1 Institut Jules Bordet, Brussels; 2 CHU Saint-Pierre, Brussels, Belgium; 3 Hôpital Albert Calmette, CHU, Lille, France; 4 CHU de Charleroi, Charleroi, Belgium; 5 Hellenic Cancer Institute, Athens, Greece; 6 Hospital de Sagunto, Valencia, Spain; 7 CHR Saint-Joseph-Warquignies, Boussu; 8 CH Peltzer-La Tourelle, Verviers; 9 Hôpital Ambroise Paré, Mons, Belgium
Received 28 July 2003; revised 6 October 2003; accepted 19 December 2003
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ABSTRACT |
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The aim of this study was to determine the role of chemotherapy dose intensity in patients with initially unresectable non-metastatic non-small-cell lung cancer (NSCLC), with survival as primary end point, by testing two different regimens as induction chemotherapy followed by thoracic irradiation.
Patients and methods:
Patients had pathologically proven NSCLC, an initially unresectable non-metastatic tumour without homolateral malignant pleural effusion, no prior history of malignancy and had received no prior therapy. Treatment was randomised for chemotherapy between three courses of MIP (mitomycin C 6 mg/m2; ifosfamide 3g/m2; cisplatin 50 mg/m2) or SuperMIP (mitomycin C 6 mg/m2; ifosfamide 4.5 g/m2; cisplatin 60 mg/m2, carboplatine 200 mg/m2), followed by chest irradiation (60 Gy; five times per week, for 6 weeks). If the tumour became resectable after chemotherapy, surgery was performed, followed by mediastinal irradiation.
Results:
A total of 351 patients were eligible: 176 in the MIP arm and 175 in the SuperMIP arm, with 43% and 51% stages IIIA and IIIB, respectively. There was a significantly higher objective response rate with SuperMIP (46%) compared with MIP (35%) (P = 0.03) [95% confidence interval (CI) for the difference between the response rates, 1% to 22%]. After induction chemotherapy, surgery was performed in 54 (15%) patients (27 per arm) and chest irradiation in 203 (57%) patients (102 in the MIP arm and 101 in the SuperMIP). In terms of survival, there was no statistically significant difference between the two study arms (P = 0.16), with median survival times of, for MIP and SuperMIP, respectively, 12.5 (95% CI 10.114.9) and 11.2 (95% CI 9.712.8) months. Haematological toxicity and dosage reductions were higher with SuperMIP, which was nevertheless associated with a significantly increased absolute dose intensity.
Conclusions:
High dose-intensity induction chemotherapy does not improve survival in initially unresectable non metastatic NSCLC.
Key words: chemotherapy, non-small-cell lung cancer, radiotherapy, stage III
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Introduction |
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In the mid-1990s, the most active drugs against NSCLC largely available in European countries were cisplatin, mitomycin C, ifosfamide, vindesine and vinblastine. In a meta-analysis performed by our group [12], in locoregional NSCLC, regimens containing one of these drugs had a positive influence on the objective response rate. Response to cisplatin-containing regimens was improved with incorporation of vinblastine, mitomycin and ifosfamide. The response rate was also better if the dose of cisplatin administered per course was 100 mg/m2 compared with a dose
70 mg/m2 (43% versus 35%).
The effect of dose intensity has been studied for cisplatin only in patients with advanced NSCLC. In five randomised trials [1317], including three with very small numbers of patients, no advantage was obtained with high cisplatin dosages (120 mg/m2) compared with moderate dosages (6080 mg/m2). A major problem concerning high doses of cisplatin is the delayed toxicity. Our group has shown that the risk of developing a neurological (polyneuropathy), auditive (hypoacousia) or renal (renal failure) toxicity of at least WHO grade II after six courses of treatment is 26% for a regimen where cisplatin alone is given at higher dosages of 120 mg/m2 [18]. This toxicity precludes further therapy and might alter the impact of cisplatin therapy on survival. The combination of moderate dosages of carboplatin (200 mg/m2 on day 1) and cisplatin (30 mg/m2 on days 2 and 3) enables the maintenance of the same activity, in terms of response and survival, as higher dosages (120 mg/m2) of cisplatin, but with a significantly reduced risk of developing long-term renal, neurological or auditive toxicity (6% for six courses of therapy). This regimen can thus be used to administer chemotherapy with platinum derivatives [1921].
