals and not enough on long-term survivals. There is a common range of 2-year survival figures between 10 and 20 % in limited-disease patients according to selection bias and prognostic factors listed above in all trials mentioned in the literature, with the exception of a handful in which radiotherapy has been applied either concomitantly or early in the course of the chemotherapy treatment; this topic will be dealt with later. As it is now clear that combination chemotherapy is better than single agent therapy, both in terms of response rate and survival, three areas have been addressed in the last series of multicenter trials, namely dose and duration of drugs and the effect of therapy on quality of life. Two important British studies have been reported, which concern the last problem and an analysis of an ongoing large EORTC trial is awaited. The Medical Research Council of



the UK randomized a total of 13 1 patients to combination chemotherapy followed by radiotherapy or to palliative therapy consisting of symptom control when and if necessary (39). Cytotoxic therapy in the first arm was conventional, viz. etoposide, cyclophosphamide, methotrexate and vincristine, whereas the only cytotoxic drug recommended in the symptomatic treatment arm was cyclophosphamide 1 g/mZ 3 weekly for as long as the clinician considered it appropriate. Apart from a taggering difference in survival in favor of the combination chemotherapy arm, both median and 2-year survival, the quality of life of patients in that arm was also considerably better as reported by the clinicians. As expected, treatment-related deaths and adverse reactions were more common in the aggressively treated group, and the quality of life daily reported by the patients, using a diary card, was probably somewhat worse for the patients treated with combination chemotherapy. The compliance with the diary card was, however, extremely poor as only one-third of the patients filled in more than 50% of the data required. An improved diary system was then applied by Geddes et al. (40) to a randomized trial which compared chemotherapy regimens in extensive disease SCLC. Patients were randomized to receive cyclophosphamide, etoposide and vincristine each three weeks or ‘as required’ due to symptoms or disease progression. The idea behind this study was that chemotherapy might be used sparingly if it were reserved for treatment of patients at the time when their disease was causing symptoms or clearly progressing as shown by regular three weekly chest radiography. Regular chemotherapy was associated with considerably less side effects with respect to sickness, appetite, pain, sleep, mood and general well-being. Only in the category ’vomiting’ was the score worse for patients receiving regular chemotheraPY. The duration of chemotherapy is of primary importance to the patient as no chemotherapy is without side effects and yet, as the above two studies have shown, too little chemotherapy is very unpleasant. A number of studies have addressed the problem of the optimal length of chemotherapy, both in limited and extensive disease patients. Bakker et al. (41) were the first to report of a small series of 12 patients achieving a complete remission after two courses of chemotherapy for limited disease SCLC that further chemotherapy did not seem to impact on survival. This was followed by a large EORTC study in which 687 patients were treated with 5 courses of chemotherapy (cyclophosphamide, doxorubicin and etoposide) with prophylactic cranial radiation to patients who achieved complete remission (1 1). Patients achieving partial or complete remission were randomized after 5 courses to receive a further 7 courses of therapy or no further therapy. 445 patients were randomized, almost 100 patients had progressive disease at that time, 45 refused randomization and 38 patients had had excessive toxicity during induction chemotherapy. There is no difference in survival be-

