New Immunotherapy and Lung Cancer. / Nueva inmunoterapia y cáncer de pulmón.

Recent research on the relationship between the immune system and cancer has revealed the molecular mechanisms by which cancer cells co-opt certain T cell receptors which block the cytotoxic response to defend themselves from the antitumor immune attack. These findings have helped identify specific targets (T cell receptors or their corresponding ligands) for the design of monoclonal antibodies that can unlock the immune response. These drugs, known as immune checkpoint inhibitors, have shown efficacy in metastatic melanoma and kidney cancer, and have been successfully tested in non-small cell lung cancer in recent trials. Immune checkpoint inhibitors were included in clinical practice as a second-line option after an initial chemotherapy (CT) regimen, and in the last year positive results have been reported from randomized trials in which they were compared in first line with standard CT. Responses have been surprising and durable, but less than 20%-25% in unselected patients, so it is essential that factors predicting efficacy be identified. One such biomarker is PD-L1, but the different methods used to detect it have produced mixed results. This non-systematic review discusses the results of the latest trials, the possibilities of incorporating these drugs in first-line regimens, the criteria for patient selection, adverse effects, and the prospects of combinations with conventional treatment modalities, such as CT, radiation therapy, and antiangiogenic agents.

[Analysis of drug therapy of lung cancer in Hungary]. / A tüdorák hazai gyógyszeres kezelésének elemzése.

Hungary is a world leader in lung cancer deaths, so it is particularly important that patients could have access to modern treatments. The aim of our analysis was to find how drug treatments are used in Hungary and how they are compatible with international practice. The in-patient and prescription database of the National Health Insurance Fund for three years (2008-2010) was used to study the frequency of certain chemotherapy protocols, the duration of therapies, and the changes in the individual protocols and drugs used for lung cancer treatment (ICD: C33H0-C34) during the reviewed period. We did not differentiate between neoadjuvant and adjuvant treatment and therapy after progression. During the study period 12326 lung cancer patients received first-line chemotherapy, one third of those (n=3791) received second-line, and one third of those (n=1174) third-line treatment. The average treatment duration was between 3 and 4 months. The first-line treatment of NSCLC mainly consisted of platinum treatment in combination with third generation cytotoxic agents. A downward trend of gemcitabine, still the most common combination compound, was observed, in parallel with the increased use of paclitaxel, and as a consequence carboplatin replaced cisplatin. Among new agents the use of pemetrexed and bevacizumab has increased. Pemetrexed appeared mainly in second-line treatment, while erlotinib also in second, but mostly in third line. The first-line treatment of SCLC consisted of a platinum-etoposide combination, and in second-line setting topotecan was the most commonly used drug. According to our results the chemotherapeutic combinations and sequencing are in accordance with international and national recommendations. Further detailed analysis of the available data may help to obtain more accurate picture of the efficacy of lung cancer treatments as well.

A critical appraisal of the adjuvant chemotherapy guidelines for patients with completely resected T3N0 non-small-cell lung cancer.

BACKGROUND: A Joint Expert Panel recently published guidelines for adjuvant cisplatin-based chemotherapy, recommending routine use in patients with completely resected stage II (T1-2N1 and T3N0) non-small-cell lung cancer (NSCLC). However, these two tumor subgroups should be considered as different entities. While the efficacy of adjuvant chemotherapy has been established in patients with T1-2N1 NSCLC, its benefit in patients with T3N0 tumor remains questionable. MATERIAL AND METHODS: We performed an extensive review of the literature using the Joint Expert Panel guidelines as a start point. Altogether, we identified 76 potentially relevant articles. Basing on inclusion and exclusion criteria, 23 of the 76 articles were eventually included in this review. RESULTS: After careful evaluation of the selected articles, we found no information on the effect of adjuvant chemotherapy in patients with T3N0 NSCLC. DISCUSSION: In the absence of evidence-based data, we recommend that the lack of information on the efficacy of adjuvant chemotherapy for T3N0 tumors be discussed with patients and propose chemotherapy as an individual option. While the efficacy of adjuvant chemotherapy will be difficult to assess prospectively through a large randomized clinical trial, a pooled-analysis of the existing data would quickly and with a limited effort provide a preliminary answer.

