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Journal of Clinical Oncology, Vol 18, Issue 14 (July), 2000: 2658-2664
© 2000 American Society for Clinical Oncology

Gemcitabine and Cisplatin as Induction Regimen for Patients With Biopsy-Proven Stage IIIA N2 Non–Small-Cell Lung Cancer: A Phase II Study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955)

By N. Van Zandwijk, E. F. Smit, G. W. P. Kramer, F. Schramel, S. Gans, J. Festen, A. Termeer, N. J. J. Schlosser, C. Debruyne, D. Curran, G. Giaccone

From the Netherlands Cancer Institute and Free University, Amsterdam; Arnhem Radiotherapy Institute and St Antonius Hospital, Nieuwegein; St Jansdal Hospital, Harderwijk; St Radboud Academic Hospital and Canisius Hospital, Nijmegen; Utrecht University Hospital, Utrecht, the Netherlands; and the European Organization for Research and Treatment of Cancer (EORTC) Data Centre, Brussels, Belgium.

Address reprint requests to N. Van Zandwijk, MD, PhD, Department of Thoracic Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; email zandwijk{at}nki.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Our objective was to better define the activity/feasibility of gemcitabine/cisplatin (GC) as induction chemotherapy in patients with stage IIIA N2 non–small-cell lung cancer (NSCLC) followed by surgery or radiotherapy within a large, ongoing comparative study (EORTC 08941).

PATIENTS AND METHODS: Forty-seven chemotherapy-naive patients with NSCLC, median age of 58 years, stage IIIA N2 disease, World Health Organization performance status of 0 or 1, and the ability to tolerate a pneumonectomy received gemcitabine 1,000 mg/m2 on days 1, 8, and 15 and cisplatin 100 mg/m2 on day 2, every 4 weeks. Patients received induction chemotherapy (three cycles) before re-evaluation and randomization to surgery or radiotherapy.

RESULTS: Grade 3/4 thrombocytopenia, the main hematologic toxicity, occurred in 60% of patients but was not associated with bleeding. Full-dose gemcitabine was given in 48% of the courses. Severe nonhematologic toxicity was uncommon. Two patients with preexisting, autoimmune pulmonary fibrosis had deterioration of pulmonary function after radiotherapy. Thirty-three (70.2%; 95% confidence interval, 55.1% to 82.7%) of the 47 eligible patients had objective responses (three complete responses and 30 partial responses). Mediastinal nodes were tumor-free after induction therapy in 53% of cases. Resections were considered complete in 71% of the patients who underwent thoracotomy after induction therapy. Median survival for all recruited patients (N = 53) was 18.9 months, with an estimated 1-year survival rate of 69%.

CONCLUSION: In patients with N2 stage IIIA NSCLC, GC is a highly active and well-tolerated induction regimen. GC should be explored in combination with surgery or radiotherapy in stage I and II patients.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE RATIONALE FOR using induction chemotherapy in locally advanced non–small-cell lung cancer (NSCLC) is based on the considerations that chemotherapy may prevent the growth of systemic disease and, at the same time, shrink the locoregional macroscopic disease, which may then be adequately treated with surgery, radiotherapy, or both.1 Several groups have shown that this approach is feasible in patients with stage III disease, who usually have better response rates than patients with stage IV disease.2,3 Moreover, three small randomized trials comparing surgery alone with a combined program of induction therapy followed by surgery have shown prolonged survival in the combined-modality arms.4-6 In many centers, induction therapy followed by surgery and/or radiotherapy has thus become standard therapy for selected groups of patients with stage III disease.7

Gemcitabine (2',2'-difluorodeoxycytidine), an analog of deoxycytidine with established activity in NSCLC, is an anticancer drug with novel properties and mechanism of action.8 The combination of gemcitabine and cisplatin (GC) has been shown to be synergistic in preclinical studies.9,10 In patients with advanced NSCLC, this combination produced objective response rates of more than 50%.11,12 In three randomized studies in the same category of patients, GC was more active than cisplatin alone13 and produced a higher response rate as well as a longer response duration and time to progressive disease than the etoposide-cisplatin combination.14 In addition, GC produced a higher response rate than the three-drug combination of mitomycin, ifosfamide, and cisplatin.15

