- Email: [email protected]
Predictive and prognostic factors in small cell lung cancer: current status
Lung Cancer 28 (2000) 173 – 185 www.elsevier.nl/locate/lungcan
Predictive and prognostic factors in small cell lung cancer: current status Desmond Yip, Peter G. Harper * Department of Medical Oncology, Guy’s Hospital, St Thomas St., London SE1 9RT, UK Received 7 September 1999; received in revised form 28 December 1999; accepted 29 December 1999
Abstract Clinical and laboratory parameters can predict response to chemotherapy and long term survival in small cell lung cancer, and may predict those at risk of early treatment related toxicity. This paper reviews the predictive models that have been developed to divide patients into prognostic groups for response and survival on the basis of clinical and laboratory parameters. These factors may be used for the stratification of patients in clinical trials and to help clinicians make appropriate treatment decisions for individual patients. A number of treatment-related factors can also affect outcomes. The evidence for interventions to prevent treatment deaths in high risk patients, such as prophylactic antibiotics, dosage modification or colony stimulating factor support are also reviewed. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Small cell lung cancer; Prognostic factors; Predictive factors; Chemotherapy; Survival; Treatment-related mortality
1. Introduction Small cell lung cancer (SCLC) is an extremely aggressive tumour with a poor clinical course. Without treatment, median length of survival after diagnosis is 1–3 months. It is however responsive to both chemotherapy and radiotherapy. Combination chemotherapy has produced overall response rates in the order of 80%, with limited This work was presented in part at the Prognostic and Predictive Factors 1st International Workshop in Lung Cancer Meeting, in Athens, Greece, June 17–19, 1999. * Corresponding author. Tel: + 44-207-9554624; fax: + 44207-9554939. E-mail address: [email protected] (P.G. Harper)
disease (LD) patients surviving a median of 14–16 months and extensive disease (ED) 8–11 months [1,2]. Long term survival is rare with only about 4% being alive at 5 years [3]. Prognostic factors are defined as those at the time of diagnosis that are able to give information on clinical outcome. Predictive factors are those that are able to provide information useful in the selection of patients likely to respond to therapies [4]. Studies have attempted to identify both the factors predictive of response and toxicity to treatment, as well as the prognostic factors that identify long term survivors. The aim of this article is to review the clinical characteristics and pretreatment laboratory factors that prognosticate survival and predict re-
0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 0 ) 0 0 1 0 5 - 7
174
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
sponse and early treatment mortality. A MEDLINE search was carried out covering the years 1980 –1999 to identify relevant studies in English-language medical journals. The following MeSH terms were used: small cell carcinoma, lung neoplasm, prognosis, survival and drug therapy.
2. Clinical characteristics
2.1. Clinical staging Clinical stage at initial presentation is one of the most powerful prognostic factors identified in most studies. The International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM (tumour, nodes, metastases) classification system was found to be inadequate for the staging of SCLC, as the extent of nodal involvement did not correlate with prognosis. This led to the development of the simple two-stage system of limited disease (LD) and extensive disease (ED) by the Veteran Affairs Administration Lung Study Group. An increasing number of metastatic sites carries a worsening prognosis in ED. Liver or cerebral metastases confer significantly shorter survival compared to bone, soft tissue or marrow involvement [5]. Shepherd [6] has defined a subgroup of patients within LD with no mediastinal node involvement (very limited disease) that has a better median survival. Superior vena caval obstruction (SVCO) in limited disease patients has not been found to be an adverse prognostic factor in multivariate analysis in 408 cases of SCLC (43 (11%) with SVCO) [7].
2.2. Performance status Poor performance status (Eastern Co-operative Oncology Group (ECOG) score 3 or 4) usually confers a poor prognosis [8 – 15]. This is a finding similar to many other tumour types. Performance status however is a subjective factor that can be affected by acute self-limited events.
2.3. Age Increasing age is associated with increasing comorbid conditions and reduced physiological reserves that can increase the toxicity of chemotherapy [16]. There may be a reluctance of clinicians to treat elderly patients because of this perceived frailty and certainly many clinical trials have excluded these patients [17]. Some retrospective studies have found that increasing age is an independent adverse prognostic factor in ED SCLC [9], in LD [18] and others in both [13]. A number of other studies [19–23] have found that the elderly (usually defined as above 70 years) experience a larger number of dosage reductions or omissions and suboptimal treatment with chemotherapy due to toxicities but their response rates and survivals are not necessarily inferior to a younger population. A review of patients treated with concurrent thoracic irradiation [24] has found that age did not appear to impact on the delivery, tolerance or efficacy of radiotherapy in combined modality therapy. The issues of treatment of the elderly with SCLC have been reviewed in detail by Johnson [25].
2.4. Sex A number of studies have suggested that female sex as a patient characteristic confers an independent survival benefit [26–29] and higher remission rate to treatment. Wolf [28] found this advantage was restricted to women aged less than 60 years, whilst Osterlind [9] observed a survival benefit only in LD.
2.5. Paraneoplastic phenomena The syndrome of ectopic corticotrophin (ACTH) secretion producing clinical Cushing’s syndrome is an uncommon association with SCLC and occurs in 3–7% of cases. Affected patients can present with increased pigmentation, oedema, hypertension, weakness, hypokalaemic metabolic alkalosis, hyperglycaemia and confusion. Four retrospective series [30–32,80] have shown that these patients have a very poor prognosis with a low response and control of the
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
hypercortisolism with chemotherapy. They are also susceptible to bacterial and opportunistic fungal or protozoal infections and gastrointestinal bleeding. The median survivals ranged up to 6 months [30]. Lambert–Eaton myasthenic syndrome (LEMS) is seen in 2–3% of patients with SCLC. It is characterised by muscle weakness and autonomic dysfunction the onset of which may precede the diagnosis of the cancer. There is a presynaptic disorder of impairment of acetylcholine release by detectable auto-antibodies to calcium channels and characteristic electromyographic features. A recent review of survival data from 15 SCLC patients with this condition found that they have a more favourable prognosis compared to matched patients without LEMS [33]. The important clinical factors related to prognosis are listed in Table 1.
3. Pre-treatment laboratory parameters Cohen first suggested in 1981 that simple laboratory results at the time of diagnosis may serve as prognostic factors [34]. A multivariate analysis of 56 patients with SCLC found that haemoglobin and albumin levels were correlated with survival. Souhami [35] carried out detailed analysis of clinical characteristics and laboratory tests at diagnosis and determined their relationship to survival in 371 patients entered on a prospective trial of chemotherapy. Eleven pretreatment variables were evaluated by multiple regression analysis. Two clinical factors were found to contribute to survival, PS (Karnofsky score (KS), above and below 70%) and clinical stage (ED and LD). No relationship to survival was found with either age Table 1 Clinical factors at presentation found significant in determining prognosis in small cell lung cancer Clinical stage Performance status Age Sex Paraneoplastic Cushings’ syndrome
175
or sex. Laboratory factors predicting survival were found to be serum alkaline phosphatase (SAP) (B 150% upper limit, \ 300% upper normal limit and in between), serum sodium and albumin. A prognostic model was developed incorporating these factors into an equation that divided patients into three groups: good prognosis, intermediate prognosis and poor prognosis. The patients in the ‘best’ prognostic group were found to have higher response rates to treatment and longer survivals. These findings were independently validated on a second data set from the Royal Marsden Hospital. Cerney [12] also produced a Cox regression analysis from a data set of 407 patients enrolled in sequential studies that divided patients into three prognostic groups. Pretreatment stage, performance status, serum sodium, lactate dehydrogenase (LDH), SAP and bicarbonate were found to be the independent factors. A simplified scoring system, the ‘Manchester score’ was also able to define the same groups with little loss of information and is thus more practical for clinical use. Further work by Souhami [36] was done on a group of patients entered on another trial of combination chemotherapy. The five previously defined factors were found to contribute prognostic information but also predicted both for early and late survivals. Interestingly the effect of performance status and SAP were found to be quantitative, with the death rate being related to the degree of abnormality of these factors. Allan [13] in a retrospective review of 411 SCLC patients from Edinburgh, found on Cox multivariate regression analysis that raised LDH and white cell count were independent adverse prognostic factors in addition to performance status, disease extent and age. If stage was eliminated from the analysis then a decreased serum chloride also became significant. In 1990 the Lung Cancer Subcommittee of the United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) produced a large overview to identify important prognostic factors in patients treated on trials [37]. Information was collected on 3873 patients from six centres in the United Kingdom. Two Medical Research Council (MRC) multicentre studies were initially excluded
176
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
Table 2 Pretreatment laboratory variables found significant in predicting prognosis Serum sodium Alkaline phosphatase Sodium bicarbonate Lactate dehydrogenase White cell count Neurone specific enolase
because they only collected minimal variables so that a total of 2303 patients were analysed. Seven variables were recorded for all data sets (age, sex, performance status, SAP, sodium and gamma glutamyl transpeptidase (GGT)). Subset analysis was carried out incorporating different variables as there were inconsistencies and incompleteness of the data collected by different centres. The laboratory ranges did vary between institutions but were not corrected for. Deaths were analysed in the first 6 months after starting treatment and also of those who were alive at the end of the 6 months. The analysis found that the main prognostic factors during the first 6 months after starting treatment were performance status, stage and alkaline phosphatase. The two excluded MRC studies were used to successfully validate these factors. Age, sex, sodium, GGT, albumin, urea and chloride provided small improvements in predicting survival. The longer-term prognostic variables (6 – 24 months) were found to be stage, performance status and sodium; with stage being the most important. Sagman [29] also carried out evaluation of retrospective data on 22 pretreatment attributes in 614 patients with SCLC of the lung to determine the effect on outcome using a number of statistical techniques. With univariate analysis, prognosis was influenced by disease extent, number of metastatic sites and spread to the mediastinum in LD. Cox regression analysis identified serum LDH and mediastinal spread in LD and performance status, number of metastatic sites, brain and bone metastases and platelet count in ED. The techniques of recursive partition and amalgamation algorithm
(RECPAM) classify patients with similar outcomes and identifies interactions between factors without them being specified beforehand. These were used to identify four risk groups stratified by disease extent, performance status, SAP, LDH, mediastinal spread, white cell count (WCC) and liver metastases. The groups had median survival times of 59, 49, 35, and 24 weeks, respectively (P= 0.0001). LDH and SAP were the most significant pretreatment laboratory variables contributing to the groupings. Kawahara [15] has also used RECPAM in a group of 300 patients from a randomised chemotherapy trial, to identify performance status, LDH and serum sodium as being factors that can divide SCLC patients into three prognostic groups. Two studies have further underscored the importance of LDH. Sagman [38] reviewed in detail 288 patients out of the 614 in the previous reported analysis [29] whom pretreatment LDH levels were available. LDH was found to correlate with stage, response to treatment and survival. The survival advantage for patients with normal LDH persisted even when adjustment was made for stage, PS and treatment protocol. Albain [18] analysed the Southwest Oncology Group (SWOG) experience of 2501 patients from ten consecutive trials from 1976–1986. Cox multivariate analysis identified good PS, female sex, age less that 70 years, white race and normal LDH as significant good prognostic factors in LD. A normal LDH and single metastatic site were found to be important favourable pretreatment variables in LD patients. RECPAM analysis found that a smaller number of variables could be used to define prognostic subgroups. The most important divisions were between LD and ED, followed by normal versus abnormal LDH level. The important pretreatment laboratory variables are listed in Table 2.