Costs associated with intravenous chemotherapy administration in patients with small cell lung cancer: a retrospective claims database analysis.

OBJECTIVES: With new oral chemotherapy drugs emerging, it is useful to understand the costs associated with traditional intravenous (IV) therapy. This study aims to assess costs associated with IV chemotherapy in patients with small cell lung cancer (SCLC) from the perspective of large employer-payers. STUDY DESIGN: Descriptive retrospective claims database analysis. METHODS: Using medical claims data from 5.5 million beneficiaries between 01/01/1998 and 01/31/2006, we identified patients with lung cancer (ICD-9 codes 162.3-162.9, 176.4, or 197.0) who received IV chemotherapy. A case-finding SCLC algorithm was then applied which selected patients who were treated with chemotherapies commonly used in SCLC (cisplatin/etoposide, cisplatin/irinotecan, carboplatin/etoposide, topotecan, or cyclophosphamide/doxorubicin/vincristine) and then excluded those who had treatments or procedures indicative of non-small cell lung cancer (NSCLC) (positron emission tomography [PET] scan imaging, lung surgery, common NSCLC chemotherapies). Average total costs paid per day of IV chemotherapy administration were computed, along with separate costs for IV chemotherapy drugs, IV chemotherapy administration procedures, and other drugs and services received on IV visit days. Costs were also estimated per course of treatment based on the assumption of four chemotherapy cycles per course with three visits per cycle. RESULTS: Among 8010 patients with a lung cancer diagnosis, 802 were identified as SCLC. In the SCLC subset, the average total daily cost was $787 ($9449/course), with $395 ($4742/course; 50.2%) attributable to IV chemotherapy drugs, $93 ($1112/course; 11.8%) to IV chemotherapy administration, and $300 ($3595/course; 38.0%) to other drugs and services. CONCLUSIONS: The proposed algorithm identified about 10% of patients with lung cancer receiving IV chemotherapy as likely SCLC cases. Future studies should validate this algorithm with medical records data. IV chemotherapy administration and other visit-related drugs and services represented about half of the total cost per IV visit day, with the remainder attributable to direct costs for IV chemotherapy drugs.

Modeling the cost effectiveness of secondary febrile neutropenia prophylaxis during standard-dose chemotherapy.

PURPOSE: Current guidelines (ie, by the American Society of Clinical Oncology and the European Organisation for Research and Treatment of Cancer) do not recommend secondary infection prophylaxis, whereas, in contrast, caregivers prefer secondary prophylaxis to chemotherapy dose reduction after an episode of febrile neutropenia (FN). Because granulocyte colony-stimulating factor (G-CSF) is expensive, this study investigates the economic consequences of secondary prophylactic use of different prophylactic strategies (antibiotics, antibiotics plus G-CSF, and a combined sequential approach) in a population at risk of FN, using a Markov model. METHODS: The input for the model is mainly based on the clinical outcome and patient-based cost data set (adopting the health care payer's perspective for the Netherlands) derived from a randomized study on primary prophylaxis in small-cell lung cancer (SCLC) patients; establishing mean cost of an episode FN of euro3,290 and prophylaxis of euro79 (antibiotics) +/- euro1,616 (G-CSF) per cycle. The economic analysis was analyzed probabilistically using first- and second-order Monte Carlo simulation. The incremental cost-effectiveness ratio (ICER) was defined as cost per FN-free cycle. RESULTS: Secondary prophylaxis with antibiotics was the least expensive strategy (mean, euro4,496/patient). The strategy antibiotics plus G-CSF was most expensive (mean, euro 8,998/patient). Comparison of these two strategies resulted in an unacceptably high ICER (euro343,110 per FN-free cycle) in the Dutch context. In scenarios using higher FN-related costs (as found in the United States), the strategies are less distinct in their monetary effects, but still favor antibiotics. CONCLUSION: This model-based economic analysis demonstrates that in the Netherlands and most likely also in the United States, if secondary prophylaxis is preferred, the strategy with antibiotics is recommended.

Psychometric validation of the Patient Symptom Assessment in Lung Cancer instrument for small cell lung cancer.