The early suggestions of increased efficacy of the GC combination prompted the European Organization for the Research and Treatment of Cancer (EORTC) Lung Cancer Cooperative Group to initiate a phase II trial to better define the toxicity and activity of this combination as an induction regimen for patients with stage IIIA NSCLC. This trial was the first of a series of phase II studies using new chemotherapy combinations within the setting of one large, ongoing randomized trial in patients with stage IIIA N2 disease (EORTC 08941) comparing surgery with radiotherapy after induction chemotherapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Eligibility criteria for study entry included the following: stage IIIA NSCLC with biopsy proof of positive N2 nodes, World Health Organization (WHO) performance status score of 0 to 1, and an adequate baseline organ function defined as a WBC count of at least 3,000/µL, liver and renal function within normal limits, and spirometric values allowing pneumonectomy. Patients who had previous chemotherapy, radiotherapy, or presence of active infection were excluded from the study. All patients gave written informed consent, and the study was approved by the EORTC Protocol Review Committee (PRC) and by the ethics committees of the participating centers.

Treatment Plan
Gemcitabine 1,000 mg/m2 was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle. On day 2, cisplatin 100 mg/m2 was infused over 30 minutes after intravenous hyperhydration with 1,500 mL saline (plus potassium chloride) and administration of standard antiemetics. The doses of gemcitabine and/or cisplatin were adjusted to the outcomes of blood counts and blood chemistry immediately before the infusion(s), and toxicity was recorded during treatment. Full doses of chemotherapy were given if WBC and platelet counts on the day of treatment were >= 3 x 109/L and >= 100 x 109/L, respectively. Chemotherapy was administered at 75% of the planned dose in the event of grade 2 hematologic toxicity and at 50% of the planned dose in the presence of grade 2 neurotoxicity or a creatinine clearance rate less than 60 mL/min. Dose reductions were handled the same way for both agents. Doses were withheld if myelotoxicity or neurotoxicity exceeded grade 2 or if creatinine clearance dropped below 40 mL/min. Three cycles of chemotherapy were administered unless progressive disease or intolerable toxicity was recorded.

Patient Evaluation
A complete history, physical examination, complete blood cell count with differential, serum biochemistry, urinalysis, spirometry, bronchoscopy, computed tomography (CT) scan of the chest and upper abdomen, and ECG were obtained at baseline. Patients were monitored throughout treatment by recording history, toxic events, and complete blood cell counts with differential (weekly); serum chemistry determinations were repeated just before the start of each chemotherapy cycle. Tumor response was evaluated by CT scan after three cycles of treatment. CT examinations were reviewed by an independent radiologist, the study chairman, and the responsible physician. A complete response (CR) was defined as the complete disappearance of all abnormalities on the CT scan. A partial response (PR) was defined as a reduction of more than 50% in the sum of the products of two perpendicular diameters of the primary tumor and hilar and mediastinal nodes (if enlarged). Stable disease was defined as a less than 50% reduction or a less than 25% increase in the sum of the products of two perpendicular diameters per site. Response rate calculations were based on all eligible patients (N = 47). Almost all patients with responsive disease gave consent to be randomized to thoracic surgery or radical radiotherapy (ongoing trial EORTC 08941). Repeated mediastinoscopy/tomy and spirometry were not included in the postchemotherapy evaluation. The combined-modality approach of this study did not allow the formal 4-week confirmation of response to chemotherapy alone according to WHO criteria. Overall, survival was measured from the date of registration to the date of death or last follow-up examination and was estimated using the Kaplan-Meier method.16