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tween the maintenance and no maintenance group, nor is there a difference in the categories limited disease or extensive disease, complete remission or partial remission. In a selected group of patients, who responded best to induction chemotherapy, the time to progression was prolonged but not survival by maintenance treatment. Smaller studies with the same overall design are reported by Cullen et al. (42) for 309 patients of whom 93 were eventually randomized. There was an advantage for extensive disease patients, who received maintenance chemotherapy compared to those who did not and although there was an imbalance in the proportion of complete remitters randomized, this was certainly not enough to account for the difference. There was no difference between limited disease patients. Clarke et al. (43) reported on 202 patients treated with cyclophosphamide, doxorubicin and vincristine and he failed to detect any difference between maintenance and no maintenance in either limited or extensive disease patients with a 4-year follow-up. ECOG studied maintenance chemotherapy in patients who were first randomized to two kinds of chemotherapy, cyclophosphamide, doxorubicin and vincristine or the same regimen alternating with hexamethylmelamine, etoposide and methotrexate (44). Of 628 patients, only 73 complete remissions were randomized to receive maintenance or not and their outcome is identical. The last study had a slightly different design in that patients were randomized at day 0 at the time of first treatment to receive 4 or 8 courses of cyclophosphamide, vincristine and etoposide (45). A second randomization was given at time of relapse when either further chemotherapy was instituted or symptomatic treatment only. Response rates to 4 courses and 8 courses were identical as was the overall survival. Again, as in the EORTC study, the time to relapse was slightly longer in the maintenance group and the survival from relapse was slightly longer for patients receiving chemotherapy for relapse compared to symptomatic therapy. The only treatment strategy which was clearly detrimental to survivaI was 4 cycles of chemotherapy followed at relapse by symptomatic treatment. Patients receiving 4 cycles of chemotherapy and then chemotherapy at the time of relapse had a median survival of 30 weeks, which was identical to that of the patients who were treated with 8 courses of chemotherapy initially irrespective of how this latter group were treated at the time of relapse. The conclusion of these studies is that maintenance chemotherapy may prolong progression-free interval in patients who have responded to induction chemotherapy but it has no impact on overall survival. The hint given in the last study that treatment at relapse might be therapeutically useful, is confirmed by several other studies reporting reinduction of remission by identical chemotherapy to that which caused the first remission. Due to the dominance of the idea that alternating chemotherapy was superior to sequential use of different chemotherapy regimens,


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the dogma existed for some time that a patient relapsing at any time after achieving a remission would be by definition resistant to the drugs which helshe had already received. Whereas this is certainly so from the cross-over studies of platinum and non-platinum containing regimens (above), those studies were carried out on patients progressing, or relapsing within 3 months from the end of chemotherapy (46). It is quite another situation for a patient who has enjoyed a year or so free of treatment and free of symptoms from SCLC. The EORTC group reported treatment of such patients included in their large trial, reported above, and noted a more than 50% total response rate (47). Vincent et al. (48) confirmed this with a different chemotherapy regimen, namely carboplatin and etoposide and mentioned a precedent for ‘rechallenge chemotherapy’ from the literature on Hodgkin’s disease and breast cancer. Two attitudes have been prevalent in clinical trial design addressing the question of drug dose. The first has been to increase dose intensity, in other words, to get as much drug as possible, as quickly as possible into the patient and then stop further therapy. As many patients with small cell lung cancer present at an advanced age with major symptoms and poor performance and nutritional status, such an approach has resulted in considerable morbidity and some mortality. This has led to the idea (also supported by cell biology studies) that patients should be selected for the ‘big bang’ by first reducing the volume of disease with conventional chemotherapy doses and schedules. This last approach is entitled ‘late intensification’ and the intensification has in some studies been to the extent of being lethal if not accompanied by autologous bone marrow reinfusion. The dose intensity issue has been lately addressed by a meta-analysis of the major trials (49). The conclusions of this analysis are that there were no correlations between dose intensity and response rate or median survival in patients with limited disease. For extensive disease, however, there seems to be a dose response for doxorubicin with respect to response rate (p=O.OOl), when included in the cyclophosphamide, doxorubicin, vincristine protocols, and again for doxorubicin with respect to complete remission (p=O.Ol) and cyclophosphamide with respect to total remission (p=0.05) in the combinations of cycophosphamide, doxorubicin, vincristine and etoposide. In studies including etoposide and cisplatin the dose intensity of both drugs is relevant for achieving higher total response rates whether patients were treated primarily or at the time of relapse. This has, however, to be countered by the knowledge that extensive disease patients will rarely ever achieve cures. They have by definition a shorter survival than limited disease patients and more symptoms related to their disease. It is in these patients in particular that cost effect analysis are most important. Little has changed since our last review of autologous bone marrow transplantation with high-dose chemothera-

