Induction chemotherapy with paclitaxel plus carboplatin followed by paclitaxel with concurrent radiotherapy in stage IIIB non-small-cell lung cancer (NSCLC) patients: A phase II trial

Lung Cancer (2007) 58, 238—245

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Induction chemotherapy with paclitaxel plus carboplatin followed by paclitaxel with concurrent radiotherapy in stage IIIB non-small-cell lung cancer (NSCLC) patients: A phase II trial C. Pallar´ es a, J. Capdevila a,∗, A. Paredes c, N. Farr´ e b, J.P. Ciria d, I. Membrive b, L. Basterrechea c, G. Gomez-Segura b, A. Barnadas a a

Department of Medical Oncology, Sant Pau University Hospital, St. Antoni Ma Claret 167, 08025 Barcelona, Spain Department of Radiotherapy Oncology, Sant Pau University Hospital, Barcelona, Spain c Department of Medical Oncology, Donostia University Hospital, San Sebastian, Spain d Department of Radiotherapy Oncology, Donostia University Hospital, San Sebastian, Spain b

Received 30 October 2006; received in revised form 2 April 2007; accepted 5 June 2007

KEYWORDS Non-small-cell lung cancer; Stage IIIB; Concurrent chemoradiotherapy; Paclitaxel; Carboplatin

∗

Summary Purpose: We conducted a prospective phase II trial to evaluate the efficacy and toxicity of induction chemotherapy with paclitaxel plus carboplatin followed by concurrent radiotherapy with weekly paclitaxel in stage IIIB non-small-cell lung cancer (NSCLC) patients. Patients and methods: Patients with stage IIIB NSCLC received two 3-week cycles of paclitaxel 200 mg/m2 combined with carboplatin (target area under the plasma concentration curve (AUC) of 6 mg/ml) followed by weekly paclitaxel 50 mg/m2 concurrently with radiotherapy consisted of 2 Gy daily, 5 days per week (60 Gy total dose in 6 weeks). The median follow-up period was 5 years. Results: Between March 1999 and January 2002, 21 patients were enrolled and analyzed. Ninety percent of patients completed the planned treatment schedule. The overall response rate was 76% (24% complete response and 52% partial response). The median overall survival time was 15 months and the 1-year, 2-year and 5-year overall survival rates were 57, 33 and 24%, respectively. The disease progression rate at 1 year was 43% and the median progression-free survival was 8 months. During the chemoradiation period, grade 3—4 oesophagitis and pneumonitis were observed in 24 and 14% of patients, respectively. Conclusions: Induction chemotherapy with carboplatin and paclitaxel followed by weekly paclitaxel with concurrent radiotherapy was found to be active and tolerable in selected stage IIIB

Corresponding author. Tel.: +34932746085; fax: +34932746059. E-mail address: [email protected] (J. Capdevila).

0169-5002/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2007.06.003

Induction chemotherapy with paclitaxel plus carboplatin

239

NSCLC patients. Further studies are needed to improve the safety profile and outcome in this setting. © 2007 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is the most common malignant disease in the western world. Non-small-cell lung cancer (NSCLC) accounts for 75% of all lung cancer cases, and approximately 30% of NSCLC patients present with locally advanced disease (stages IIIA and IIIB) [1]. Regionally advanced, unresectable NSCLC stage IIIB (T4 without pleural effusion or N3) is characterized by large primary lesions or widespread involvement of contralateral mediastinum or supraclavicular regions. Thoracic radiation therapy has been the standard treatment approach for patients with unresectable NSCLC stages IIIA and IIIB. The clinical outcomes of radiotherapy alone are far from satisfactory, with a median survival of 8—10 months and a 5-year survival of 6—10% [2,3]. In the 1990s, several clinical trials were performed comparing induction chemotherapy with radiotherapy alone. A randomised trial reported in 1990 by the Cancer and Leukaemia Group B (CALGB) compared standard thoracic radiation therapy (TRT) (60 Gy in 6 weeks) with induction chemotherapy with cisplatin plus vinblastine followed by TRT in stage III NSCLC patients. The authors reported an increase in median survival (9.7 months versus 13.8 months) and in 5-year survival (13% versus 24%) in the induction chemotherapy group. These results were confirmed by other groups in randomized phase III trials [4,5]. A phase III randomised trial conducted by EORTC demonstrated a significant increase in 3-year survival (16% versus 2%) in patients treated with TRT and concurrent chemotherapy with low doses of cisplatin, compared with TRT alone [6]. Other randomised phase III trials demonstrated the advantages of concurrent chemotherapy and radiotherapy over sequential treatment [7—9]. Both randomised trials evaluated cisplatin-based regimens with radiotherapy. Newer chemotherapeutic agents, such as paclitaxel, have been successfully integrated with radiotherapy in combined modality programs [10—12]. The optimal timing sequence of combined therapy has yet to be determined, although concurrent therapy appears to be superior to sequential therapy. The concurrent approach seems to increase the rate of adverse events, particularly oesophagitis and pneumonitis. Several more recent phase II trials that combined carboplatin, paclitaxel and concurrent radiotherapy have reported improvements in survival, with acceptable rates of adverse effects [11—14]. In view of these observations, concurrent chemotherapy integrating both radiation-sensitizing agents and doses of chemotherapy that are effective against micrometastases may prove to be most efficacious. However, the therapeutic benefit of either induction or consolidation full-dose chemotherapy in conjunction with concurrent chemoradiotherapy is not yet clearly established. We conducted a phase II trial of induction chemotherapy with paclitaxel plus carboplatin followed by weekly