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
From March 1996 to August 1997, 53 patients were enrolled onto the study. Six patients were ineligible: three patients had stage IIIB disease and another three patients had started protocol treatment before registration. Characteristics of the 47 eligible patients (listed in Table 1) included a median age of 58 years (range, 44 to 78 years), WHO performance status of 0 in 60% of the patients, and squamous cell carcinoma as the predominant histologic subtype (43%). All patients had N2 disease. In one case, the N2 involvement was found by thoracotomy (open-close): one of the mediastinal nodes appeared less than 1 cm on the CT scan and was found to be adherent to the superior caval vein; thus no primary surgery was attempted. In all other cases, mediastinal lymph node involvement was confirmed by mediastinoscopy/tomy (42 cases) or needle biopsy/aspiration cytology (four cases). In 32 of the 47 patients, baseline CT scans provided an estimate of the largest diameter of the N2 nodes. This diameter was less than 10 mm in one case, between 10 and 20 mm in 10 cases, between 20 and 30 mm in 11 cases, and more than 30 mm in 10 cases. Among the 15 remaining patients in whom CT did not allow an exact measurement, there were at least five patients with mediastinal lymph node enlargement on plain-chest roentgenograms.


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  		Table 1. Patient Characteristics
 
Hematologic Toxicity
During 127 treatment cycles with GC, grade 3/4 neutropenia was observed in 38.3% of the patients. Only one patient (2.1%) had febrile neutropenia. Grade 3/4 anemia was seen in 14.9% of the patients. Thrombocytopenia was the predominant hematologic toxicity: grade 3/4 thrombocytopenia was seen in 46% of the treatment cycles (59.6% of the patients; Table 2); however, thrombocytopenia was not associated with an increased number of bleeding events, and no platelet transfusions were administered. Overall, hematologic toxicity frequently caused dose omission (34%) or reduction (23%) of the gemcitabine doses on day 15.


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  		Table 2. Hematologic Toxicity (N = 47)
 
Nonhematologic Toxicity
Nonhematologic adverse events were typical of conventional cisplatin-based combinations used in patients with NSCLC (Table 3). Nausea and vomiting occurred frequently but reached grade 3 in only a minority of patients (14.8% and 10.6%, respectively). Grade 3/4 neurotoxicity mainly involved ototoxicity (four patients). Sensory neuropathy never exceeded grade 1. Flu-like symptoms were occasionally seen, and alopecia (grade 2 or more) was noted in 40% of patients. In two patients with known seropositive rheumatoid arthritis and pulmonary fibrosis, pulmonary dysfunction deteriorated after radiotherapy. One patient died 1 month after the radiotherapy. The autopsy confirmed a complete remission but also revealed the presence of organizing diffuse alveolar damage in addition to pulmonary fibrosis. The other patient died 7 months after radiotherapy with signs of pulmonary dysfunction in addition to recurrent disease that was diagnosed 5 months earlier.


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  		Table 3. Number of Patients With Nonhematologic Toxicities (N = 47)
 
Dose-Intensity
Cisplatin was administered within the 90% to 110% range of the intended dose in 92% of the courses. As a result of omissions and dose reductions, only 48% of the courses were at the intended dose of gemcitabine, which translated into 259 infusions at the intended dose, 66 infusions at reduced dose, and 55 omitted infusions. Thrombocytopenia on day 15 was the main reason for dose reductions or withholding of gemcitabine. Because of a miscalculation of body-surface area, one patient received more than 110% of the intended doses of cisplatin and gemcitabine during cycle 2.

Response to Induction Therapy and Additional Treatment
The CT scans of responding patients were reviewed and all were independently confirmed, with the exception of one patient for whom CT scans could not be obtained. A summary of treatment and responses is presented in Fig 1. Of the 38 patients who received the planned induction therapy of three cycles of GC, 33 patients responded (three CRs and 30 PRs), for an overall response rate of 70.2% (95% confidence interval, 55.1% to 82.7%). In addition, there were three patients with no change (minor response in two) and two with progressive disease. Among the nine patients who did not receive the planned induction therapy of GC, seven discontinued GC therapy because of toxicity (ototoxicity in three cases). Three of these seven patients achieved PR with other gemcitabine combinations and were subsequently randomized to additional treatment with surgery or radiotherapy per EORTC 08941.