4. Histological factors The World Health Organisation (WHO) histopathological system of SCLC classifies tumours
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
into oat cell carcinoma, intermediate type and combined oat and intermediate type carcinoma. This is based on light microscopy appearance. Carney [39] has reviewed the histological subtypes of a series of 104 patients with SCLC treated with chemotherapy. No significant difference was found in the initial PS, extent of disease, chemotherapeutic response rate, or survival noted among these histologic subtypes. In addition some patients had more than one histological subtype found when biopsies were taken from more than one site. The concordance rate was 74% with the remaining exhibiting two or three subtypes. The Pathology Committee of the International Association for the Study of Lung Cancer proposed dividing SCLC into three subtypes: pure SCLC, mixed small cell/large cell carcinoma and combined SCLC with squamous components. Histological and cytological specimens from 430 patients [40] have shown that the presence of a large cell component confers a poorer response to treatment and worse prognosis than those with pure SCLC. This supports the findings of other investigators [41–43]. Immunohistochemistry in SCLC has not been found to give consistent useful prognostic information. A study [44] was carried out on archival specimens obtained from fibre-optic bronchoscopy of 70 age-matched short term survivors (died within 3 months) and long term survivors (survived more than 3 years). There was no correlation with survival found on a bank of 11 immunohistochemical neuroendocrine and epithelial markers. DNA ploidy and S-phase fraction has been correlated with treatment response and prognosis in a number of tumour types. Flow cytometric examination of a series of 36 SCLC [45] patients has found no difference in survival between diploid and aneuploid or high and low S-phase tumours. No relation to treatment response was found either supporting a previous study [46]. The main importance of histopathology now is to distinguish SCLC from non small cell lung cancer and bronchial carcinoid tumours. This may require the use of immunohistochemistry techniques.
177
5. Serum markers
5.1. Neurone specific enolase Neurone specific enolase (NSE) is a glycolytic enzyme secreted by neural and neuroendocrine tissue. The serum level is elevated in 80% of patients with SCLC and is probably the most sensitive marker for SCLC at the time of diagnosis. The level is generally higher in extensive compared to limited disease. Jorgensen [47] has attempted to derive a prognostic model for survival based on analysis of NSE in combination with other factors (stage, PS, age, sex, lactate dehydrogenase, SAP and carcinoembryonic antigen) in 787 patients from nine centres in six countries. Multivariate regression analysis showed that elevated serum NSE was the most important adverse prognostic factor followed by poor performance status and extensive disease. Fizazi [48] assessed the predictive value, in terms of survival and complete response, of the serum NSE measured before and after a cycle of chemotherapy in patients with SCLC. In a group of 135 patients studied, complete response was seen in 62% of patients who had normalised NSE at day 28 post-chemotherapy as opposed to 34% otherwise. Median and 2-year overall survival was also found to be significantly improved (PB 0.03) if NSE was normalised. This study also confirmed that a normal day-28 serum NSE, disease extent and performance status were independent prognostic factors for survival on multivariate analysis.
5.2. Anti-Hu antibodies There is anecdotal observation [49] that SCLC patients with paraneoplastic neurological manifestations (e.g. peripheral neuropathy, cerebellar degeneration) have a more indolent course than those without. Patients with paraneoplastic encephalomyelitis/sensory neuronopathy from SCLC almost always have high titre antineuronal antibodies (anti-Hu) detectable in the serum and cerebrospinal fluid. Low titres of anti-Hu are found in a proportion of patients without paraneoplastic neurological manifestations. Graus [50]
178
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
collected serum samples from 196 SCLC patients without paraneoplastic encephalomyelitis – sensory neuropathy and screened them for anti-Hu. In patients who received treatment, anti-Hu was found to be associated with limited disease stage, complete response to treatment and a longer survival. Anti-Hu was found to be an independent predictive factor for complete response to therapy but not survival on multivariate analysis.
6. Predicting early chemotherapy related mortality In a number of large chemotherapy trials [10,11,51,52] of SCLC, an abrupt fall off in the survival curves has been noted in the period after commencement of chemotherapy. This early mortality is related to chemotherapy toxicity producing neutropenic sepsis. Poplin [10,11] analysed the influence of age on outcome of 223 patients with SCLC and found that increasing age was correlated with increasing degrees of myelosuppression and first course admissions with febrile neutropenia. Sudden and toxic deaths were found to correlate with poor performance status rather than age. Morittu [52] analysed the clinical and biochemical factors to determine those that predicted early mortality. In this series of 610 patients on a combination chemotherapy study, 71 patients died in the first 3 weeks of commencing therapy. The peak incidence was noted between 7 and 10 days corresponding to the period of neutrophil nadir. The characteristics of these patients were compared with those of a matched cohort that did not die in the first 3 weeks. The factors highly significant in predicting early mortality were found to be poor PS (P B 0.00001), clinical hepatomegaly (P B 0.0001), raised SAP (P B0.00001), elevated blood urea (P B 0.00001), low albumin (P B 0.00005) and low serum sodium (P B 0.02). These data suggest that hepatic involvement and reduced renal clearance are associated with high risk of early death, possibly because of altered pharmacokinetics of etoposide in these regimens.
Radford [53] also analysed the incidence and risk of septic complications in a group of 382 SCLC patients treated in five consecutive chemotherapy trials at the one institution. The unit policy was to utilise full protocol doses throughout the treatment despite episodes of severe or life-threatening sepsis. The study found that second or further septic episodes were more likely after a first episode than if the cycles of chemotherapy had been free from sepsis. A model of four risk factors was developed that predicted the odds of treatment related sepsis occurring. These factors were an age of greater than 50 years, treatment with a three-drug regimen (as compared to two drugs), Karnofsky score less than or equal to 50 and a previous episode of severe or life-threatening sepsis. The MRC [54] reviewed a total of 2196 patients in 1994 enrolled in six randomised studies carried out over a 30-year period. The majority received combination chemotherapy but patients who had initial surgery or radiotherapy were also included. There was an excess of deaths found in the second week after commencement of the first cycle of chemotherapy. This was in excess of the underlying rate of natural attrition. The Radford model was refined further by regression analysis to improve discrimination of the groups. The performance status was adjusted to PS] 2 (KS 5 70) and, age\ 70 years and four or more drugs. WCC] 10 was found to be a better discriminator than age. A simple model of the presence of three main factors (PS] 2, WCC] 10 and four or more drugs in chemotherapy regimen) predicted the high-risk category of those likely to die from treatment related causes. This model requires further validation in other data sets.
7. Prevention of early chemotherapy related mortality The question thus arises of how to identify and manage those SCLC patients who are at high risk of treatment related mortality.
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
7.1. Dose reduction Radford [53] has suggested an empirical half dosing of the chemotherapy on the first cycle of treatment, escalating towards full dosage on subsequent cycles on the basis of toxicity and nadir counts. With the relatively short median survivals of ED SCLC this fall in dosage intensity is not likely to make a large difference in the survival of these patients. There is no direct data to support this practice. However James [55] reported a randomised study in 167 poor prognosis ED SCLC patients comparing a standard chemotherapy regimen with a half dose regimen that was given with twice the frequency with the same intended dose intensity. The standard arm was found to have a toxic death rate of 7.9% while no toxic deaths were observed in the half dose arm despite there being a higher infection rate and haematological toxicity. Response and median survival were similar.
7.2. Prophylactic antibiotics The use of prophylactic antibiotics in the prevention of infection in neutropenic patients with malignancy has been investigated in a number of clinical studies. The results however have been conflicting. The studies have involved relatively small numbers of patients with not all trials being blinded in their treatment arms, giving rise to the possibility of bias in the assessment of febrile episodes. None have looked specifically at SCLC patients. A meta-analysis [56] of nine trials of quinolone antibiotic prophylaxis versus no antibiotic prophylaxis was carried out in 1998 and included 704 patients. This found that quinolones produced significant reductions in the relative risk of Gram negative infections (which make up the majority of life-threatening neutropenic sepsis episodes), Gram negative bacteraemia, microbiologically documented infections, fever and total infections. No increase was seen in the incidence of Gram positive or fungal infections that may be selected out by the quinolones that have a mainly Gram negative spectrum of activity. A second part of the meta-analysis [56] looked at nine trials involving 677 patients and compared quinolone
179
with cotrimoxazole prophylaxis finding that quinolones resulted in reductions of Gram negative infection, Gram negative bacteraemia, microbiologically proven infections and the total number of infections. The risk reduction was similar to the order of magnitude seen in the comparison of quinolones to no prophylaxis meta-analysis suggesting there was little benefit to the use of cotrimoxazole. Another meta-analysis [57] compared trials of quinolones alone or in combination with antibiotics active against Gram positive infections (penicillin, vancomycin, or macrolides). Whilst the incidence of Gram positive bacteraemia was reduced, the rate of mortality or febrile episodes was found to be unaffected. The answer to whether antibiotic prophylaxis has a true role in prevention of clinical infection from chemotherapy induced neutropenia should be provided by the ‘Significant Trial’. This is an ongoing prospective randomised double-blind controlled study of prophylactic levofloxacin (a quinolone) versus placebo following chemotherapy in patients with solid tumours and lymphoma. The trial is coordinated by the United Kingdom Cancer Research Campaign and plans to accrue 1500 subjects.
7.3. Growth factor support The use of the colony stimulating factor G-CSF to prevent chemotherapy induced neutropenia has been investigated in SCLC. A meta-analysis [58] of three studies that enrolled 606 SCLC patients receiving conventional dose chemotherapy with or without G-CSF support, found that there was a significant reduction in the rate of febrile neutropenia with G-CSF (68.3–38.7%) but no reduction in mortality. The patients in these trials were not all at high risk and the power of the studies combined may still not have been enough to detect a difference in mortality of all comers with SCLC.