py in SCLC in 1985 (50). A review of eight studies by Ihde in 1986 confirmed our conclusion that the approach was of academic interest in that it showed that an increase of dose could convert certain patients who had only achieved partial remission with conventional doses of chemotherapy into complete remission but this was accompanied by significant mortality related to the procedure and any impact on the survival was not evident (51). Recent phase I1 studies by Marangolo et al. (52) and Cornbleet et al. (53) using high-dose etoposide and highdose melphalan respectively have not produced the desired breakthrough and Humblet et al. (54) who have published the only randomized trial of late intensification versus conventional maintenance therapy conclude that whereas the procedure is certainly of no value in extensive disease, if it should have any place it would be in good performance status patients with small volume disease, who achieve complete or almost complete response with conventional chemotherapy and only then, if treated with high-doses of non cross-resistant chemotherapy. As mentioned earlier there is little evidence that truly non cross-resistant chemotherapy regimens exist, possibly with the exception of high-dose cisplatin, with or without etoposide, but the problem of cisplatin, as also mentioned earlier, is its considerable toxicity. The analogue carboplatin is less emetogenic than cisplatin and much less nephrotoxic and neurotoxic. It is also active in SCLC and is currently being incorporated in high-dose regimens in both teratoma and SCLC, in the hope of improving cure rates. The development of colony stimulating factors may make the approach of high-dose chemotherapy with myelotoxic drugs more feasible in the future. A pilot study reported by Morstyn et al. ( 5 9 , with carboplatin and etoposide has incorporated granulocyte macrophage colony-stimulating factor (GM-CSF) given daily for 7 days following cytotoxic therapy. Grade IV neutropenia was only observed in 1 out of 11 patients, compared to a historical series of 3 1 % of 82 patients using the same chemotherapy without GM-CSF. Randomized studies are now ongoing to confiim this finding but also to test whether actual infection rate can be reduced by such an approach. Previous attempts using lithium carbonate to cut down leukopenia and infection rates were not impressive enough to be translated into everyday practice (56). On the other hand, prophylactic treatment with co-trimoxazole during high-dose chemotherapy in small cell lung cancer is now standard in many groups, based on the experience of Figueredo et al. (57). Gamma globulin may also be effective in this group of patients (58). The only study showing an increase of infectious episodes due to a supportive care intervention was a randomized study of intravenous hyperalimentation in 119 patients (59). Weight loss is characteristic of SCLC and this intervention was designed to supplement the nutritional status of patients and thus improve their general capacity

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Table 1


Dgferent designs in trials of combined modality therapy versus chemotherapy alone in SCLC

I. Randomize

I . Radiotherapy + Chemotherapy + Chemotherapy 2. Chemotherapy (3 cycles) + Radiotherapy Chemotherapy -+ Chemotherapy 3. Chemotherapy + Chemotherapy

11. Chemotherapy + Randomize

1. Radiotherapy + Chemotherapy 2. Chemotherapy

+

Trial

Year

Design

Williams Fox et al. Wilson Souhami Perez et al. Ohnoshi gsterlind Perry Kies Bunn Ndu Birch et al.

1077 1980 1983 1984 1984 1986 1986 1987 1987 1987 1988 1988

I1 I1 I I I I I I I1 I I1 I

Comment only CR and PR randomized route 2 & 3; RT week 4, 5 (chest) 7, 8 (abdomen) route 2 & 3; after 4 cycles (12 wks); only CR, PR, SD route 2 & 3; RT week 5 , 8, 11; only CR, PR, SD route 2 & 3; RT between first and second cycle of CT route 2 & 3; RT during second and third course complete ; CR received chest RT; PR & SD received HBI route 1 & 3; RT starting within 3rd day first course CT route 1 & 3; or RT initially (week 1, 2, 7) or RT delayed (week 5 , 8, 11)

Table 2 Overview randomized trials of combined modality therapy versus chemotherapy alone in SCLC

Trials

Williams

Year

1977

No. patients LDIED (entered1 randomized)

27125

CT

CT+RT Drugs

RT (Gylfr)

Treatment schedule (wks) 01..4..7..10..13..16..19

12

13

POCC

ccc

30110

ccc RR

Fox et al.