The concept of high dose-intensity chemotherapy has so far been tested in advanced NSCLC, and principally with cisplatin. As response rates to chemotherapy are higher in non-metastatic NSCLC [12], and high-dose chemotherapy had not been tested in locoregionally advanced NSCLC, in 1996 our group began a randomised trial testing two different dose-intensity regimens as induction chemotherapy followed by thoracic irradiation in stage III, initially unresectable NSCLC, with survival as the primary end point.
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Patients and methods |
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Eligible patients were randomised for chemotherapy regimen, by calling the ELCWP data centre, to receive three courses of MIP (mitomycin C 6 mg/m2; ifosfamide 3g/m2; cisplatin 50 mg/m2) or SuperMIP (mitomycin C 6 mg/m2; ifosfamide 4.5 g/m2; cisplatin 60 mg/m2, carboplatine 200 mg/m2). Centralised randomisation was performed at our data centre, and we used a minimisation technique [22]. Stratification took into account initial tumournodemetastasis (TNM) staging, histological subtype, Karnofsky PS and centre. In the MIP regimen, mitomycin C was given as a bolus followed by ifosfamide infused over 3 h. Cisplatin was administered over 1 h, 3 h after the end of the ifosfamide infusion. Mesna (1 g/m2 3-h infusion together with ifosfamide, followed by 500 mg/m2 bolus at 4 and 8 h) was provided to avoid urotoxicity. In the SuperMIP regimen, mitomycin C was given as a bolus after prehydration with 1 l of NaCl 0.9%, and carboplatine as a short 30-min infusion, followed by cisplatin infused over 30 min in 250 ml of 3% NaCl and ifosfamide infused in 1 l of normal saline over 20 h. Post-hydration consisted of 2 l of NaCl 0.9% over 10 h. Mesna (4.5 g/m2 20-h infusion together with ifosfamide, followed by 2.25 g/m2 over 8 h in 1 l NaCl 0.9%) was provided to avoid urotoxicity. Courses were repeated every 34 weeks, as soon as haematological (WBC >4000/mm3 and platelets >100 000/mm3) and renal (serum creatinine <1.5 mg/dl) functions had recovered. If the delay between two courses was >5 weeks, the patient went off treatment. If the WBC nadir was <1000/mm3 and/or platelet nadir <25 000/mm3, carboplatine, ifosfamide and mitomycin C dosages were reduced to 75% for the following course. For serum creatinine peak between 1.5 and 3 mg/dl, the cisplatin dosage was reduced to 50%, and if it was >3 mg/dl, cisplatin was stopped. If serum creatinine was not within the normal range on day 21, patients went off study.
Evaluation of tumour response was performed on week 9 (later if chemotherapy had to be delayed because of haematological toxicity). If the tumour became resectable, surgery was performed, followed by mediastinal irradiation (60 Gy over 6 weeks, to be given on the second month after surgery). For non-resectable tumours with objective response, no change or local progression, the patient received chest irradiation (60 Gy over 6 weeks, with 2 Gy daily fractions to the primary tumour and the known area of lymph node involvement). If the distant metastases developed, the patient went off treatment.
Chest irradiation was to start between 3 and 5 weeks after the last chemotherapy administration and after full haematological recovery. In cases of thoracotomy, it was to begin within 6 weeks after surgery. Megavoltage equipment was used and computed tomography (CT) scan-based treatment planning was mandatory. The initial volume should include, as determined before chemotherapy, the complete extent of the initial lung tumour, with a safety margin of 2 cm of normal lung, the ipsilateral hilum and mediastinal lymph nodes, from the thoracic inlet to 5 cm below the carina. The inferior mediastinal nodes were included only in cases of lower lobe lesions, and the supraclavicular nodes in cases of upper lobe lesions or positive high mediastinal nodes. After the first 45 Gy, the cone down volume included the area of tumour involvement with a minimal 1-cm safety margin. Delivering doses in >45 Gy to the spinal cord and the whole heart was avoided. In cases of positive mediastinal lymph nodes, adequate oblique fields were recommended. A total dose of 60 Gy had to be given in 6 weeks, with daily 2 Gy fractions (5 per week). For the first part of the treatment, the dose was specified on the central axis. For the second part, it was specified at the isocentre in the central plane. The isodose encompassing the target volume should not be <56 Gy. If performed after surgery, the target volume included the ipsilateral hilum, including the bronchial stump, with a 2-cm margin of uninvolved pulmonary tissue, the entire mediastinum from the suprasternal notch to not less than 5 cm below the carina and across the trachea, to include 1 cm of contralateral lung.