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  		Fig 1. Summary of treatment and response. Abbreviations: NC, no change; MR, minor response. aPatients not randomized to radiotherapy or surgery (n = 12). bOne patient was judged to have stable disease by the attending physician, but the review panel documented a PR.

 
Thus a total of 35 patients were randomized to additional surgery (n = 17) or radiotherapy (n = 18) per EORTC 08941. In the group of patients who underwent thoracotomy, minor (n = 1), partial (n = 15), and complete (n = 1) clinical responses were confirmed. The surgeon decided to perform an open-close thoracotomy in one case and resection in 16 cases. Resections were judged to be complete in 71% of the patients. After induction therapy, the mediastinal nodes of 53% of the cases were tumor-free.

Twelve patients were not randomized to additional surgery or radiotherapy. Reasons for nonrandomization included cerebral infarction for one patient, lack of response for five patients (one was later corrected to PR by review panel) for patients who received three cycles of GC, toxicity for two patients who received two cycles of GC, and toxicity, progression, and second primary tumor in two, one, and one patient(s), respectively, who received one cycle of GC. After induction treatment, one patient received laser therapy (second primary tumor) and nine received radiotherapy. Two patients, who stopped protocol treatment with GC, continued with other chemotherapy combinations followed by surgery.

Survival
At the time of this analysis, after a median follow-up period of 19 months, 29 of the 53 patients have died. In 27 cases, the deaths were related to the malignant diagnosis. One patient died from a cardiovascular cause. In another case, a (viral) infection was noted as the cause of death. The median duration of survival was 18.9 months, and the estimated 1-year survival rate was 69% (95% confidence interval, 56% to 82%). The survival curve is depicted in Fig 2.



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  		Fig 2. Duration of survival.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the last 10 to 15 years, many phase II trials have investigated multimodality treatment strategies that included induction chemotherapy and surgical resection in patients with stage III NSCLC. The substantial variability in the design of these trials makes interpretation of the results difficult. However, it has been well recognized that patients with stage III NSCLC are consistently more sensitive to preoperative chemotherapy than patients with stage IV disease.17 Therefore, the EORTC Lung Cancer Cooperative Group decided to further study new chemotherapy combinations within the framework of a comparative study in patients with NSCLC IIIA N2, evaluating the role of surgery and radiotherapy after induction therapy.

GC was selected as the first combination tested. Preclinical data led this research group to adopt the GC schedule developed by Crinò et al,11 in which gemcitabine is given on days 1, 8, and 15 and cisplatin on day 2. This regimen allows incorporation of gemcitabine in the DNA before cisplatin is given, which in experimental studies seems to favor synergistic interaction.9,10 In this context, it is worth mentioning that reanalysis of clinical (phase II) studies also suggested better efficacy of cisplatin when given after gemcitabine.18,19

When comparing the toxicities of different GC schedules, the administration of cisplatin on day 2 has been associated with more pronounced thrombocytopenia than that observed with cisplatin administration on day 15. The results of this study, in which almost 60% of patients had grade 3/4 thrombocytopenia, are in line with this observation. Fortunately, this thrombocytopenia was not associated with an increase in bleeding events.

Nonhematologic toxicities were typical for a cisplatin-containing combination. The worsening of pulmonary function that occurred after radiotherapy in two patients with preexisting pulmonary fibrosis reinforces the fact that radiation pneumonitis is seen more often after combined-modality treatment. Gemcitabine is a potent radiosensitizer that has been associated with severe radiation pneumonitis when given at full dose concurrently with radiotherapy.20,21 On the other hand, the data showing the feasibility of combining gemcitabine at lower doses with concurrent radiotherapy in patients with stage III NSCLC22 indicate that the preexisting fibrotic pulmonary lesions must have contributed to the pulmonary dysfunction observed. Patients with preexistent fibrotic pulmonary disorders must, therefore, be excluded from the combination of GC and radiotherapy until the interactions with pulmonary fibrosis are better understood. Overall, the clinical results of this study confirm previous observations that the GC combination has acceptable toxicity.