1980

125169

Wilson

1983

1451118

Souhami UCH Perez et al. SCSG-78 Ohnoshi

1984

3801371

57135

35

34

CAV

40120

ccc ccccc

70

48

40120

c c c c c

198

173

CCNU CM AV CM

40120

cccc

RRR

1301241

RR RR

cccc RRR

I984

2911218

2 181-

103

115

1986

50150

501-

26

24

CAV

ccccccccc

40115

RR CMCIMEP 40120

C

c

R

c

RRRR

gsterlind FINSEN Perry CALGB

1986

1451125

1251-

65

60

CMVL

40110

1987

4261390

3901-

128

121

CAEV

50125

cc ccccc RR RR

I

ccccccccc RRRR

141

I1

ccccccccc RRRR

Bunn NCI-77 Kies S WOG Ndu

1987

120196

961-

49

47

CMLIVAP 40115

1987

103193

931-

53

40

AV CM

1988

1331110

Birch et al. SCSG-81

1988

3861369

c c c c c RRR

38110-12

cccc

ccc

RR RR

56154 3691-

57

53

222

147

AV CML

40120 (2 Gyld)

CAV

45115

ccc ccc RRRR ccccccccc R R R

Abbreviations: SCLC, Small Cell Lung Cancer; Staging: LD, limited disease; ED, extensive disease; CR, complete response; PR, partial response; Treatment arm: CT, chemotherapy; RT, radiotherapy; Drugs: C, cyclophosphamide; M, methotrexate; L, lomustine; V, vincristine; A , doxorubicine; P, procarbizine; E , etoposide; Radiation: Gy, Gray units; fr, fractions; d , day; Treatment Schedule: C, chemotherapy; R , radiotherapy

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Table 3 Overview randomized trials of combined modafity therapy versus chemotherapy in SCLC. Response and survival

Trials

Year

Response CR+RT

CT CR

PR

50%

Williams Fox et al.

1977 1980

42%

Wilson

1983

8%

Souhami

1984

23%

SD

8%

7%

CR

PR

SD

38%

31%

31%

LD ED resp non-res

48 %


LD+resp LD+non ED+resp ED+non Perez et al.

1984

48%

22%

Ohnoshi 0sterlind Perry

1986 1986 1987

50% 37% 36%

35% 45% 28%

24%

Bunn

1987

43%

39%

18%

Kies NBu

1988 1988

only CR 68% 26%

LD ED

Birch et al.

8%

62%

62%

18%

54% 46% I 49% I1 58%

33% 42% 30% 25%

14% 9%

CR D-F D-F

81%

17%

2%

CR D-F PR D-F

0-s 0-s

(N=31)

64%

28%

(N=25)

CR D-F PR D-F

(N=26)

11%

75%

(N=28)

CR D-F PR D-F

1988

local cont Abbreviations: SCLC, Small Cell Lung Cancer; Therapy: CT, chemotherapy; RT radiotherapy; Response: CR, Complete response; PR, partial response; SD, stable disease; D-F, Disease-free; 0 - S , Overall-survival; Statistics: NS, not significant.

to withstand chemotherapy (60). Significantly more fever was seen in the intravenous hyperalimentation group (p=O.OOl), possibly related to the presence of indwelling catheters. The intervention also failed to make any impact on survival and this study has been mirrored by several others in the area of NSCLC. Before leaving the subject of high-dose chemotherapy, it should be pointed out that several reports on response of brain metastases to intravenously administered cytotoxic drugs have appeared in the last two years. Twelves et al. (61) reported 9 out of 14 patients with a radiological complete or partial remission treated with conventional doses of cyclophosphamide, vincristine and etoposide i.v. and Giaccone et al. (62) showed that 3 of 8 patients responded to teniposide, 120 mg/m2 on days 1, 3 and 5 given i.v. The EORTC have reported a phase I1 study of high-dose etoposide in which 3 patients achieved com-

plete remission and 7 a partial remission in 23 evaluable patients (39). Toxicity was severe in 5 patients, all of them heavily pretreated. Of considerable interest was that 7 of the responses were achieved in patients who had previously undergone prophylactic cranial radiation. The EORTC (63) is now testing high-dose teniposide, based on pilot data reported by Giaccone et al. (23, 62). Radiotherapy