OBJECTIVE: Patient Symptom Assessment in Lung Cancer (PSALC) is a symptom scale developed for use in patients with small cell lung cancer (SCLC) to assess nine lung cancer symptoms (shortness of breath, cough, chest pain, hemoptysis, appetite loss, sleep interference, hoarseness, fatigue, interference with daily activities) scored from 1 (not at all) to 4 (very much). This study aims to retrospectively evaluate the psychometric properties of PSALC using clinical trial data. METHODS: Data were analyzed from a randomized, open-label, multicenter trial with 211 patients with SCLC receiving i.v. topotecan versus cyclophosphamide, doxorubicin, and vincristine. PSALC was evaluated at baseline and at 3-week intervals. Internal consistency, reliability, construct validity, and responsiveness were evaluated. RESULTS: Factor analysis indicated that one factor could represent all symptom items, so a PSALC total score (PSALC-TS) was used for psychometric validation. Internal consistency was supported by Cronbach's alpha of 0.74. Reliability of PSALC was supported by an intraclass correlation coefficient of 0.61 and concordance correlation coefficient of 0.72. Construct validity was supported by associations of lower PSALC-TS (less severe symptoms) with better ECOG performance status (p < 0.0001), and of PSALC-TS changes with clinical response. PSALC-TS was responsive to tumor progression (responsiveness statistic = 0.64). LIMITATIONS: The validation was performed retrospectively and was limited by small sample sizes at later assessment timepoints due to disease progression. CONCLUSIONS: A retrospective analysis suggests that the PSALC is a reliable, valid, and responsive instrument for measuring SCLC symptoms. If feasible in this population, a prospective validation study could be used to further evaluate these findings.

Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer.

PURPOSE: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. EXPERIMENTAL DESIGN: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. RESULTS: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. CONCLUSION: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.

[Radiotherapy for lung cancer. Integration with chemotherapy]. / Radioterapia combinada con quimioterapia en el tratamiento del cáncer de pulmón.

The combination of radiotherapy and chemotherapy in lung cancer (locally advanced non-small and small cell) may offer the benefits of radiotherapy in terms of local control and those of chemotherapy in terms of reducing metastatic dissemination of the disease. Several randomized studies have showed that radical radiotherapy combined with chemotherapy improves the survival of these patients at the expense of an increase in toxicity. The technological development and the improvements in software have allowed the introduction of new linear accelerators and a three-dimensional planning system with the intention of delivering higher irradiation doses in the tumor target, and minimizing the dose in adjacent normal tissues (lung, heart, esophagus and spinal cord). The volume of irradiation, the total dose, the fractionation, the schedule for the combination of radiotherapy and chemotherapy, as well as the influence of the prophylactic cranial irradiation in small cell lung cancer are points for discussion at the moment.

Cost effectiveness of increasing the dose intensity of chemotherapy with granulocyte colony-stimulating factor in small-cell lung cancer: based on data from the Medical Research Council LU19 trial.

BACKGROUND: The use of granulocyte colony-stimulating factor (G-CSF) can enable dose intensification of chemotherapy in small-cell lung cancer (SCLC). However, given its acquisition cost, it is important to assess its cost effectiveness within a resource-constrained health service. OBJECTIVE: To assess the cost effectiveness, from the UK NHS perspective, of G-CSF given in addition to doxorubicin, cyclophosphamide and etoposide (ACE) versus ACE alone in the management of SCLC. METHODS: Using data from a UK Medical Research Council trial (LU19) to assess chemotherapy dose intensification in patients with previously untreated SCLC of any disease extent, a retrospective cost-effectiveness analysis was undertaken. Resource use data, including hospitalisations and non-protocol cancer treatments, were collected during the first 6-month treatment phase of the trial. Mean costs ( pound, 2003 values) of managing patients in the two arms of the trial were calculated. Mean survival duration was calculated for the two groups using patient-specific follow-up data collected in the trial. Incremental cost-effectiveness analysis was undertaken, and uncertainty in cost effectiveness was expressed using cost-effectiveness acceptability curves. RESULTS: The use of G-CSF in addition to ACE chemotherapy is more costly ( 4647 pounds) but results in longer mean survival duration (0.20 years; 0.18 years when discounted). This generates an incremental cost per additional life-year of 25,816 pounds for ACE + G-CSF therapy. The probability of the addition of G-CSF being cost effective, if decision makers are willing to pay 30,000 pounds for an additional life-year, is 0.57. Secondary analysis suggests that cost effectiveness is likely to be sensitive to assumptions about the health-related quality of life (HR-QOL) experienced by patients. CONCLUSION: Based on data collected in the LU19 trial, chemotherapy dose intensification using G-CSF in SCLC adds to health service costs but increases survival duration. Its overall cost effectiveness is likely to be finely balanced.