8. Treatment related predictive factors There has been a trend towards the use of more active agents and more intensive chemotherapy
180
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
regimens in the treatment of SCLC over the past three decades. Several retrospective analyses [18,26,27] have found that the use of intensive multidrug regimens appears to be independently prognostic after adjustment for other variables. A selective review [2] of recent non-randomised phase II aggressive protocols in ED SCLC suggests that despite the higher toxicities, there are higher total response rates and complete remissions produced with lengthening of median survivals when compared to intermediate intensity regimens.
8.1. Dose intensification Klassa [59] performed a meta-analysis of 60 studies (randomised and non randomised) of chemotherapy regimens in SCLC, published between 1975 and 1988, to assess the relationship between intended dose intensity, response and median survival. No consistent correlations were found. Randomised trials have been performed to specifically determine the effect of dose intensity on outcome.
8.1.1. Dose intensity An MRC randomised trial [60] found that some patients may not necessarily benefit from more intensive treatment. This study randomised 310 poor prognosis (ED or LD with poor PS) SCLC patients between a four drug regimen (etoposide, cyclophosphamide, methotrexate and vincristine (ECMV)) and a less intensive two drug regimen (etoposide and vincristine (EV)). No difference was seen in response or survival, but the ECMV regimen was associated with higher toxicity as well as early deaths. Another randomised study [61] in 105 LD patients has suggested that moderately higher initial doses of chemotherapy (cyclophosphamide and cisplatin) in a four drug regimen that included doxorubicin and etoposide can improve disease free and overall survival. Conversely there is a risk of compromising outcomes with minimally intensive protocols in poor prognosis patients. The MRC [60] and the London Lung Cancer Group [62] both carried out studies comparing single agent oral etoposide
against intravenous combination chemotherapy regimens. Both studies were prematurely terminated when interim analyses showed that oral etoposide was associated with inferior response rates, higher haematological toxicity and reduced survival.
8.1.2. Dose density Relative dose intensity can be increased by reducing the interval between treatments; so called dose density. A recent intergroup study [63] conducted by the National Cancer Institute of Canada (NCIC) and Southwest Oncology (SWOG) Group compared alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/PE) with an intensive weekly regimen of cisplatin, vincristine, doxorubicin and etoposide (CODE) in 220 patients with ED SCLC aged under 68. Consolidative thoracic irradiation and prophylactic cranial radiotherapy was administered to patients in the CODE group who responded. The CODE regimen delivered double the dose intensity of the CAV/PE regimen while administering approximately the same total dose of drugs. It also incorporated additional supportive care with corticosteroids and prophylactic antibiotics but not G-CSF. Although the response rate was higher with CODE (87 vs. 70%) there was an excess treatment related mortality (8.2 vs. 1%) and no overall difference seen in the progression free survival or over survival compared with CAV/PE. These results confirm the findings of two previous randomised studies [64,65] of combination chemotherapy comparing dose-dense weekly regimens to conventional 3-weekly regimens. No benefit for weekly therapy was found with either study. 8.1.3. Dose intensification with growth factors A small study from Manchester randomised 65 SCLC patients with one or no adverse prognostic factors to treatment by dose escalated VICE (vincristine, ifosfamide, carboplatin, and etoposide) with or without G-CSF. Dosing interval was not fixed and subsequent cycles were administered when blood counts had recovered. Significantly higher dose intensity was achieved with G-CSF
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
and a higher 2-year survival of 32 vs. 15% was seen. A French group [66] investigated a high dose regimen of cyclophosphamide, epirubicin, etoposide and cisplatin with GM-CSF support compared to a standard dose regimen without cytokine in 125 patients with ED. No difference was seen in response rates. A higher haematological toxicity rate was seen with the dose intense arm as well as an adverse effect on median overall survival (8.9 vs. 10.8 months, P =0.0005) Two large randomised studies have shown promising results. Steward et al. [67] compared standard VICE (4-weekly) with dose intensified VICE (3-weekly) in 300 patients of good and intermediate prognosis on ‘Manchester score’ [12]. A secondary randomisation was made to granulocyte-macrophage colony stimulating factor (GM-CSF). Dose intensification in this schedule was associated with an increase in 2year survival and no increase in toxicity. GMCSF had no influence on myelosuppressive complications. The MRC [68] compared ACE (doxorubicin, cyclophosphamide and etoposide) given 3 weekly with ACE plus G-CSF scheduled fortnightly in 403 patients with good performance status SCLC. Improved 1-year survival was been seen with the dose intense arm.
8.1.4. Dose escalation with stem cell support A randomised study of late intensification in LD patients with high dose chemotherapy followed by autologous bone marrow transplantation found an increased complete remission rate and relapse free survival rate but no increase in overall survival on the intensified arm [69]. Numbers were small and there was a high toxic death rate with intensification. Intensive protocols delivering relative dose intensities approaching 300% of conventional therapy by the use of peripheral stem cell support have been shown to be feasible with lower toxic deaths [70]. The results of a randomised trial of a high dose ICE (ifosfamide, cisplatin and etoposide) compared to standard ICE are awaited.
181
8.2. Thoracic irradiation Two meta-analyses [71,72] have shown that the addition of thoracic radiotherapy to consolidate response in LD SCLC improves survival at 2 and 3 years by 5.4%. Multivariate analysis of both the SWOG database [18,73] of SCLC patients treated from 1976 to 1986 and a French series [74] of 1986–1995 also found that chest radiotherapy was a consistent independent favourable factor for long term survival.
8.3. Prophylactic cranial irradiation The role of prophylactic cranial irradiation (PCI) in patients who have achieved complete response in SCLC has been controversial. Studies performed have suffered from methodological problems or insufficient statistical power. A recent meta-analysis [75] of seven randomised studies has found that overall survival is improved by 5.4% in absolute terms at 3 years with the additional of PCI.
8.4. O6er6iew Two large retrospective studies have reviewed the outcomes of patients over a 20-year period to see whether there has actually been any treatment related progress. Chute [14] has reviewed all the SCLC patients treated at the US National Cancer Institute from 1973 to 1993. The patients were divided into two groups based on the decade of diagnosis, 1973–1983, when cyclophosphamide-based chemotherapy regimens were used and 1983–1993, when cisplatin-based regimens were used. No significant change was found in the pretreatment factors in these two groups and no significant difference was found in the survivals of the patients despite the change in treatment regimens. On a multivariate analysis a modest survival benefit was noted in LD patients who received cisplatin chemotherapy in combination with radiotherapy when compared to cyclophosphamide containing regimens. Lassen [76] reviewed 1111 patients with ED SCLC treated on six consecutive chemotherapy trials from 1973 to 1992 in Danish and Swedish
182
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
centres. Patients treated in the period 1973 – 1981 were compared to those treated from 1981 to 1992. On comparing pretreatment prognostic factors there was an increase in the percentage of female patients in the later period (35 vs. 27%) and also a higher detection of liver metastases at diagnosis (40 vs. 33%). The frequency of extensive disease patients was unchanged in the two periods. No significant differences in overall response rates and survival were seen. An interesting observation in this study was a steep initial slope of the survival curve from the later period suggesting that the more intense regimens were producing toxic deaths. The phenomenon of stage migration can confound the comparisons of patients treated in different periods of time [77]. This may arise due to the improvement in imaging modalities [78] such as computed tomography (CT) scanning, magnetic resonance imaging (MRI) improving the sensitivity in detection of metastatic disease. The effect in SCLC would be the upstaging of more LD patients by the detection of other sites of involvement and thus making the survivals of both LD and ED appear better. However this effect was not apparent in either of the above studies as neither LD or ED patient survival improved.
9. Conclusion Clinical and laboratory parameters can predict response to chemotherapy, and may predict those at risk of treatment related toxicity as well as the long term survivors in SCLC. Performance status and disease extent are almost uniformly found to be the most important clinical factors. Retrospective analyses by different investigators have found different sets of laboratory factors and serum markers that are of independent prognostic or predictive value. LDH is possibly the most important pretreatment laboratory factor. Few of these sets have been prospectively validated. These factors may be used for patient stratification in clinical trials and to help clinicians make appropriate treatment decisions for individuals. A recent survey [79] of consultants in the United
Kingdom who treat SCLC, has found that there is general agreement that the goals of therapy are different in good and bad prognosis patient groups however they are defined. The aim is to produce a proportion of long term survivors in good prognosis patients, whilst ensuring maximal palliation with minimal toxicity is the goal in poor prognosis. This in turn influences the treatments that are prescribed. It is possible to identify individuals at risk of early treatment mortality and toxicity using the models that have been described. Further studies are required to determine how to best deal with these high-risk patients, to minimise the early treatment related mortality and to give them the best form of palliation and prolongation of life. Despite the use of more active drugs and more intensive regimens, chemotherapy response rates and median survivals do not seem to have improved significantly overall in the past two decades. Although individual studies and overviews have shown a benefit from treatment related factors in different settings, there has not been consistency in the grouping of patients for these trials. This also makes generalisation of results to clinical practice difficult as well as crosscomparison of studies. It is 15 years since Souhami performed the first analysis of clinical and laboratory factors influencing prognosis. There now needs to be agreement amongst investigators as to which of these factors are incorporated into clinical trial stratification to allow valid comparisons between studies.
References [1] Hansen H, Pappot H. Primary malignant tumours of the lung and pleura. In: Cavalli F, Hansen H, Kaye S, editors. Textbook of Medical Oncology. London: Martin Dunitz, 1997:139 – 57. [2] Aisner J. Extensive-disease small cell lung cancer: the thrill of victory; the agony of defeat. J Clin Oncol 1996;12:658 – 65. [3] Souhami R, Law K. Longevity in small cell lung cancer. Br J Cancer 1990;61:584 – 9. [4] Gasparini G, Pozza F, Harris AL. Evaluating the potential usefulness of new prognostic and predictive indicators in node-negative breast cancer patients. J Natl Cancer Inst 1993;85:1206 – 19.