Radiotherapy has been used in three contexts in the treatment of small cell lung cancer. It has been used as a kind of systemic therapy, namely in the form of half-body irradiation, as direct treatment to the thoracic tumor and as mentioned earlier in the chapter, as prophylactic cranial radiation. Half-body irradiation has only been tested in one small randomized trial compared to combination che-


Survival

Comment

Median


CT

2 yrs disease-free

(wks)

CT+RT (wks

44 62 37 26.9 9.6 28.2 52 29.4 37.1 13.7 49

36 68 39 17.5 17.3 33.2 56.8 34.7 36.6 17.4 60

57

90

p=0.04

40 40

44 52

NS NS

48.4 24 46.4 54 31.6 40.4

52 37.6 60 54 46.8 20

50 16 50.8

49.6 18.8 45.4

69.3

127.6

p

CT

CT+RT

NS

only results 1 yr (20/24)

4%

4%

19% 15% 23%

28% 20% 40%

0-S 8%

24% NS 115% I1 25%

NS NS p=0.035

12%

28%

NS

12.9% 24%

(4/31 ; 6/25) (12% (3/25)+ D-F >4 yr)

NS

21%

(both arms N>10) (N =20/58)

NS

p=0.03

29%

(3-yr survival) (consolidation) therapy N=40)

tox. ***

motherapy (64).Patients in both arms of the trial received a boost radiation dose to the primary tumor. Response rates were identical, 88 % versus 87 %, and median survival for limited disease patients was 43 weeks and 42 weeks. The major difference was to be seen in the patients with extensive disease, who had a median survival of 15 weeks on half-body irradiation compared to 44 weeks on combination chemotherapy. Several other pilot studies are mentioned in the literature, but as yet this technique has not found favor (65, 66). Prophylactic cranial radiation, on the other hand, is standard therapy for patients who achieve complete remission by other means (radiotherapy-chemotherapy). The last review in 1986 needs to be updated since two further trials have been reported. The conclusion of 7 trials reported (67-73), is that prophylactic cranial irradiation reduces the incidence of brain metastases, but does

737

not prolong survival. The only remaining discussion presently addressed by current randomized studies is the question of dose rate, as in most therapy studies doses and dose rates have been different in different trials. Late neurological sequelae of whole brain irradiation, though obviously not nearly having the significance that they have in children treated for leukemia, are nevertheless noteworthy in some patients who survive long term from SCLC (74). A general assessment of the incidence (39% of 283 patients) would tend to suggest that neurological complications were more frequent in patients treated with high-dose fractions of radiotherapy (75). It is also not completely clear what the optimal total dose of radiation is. Variations are between 20 and 40 Gy. It will require a long follow-up of ongoing trials in large numbers of patients and careful neurological monitoring to produce any further light on this question. The major issue concerning radiotherapy is unquestionably the place of local irradiation to the primary tumor. Four reviews up till 1986 (21, 76-78) had six randomized trials available for comment. In only one of these was there a survival advantage in favor of patients receiving chemotherapy and radiotherapy compared to chemotherapy alone. There is general agreement on the beneficial effect of local irradiation on the incidence of local recurrence, but the debate has raged on what is the value of this since, as was noted above, local recurrence frequently signals metastatic flare up. There are now 12 fully documented trials to be reviewed and a glance at Table 1 will show that one of the major problems is difference in design. Radiotherapy is sometimes given intercalated with cycles of chemotherapy, sometimes given after induction remission by chemotherapy and sometimes concomitantly with chemotherapy. The doses, volumes and the dose fraction size, vary dramatically (Table 2 ) and so does the choice of drugs. Unfortunately not all authors report on a 2-year disease-free survival, relying on median survival figures, and the reporting of response is also frequently unclear with respect to the time that the response is measured. Some authors report the best response ever achieved, others report the combined response after chemotherapy and radiotherapy and yet others make no mention of the time of assessment. It is not yet possible to draw any conclusions, despite the large total number of patients in these trials, although there is a clear trend in favor of radiotherapy. This question is now the subject of a rneta analysis being conducted in the Netherlands Cancer Institute by Dalesio and Van Tinteren. If the treatment schedules, with respect to timing of radiotherapy (early or late), are laid next to the results in Table 3, there is also a trend emerging in favor of the better results appearing with early radiotherapy. This caused several cooperative groups to re-examine the possibilities of increasing the intensity of therapy concentrating as much treatment as possible in the first three months. Delivery of drugs with radiotherapy has been re-exam-