Granulocyte colony--stimulating factor for chemotherapy-induced neutropenia in patients with small cell lung cancer : the 40% rule revisited.

Recombinant granulocyte colony-stimulating factor (G-CSF) [filgrastim and lenograstim] and pegylated G-CSF (pegfilgrastim) have been shown to reduce the severity and duration of chemotherapy-associated febrile neutropenia (FN) when administered prophylactically to cancer patients receiving chemotherapeutic regimens. The American Society of Clinical Oncology (ASCO) evidence-based clinical guidelines published in 1994, 1996 and 1997 recommended primary prophylaxis with G-CSF for cancer patients. The 2000 ASCO update, with the same recommendation, highlights the importance of economic considerations in decision making for CSFs. This paper reviews the available cost-effectiveness evidence on the use of G-CSF as primary prophylaxis against FN in patients with small cell lung cancer (SCLC).Cost-effectiveness ratios from a healthcare payer perspective supported the use of filgrastim as primary prophylaxis for people with SCLC, on the basis of both clinical and economic benefits, treated with chemotherapeutic regimens that have an FN rate in the range of 40-60%. However, when indirect and patient out-of-pocket costs attributable to severe FN are included, available evidence suggests that the risk threshold may be reduced by more than half. Given that FN rates associated with chemotherapeutic regimens for SCLC are generally <40%, then few circumstances would warrant the use of G-CSFs (filgrastim and lenograstim) under the current rule. However, inclusion of indirect costs would lower the cost-effectiveness threshold. Future cost-effectiveness studies of medications such as pegfilgrastim should attempt to capture the societal perspective by incorporating productivity-related costs and using base-case rates of FN reported in the literature.

Prospective randomized phase III trial of etoposide/cisplatin versus high-dose epirubicin/cisplatin in small-cell lung cancer.

High-dose epirubicin plus cisplatin was compared with the reference regimen of etoposide/cisplatin in small-cell lung cancer (SCLC). Four hundred two previously untreated patients with SCLC were randomized to receive etoposide 100 mg/m(2) on days 1-3 and cisplatin 100 mg/m(2) on day 1 or epirubicin 100 mg/m(2) and cisplatin 100 mg/m(2) on day 1 every 21 days for a total of 6 cycles. Patients were stratified according to treatment center and extent of disease (limited disease, n = 207; extensive disease, n = 195). Patients with limited disease were treated with thoracic radiation therapy after completion of chemotherapy, and those who exhibited a complete response were advised to receive prophylactic cranial irradiation. The primary endpoint was survival, and secondary endpoints were time to progression (TTP), response, toxicity, and costs. Patient characteristics were generally well balanced in the 2 arms, even though more patients in the epirubicin/cisplatin arm had > 5% weight loss and poor Karnofsky performance index compared with the etoposide/cisplatin arm. One hundred thirty-four patients (66.3%) in the etoposide/cisplatin arm and 126 (63.0%) in the epirubicin/cisplatin arm received all 6 planned cycles of chemotherapy. Response rate, TTP, and survival did not differ significantly between the 2 arms. Grade 3/4 neutropenia and toxic deaths occurred more frequently in the etoposide/cisplatin arm. Epirubicin/cisplatin showed a similar activity with a slightly lower toxicity profile than the reference regimen of etoposide/cisplatin. The epirubicin/cisplatin regimen may be recommended in the treatment of SCLC.

Cost analyses of granulocyte colony stimulating factor: a focus on older patients with cancer.