paclitaxel with concurrent radiotherapy in stage IIIB NSCLC patients. The primary objective was to evaluate the response rate and feasibility of this regimen. As secondary endpoints, we evaluated toxicity, response duration, time-to-progression and overall survival at 2, 3 and 5 years.

2. Patients and methods 2.1. Patient eligibility Between March 1999 and January 2002, 21 patients were enrolled in this trial. Although the planned sample size was 24, we stopped earlier as the recruitment rate at 2 years was low. In this study we present the treatment results after 5 years’ follow-up. The main eligibility criteria for this study were a histologically or cytologically confirmed diagnosis of NSCLC (including squamous cell carcinoma, adenocarcinoma, large cell anaplastic carcinoma and poorly differentiated NSCLC) and a surgically unresectable Stage IIIB tumour (without pleural effusion) as determined by the American Joint Committee on Cancer (AJCC) TNM staging system [15]. Patients were required to have measurable disease and a Karnofsky performance status ≥70%. Additional eligibility criteria included age ≥18 years, life expectancy ≥12 weeks, adequate renal, hepatic and bone marrow function (haemoglobin ≥10.5 g/dL, granulocyte count ≥2.0 × 109 /L, platelet count ≥100 × 109 /L, serum bilirubin ≤1.25 × normal, serum albumin ≥35 g/dL, serum creatinine ≤ 120 ␮mol/L (≤1.5 mg/dL), and creatinine clearance ≥50 mL/min), and a normal pulmonary function test (forced expiratory volume in 1 s ≥1600 mL and forced vital capacity ≥3000 mL). Patients with prior or active concurrent malignancy, previous antineoplastic treatment, mixed cellular histology (large cell/small cell), severe medical or psychiatric illness, or history of cardiac disease were excluded. All patients were informed of the investigational nature of this study and gave written informed consent in accordance with the local institutional review board and national regulatory guidelines.

2.2. Treatment schedule Treatment consisted of an induction chemotherapy phase followed by a consolidation phase with chemotherapy and radiotherapy given concurrently. The induction treatment consisted of two 3-week cycles of paclitaxel 200 mg/m2 infused over 3 h combined with carboplatin (target area under the plasma concentration—time curve (AUC) of 6 mg/mL) as an intravenous infusion over 1 h. The dose of carboplatin was calculated using the Calvert formula with the creatinine clearance estimated using the

240 Cockroft—Gault equation [16]. Antiemetic drugs were administered as required. Within 3—6 weeks after completing the two cycles of chemotherapy, patients underwent concurrent chemoradiation. The schedule consisted of weekly paclitaxel 50 mg/m2 via intravenous infusion over 1 h, concurrently with radiotherapy (TRT) consisting of 2 Gy daily, 5 days per week (60 Gy target dose in 6 weeks to the initial field) performed with photons of Co60 or linear accelerator, with a field covering the tumour and the macroscopic nodal disease. Prophylactic node radiation was made (mediastinum, contralateral hillum or supraclavicular fossae depending the case) performing a total dose of 45 Gy in these areas. All patients first underwent a CT scan to plan threedimensional conformal radiation therapy (3D-CRT). Patients were positioned with arms above the head. No respiratory gating techniques were used. The gross tumour volume (GTV) was defined and contoured for all patients. It included the primary disease as well as any regional lymph nodes involved. The primary tumour was contoured using pulmonary window CT settings and nodal GTV using the mediastinal window. Generally, elective nodal coverage included the ipsilateral hilum and ipsilateral and contralateral mediastinum. Supraclavicular areas were treated electively in patients with apical tumours or upper mediastinal adenopathy. First planned tumour volume (PTV1) was contoured around the GTV (tumour and nodal) and nodal elective areas using a margin of 10 mm for elective node areas and 15 mm for GTV. The prescribed dose in PTV1 was 44 Gy. PTV2 was contoured around the GTV with the same margin. The dose prescribed in PTV2 was 16 Gy. Treatment was delivered using isocentric techniques with two or three fields. We used the modified Batho inhomogeneity correction algorithm. Dose constraints for lung and spinal cord were calculated using the dose volume histogram (DVH). The limiting dose for lung was V20 (lung volume receiving 20 Gy). The dose to the spinal cord did not exceed 45 Gy. Radiotherapy was delivered either with Co60 or linear accelerator photons, and the schedule was 2 Gy daily, 5 days a week.