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185 [5] Ihde DC, Makuch RW, Carney DN, et al. Prognostic implications of stage of disease and sites of metastases in patients with small cell carcinoma of the lung treated with intensive combination chemotherapy. Am Rev Respir Dis 1981;123:500 – 7. [6] The University of Toronto Lung Oncology Group, Shepherd FA, Ginsberg RJ, Haddad R, et al. Importance of clinical staging in limited small-cell lung cancer: a valuable system to separate prognostic subgroups. J Clin Oncol 1993;11:1592 –7. [7] Wurschmidt F, Bunemann H, Heilmann HP. Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 1995;33:77–82. [8] Maurer LH, Pajak TF. Prognostic factors in small cell carcinoma of the lung: a cancer and leukemia group B study. Cancer Treat Rep 1981;65:767–74. [9] Osterlind K, Andersen PK. Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation. Cancer Res 1986;46:4189–94. [10] Anonymous. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Br J Cancer 1989;59:584–90 Report to the Medical Research Council by its Lung Cancer Working Party. [11] Poplin E, Thompson B, Whitacre M, et al. Small cell carcinoma of the lung: influence of age on treatment outcome. Cancer Treat Rep 1987;71:291–6. [12] Cerny T, Blair V, Anderson H, et al. Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 1987;39:146–9. [13] Allan SG, Stewart ME, Love S, et al. Prognosis at presentation of small cell carcinoma of the lung. Eur J Cancer 1990;26:703 –5. [14] Chute JP, Venzon DJ, Hankins L, et al. Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 1997;72:901–12. [15] Kawahara M, Fukuoka M, Saijo N, et al. Prognostic factors and prognostic staging system for small cell lung cancer. Jpn J Clin Oncol 1997;27:158–65. [16] 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. [17] Yip D, Harper PG. Cancer in the elderly: gathering the evidence. Med J Aust 1999;170:577–8. [18] Albain KS, Crowley JJ, LeBlanc M, et al. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563–74. [19] Kelly P, O’Brien A, Daly P, et al. Small cell carcinoma in elderly patients: the case for chemotherapy. Age Ageing 1991;20:19 – 22. [20] Goss G, Logan D, Maroun J, et al. Chemotherapy in small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 1992;11:290 Abstract.
183
[21] Paccagnella A, Favaretto A, Cipriani A, et al. Treatment of small cell lung cancer (SCLC) in elderly patients. Proc Annu Meet Am Soc Clin Oncol 1996;15:A1164 Meeting abstract. [22] 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. [23] Siu LL, 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. [24] Quon H, Shepherd FA, Payne DG, et al. The influence of age on the delivery, tolerance, and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1999;43:39 – 45. [25] Johnson DH. Small cell lung cancer in the elderly patient. Semin Oncol 1997;24:484 – 91. [26] Osterlind K, Hansen HH, Hansen M, et al. Long-term disease-free survival in small-cell carcinoma of the lung: a study of clinical determinants. J Clin Oncol 1986;4:1307 – 13. [27] Spiegelman D, Maurer LH, Ware JH, et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1521 patients. J Clin Oncol 1989;7:344 – 54. [28] Wolf M, Holle R, Hans K, et al. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival. Br J Cancer 1991;63:986 – 92. [29] Sagman U, Maki E, Evans WK, et al. Small-cell carcinoma of the lung: derivation of a prognostic staging system. J Clin Oncol 1991;9:1639 – 49. [30] Shepherd FA, Laskey J, Evans WK, et al. Cushing’s syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol 1992;10:21 – 7. [31] Delisle L, Boyer MJ, Warr D, et al. Ectopic corticotropin syndrome and small-cell carcinoma of the lung. Clinical features, outcome, and complications. Arch Intern Med 1993;153:746 – 52. [32] Dimopoulos MA, Fernandez JF, Samaan NA, et al. Paraneoplastic Cushing’s syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer. Cancer 1992;69:66 – 71. [33] Maddison P, Newsom-Davis J, Mills KR, et al. Favourable prognosis in Lambert – Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet 1999;353:117 – 8 letter. [34] Cohen MH, Makuch R, Johnston-Early A, et al. Laboratory parameters as an alternative to performance status in prognostic stratification of patients with small cell lung cancer. Cancer Treat Rep 1981;65:187 – 95. [35] Souhami RL, Bradbury I, Geddes DM, et al. Prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung. Cancer Res 1985;45:2878 – 82. [36] Souhami RL, Earl HM, Ash CM, et al. Prognostic factors in patients with small-cell lung cancer: preliminary results
184
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185 from a large randomised study. Antibiot Chemother 1988;41:77 – 82. Rawson NS, Peto J. An overview of prognostic factors in small cell lung cancer. Br J Cancer 1990;61:597–604 A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Published erratum appears in Br J Cancer 1990;62(3):550. Sagman U, Feld R, Evans WK, et al. The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer. J Clin Oncol 1991;9:954 – 61. Carney DN, Matthews MJ, Ihde DC, et al. Influence of histologic subtype of small cell carcinoma of the lung on clinical presentation, response to therapy, and survival. J Natl Cancer Inst 1980;65:1225–30. Fushimi H, Kukui M, Morino H, et al. Detection of large cell component in small cell lung carcinoma by combined cytologic and histologic examinations and its clinical implication. Cancer 1992;70:599–605. Hirsch FR, Osterlind K, Hansen HH. The prognostic significance of histopathologic subtyping of small cell carcinoma of the lung according to the classification of the World Health Organization. A study of 375 consecutive patients. Cancer 1983;52:2144–50. Radice PA, Matthews MJ, Ihde DC, et al. The clinical behavior of ‘mixed’ small cell/large cell bronchogenic carcinoma compared to ‘pure’ small cell subtypes. Cancer 1982;50:2894 – 902. Sehested M, Hirsch FR, Osterlind K, et al. Morphologic variations of small cell lung cancer. A histopathologic study of pretreatment and post-treatment specimens in 104 patients. Cancer 1986;57:804–7. Bobrow LG, Hirsch FR, Hay FG, et al. An immunohistochemical investigation of diagnostic biopsy material taken from short and long term survivors with small cell lung cancer. Br J Cancer 1992;66:547–51. Viren MM, Ojala AT, Kataja VV, et al. Flow cytometric analysis of tumor DNA profile related to response to treatment and survival in small-cell lung cancer. Med Oncol 1997;14:35 – 8. Kimura T, Sato T, Onodera K. Clinical significance of DNA measurements in small cell lung cancer. Cancer 1993;72:3216 – 22. Jorgensen LG, Osterlind K, Genolla J, et al. Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres. Br J Cancer 1996;74:463 – 7 published erratum appears in Br J Cancer 1996;74(12):2043. Fizazi K, Cojean I, Pignon JP, et al. Normal serum neuron specific enolase (NSE) value after the first cycle of chemotherapy: an early predictor of complete response and survival in patients with small cell lung carcinoma. Cancer 1998;82:1049–55. Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 1993;341:21–2.
[50] Graus F, Dalmou J, Rene R, et al. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997;15:2866 – 72. [51] Hirsch FR, Hansen HH, Hansen M, et al. The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: a randomized trial of 288 consecutive patients. J Clin Oncol 1987;5:585 – 91. [52] Morittu L, Earl HM, Souhami RL, et al. Patients at risk of chemotherapy-associated toxicity in small cell lung cancer. Br J Cancer 1989;59:801 – 4. [53] Radford JA, Ryder WD, Dodwell D, et al. Predicting septic complications of chemotherapy: an analysis of 382 patients treated for small cell lung cancer without dose reduction after major sepsis. Eur J Cancer 1992;29A:81 – 6. [54] Stephens RJ, Girling DJ, Machin D. Treatment-related deaths in small cell lung cancer trials: can patients at risk be identified? Medical Research Council Lung Cancer Working Party. Lung Cancer 1994;11:259 – 74. [55] James LE, Gower NH, Rudd RM, et al. A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1996;73:1563 – 8. [56] Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998;16:1179 – 87. [57] Cruciani M, Rampazzo R, Malena M, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996;23:795 – 805. [58] Messori A, Trippoli S, Tendi E. G-CSF for the prophylaxis of neutropenic fever in patients with small cell lung cancer receiving myelosuppressive antineoplastic chemotherapy: meta-analysis and pharmacoeconomic evaluation. J Clin Pharm Ther 1996;21:57 – 63. [59] Klasa RJ, Murray N, Coldman AJ. Dose-intensity metaanalysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 1991;9:499 – 508. [60] 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. [61] Arriagada R, Le Chavalier T, Pignon JP, et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. New Engl J Med 1993;329:1848– 52. [62] Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577 – 80. [63] Murray N, Livingston R, Shepherd F, et al. Randomized study of CODE versus alternating CAV/PE for extensivestage small cell lung cancer: an intergroup study of the
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
[64]
[65]
[66]
[67]
[68]
[69]
[70]
National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999;17:2300 – 8. Sculier JP, Paesmans M, Bureau G, et al. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol 1993;11:1858–65. Souhami RL, Rudd R, Ruiz de Elvira MC, et al. Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial. J Clin Oncol 1994;12:1806–13. Pujol JL, Douillard JY, Riviere A, et al. Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 1997;15:2082 – 9. Steward WP, von Pawel J, Gatzemeier U, et al. Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 1998;16:642–50. Thatcher N, Sambrook R, Stephens R, et al. Dose intensification with G-CSF improves survival in small-cell lung cancer: results of a randomized trial. Proc Am Soc Clin Oncol 1998;17:456a. Humblet Y, Symann M, Bosly A, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study. J Clin Oncol 1987;5:1864–73. Leyvraz S, Perey L, Rosti G, et al. Multiple courses of high dose ifophamide, carboplatin and etoposide with peripheral-blood progenitor cells and filgrastim for smallcell lung cancer: a feasibility study by the European Group for blood and marrow transplantation. J Clin Oncol 1999;17:3531 –9.
.
185
[71] 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. [72] Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New Engl J Med 1992;327:1618 – 24. [73] Albain KS, Crowley JJ, Livingston RB. Long-term survival and toxicity in small cell lung cancer. Expanded Southwest Oncology Group experience. Chest 1991;99:1425 – 32. [74] Jacoulet P, Depierre A, Moro D, et al. Long-term survivors of small-cell lung cancer (SCLC): a French multicenter study. Groupe d’Oncologie de Langue Francaise. Ann Oncol 1997;8:1009 – 14. [75] Auperin A, Arriagada R, Pignon J, et al. Prophylactic cranial irradiation for patients with small cell cancer in complete remission. New Engl J Med 1999;341:476 – 84. [76] Lassen UN, Hirsch FR, Osterlind K, et al. Outcome of combination chemotherapy in extensive stage small-cell lung cancer: any treatment related progress? Lung Cancer 1998;20:151 – 60. [77] Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. New Engl J Med 1985;312:1604– 8. [78] Hirsch FR, Osterlind K, Jensen LI, et al. The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer. Ann Oncol 1992;3:469 – 74. [79] Sambook R, Girling D. A national survey of chemotherapy (CT) in small cell lung cancer (SCLC). Br J Cancer 1999;80(Suppl 2):14. [80] Collichio FA, Woolf PD, Brower M. Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion. Cancer 1994;73:1361 – 7.