The initial work-up consisted of a complete history and physical examination with weight, height and surface area measurements; recording of PS; fibre-optic bronchoscopy with biopsy, chest X-ray and CT scan; bone scintigraphy with X-ray of suspected lesions; liver and adrenals CT scan or echography; brain CT scan; blood chemistries including complete blood cell count, electrolytes, serum creatinine and liver function tests; and EKG and pulmonary function tests. Except for bulky involvement (defined as a disease considered by the local surgeon as too massive to permit surgical resection), mediastin-oscopy with biopsy was recommended prior to chemotherapy to confirm mediastinal dissemination and unresectability. Blood chemistries, chest X-ray and clinical examination were repeated before each new course. Restaging with all of the tests performed during the initial work-up was repeated after the first three courses of chemotherapy, except for mediastinoscopy, and for the responders and those with no change at the end of therapy. After treatment discontinuation, patients were examined with biological tests (as initially performed) and chest X-ray every 2 months for the first 6 months, and every 3 months thereafter. A complete work-up was recommended every 6 months.
Evaluation for response after completion of three courses of chemotherapy, as well as the initial TNM stage, was evaluated during regular meetings of the group by at least three independent observers. Complete response (CR) was defined as the disappearance of all signs of disease. Partial response (PR), in measurable disease, was defined as a 50% decrease of the total tumour load, without the appearance of new lesions or progression of any lesion. The tumour load was estimated as the tumour area calculated by the multiplication of the longest diameter by the greatest perpendicular diameter. In assessable disease, PR was defined as an estimated decrease in tumour size of
50%. Progression was considered to be an increase of >25% in one or more measurable or assessable lesions, or the appearance of a new lesion. All other circumstances were classified as no change (NC). Patients with early death (ED) due to progression before evaluation, toxic death due to chemotherapy, or early stopping of chemotherapy because of toxicity were regarded as treatment failures, and were considered assessable for response. WHO criteria were used to assess toxicity and histological subtypes.
The primary end point of the trial was to determine whether an increase in the dosage of platinum derivatives and ifosfamide (SuperMIP) would improve survival compared with standard induction chemotherapy (MIP) in patients with unresectable non-metastatic NSCLC prior to chest irradiation. In order to detect an increase of 1-year survival from 40% (rate estimated according to the data obtained in our prior trial [23] conducted in stage III NSCLC treated with MIP) to 55%, 169 eligible patients had to be randomised in each arm ( = 0.05; ß = 0.20; two-sided test) and followed until observation of a total of 178 events. Secondary end points were surgical resectability rate, toxicity and local control.
Overall survival and response duration were dated from the day of randomisation. Survival distributions were estimated by the KaplanMeier method. Duration of response was calculated from the day of randomisation until the date of the first observation of progression. The log-rank test was used to compare survival distributions. P values (two-tailed) for testing the null hypothesis of the equality of proportions were calculated using Fishers exact test or the 2-test. Multivariate analyses for prognostic factors were performed by adjusting the data with Cox models for duration of survival and logistic regression models for objective response, using a backwards stepwise method for the selection of variables to be retained in the final model. Coefficient estimates were obtained by the maximum likelihood method. The evaluation of chemotherapy intensity was performed by calculating absolute and relative dose intensities.
The absolute dose intensity was defined as the ratio of the received dose per m2 of body surface to the actual duration of treatment (expressed in mg/m2 and per week). Carboplatin was considered equivalent to cisplatin in the ratio 100/30. All the formulae have been published previously [24]. Comparisons of the distributions of the dose-intensity variables between regimens were carried out using the MannWhitney test.