The high response rate produced by three courses of GC is accounted for by the inclusion of all eligible patients and the exclusion of responding patients completing fewer than three courses of GC. The response rate of 70.2% is far greater than the percentages demonstrated in previous phase II and III studies in patients with advanced or metastatic NSCLC. This difference is likely related at least in part to the increased sensitivity to chemotherapy of patients with stage III disease who have a good performance status. On the other hand, this response rate, which is among the highest for preoperative chemotherapy, occurred despite significant tumor bulk; in fact, the large majority of patients had significant N2 enlargement on CT and a relatively low exposure to gemcitabine. It may be theorized, therefore, that a day 2 cisplatin schedule clearly exhibits synergism, resulting in greater activity and increased hematologic toxicity.

In the past, it has been difficult to prove the superiority of one chemotherapy regimen against NSCLC over another. Taking into account the activity of the GC combination as induction treatment in this trial, there is a good reason to consider GC for induction therapy in patients with earlier-stage disease. A preliminary report also indicates that this group of patients may benefit from induction chemotherapy.3 Of the 17 patients randomized to the surgical arm after induction therapy, 94% were operable; in 71% of these cases, the resection was considered complete. Especially important is the fact that mediastinal lymph nodes were rendered tumor-free in 53% of cases. This figure is somewhat higher than that obtained in the Memorial Sloan-Kettering Cancer Center experience, but exactly the same as that reported after the trimodality approach (concurrent chemotherapy and irradiation followed by surgery) used by the Southwest Oncology Group (SWOG). Nodal downstaging is of particular interest, as it was the only significant prognostic factor in a multivariate analysis of this SWOG (8805) trial.23 Other data in this SWOG study, including a 46% major pathologic response rate in patients with stable disease, suggested that chemotherapy given concurrently with radiotherapy may be more effective than chemotherapy alone. Interestingly, the percentage of patients who underwent complete resection in this study was identical (71%) to that of the SWOG study, and median survival was similar (18.9 months in EORTC 08955 v 15 months in SWOG 8805). The question of whether radiotherapy is necessary in the induction regimen24 remains important, and it is expected that the outcomes of this study will encourage investigations optimizing the addition of radiotherapy to GC.22

Concerning the GC schedule, the present experience indicates that slight modifications may be advisable. While keeping dose-intensity largely unchanged, the schedule can be limited to 3 weeks by giving gemcitabine (1,250 mg/m2) on days 1 and 8 only and cisplatin (75 mg/m2) on day 2. An almost identical schedule has already been shown to be feasible.14

In conclusion, our data show that GC with cisplatin on day 2 is highly active in patients with stage IIIA N2 NSCLC. The combination of GC with surgery and radiotherapy was feasible, and the present results encourage the exploration of this combination in patients with resectable, early-stage disease.


   ACKNOWLEDGMENTS
 
Supported in full by the EORTC Lung Cancer Cooperative Group.


   NOTES
 
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Lilenbaum RC, Green M: Multimodality therapy for non-small cell lung cancer. Oncology 8:25-31, 1994[Medline]

2. Martini N, Kris MG, Flehinger BJ, et al: Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients. Ann Thorac Surg 55:1365-1373, 1993[Abstract]

3. Depierre A, Milleron B, Moro D, et al: Phase III trial of neo-adjuvant chemotherapy (NCT) in resectable stage I (except T1N0), II, IIIa non-small cell lung cancer (NSCLC): The French experience. Proc Am Soc Clin Oncol 18:465a, 1999 (abstr 1792)

4. Rosell R, Gomez-Codina J, Camps C, et al: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330:153-158, 1994[Abstract/Free Full Text]

5. Roth JA, Fossella F, Komaki R, et al: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 86:673-680, 1994[Abstract/Free Full Text]

6. Pass HI, Pogrebniak HW, Steinberg SM, et al: Randomized trial of neoadjuvant therapy for lung cancer: Interim analysis. Ann Thorac Surg 53:992-998, 1992[Abstract]