Granulocyte colony stimulating factor (G-CSF) can reduce the duration of neutropenia following intensive chemotherapy in a variety of settings. The majority of these studies have focused on small cell lung cancer. We review herein published information on costs and cost-effectiveness of G-CSF from clinical studies with patients with small cell lung cancer (SCLC). Medline and Healthstar databases were searched for original research articles that contain cost or cost-effectiveness analyses on the subject. The cost of adjunct treatment with G-CSF was evaluated from four studies of SCLC patients. Benefits included decreased rates of febrile neutropenic events, while cost savings were not identified in three of four studies. These data may be useful to physicians faced with concerns over clinical and economic factors associated with G-CSF use as adjunct therapy for SCLC.

Docetaxel in non-small cell lung cancer: a review.

Docetaxel (Taxotere, Aventis Pharma), a semisynthetic taxane targeting the beta-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel-platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.

Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923).

BACKGROUND: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL). PATIENTS AND METHODS: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed. RESULTS: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle. CONCLUSIONS: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.

G-CSF as prophylaxis of febrile neutropenia in SCLC.

OBJECTIVES: In 1991, small cell lung cancer (SCLC) was reported as the first tumour type where colony stimulating factor (CSF) support was clinically effective. We reviewed 13 health services research studies that addressed CSF use as supportive care for SCLC. METHODS: Findings from American Society of Clinical Oncology (ASCO) membership surveys, patterns of care studies, ASCO evidence-based guidelines and cost-effectiveness studies for CSF use were reviewed. RESULTS: For primary prophylaxis for SCLC, ASCO CSF clinical guidelines clearly do not support granulocyte (G)-CSF use. Cost-effectiveness models indicate that CSF use in this setting is associated with as much as US$1900 incremental patient care costs per cycle given an 18% febrile neutropenia rate. ASCO membership surveys found that < 10% of respondents supported CSF as primary prophylaxis while a patterns-of-care study found 55% use. In the secondary prophylaxis setting, ASCO CSF guidelines in 1994, 1996 and 1997 were equally supportive of CSF use versus dose reduction but dose-reduction was considered the preferred option in 2000. Over half of the ASCO member respondents in 1994 and in 1997 supported G-CSF use; cost-effectiveness models indicated that CSF use incurred an additional US$144 and 277 per cycle and the patterns of care study found 27% use of CSF in the community practice setting. CONCLUSIONS: In 2002, the findings of a decade of health services studies have shifted towards not being supportive of CSF use for primary or secondary prophylaxis for SCLC patients.

Comparison of changes in the NSE levels with clinical assessment in the therapy monitoring of patients with SCLC.

In a series of 130 consecutive patients suffering from small cell lung cancer (SCLC), we compared response evaluations according to standard criteria of the WHO with response evaluations according to changes in the neuron-specific enolase (NSE) levels during systemic therapy. For assessment by changes in the marker levels, the difference between two consecutive levels must exceed 30%. This value is based on the formula: Dc = 2(square root 2) x CV (CV: inter-assay coefficient of variation of the NSE test, set at 10 %). Of the 130 patients who entered this study, 18 patients received best supportive care and were excluded from the therapy monitoring. In the remaining 112 patients, 502 evaluations for response to therapy by both methods were performed, ie. 4.5 observations per patient. We found a concordance between the response evaluations according to the marker criteria and the clinical assessment in 69.7 % of the observations when including cases with positive lead-time and those with a temporary drop in the NSE levels due to a short-term response to therapy. The latter cases met the criteria consistent with the clinical evaluations at the next observation. The concordance with the clinical response evaluation increased to 84.2% when considering only those changes in the NSE levels where at least one of the consecutive marker levels was in the pathological range (> 14.5 ng/ml). Most discordant results were due to insufficient changes in the NSE levels at clinical remission or progression. A further limitation to the general use of NSE for therapy monitoring was founded on the marker negativity throughout the follow-up period, despite tumor progression or relapse. Changes in the levels between pretreatment NSE and after the first cycle of chemotherapy were shown to provide prognostic information. Patients with a drop in the NSE levels proved to have a significantly better survival probability than those with unchanging or rising marker values (p = 0.004). It is concluded that in the majority of evaluations, changes in the NSE levels are consistent with clinical findings based on imaging techniques but remain of doubtful utility in an individualpatient. NSE measurement can only be recommended as an adjunct to the clinical assessment in the follow-up of SCLC patients.