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Results |
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The main characteristics of the eligible patients are shown in Table 1. The two arms were well balanced for the main patient characteristics. Fifteen percent were female; the median age was 60 years. The most frequent histological type was squamous cell carcinoma. Only 12% of the patients had a PS <80. About two-thirds of the lesions were measurable. Only 7% of the patients had stages I or II, the majority being T3N0 (stage IIIA in the 1986 classification) and some being ineligible for surgery for functional reasons. Stages IIIA and IIIB [1997 International Staging System (ISS)] accounted for, respectively, 43% and 51% of the patients. Median follow-up duration at time of analysis was 47.7 months (range 0.482.4). There were 287 deceased patients, seven were lost to follow-up and 57 are alive.
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Radiotherapy was performed in the MIP arm in 38 patients in PR after chemotherapy, in 51 with NC, in seven with local progression, in four for whom treatment was stopped owing to unacceptably high toxicity and in two in whom chemotherapy was discontinued for concomitant disease. Radiotherapy was performed in the SuperMIP arm in one patient with CR, in 58 with PR, in 25 with NC, in 12 with local progression and in five for whom treatment was stopped owing to unacceptably high toxicity. For MIP and SuperMIP, respectively, chest irradiation was delayed in 58 and 50 patients, and dose was reduced in nine and 11 patients. Chest irradiation was discontinued for occurrence of metastases during treatment administration in three patients in each arm. At assessment of response after radiotherapy, there were 33 PRs in the MIP arm (32%), and two CRs and 34 PRs in the SuperMIP arm (objective response 36%). Radiation pneumonitis was documented in 42% and 47%, respectively, of the assessable patients. Seven toxic deaths were attributed to lung complications due to radiotherapy (four with MIP and three with SuperMIP).
Response median duration for the MIP and SuperMIP arms, respectively, was 9.4 (95% CI 6.512.3) and 9.9 (95% CI 7.112.7) months (P = 0.88). Time without progression (progression-free survival) was 9.1 (95% CI 7.011.3) and 8.1 (95% CI 5.710.4) months, respectively (P = 0.70). There was no difference between the two study arms in terms of time without local progression (63% and 66% at 1 year, respectively, for MIP and SuperMIP) or without distant progression (53% and 49%, respectively).
As shown in Figure 1, there was no statistically significant difference (P = 0.16) in survival between the two study arms: median survival times for the MIP and SuperMIP arms were, respectively, 12.5 (95% CI 10.114.9) and 11.2 (95% CI 9.712.8) months, with 1-year survival rates of 51% (95% CI 43% to 59%) and 46% (95% CI 38% to 54%), 3-year survival rates of 17% (95% CI 11% to 23%) and 11% (95% CI 6% to 16%), and 5-year survival rates of 9% (95% CI 2% to 16%) and 9% (95% CI 3% to 15%). In some subgroups with similar characteristics (Table 3), there was a significantly better survival in favour of MIP: age 60 years; stage IIIB (ISS 1986 and ISS 1997); and normal platelet count.
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Discussion |
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Our trial is the first one that has been performed to test the role of drug dosage in chemotherapy induction before chest irradiation in stage III NSCLC. The standard regimen (MIP) was administered according to the original description of Cullen et al. [25], as we have used in prior trials [20, 23]. The higher dosage regimen (SuperMIP) was designed by increasing by 50% the ifosfamide dosage, and by using a combination of cisplatin and carboplatin theoretically corresponding to 120 mg/m2 cisplatin (instead of 50 mg/m2 cisplatin in the MIP arm), according to our prior publication [18]. The rationale for this approach is explained in the Introduction. We prescribed carboplatin in mg/m2 and not in by AUC because the trial was designed before the validation of this approach. We have shown in a retrospective study that 200 mg/m2 corresponds to AUC 3, and that the tolerance is better predicted when AUCs are used, but without a significant impact on outcomes [26]. The higher dosage regimen led to a significantly higher response rate (46% versus 35%). It is interesting to note that in advanced disease (mainly stage IV), higher dosages of platinum derivatives have failed to improve response rate or survival in randomised trials [14, 16, 20], while the addition of ifosfamide to platinum derivatives significantly improved the response rate in a prior trial by our group [19], as well as in the study by Erkisi et al. [27]. We can thus speculate that a higher dosage of ifosfamide, alone or in combination with increased doses of platinum derivatives, leads to better response rate. Nevertheless, this advantage, in terms of dose intensity (Table 5), failed to translate into better response duration, distant relapse control or overall survival. It also did not allow the performance of more secondary complete surgical resections. Moreover, higher dosages resulted in higher toxicity, mainly haematological, leading to more frequent dosage adaptation. The high toxicity of SuperMIP on platelets indicates that a further increase of the drug dosage could have been dangerous for the patients.