Predictive and prognostic factors in small cell lung cancer: current status Desmond Yip, Peter G. Harper * Department of Medical Oncology, Guy’s Hospital, St Thomas St., London SE1 9RT, UK Received 7 September 1999; received in revised form 28 December 1999; accepted 29 December 1999
Abstract Clinical and laboratory parameters can predict response to chemotherapy and long term survival in small cell lung cancer, and may predict those at risk of early treatment related toxicity. This paper reviews the predictive models that have been developed to divide patients into prognostic groups for response and survival on the basis of clinical and laboratory parameters. These factors may be used for the stratification of patients in clinical trials and to help clinicians make appropriate treatment decisions for individual patients. A number of treatment-related factors can also affect outcomes. The evidence for interventions to prevent treatment deaths in high risk patients, such as prophylactic antibiotics, dosage modification or colony stimulating factor support are also reviewed. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Small cell lung cancer; Prognostic factors; Predictive factors; Chemotherapy; Survival; Treatment-related mortality
1. Introduction Small cell lung cancer (SCLC) is an extremely aggressive tumour with a poor clinical course. Without treatment, median length of survival after diagnosis is 1–3 months. It is however responsive to both chemotherapy and radiotherapy. Combination chemotherapy has produced overall response rates in the order of 80%, with limited This work was presented in part at the Prognostic and Predictive Factors 1st International Workshop in Lung Cancer Meeting, in Athens, Greece, June 17–19, 1999. * Corresponding author. Tel: + 44-207-9554624; fax: + 44207-9554939. E-mail address: [email protected] (P.G. Harper)
disease (LD) patients surviving a median of 14–16 months and extensive disease (ED) 8–11 months [1,2]. Long term survival is rare with only about 4% being alive at 5 years [3]. Prognostic factors are defined as those at the time of diagnosis that are able to give information on clinical outcome. Predictive factors are those that are able to provide information useful in the selection of patients likely to respond to therapies [4]. Studies have attempted to identify both the factors predictive of response and toxicity to treatment, as well as the prognostic factors that identify long term survivors. The aim of this article is to review the clinical characteristics and pretreatment laboratory factors that prognosticate survival and predict re-
0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 0 ) 0 0 1 0 5 - 7
174
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
sponse and early treatment mortality. A MEDLINE search was carried out covering the years 1980 –1999 to identify relevant studies in English-language medical journals. The following MeSH terms were used: small cell carcinoma, lung neoplasm, prognosis, survival and drug therapy.
2. Clinical characteristics
2.1. Clinical staging Clinical stage at initial presentation is one of the most powerful prognostic factors identified in most studies. The International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM (tumour, nodes, metastases) classification system was found to be inadequate for the staging of SCLC, as the extent of nodal involvement did not correlate with prognosis. This led to the development of the simple two-stage system of limited disease (LD) and extensive disease (ED) by the Veteran Affairs Administration Lung Study Group. An increasing number of metastatic sites carries a worsening prognosis in ED. Liver or cerebral metastases confer significantly shorter survival compared to bone, soft tissue or marrow involvement [5]. Shepherd [6] has defined a subgroup of patients within LD with no mediastinal node involvement (very limited disease) that has a better median survival. Superior vena caval obstruction (SVCO) in limited disease patients has not been found to be an adverse prognostic factor in multivariate analysis in 408 cases of SCLC (43 (11%) with SVCO) [7].
2.2. Performance status Poor performance status (Eastern Co-operative Oncology Group (ECOG) score 3 or 4) usually confers a poor prognosis [8 – 15]. This is a finding similar to many other tumour types. Performance status however is a subjective factor that can be affected by acute self-limited events.
2.3. Age Increasing age is associated with increasing comorbid conditions and reduced physiological reserves that can increase the toxicity of chemotherapy [16]. There may be a reluctance of clinicians to treat elderly patients because of this perceived frailty and certainly many clinical trials have excluded these patients [17]. Some retrospective studies have found that increasing age is an independent adverse prognostic factor in ED SCLC [9], in LD [18] and others in both [13]. A number of other studies [19–23] have found that the elderly (usually defined as above 70 years) experience a larger number of dosage reductions or omissions and suboptimal treatment with chemotherapy due to toxicities but their response rates and survivals are not necessarily inferior to a younger population. A review of patients treated with concurrent thoracic irradiation [24] has found that age did not appear to impact on the delivery, tolerance or efficacy of radiotherapy in combined modality therapy. The issues of treatment of the elderly with SCLC have been reviewed in detail by Johnson [25].
2.4. Sex A number of studies have suggested that female sex as a patient characteristic confers an independent survival benefit [26–29] and higher remission rate to treatment. Wolf [28] found this advantage was restricted to women aged less than 60 years, whilst Osterlind [9] observed a survival benefit only in LD.
2.5. Paraneoplastic phenomena The syndrome of ectopic corticotrophin (ACTH) secretion producing clinical Cushing’s syndrome is an uncommon association with SCLC and occurs in 3–7% of cases. Affected patients can present with increased pigmentation, oedema, hypertension, weakness, hypokalaemic metabolic alkalosis, hyperglycaemia and confusion. Four retrospective series [30–32,80] have shown that these patients have a very poor prognosis with a low response and control of the
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
hypercortisolism with chemotherapy. They are also susceptible to bacterial and opportunistic fungal or protozoal infections and gastrointestinal bleeding. The median survivals ranged up to 6 months [30]. Lambert–Eaton myasthenic syndrome (LEMS) is seen in 2–3% of patients with SCLC. It is characterised by muscle weakness and autonomic dysfunction the onset of which may precede the diagnosis of the cancer. There is a presynaptic disorder of impairment of acetylcholine release by detectable auto-antibodies to calcium channels and characteristic electromyographic features. A recent review of survival data from 15 SCLC patients with this condition found that they have a more favourable prognosis compared to matched patients without LEMS [33]. The important clinical factors related to prognosis are listed in Table 1.
3. Pre-treatment laboratory parameters Cohen first suggested in 1981 that simple laboratory results at the time of diagnosis may serve as prognostic factors [34]. A multivariate analysis of 56 patients with SCLC found that haemoglobin and albumin levels were correlated with survival. Souhami [35] carried out detailed analysis of clinical characteristics and laboratory tests at diagnosis and determined their relationship to survival in 371 patients entered on a prospective trial of chemotherapy. Eleven pretreatment variables were evaluated by multiple regression analysis. Two clinical factors were found to contribute to survival, PS (Karnofsky score (KS), above and below 70%) and clinical stage (ED and LD). No relationship to survival was found with either age Table 1 Clinical factors at presentation found significant in determining prognosis in small cell lung cancer Clinical stage Performance status Age Sex Paraneoplastic Cushings’ syndrome
175
or sex. Laboratory factors predicting survival were found to be serum alkaline phosphatase (SAP) (B 150% upper limit, \ 300% upper normal limit and in between), serum sodium and albumin. A prognostic model was developed incorporating these factors into an equation that divided patients into three groups: good prognosis, intermediate prognosis and poor prognosis. The patients in the ‘best’ prognostic group were found to have higher response rates to treatment and longer survivals. These findings were independently validated on a second data set from the Royal Marsden Hospital. Cerney [12] also produced a Cox regression analysis from a data set of 407 patients enrolled in sequential studies that divided patients into three prognostic groups. Pretreatment stage, performance status, serum sodium, lactate dehydrogenase (LDH), SAP and bicarbonate were found to be the independent factors. A simplified scoring system, the ‘Manchester score’ was also able to define the same groups with little loss of information and is thus more practical for clinical use. Further work by Souhami [36] was done on a group of patients entered on another trial of combination chemotherapy. The five previously defined factors were found to contribute prognostic information but also predicted both for early and late survivals. Interestingly the effect of performance status and SAP were found to be quantitative, with the death rate being related to the degree of abnormality of these factors. Allan [13] in a retrospective review of 411 SCLC patients from Edinburgh, found on Cox multivariate regression analysis that raised LDH and white cell count were independent adverse prognostic factors in addition to performance status, disease extent and age. If stage was eliminated from the analysis then a decreased serum chloride also became significant. In 1990 the Lung Cancer Subcommittee of the United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) produced a large overview to identify important prognostic factors in patients treated on trials [37]. Information was collected on 3873 patients from six centres in the United Kingdom. Two Medical Research Council (MRC) multicentre studies were initially excluded
176
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
Table 2 Pretreatment laboratory variables found significant in predicting prognosis Serum sodium Alkaline phosphatase Sodium bicarbonate Lactate dehydrogenase White cell count Neurone specific enolase
because they only collected minimal variables so that a total of 2303 patients were analysed. Seven variables were recorded for all data sets (age, sex, performance status, SAP, sodium and gamma glutamyl transpeptidase (GGT)). Subset analysis was carried out incorporating different variables as there were inconsistencies and incompleteness of the data collected by different centres. The laboratory ranges did vary between institutions but were not corrected for. Deaths were analysed in the first 6 months after starting treatment and also of those who were alive at the end of the 6 months. The analysis found that the main prognostic factors during the first 6 months after starting treatment were performance status, stage and alkaline phosphatase. The two excluded MRC studies were used to successfully validate these factors. Age, sex, sodium, GGT, albumin, urea and chloride provided small improvements in predicting survival. The longer-term prognostic variables (6 – 24 months) were found to be stage, performance status and sodium; with stage being the most important. Sagman [29] also carried out evaluation of retrospective data on 22 pretreatment attributes in 614 patients with SCLC of the lung to determine the effect on outcome using a number of statistical techniques. With univariate analysis, prognosis was influenced by disease extent, number of metastatic sites and spread to the mediastinum in LD. Cox regression analysis identified serum LDH and mediastinal spread in LD and performance status, number of metastatic sites, brain and bone metastases and platelet count in ED. The techniques of recursive partition and amalgamation algorithm
(RECPAM) classify patients with similar outcomes and identifies interactions between factors without them being specified beforehand. These were used to identify four risk groups stratified by disease extent, performance status, SAP, LDH, mediastinal spread, white cell count (WCC) and liver metastases. The groups had median survival times of 59, 49, 35, and 24 weeks, respectively (P= 0.0001). LDH and SAP were the most significant pretreatment laboratory variables contributing to the groupings. Kawahara [15] has also used RECPAM in a group of 300 patients from a randomised chemotherapy trial, to identify performance status, LDH and serum sodium as being factors that can divide SCLC patients into three prognostic groups. Two studies have further underscored the importance of LDH. Sagman [38] reviewed in detail 288 patients out of the 614 in the previous reported analysis [29] whom pretreatment LDH levels were available. LDH was found to correlate with stage, response to treatment and survival. The survival advantage for patients with normal LDH persisted even when adjustment was made for stage, PS and treatment protocol. Albain [18] analysed the Southwest Oncology Group (SWOG) experience of 2501 patients from ten consecutive trials from 1976–1986. Cox multivariate analysis identified good PS, female sex, age less that 70 years, white race and normal LDH as significant good prognostic factors in LD. A normal LDH and single metastatic site were found to be important favourable pretreatment variables in LD patients. RECPAM analysis found that a smaller number of variables could be used to define prognostic subgroups. The most important divisions were between LD and ED, followed by normal versus abnormal LDH level. The important pretreatment laboratory variables are listed in Table 2.