738

J. G. MCVIE, 0. B. DALES10 A N D H . VAN TINTEREN

ined in a recent pilot study (79) employing platinum and etoposide together with radiation therapy. It was possible to give 45 Gy at 1.8 Gytday, beginning on day 1 with the injection of cisplatin 15 mglm’ and etoposide 50 mg/m2. Out of 40 patients treated with this regimen plus consolidation therapy, 24 complete remissions were noted (60%) and 9 partial remissions (22 %), with a median survival of this group of limited disease patients of 19.2 months. Toxicity with respect to bone marrow and local radiation effects was acceptable and the local relapse rate was remarkably low at 11%. Two reports of pilot studies, using hyperfractionated radiotherapy (twice a day radiotherapy) have shown that this is also feasible together with chemotherapy (80, 81). Both acute toxicity and chronic toxicity, mostly esophagitis were acceptable and long-term results are awaited. Intercalated radiotherapy and chemotherapy has been piloted by Chevalier et al. (82), again relying on cisplatinbased therapy with one cycle of chemotherapy alternating with one week of radiation therapy, given at a total dose of 45-65 Gy. Bone marrow toxicity was the major problem and was seen in all patients lethal in 3%. This is balanced by extremely high 2-year survival of 35 % and in the earliest patients a 3-year survival of 21 %. Two other pilot studies, examining this approach, have confirmed a low local relapse rate varying between 11 and 15%. Three European groups are now addressing early radiation therapy combined or intercalated with chemotherapy in randomized studies and the results, along with the result of the meta-analysis, will hopefully provide the basis for clearer guidelines for future treatment. Miscellaneous

Two areas of therapeutic research are noteworthy with respect to SCLC; one is immunotherapy and the other the use of anticoagulants. There have been 5 randomized trials of immunotherapy, with a substantial number of patients. Two trials used BCG, one levamisole, one KP45 and one thymosin fraction VI (32, 83-86). Three of these studies showed some improvement in median survival and this approach has been further explored with the addition to the immunologist’s armamentarium of the biological response modifiers. Ongoing studies concern the value of a-interferon and interferon in the maintenance of patients who have achieved complete remissions with conventional therapy (87). To judge from the trials until now it is clear that the appropriate patients for treatment are those who have minimal residual disease. It is furthermore clear that immunotherapy is not without toxic side effects (88, 89) and finally also that the regrettable fact is that improvement of parameters, such as median survival, has not been accompanied by detectable changes in immune parameters. Monitoring of immunotherapy has proved to be very difficult. As yet no study has shown a major effect of immunotherapy on the total survival but

the possible use of interferons, with or without monoclonal antibodies and interleukins, is of considerable interest. Anticoagulants should be mentioned for the sake of completeness since there are now two randomized trials which show effect on median and overall survival for patients given conventional chemotherapy with addition of warfarin (90, 91). The rationale for this approach has been the diminution of metastatic potential of small cell lung cancer cells, but it would not be surprising if the mechanism were completely different. A large French national study has failed to show any effect of aspirin in addition to conventional chemotherapy in terms of either response rate, median survival or total survival (Lebeau, personal communication). Anticoagulants are of course not without own side effects and both trials mentioned above reported excess bleeding in some patients in the trial arm. Request for reprints: Dr 0. Dalesio, Department of Clinical Research, the Netherlands Cancer Institute, Plesmanlaan 121, NL-1066 CX Amsterdam, Holland.

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74 1

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