7. American Society of Clinical Oncology: Clinical practice guidelines for the treatment of unresectable non-small cell lung cancer: Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol 15:2996-3018, 1997[Abstract]

8. Luud B, Kristjanson PEG, Hansen HH: Clinical and preclinical activity of 2',2'-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev 19:45-55, 1994

9. Bergman AM, Ruiz van Haperen VWT, Veerman G, et al: Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 2:521-530, 1996[Abstract]

10. Peters GJ, Ruiz van Haperen VWT, Bergman AM, et al: Preclinical combination therapy with gemcitabine and mechanisms of resistance. Semin Oncol 23:16-24, 1996

11. Crinò L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non-small cell lung cancer: A phase II study. J Clin Oncol 15:297-303, 1997[Abstract/Free Full Text]

12. Abratt RP, Bezwoda WR, Goedhals L, et al: Weekly gemcitabine with monthly cisplatin: Effective chemotherapy for advanced non-small cell lung cancer. J Clin Oncol 15:744-749, 1997[Abstract/Free Full Text]

13. Sandler A, Nemunaitis J, Dehnam C, et al: Phase III study of cisplatin with or without gemcitabine in patients with advanced NSCLC. Proc Am Soc Clin Oncol 17:454, 1998 (abstr 1747)

14. Cardenal F, Paz López-Cabrerizo M, Antón A, et al: Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 17:12-18, 1999[Abstract/Free Full Text]

15. Crinò L, Conte P, De Marinis F, et al: A randomized trial of gemcitabine cisplatin versus mitomycin, ifosfamide and cisplatin (MIC) in advanced non-small cell lung cancer (NSCLC): A multicenter phase III study. Proc Am Soc Clin Oncol 17:455, 1998 (abstr 1750)

16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

17. Lynch TJ: Treatment of stage III non-small-cell lung cancer. ASCO Educational Book, Spring:265-275, 1998

18. Shepherd FA, Anglin G, Abratt R, et al: Influence of gemcitabine (GEM) and cisplatin (CP) schedule on response and survival in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:472a, 1998 (abstr 1816)

19. Abratt RP, Sandler A, Crinò L: Combined cisplatin and gemcitabine for non-small cell lung cancer: Influence of scheduling on toxicity and drug delivery. Semin Oncol 25:35-43, 1998

20. Raach M, Fandara DR, Yuo M-S, et al: Radiation pneumonitis following combined modality therapy for lung cancer: Analysis of prognostic factors. J Clin Oncol 13:2606-2612, 1995[Abstract]

21. Goor C, Scalliet P, Van Meerbeeck J, et al: A phase II study combining gemcitabine and radiotherapy in stage III NSCLC. Ann Oncol 7:S101, 1996 (suppl 5) (abstr)

22. Vokes EE, Leopols KA, Herndon JE, et al: A randomized phase II study of gemcitabine or paclitaxel or vinorelbine with cisplatin as induction chemotherapy and concomitant chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC) (CALGB study 9431). Proc Am Soc Clin Oncol 18:459a, 1999 (abstr 1771)

23. Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13:1880-1892, 1995[Abstract/Free Full Text]

24. Albain KS: Induction chemotherapy with or without radiation followed by surgery in stage III non-small cell lung cancer: Update and perspectives. Oncology 11:S51-S57, 1997 (suppl 9)

Submitted October 12, 1999; accepted March 8, 2000.


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C. C.M. Pitz, K. W. Maas, H. A. V. Swieten, A. Brutel de la Riviere, P. Hofman, and F. M.N.H. Schramel
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C. Pottgen, W. Eberhardt, S. Bildat, G. Stuben, G. Stamatis, L. Hillejan, S. Sohrab, H. Teschler, S. Seeber, H. Sack, et al.
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L. Trodella, P. Granone, S. Valente, A. Turriziani, G. Macis, G. M. Corbo, S. Margaritora, A. Cesario, R. M. D'Angelillo, G. Gualano, et al.
Phase I Trial of Weekly Gemcitabine and Concurrent Radiotherapy in Patients With Inoperable Non-Small-Cell Lung Cancer
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