4. Histological factors The World Health Organisation (WHO) histopathological system of SCLC classifies tumours
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
into oat cell carcinoma, intermediate type and combined oat and intermediate type carcinoma. This is based on light microscopy appearance. Carney [39] has reviewed the histological subtypes of a series of 104 patients with SCLC treated with chemotherapy. No significant difference was found in the initial PS, extent of disease, chemotherapeutic response rate, or survival noted among these histologic subtypes. In addition some patients had more than one histological subtype found when biopsies were taken from more than one site. The concordance rate was 74% with the remaining exhibiting two or three subtypes. The Pathology Committee of the International Association for the Study of Lung Cancer proposed dividing SCLC into three subtypes: pure SCLC, mixed small cell/large cell carcinoma and combined SCLC with squamous components. Histological and cytological specimens from 430 patients [40] have shown that the presence of a large cell component confers a poorer response to treatment and worse prognosis than those with pure SCLC. This supports the findings of other investigators [41–43]. Immunohistochemistry in SCLC has not been found to give consistent useful prognostic information. A study [44] was carried out on archival specimens obtained from fibre-optic bronchoscopy of 70 age-matched short term survivors (died within 3 months) and long term survivors (survived more than 3 years). There was no correlation with survival found on a bank of 11 immunohistochemical neuroendocrine and epithelial markers. DNA ploidy and S-phase fraction has been correlated with treatment response and prognosis in a number of tumour types. Flow cytometric examination of a series of 36 SCLC [45] patients has found no difference in survival between diploid and aneuploid or high and low S-phase tumours. No relation to treatment response was found either supporting a previous study [46]. The main importance of histopathology now is to distinguish SCLC from non small cell lung cancer and bronchial carcinoid tumours. This may require the use of immunohistochemistry techniques.
177
5. Serum markers
5.1. Neurone specific enolase Neurone specific enolase (NSE) is a glycolytic enzyme secreted by neural and neuroendocrine tissue. The serum level is elevated in 80% of patients with SCLC and is probably the most sensitive marker for SCLC at the time of diagnosis. The level is generally higher in extensive compared to limited disease. Jorgensen [47] has attempted to derive a prognostic model for survival based on analysis of NSE in combination with other factors (stage, PS, age, sex, lactate dehydrogenase, SAP and carcinoembryonic antigen) in 787 patients from nine centres in six countries. Multivariate regression analysis showed that elevated serum NSE was the most important adverse prognostic factor followed by poor performance status and extensive disease. Fizazi [48] assessed the predictive value, in terms of survival and complete response, of the serum NSE measured before and after a cycle of chemotherapy in patients with SCLC. In a group of 135 patients studied, complete response was seen in 62% of patients who had normalised NSE at day 28 post-chemotherapy as opposed to 34% otherwise. Median and 2-year overall survival was also found to be significantly improved (PB 0.03) if NSE was normalised. This study also confirmed that a normal day-28 serum NSE, disease extent and performance status were independent prognostic factors for survival on multivariate analysis.
5.2. Anti-Hu antibodies There is anecdotal observation [49] that SCLC patients with paraneoplastic neurological manifestations (e.g. peripheral neuropathy, cerebellar degeneration) have a more indolent course than those without. Patients with paraneoplastic encephalomyelitis/sensory neuronopathy from SCLC almost always have high titre antineuronal antibodies (anti-Hu) detectable in the serum and cerebrospinal fluid. Low titres of anti-Hu are found in a proportion of patients without paraneoplastic neurological manifestations. Graus [50]
178
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
collected serum samples from 196 SCLC patients without paraneoplastic encephalomyelitis – sensory neuropathy and screened them for anti-Hu. In patients who received treatment, anti-Hu was found to be associated with limited disease stage, complete response to treatment and a longer survival. Anti-Hu was found to be an independent predictive factor for complete response to therapy but not survival on multivariate analysis.
6. Predicting early chemotherapy related mortality In a number of large chemotherapy trials [10,11,51,52] of SCLC, an abrupt fall off in the survival curves has been noted in the period after commencement of chemotherapy. This early mortality is related to chemotherapy toxicity producing neutropenic sepsis. Poplin [10,11] analysed the influence of age on outcome of 223 patients with SCLC and found that increasing age was correlated with increasing degrees of myelosuppression and first course admissions with febrile neutropenia. Sudden and toxic deaths were found to correlate with poor performance status rather than age. Morittu [52] analysed the clinical and biochemical factors to determine those that predicted early mortality. In this series of 610 patients on a combination chemotherapy study, 71 patients died in the first 3 weeks of commencing therapy. The peak incidence was noted between 7 and 10 days corresponding to the period of neutrophil nadir. The characteristics of these patients were compared with those of a matched cohort that did not die in the first 3 weeks. The factors highly significant in predicting early mortality were found to be poor PS (P B 0.00001), clinical hepatomegaly (P B 0.0001), raised SAP (P B0.00001), elevated blood urea (P B 0.00001), low albumin (P B 0.00005) and low serum sodium (P B 0.02). These data suggest that hepatic involvement and reduced renal clearance are associated with high risk of early death, possibly because of altered pharmacokinetics of etoposide in these regimens.
Radford [53] also analysed the incidence and risk of septic complications in a group of 382 SCLC patients treated in five consecutive chemotherapy trials at the one institution. The unit policy was to utilise full protocol doses throughout the treatment despite episodes of severe or life-threatening sepsis. The study found that second or further septic episodes were more likely after a first episode than if the cycles of chemotherapy had been free from sepsis. A model of four risk factors was developed that predicted the odds of treatment related sepsis occurring. These factors were an age of greater than 50 years, treatment with a three-drug regimen (as compared to two drugs), Karnofsky score less than or equal to 50 and a previous episode of severe or life-threatening sepsis. The MRC [54] reviewed a total of 2196 patients in 1994 enrolled in six randomised studies carried out over a 30-year period. The majority received combination chemotherapy but patients who had initial surgery or radiotherapy were also included. There was an excess of deaths found in the second week after commencement of the first cycle of chemotherapy. This was in excess of the underlying rate of natural attrition. The Radford model was refined further by regression analysis to improve discrimination of the groups. The performance status was adjusted to PS] 2 (KS 5 70) and, age\ 70 years and four or more drugs. WCC] 10 was found to be a better discriminator than age. A simple model of the presence of three main factors (PS] 2, WCC] 10 and four or more drugs in chemotherapy regimen) predicted the high-risk category of those likely to die from treatment related causes. This model requires further validation in other data sets.
7. Prevention of early chemotherapy related mortality The question thus arises of how to identify and manage those SCLC patients who are at high risk of treatment related mortality.
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
7.1. Dose reduction Radford [53] has suggested an empirical half dosing of the chemotherapy on the first cycle of treatment, escalating towards full dosage on subsequent cycles on the basis of toxicity and nadir counts. With the relatively short median survivals of ED SCLC this fall in dosage intensity is not likely to make a large difference in the survival of these patients. There is no direct data to support this practice. However James [55] reported a randomised study in 167 poor prognosis ED SCLC patients comparing a standard chemotherapy regimen with a half dose regimen that was given with twice the frequency with the same intended dose intensity. The standard arm was found to have a toxic death rate of 7.9% while no toxic deaths were observed in the half dose arm despite there being a higher infection rate and haematological toxicity. Response and median survival were similar.
7.2. Prophylactic antibiotics The use of prophylactic antibiotics in the prevention of infection in neutropenic patients with malignancy has been investigated in a number of clinical studies. The results however have been conflicting. The studies have involved relatively small numbers of patients with not all trials being blinded in their treatment arms, giving rise to the possibility of bias in the assessment of febrile episodes. None have looked specifically at SCLC patients. A meta-analysis [56] of nine trials of quinolone antibiotic prophylaxis versus no antibiotic prophylaxis was carried out in 1998 and included 704 patients. This found that quinolones produced significant reductions in the relative risk of Gram negative infections (which make up the majority of life-threatening neutropenic sepsis episodes), Gram negative bacteraemia, microbiologically documented infections, fever and total infections. No increase was seen in the incidence of Gram positive or fungal infections that may be selected out by the quinolones that have a mainly Gram negative spectrum of activity. A second part of the meta-analysis [56] looked at nine trials involving 677 patients and compared quinolone
179
with cotrimoxazole prophylaxis finding that quinolones resulted in reductions of Gram negative infection, Gram negative bacteraemia, microbiologically proven infections and the total number of infections. The risk reduction was similar to the order of magnitude seen in the comparison of quinolones to no prophylaxis meta-analysis suggesting there was little benefit to the use of cotrimoxazole. Another meta-analysis [57] compared trials of quinolones alone or in combination with antibiotics active against Gram positive infections (penicillin, vancomycin, or macrolides). Whilst the incidence of Gram positive bacteraemia was reduced, the rate of mortality or febrile episodes was found to be unaffected. The answer to whether antibiotic prophylaxis has a true role in prevention of clinical infection from chemotherapy induced neutropenia should be provided by the ‘Significant Trial’. This is an ongoing prospective randomised double-blind controlled study of prophylactic levofloxacin (a quinolone) versus placebo following chemotherapy in patients with solid tumours and lymphoma. The trial is coordinated by the United Kingdom Cancer Research Campaign and plans to accrue 1500 subjects.
7.3. Growth factor support The use of the colony stimulating factor G-CSF to prevent chemotherapy induced neutropenia has been investigated in SCLC. A meta-analysis [58] of three studies that enrolled 606 SCLC patients receiving conventional dose chemotherapy with or without G-CSF support, found that there was a significant reduction in the rate of febrile neutropenia with G-CSF (68.3–38.7%) but no reduction in mortality. The patients in these trials were not all at high risk and the power of the studies combined may still not have been enough to detect a difference in mortality of all comers with SCLC.