The combined therapeutic modality used in this trial is a sequential treatment, with induction chemotherapy followed by standard local irradiation. As already pointed in the Introduction, this approach has been shown superior to chest radiotherapy alone in terms of survival. Induction chemotherapy allows the reconsideration of surgery in cases of documented tumour size reduction at the work-up preceding irradiation. In the randomised trials so far published on the topic [1, 7, 2834], secondary surgery was not performed (or not mentioned). Secondary surgery was performed in 5.6% of the patients in our prior trial with stage III NSCLC [23], and in 11.1% in the present study; it thus concerns a minority of the patients. The beneficial effect of secondary surgery is controversial. Randomised trials on the topic are difficult to conduct because of the a priori opinion of many physicians in favour of surgery. The single study published comparing radiotherapy with surgery after induction chemotherapy in N2 disease was inconclusive, because of patient accrual problems [35]. Nevertheless, in the absence of the demonstration of a similar or superior benefit with a non-surgical approach, and taking into consideration our previous trial [23] failing to show survival improvement in responders when radiotherapy was delivered in spite of further chemotherapy, we prefer to operate on lung cancer as soon as it becomes resectable. It should be noted that surgery was not favoured in our present trial by the higher dosage regimen, despite a significantly better objective response rate.
Chest irradiation (and, for some patients, surgery) was not able to consolidate further the better response rate obtained with the higher dose chemotherapy. Some explanations can be proposed. Objective response of the tumour, as defined by the WHO criteria, does not correspond to a discriminating biological effect, because the cut-off (arbitrarily fixed at 50% reduction by expert opinion) between responding and non-responding disease could be lower, and includes stable tumours. There may have been too long a delay between the end of chemotherapy and the beginning of radiotherapy. However, there were no differences between the two study arms. There was also no evidence of increased severe treatment toxicity in the SuperMIP arm to cancel out the possible benefit of a better response rate. The consolidation radiotherapy regimen might have been adequate. As already discussed in our prior trial in stage III NSCLC [23], we failed to show a survival improvement in responders by administering chest irradiation instead of further chemotherapy. So far, one trial is in favour of concurrent chemoradiotherapy instead of sequential chemotherapy and radiotherapy [36]; in that study a regimen containing cisplatin, mitomycin and vindesine was used, and survival results were reported significantly improved with the concurrent regimen. The results of this trial seem to have been confirmed by the Radiation Therapy Oncology Group in a controlled study, but data have not yet been published.
The last part of this Discussion is related to the patient population selection and prognostic factors. Patients selected for the trial had non-metastatic NSCLC that was judged inoperable or unresectable, but suitable for radical chest irradiation. In order to obtain results as generalisable as possible, we avoided excluding patients with poor prognostic factors such as increased body weight loss or a Karnofsky PS of 60%. Except for a few cases of inoperable patients, the majority had stage III disease. Stage III is a heterogeneous group [37], including resectable tumours and tumours that cannot be treated with a strategy including a loco-regional (surgical or radiotherapeutic) approach. The limits between resectable and unresectable or between irradiable or non-irradiable depend not only on the anatomical extent of the tumour, but also on the judgement of the local surgeon or radiation oncologist. It is thus impossible to propose universally acceptable criteria for study entry. In addition, during our trial, the ISS classification changed [38, 39], with a main modification being the moving of substage T3N0M0 from stage IIIA to stage IIB. As shown in Table 1, this concerned <5% of our patients. In comparison to our prior trial [40], the percentages of patients with stage IIIA and IIIB disease and of those with N3 substages were remarkably similar. The main differences between the two studies were that a higher number of women (15% compared with 8%) and more patients with adenocarcinoma (34% compared with 20%) were included in this study. We had also fewer patients with poor Karnofsky PS <80% (12% compared with 22%). In the present trial, we identified chemotherapy regimen as the only prognostic factor for response, while in our prior trial [40], we identified T34N3 disease and neutrophil count as independent prognostic factors. As prognostic factors for survival, we here identified N3 disease, Karnofsky PS and haemoglobin level, while in our preceding study [40] we identified multiple independent factors, including PS, age, neutrophils, platelets and T34N3 disease. These differences can probably be explained by a different case-mix in the two study populations, as well as perhaps by a different therapeutic approach. It is nevertheless interesting to note that N3 disease is a poor prognostic factor in both studies. We have already described the heterogeneity among stages IIIB that could probably be split in a different way to give a better prognostic value.