Role of granulocyte and granulocyte-macrophage colony-stimulating factors in the treatment of small-cell lung cancer: a systematic review of the literature with methodological assessment and meta-analysis.

In order to clarify the role of haematological colony-stimulating factors (CSF) in the treatment of small-cell lung cancer, we performed a systematic review of the randomised trials published on this topic. Since 1991, 12 studies were eligible, including a total of 2107 randomised patients. They were divided into three groups: (1) maintenance of dose-intensity when chemotherapy was given at conventional doses and time intervals (seven trials); (2) accelerated chemotherapy with increased dose-intensity by reducing the delay between chemotherapy cycles (five trials); (3) concentration of chemotherapy on an overall shorter duration time with a lower number of cycles (one trial). Before quantitative aggregation, we performed a methodological assessment using two previously published quality scales (Chalmers and ELCWP). The median quality scores for the pooled 12 trials was 59.9% (range: 42.2-82.0%) for the ELCWP scale and 55.8% (range: 38.0-76.8%) for the Chalmers scale. No statistically significant difference was observed between positive (significant) and negative (non-significant) studies allowing us to perform a meta-analysis. A detrimental effect on response rate was associated with CSF administration in the maintenance group (RR 0.92; 95% confidence interval [CI] 0.87-0.97) without significant effect on survival (HR 1.004; 95% CI, 0.89-1.13). In the accelerated group, no significant impact on response rate (RR 1.02; 95% CI, 0.94-1.09) or survival (HR 0.82; 95% CI, 0.67-1.00) was found. Although no difference in response rate was observed, a reduced survival was associated with concentrated chemotherapy. In conclusion, the published data do not support the routine use of haematological colony-stimulating factors in the treatment of small-cell lung cancer (SCLC).

Prophylactic cranial irradiation revisited: cost-effectiveness and quality of life in small-cell lung cancer.

PURPOSE: To investigate the therapeutic usefulness and cost-effectiveness of prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer (SCLC) who had achieved a complete remission. METHODS: A retrospective chart review was undertaken of all patients diagnosed in Saskatchewan with SCLC between 1987 and 1998 inclusive. Patients who achieved a complete remission were divided into two groups, depending on whether they underwent PCI (PCI+ and PCI-, respectively). The quality-of-life-adjusted survival was estimated by the Q-TWiST method (quality time without symptoms and toxicity). The mean incremental costs per month of incremental OS were calculated in a cost-effectiveness analysis. RESULTS: Among the 98 complete remission patients, the median OS for PCI+ and PCI- patients was 20.0 and 19.0 months, respectively (p > 0.05, nonsignificant). The median disease-free survival was 14.7 and 10.0 months, respectively (p < 0.05). The difference in the mean Q-TWiST survival was significant (p < 0.01). The mean marginal cost was $18,834/PCI+ patient and $17,885/PCI- patient (p > 0.05, nonsignificant). The cost-effectiveness ratio was $70/mo of incremental OS if u(tox) and u(rel) (the utility coefficients to reflect the value of time in health states of toxicity and relapse) were assumed to be 1.0. CONCLUSION: PCI is a cost-effective treatment that improves the quality-of-life-adjusted survival for patients with a complete remission of SCLC.

Limited stage small cell lung cancer.

The management of limited stage small cell lung cancer begins with a firm pathologic diagnosis and careful staging. Patients with adequate pulmonary function, ambulatory performance status, and no evidence of metastatic disease outside a "tolerable" local radiotherapy volume should have consultation from both medical and radiation oncology disciplines for planning of integrated therapy. The chemotherapy prescription recommended is cisplatin plus etoposide at standard doses for four chemotherapy cycles. Thoracic irradiation should be administered concurrently with the first or second cycle of cisplatin and etoposide. Patients with complete response and excellent partial response should receive prophylactic cranial irradiation after completion of all chemotherapy.