8. Treatment related predictive factors There has been a trend towards the use of more active agents and more intensive chemotherapy
180
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
regimens in the treatment of SCLC over the past three decades. Several retrospective analyses [18,26,27] have found that the use of intensive multidrug regimens appears to be independently prognostic after adjustment for other variables. A selective review [2] of recent non-randomised phase II aggressive protocols in ED SCLC suggests that despite the higher toxicities, there are higher total response rates and complete remissions produced with lengthening of median survivals when compared to intermediate intensity regimens.
8.1. Dose intensification Klassa [59] performed a meta-analysis of 60 studies (randomised and non randomised) of chemotherapy regimens in SCLC, published between 1975 and 1988, to assess the relationship between intended dose intensity, response and median survival. No consistent correlations were found. Randomised trials have been performed to specifically determine the effect of dose intensity on outcome.
8.1.1. Dose intensity An MRC randomised trial [60] found that some patients may not necessarily benefit from more intensive treatment. This study randomised 310 poor prognosis (ED or LD with poor PS) SCLC patients between a four drug regimen (etoposide, cyclophosphamide, methotrexate and vincristine (ECMV)) and a less intensive two drug regimen (etoposide and vincristine (EV)). No difference was seen in response or survival, but the ECMV regimen was associated with higher toxicity as well as early deaths. Another randomised study [61] in 105 LD patients has suggested that moderately higher initial doses of chemotherapy (cyclophosphamide and cisplatin) in a four drug regimen that included doxorubicin and etoposide can improve disease free and overall survival. Conversely there is a risk of compromising outcomes with minimally intensive protocols in poor prognosis patients. The MRC [60] and the London Lung Cancer Group [62] both carried out studies comparing single agent oral etoposide
against intravenous combination chemotherapy regimens. Both studies were prematurely terminated when interim analyses showed that oral etoposide was associated with inferior response rates, higher haematological toxicity and reduced survival.
8.1.2. Dose density Relative dose intensity can be increased by reducing the interval between treatments; so called dose density. A recent intergroup study [63] conducted by the National Cancer Institute of Canada (NCIC) and Southwest Oncology (SWOG) Group compared alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/PE) with an intensive weekly regimen of cisplatin, vincristine, doxorubicin and etoposide (CODE) in 220 patients with ED SCLC aged under 68. Consolidative thoracic irradiation and prophylactic cranial radiotherapy was administered to patients in the CODE group who responded. The CODE regimen delivered double the dose intensity of the CAV/PE regimen while administering approximately the same total dose of drugs. It also incorporated additional supportive care with corticosteroids and prophylactic antibiotics but not G-CSF. Although the response rate was higher with CODE (87 vs. 70%) there was an excess treatment related mortality (8.2 vs. 1%) and no overall difference seen in the progression free survival or over survival compared with CAV/PE. These results confirm the findings of two previous randomised studies [64,65] of combination chemotherapy comparing dose-dense weekly regimens to conventional 3-weekly regimens. No benefit for weekly therapy was found with either study. 8.1.3. Dose intensification with growth factors A small study from Manchester randomised 65 SCLC patients with one or no adverse prognostic factors to treatment by dose escalated VICE (vincristine, ifosfamide, carboplatin, and etoposide) with or without G-CSF. Dosing interval was not fixed and subsequent cycles were administered when blood counts had recovered. Significantly higher dose intensity was achieved with G-CSF
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
and a higher 2-year survival of 32 vs. 15% was seen. A French group [66] investigated a high dose regimen of cyclophosphamide, epirubicin, etoposide and cisplatin with GM-CSF support compared to a standard dose regimen without cytokine in 125 patients with ED. No difference was seen in response rates. A higher haematological toxicity rate was seen with the dose intense arm as well as an adverse effect on median overall survival (8.9 vs. 10.8 months, P =0.0005) Two large randomised studies have shown promising results. Steward et al. [67] compared standard VICE (4-weekly) with dose intensified VICE (3-weekly) in 300 patients of good and intermediate prognosis on ‘Manchester score’ [12]. A secondary randomisation was made to granulocyte-macrophage colony stimulating factor (GM-CSF). Dose intensification in this schedule was associated with an increase in 2year survival and no increase in toxicity. GMCSF had no influence on myelosuppressive complications. The MRC [68] compared ACE (doxorubicin, cyclophosphamide and etoposide) given 3 weekly with ACE plus G-CSF scheduled fortnightly in 403 patients with good performance status SCLC. Improved 1-year survival was been seen with the dose intense arm.
8.1.4. Dose escalation with stem cell support A randomised study of late intensification in LD patients with high dose chemotherapy followed by autologous bone marrow transplantation found an increased complete remission rate and relapse free survival rate but no increase in overall survival on the intensified arm [69]. Numbers were small and there was a high toxic death rate with intensification. Intensive protocols delivering relative dose intensities approaching 300% of conventional therapy by the use of peripheral stem cell support have been shown to be feasible with lower toxic deaths [70]. The results of a randomised trial of a high dose ICE (ifosfamide, cisplatin and etoposide) compared to standard ICE are awaited.
181
8.2. Thoracic irradiation Two meta-analyses [71,72] have shown that the addition of thoracic radiotherapy to consolidate response in LD SCLC improves survival at 2 and 3 years by 5.4%. Multivariate analysis of both the SWOG database [18,73] of SCLC patients treated from 1976 to 1986 and a French series [74] of 1986–1995 also found that chest radiotherapy was a consistent independent favourable factor for long term survival.
8.3. Prophylactic cranial irradiation The role of prophylactic cranial irradiation (PCI) in patients who have achieved complete response in SCLC has been controversial. Studies performed have suffered from methodological problems or insufficient statistical power. A recent meta-analysis [75] of seven randomised studies has found that overall survival is improved by 5.4% in absolute terms at 3 years with the additional of PCI.
8.4. O6er6iew Two large retrospective studies have reviewed the outcomes of patients over a 20-year period to see whether there has actually been any treatment related progress. Chute [14] has reviewed all the SCLC patients treated at the US National Cancer Institute from 1973 to 1993. The patients were divided into two groups based on the decade of diagnosis, 1973–1983, when cyclophosphamide-based chemotherapy regimens were used and 1983–1993, when cisplatin-based regimens were used. No significant change was found in the pretreatment factors in these two groups and no significant difference was found in the survivals of the patients despite the change in treatment regimens. On a multivariate analysis a modest survival benefit was noted in LD patients who received cisplatin chemotherapy in combination with radiotherapy when compared to cyclophosphamide containing regimens. Lassen [76] reviewed 1111 patients with ED SCLC treated on six consecutive chemotherapy trials from 1973 to 1992 in Danish and Swedish
182
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
centres. Patients treated in the period 1973 – 1981 were compared to those treated from 1981 to 1992. On comparing pretreatment prognostic factors there was an increase in the percentage of female patients in the later period (35 vs. 27%) and also a higher detection of liver metastases at diagnosis (40 vs. 33%). The frequency of extensive disease patients was unchanged in the two periods. No significant differences in overall response rates and survival were seen. An interesting observation in this study was a steep initial slope of the survival curve from the later period suggesting that the more intense regimens were producing toxic deaths. The phenomenon of stage migration can confound the comparisons of patients treated in different periods of time [77]. This may arise due to the improvement in imaging modalities [78] such as computed tomography (CT) scanning, magnetic resonance imaging (MRI) improving the sensitivity in detection of metastatic disease. The effect in SCLC would be the upstaging of more LD patients by the detection of other sites of involvement and thus making the survivals of both LD and ED appear better. However this effect was not apparent in either of the above studies as neither LD or ED patient survival improved.
9. Conclusion Clinical and laboratory parameters can predict response to chemotherapy, and may predict those at risk of treatment related toxicity as well as the long term survivors in SCLC. Performance status and disease extent are almost uniformly found to be the most important clinical factors. Retrospective analyses by different investigators have found different sets of laboratory factors and serum markers that are of independent prognostic or predictive value. LDH is possibly the most important pretreatment laboratory factor. Few of these sets have been prospectively validated. These factors may be used for patient stratification in clinical trials and to help clinicians make appropriate treatment decisions for individuals. A recent survey [79] of consultants in the United
Kingdom who treat SCLC, has found that there is general agreement that the goals of therapy are different in good and bad prognosis patient groups however they are defined. The aim is to produce a proportion of long term survivors in good prognosis patients, whilst ensuring maximal palliation with minimal toxicity is the goal in poor prognosis. This in turn influences the treatments that are prescribed. It is possible to identify individuals at risk of early treatment mortality and toxicity using the models that have been described. Further studies are required to determine how to best deal with these high-risk patients, to minimise the early treatment related mortality and to give them the best form of palliation and prolongation of life. Despite the use of more active drugs and more intensive regimens, chemotherapy response rates and median survivals do not seem to have improved significantly overall in the past two decades. Although individual studies and overviews have shown a benefit from treatment related factors in different settings, there has not been consistency in the grouping of patients for these trials. This also makes generalisation of results to clinical practice difficult as well as crosscomparison of studies. It is 15 years since Souhami performed the first analysis of clinical and laboratory factors influencing prognosis. There now needs to be agreement amongst investigators as to which of these factors are incorporated into clinical trial stratification to allow valid comparisons between studies.
References [1] Hansen H, Pappot H. Primary malignant tumours of the lung and pleura. In: Cavalli F, Hansen H, Kaye S, editors. Textbook of Medical Oncology. London: Martin Dunitz, 1997:139 – 57. [2] Aisner J. Extensive-disease small cell lung cancer: the thrill of victory; the agony of defeat. J Clin Oncol 1996;12:658 – 65. [3] Souhami R, Law K. Longevity in small cell lung cancer. Br J Cancer 1990;61:584 – 9. [4] Gasparini G, Pozza F, Harris AL. Evaluating the potential usefulness of new prognostic and predictive indicators in node-negative breast cancer patients. J Natl Cancer Inst 1993;85:1206 – 19.