In conclusion, in a therapeutic strategy with induction chemotherapy followed by conventional chest irradiation, higher dosages of platinum derivatives and ifosfamide resulted in significantly higher response rate in relation to dose intensity, but induced increased haematological toxicity and failed to improve survival. Secondly, surgery was made possible in 10% of the patients with both regimens. These results are not very encouraging regarding the further testing of the concept of dose intensity in this type of NSCLC presentation. Future efforts should rather focus on the determination of the role of concurrent chemoradiotherapy and of new drugs, and the identification of biological characteristics associated with treatment outcome.
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Acknowledgements |
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FOOTNOTES |
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Participating institutions are listed in the Acknowledgements.
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REFERENCES |
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2. Dillman RO, Seagren SL, Propert KJ et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990; 323: 940945.[Abstract]
3. Dillman RO, Seagren SL, Propert KJ et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990; 323: 940945.[Abstract]
4. Dillman RO, Herndon J, Seagren SL et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88: 12101215.
5. Le Chevalier T, Arriagada R, Quoix E et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991; 83: 417423.[Abstract]
6. Arriagada R, Le Chevalier T, Pignon JP et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 1993; 329: 18481852.
7. Sause WT, Scott C, Taylor S et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995; 87: 198205.[Abstract]
8. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899909.
9. Sculier JP, Berghmans T, Paesmans M et al. The role of chemotherapy in the treatment of non-metastatic, non-small cell bronchial cancers. Rev Med Brux 2001; 22: 477487.[Medline]
10. Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer 1995; 76: 593601.[ISI][Medline]
11. Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. A meta-analysis (published erratum appears in Ann Intern Med 1997; 126: 670). Ann Intern Med 1996; 125: 723729.
12. Donnadieu N, Paesmans M, Sculier JP. Chimiothérapie des cancers bronchiques non à petites cellules. Méta-analyse de la littérature en fonction de lextension de la maladie. Rev Mal Respir 1991; 8: 197204.[ISI][Medline]
13. Gralla RJ, Casper ES, Kelsen DP et al. Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules. Ann Intern Med 1981; 95: 414420.[ISI][Medline]
14. Klastersky J, Sculier JP, Ravez P et al. A randomized study comparing a high and a standard dose of cisplatin in combination with etoposide in the treatment of advanced non-small-cell lung carcinoma. J Clin Oncol 1986; 4: 17801786.[Abstract]
15. Shinkai T, Saijo N, Eguchi K et al. Cisplatin and vindesine combination chemotherapy for non-small cell lung cancer: a randomized trial comparing two dosages of cisplatin. Jpn J Cancer Res 1986; 77: 782789.[ISI][Medline]
16. Gandara DR, Crowley J, Livingston RB et al. Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: a phase III study of the Southwest Oncology Group. J Clin Oncol 1993; 11: 873878.[Abstract]
17. Rinaldi M, Crino L, Scagliotti GV et al. A three-week schedule of gemcitabinecisplatin in advanced non-small-cell lung cancer with two different cisplatin dose levels: a phase II randomized trial. Ann Oncol 2000; 11: 12951300.[Abstract]
18. Sculier JP, Klastersky J, Giner V et al. Phase II randomized trial comparing high-dose cisplatin with moderate-dose cisplatin and carboplatin in patients with advanced non-small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 1994; 12: 353359.[Abstract]
19. Sculier JP, Paesmans M, Thiriaux J et al. Phase III randomized trial comparing cisplatin and carboplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 1998; 16: 13881396.[Abstract]
20. Sculier JP, Lafitte JJ, Paesmans M et al. Phase III randomized trial comparing moderate-dose cisplatin to combined cisplatin and carboplatin in addition to mitomycin and ifosfamide in patients with stage IV non-small-cell lung cancer. Br J Cancer 2000; 83: 11281135.[CrossRef][ISI][Medline]
21. Sculier JP, Lafitte JJ, Lecomte J et al. A three-arm phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small-cell lung cancer. Ann Oncol 2002; 13: 874882.
22. Freedman LS, White SJ. On the use of Pocock and Simons method for balancing treatment numbers over prognostic factors in the controlled clinical trial. Biometrics 1976; 32: 691694.[ISI][Medline]
23. Sculier JP, Paesmans M, Lafitte JJ et al. A randomised phase III trial comparing consolidation treatment with further chemotherapy to chest irradiation in patients with initially unresectable locoregional non-small-cell lung cancer responding to induction chemotherapy. European Lung Cancer Working Party. Ann Oncol 1999; 10: 295303.[Abstract]
24. Sculier JP, Paesmans M, Bureau G et al. Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 1996; 14: 23372344.[Abstract]
25. Cullen MH, Billingham LJ, Woodroffe CM et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 31883194.
26. Sculier JP, Paesmans M, Thiriaux J et al. A comparison of methods of calculation for estimating carboplatin AUC with a retrospective pharmacokinetic-pharmacodynamic analysis in patients with advanced non-small cell lung cancer. European Lung Cancer Working Party. Eur J Cancer 1999; 35: 13141319.[CrossRef][ISI][Medline]
27. Erkisi M, Doran F, Burgut R, Kocabas A. A randomised trial of two cisplatin-containing chemotherapy regimens in patients with stage III-B and IV non-small cell lung cancer. Lung Cancer 1995; 12: 237246.[CrossRef][ISI][Medline]
28. Dillman RO, Seagren SL, Propert KJ et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990; 323: 940945.[Abstract]
29. Le Chevalier T, Arriagada R, Quoix E et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991; 83: 417423.[Abstract]
30. Crino L, Latini P, Meacci M et al. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer. Ann Oncol 1993; 4: 847851.[Abstract]
31. Gregor A, Macbeth FR, Paul J et al. Radical radiotherapy and chemotherapy in localized inoperable non-small-cell lung cancer: a randomized trial. J Natl Cancer Inst 1993; 85: 997999.[ISI][Medline]
32. Wolf M, Hans K, Becker H et al. Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced non-small cell lung cancer. Semin Oncol 1994; 21 (3 Suppl 4): 4247.
33. Planting A, Helle P, Drings P et al. A randomized study of high-dose split course radiotherapy preceded by high-dose chemotherapy versus high-dose radiotherapy only in locally advanced non-small-cell lung cancer. An EORTC Lung Cancer Cooperative Group trial. Ann Oncol 1996; 7: 139144.[Abstract]
34. Brodin O, Nou E, Mercke C et al. Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. The Swedish Lung Cancer Study Group. Eur J Cancer 1996; 32A: 18931900.
35. Johnstone DW, Byhardt RW, Ettinger D, Scott CB. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2002; 54: 365369.[ISI][Medline]
36. Furuse K, Fukuoka M, Kawahara M et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17: 2692.
37. Grunenwald D, Le Chevalier T. Re: Stage IIIA category of non-small-cell lung cancer: a new proposal (published erratum appears in J Natl Cancer Inst 1997; 89: 328). J Natl Cancer Inst 1997; 89: 8889.
38. Mountain CF. A new international staging system for lung cancer. Chest 1986; 89 (4 Suppl): 225S233S.[Medline]
39. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 17101717.
40. Sculier JP, Paesmans M, Lafitte JJ et al. Prognostic factors analysis for response to chemotherapy and survival in a prospective cohort of patients with unresectable locoregional non small cell lung cancer initially treated by induction chemotherapy. Rev Oncologia 1999; 1: 92100.