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185 [5] Ihde DC, Makuch RW, Carney DN, et al. Prognostic implications of stage of disease and sites of metastases in patients with small cell carcinoma of the lung treated with intensive combination chemotherapy. Am Rev Respir Dis 1981;123:500 – 7. [6] The University of Toronto Lung Oncology Group, Shepherd FA, Ginsberg RJ, Haddad R, et al. Importance of clinical staging in limited small-cell lung cancer: a valuable system to separate prognostic subgroups. J Clin Oncol 1993;11:1592 –7. [7] Wurschmidt F, Bunemann H, Heilmann HP. Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 1995;33:77–82. [8] Maurer LH, Pajak TF. Prognostic factors in small cell carcinoma of the lung: a cancer and leukemia group B study. Cancer Treat Rep 1981;65:767–74. [9] Osterlind K, Andersen PK. Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation. Cancer Res 1986;46:4189–94. [10] Anonymous. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Br J Cancer 1989;59:584–90 Report to the Medical Research Council by its Lung Cancer Working Party. [11] Poplin E, Thompson B, Whitacre M, et al. Small cell carcinoma of the lung: influence of age on treatment outcome. Cancer Treat Rep 1987;71:291–6. [12] Cerny T, Blair V, Anderson H, et al. Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 1987;39:146–9. [13] Allan SG, Stewart ME, Love S, et al. Prognosis at presentation of small cell carcinoma of the lung. Eur J Cancer 1990;26:703 –5. [14] Chute JP, Venzon DJ, Hankins L, et al. Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 1997;72:901–12. [15] Kawahara M, Fukuoka M, Saijo N, et al. Prognostic factors and prognostic staging system for small cell lung cancer. Jpn J Clin Oncol 1997;27:158–65. [16] 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. [17] Yip D, Harper PG. Cancer in the elderly: gathering the evidence. Med J Aust 1999;170:577–8. [18] Albain KS, Crowley JJ, LeBlanc M, et al. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563–74. [19] Kelly P, O’Brien A, Daly P, et al. Small cell carcinoma in elderly patients: the case for chemotherapy. Age Ageing 1991;20:19 – 22. [20] Goss G, Logan D, Maroun J, et al. Chemotherapy in small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 1992;11:290 Abstract.
183
[21] Paccagnella A, Favaretto A, Cipriani A, et al. Treatment of small cell lung cancer (SCLC) in elderly patients. Proc Annu Meet Am Soc Clin Oncol 1996;15:A1164 Meeting abstract. [22] 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. [23] Siu LL, 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. [24] Quon H, Shepherd FA, Payne DG, et al. The influence of age on the delivery, tolerance, and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1999;43:39 – 45. [25] Johnson DH. Small cell lung cancer in the elderly patient. Semin Oncol 1997;24:484 – 91. [26] Osterlind K, Hansen HH, Hansen M, et al. Long-term disease-free survival in small-cell carcinoma of the lung: a study of clinical determinants. J Clin Oncol 1986;4:1307 – 13. [27] Spiegelman D, Maurer LH, Ware JH, et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1521 patients. J Clin Oncol 1989;7:344 – 54. [28] Wolf M, Holle R, Hans K, et al. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival. Br J Cancer 1991;63:986 – 92. [29] Sagman U, Maki E, Evans WK, et al. Small-cell carcinoma of the lung: derivation of a prognostic staging system. J Clin Oncol 1991;9:1639 – 49. [30] Shepherd FA, Laskey J, Evans WK, et al. Cushing’s syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol 1992;10:21 – 7. [31] Delisle L, Boyer MJ, Warr D, et al. Ectopic corticotropin syndrome and small-cell carcinoma of the lung. Clinical features, outcome, and complications. Arch Intern Med 1993;153:746 – 52. [32] Dimopoulos MA, Fernandez JF, Samaan NA, et al. Paraneoplastic Cushing’s syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer. Cancer 1992;69:66 – 71. [33] Maddison P, Newsom-Davis J, Mills KR, et al. Favourable prognosis in Lambert – Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet 1999;353:117 – 8 letter. [34] Cohen MH, Makuch R, Johnston-Early A, et al. Laboratory parameters as an alternative to performance status in prognostic stratification of patients with small cell lung cancer. Cancer Treat Rep 1981;65:187 – 95. [35] Souhami RL, Bradbury I, Geddes DM, et al. Prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung. Cancer Res 1985;45:2878 – 82. [36] Souhami RL, Earl HM, Ash CM, et al. Prognostic factors in patients with small-cell lung cancer: preliminary results
184
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185 from a large randomised study. Antibiot Chemother 1988;41:77 – 82. Rawson NS, Peto J. An overview of prognostic factors in small cell lung cancer. Br J Cancer 1990;61:597–604 A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Published erratum appears in Br J Cancer 1990;62(3):550. Sagman U, Feld R, Evans WK, et al. The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer. J Clin Oncol 1991;9:954 – 61. Carney DN, Matthews MJ, Ihde DC, et al. Influence of histologic subtype of small cell carcinoma of the lung on clinical presentation, response to therapy, and survival. J Natl Cancer Inst 1980;65:1225–30. Fushimi H, Kukui M, Morino H, et al. Detection of large cell component in small cell lung carcinoma by combined cytologic and histologic examinations and its clinical implication. Cancer 1992;70:599–605. Hirsch FR, Osterlind K, Hansen HH. The prognostic significance of histopathologic subtyping of small cell carcinoma of the lung according to the classification of the World Health Organization. A study of 375 consecutive patients. Cancer 1983;52:2144–50. Radice PA, Matthews MJ, Ihde DC, et al. The clinical behavior of ‘mixed’ small cell/large cell bronchogenic carcinoma compared to ‘pure’ small cell subtypes. Cancer 1982;50:2894 – 902. Sehested M, Hirsch FR, Osterlind K, et al. Morphologic variations of small cell lung cancer. A histopathologic study of pretreatment and post-treatment specimens in 104 patients. Cancer 1986;57:804–7. Bobrow LG, Hirsch FR, Hay FG, et al. An immunohistochemical investigation of diagnostic biopsy material taken from short and long term survivors with small cell lung cancer. Br J Cancer 1992;66:547–51. Viren MM, Ojala AT, Kataja VV, et al. Flow cytometric analysis of tumor DNA profile related to response to treatment and survival in small-cell lung cancer. Med Oncol 1997;14:35 – 8. Kimura T, Sato T, Onodera K. Clinical significance of DNA measurements in small cell lung cancer. Cancer 1993;72:3216 – 22. Jorgensen LG, Osterlind K, Genolla J, et al. Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres. Br J Cancer 1996;74:463 – 7 published erratum appears in Br J Cancer 1996;74(12):2043. Fizazi K, Cojean I, Pignon JP, et al. Normal serum neuron specific enolase (NSE) value after the first cycle of chemotherapy: an early predictor of complete response and survival in patients with small cell lung carcinoma. Cancer 1998;82:1049–55. Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 1993;341:21–2.
[50] Graus F, Dalmou J, Rene R, et al. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997;15:2866 – 72. [51] Hirsch FR, Hansen HH, Hansen M, et al. The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: a randomized trial of 288 consecutive patients. J Clin Oncol 1987;5:585 – 91. [52] Morittu L, Earl HM, Souhami RL, et al. Patients at risk of chemotherapy-associated toxicity in small cell lung cancer. Br J Cancer 1989;59:801 – 4. [53] Radford JA, Ryder WD, Dodwell D, et al. Predicting septic complications of chemotherapy: an analysis of 382 patients treated for small cell lung cancer without dose reduction after major sepsis. Eur J Cancer 1992;29A:81 – 6. [54] Stephens RJ, Girling DJ, Machin D. Treatment-related deaths in small cell lung cancer trials: can patients at risk be identified? Medical Research Council Lung Cancer Working Party. Lung Cancer 1994;11:259 – 74. [55] James LE, Gower NH, Rudd RM, et al. A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1996;73:1563 – 8. [56] Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998;16:1179 – 87. [57] Cruciani M, Rampazzo R, Malena M, et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996;23:795 – 805. [58] Messori A, Trippoli S, Tendi E. G-CSF for the prophylaxis of neutropenic fever in patients with small cell lung cancer receiving myelosuppressive antineoplastic chemotherapy: meta-analysis and pharmacoeconomic evaluation. J Clin Pharm Ther 1996;21:57 – 63. [59] Klasa RJ, Murray N, Coldman AJ. Dose-intensity metaanalysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 1991;9:499 – 508. [60] 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. [61] Arriagada R, Le Chavalier T, Pignon JP, et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. New Engl J Med 1993;329:1848– 52. [62] Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577 – 80. [63] Murray N, Livingston R, Shepherd F, et al. Randomized study of CODE versus alternating CAV/PE for extensivestage small cell lung cancer: an intergroup study of the
D. Yip, P.G. Harper / Lung Cancer 28 (2000) 173–185
[64]
[65]
[66]
[67]
[68]
[69]
[70]
National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999;17:2300 – 8. Sculier JP, Paesmans M, Bureau G, et al. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol 1993;11:1858–65. Souhami RL, Rudd R, Ruiz de Elvira MC, et al. Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial. J Clin Oncol 1994;12:1806–13. Pujol JL, Douillard JY, Riviere A, et al. Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 1997;15:2082 – 9. Steward WP, von Pawel J, Gatzemeier U, et al. Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 1998;16:642–50. Thatcher N, Sambrook R, Stephens R, et al. Dose intensification with G-CSF improves survival in small-cell lung cancer: results of a randomized trial. Proc Am Soc Clin Oncol 1998;17:456a. Humblet Y, Symann M, Bosly A, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study. J Clin Oncol 1987;5:1864–73. Leyvraz S, Perey L, Rosti G, et al. Multiple courses of high dose ifophamide, carboplatin and etoposide with peripheral-blood progenitor cells and filgrastim for smallcell lung cancer: a feasibility study by the European Group for blood and marrow transplantation. J Clin Oncol 1999;17:3531 –9.
.
185
[71] 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. [72] Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New Engl J Med 1992;327:1618 – 24. [73] Albain KS, Crowley JJ, Livingston RB. Long-term survival and toxicity in small cell lung cancer. Expanded Southwest Oncology Group experience. Chest 1991;99:1425 – 32. [74] Jacoulet P, Depierre A, Moro D, et al. Long-term survivors of small-cell lung cancer (SCLC): a French multicenter study. Groupe d’Oncologie de Langue Francaise. Ann Oncol 1997;8:1009 – 14. [75] Auperin A, Arriagada R, Pignon J, et al. Prophylactic cranial irradiation for patients with small cell cancer in complete remission. New Engl J Med 1999;341:476 – 84. [76] Lassen UN, Hirsch FR, Osterlind K, et al. Outcome of combination chemotherapy in extensive stage small-cell lung cancer: any treatment related progress? Lung Cancer 1998;20:151 – 60. [77] Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. New Engl J Med 1985;312:1604– 8. [78] Hirsch FR, Osterlind K, Jensen LI, et al. The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer. Ann Oncol 1992;3:469 – 74. [79] Sambook R, Girling D. A national survey of chemotherapy (CT) in small cell lung cancer (SCLC). Br J Cancer 1999;80(Suppl 2):14. [80] Collichio FA, Woolf PD, Brower M. Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion. Cancer 1994;73:1361 – 7.