C. Pallar´ es et al.

2.4. Evaluation of the treatment-related toxicities Patients were evaluated by chest X-ray or CT scan after induction chemotherapy, and by chest X-ray, CT scan and pulmonary function tests at 4—6 weeks after chemoradiation treatment. Toxicity was evaluated weekly during chemoradiation treatment. Toxicity was graded based on the NCI common toxicity criteria (CTC) and the Radiation Therapy Oncology Group (RTOG) criteria for oesophagic and pulmonary toxicities. During treatment we monitored patients for signs and symptoms of haematology, pulmonary and gastrointestinal toxicity.

2.5. Follow-up evaluation and statistical analysis After chemoradiation the patients were evaluated by chest X-ray or CT scan monthly during the first 3 months and every 2 months thereafter. Treatment response was defined following the standard criteria for response by the World Health Association: a complete response was defined as complete tumour disappearance for at least 4 weeks. A partial response required a reduction of at least 50% in the volume of the tumour for at least 4 weeks. Stable disease was defined as no change or <50% reduction or <25% increase, and progressive disease was defined as an increase >25% in the volume of the initial tumour volume or the appearance of a new lesion. Treatment failure was analysed for local, regional and distant metastases. The primary end point was response rate and toxicity. We evaluated the tolerability and toxicity of the two treatment phases: the induction chemotherapy and the chemoradiation therapy. As secondary endpoints, we also evaluated the time-to-progression disease and the overall survival. Statistical analysis of overall survival and time-toprogression disease were performed using a one-sided log-rank of Kaplan—Meier survival estimates.

3. Results 2.3. Treatment modifications If patients presented grade 3/4 granulocytopenia induction chemotherapy was delayed till the patient’s bone marrow had recovered; no dose modification was made. If grade 2/3 thrombocytopaenia appeared, the paclitaxel dose was reduced by 20% (160 mg/m2 ) and carboplatin by 1.5 in AUC (AUC 4.5) during the second cycle. While on concurrent chemoradiotherapy, doses of paclitaxel were reduced by 50% if the granulocyte count was below 1500/␮L or if the platelet count was lower than 100,000/␮L. If the granulocyte count fell below 1000/␮L or if the platelet count was less than 75,000/␮L, the chemotherapy dose was omitted. If the granulocyte count fell below 500/␮L or the platelet count to less than 50,000/␮L, radiotherapy was stopped. If grade 3/4 esophagitis occurred chemoradiation was interrupted for 2 weeks. Treatment was reinitiated once the patient recovered.

3.1. Patient characteristics Patients’ characteristics are shown in Table 1. Median age was 55 years (range 38—67 years). Nineteen patients were male and two were female. The majority of patients had a baseline Karnofsky performance status of 80 or higher, with only 10% of patients with performance status of 70. Squamous cell carcinoma (43%) and adenocarcinoma (33%) were the most common histologies. The distributions of T and N stages are shown in Table 2. Nineteen percent of patients had a N0/N1 involvement, 33% a N2 and 48% a N3 involvement. Twenty-one patients were assessable for toxicity and response.

3.2. Treatment compliance Nineteen patients (90%) completed the planned treatment schedule. Only two patients who did not complete

Induction chemotherapy with paclitaxel plus carboplatin Table 1

241 Table 3

Patients characteristics

Radiation-associated toxicities (RTOG scale)

Characteristics

Number of patients (%)

Grade

Oesophagitis

Pneumonitis

Age (years) Median Range

55 38—67

7 (33%) 6 (28%) 5 (24%)

Gender Male Female

I II III IV

3 (14%) 6 (28%) 3 (14%) 1 (5%)

19 (90%) 2 (10%)

Karnofsky PS 80—100 ≤70

19 (90%) 2 (10%)

Histology Squamous Adenocarcinoma Large cell Poorly differenciated

Table 4

9 (43%) 7 (33%) 2 (10%) 3 (14%)

3.3. Treatment-related toxicites A. Induction period: Common treatment-related toxicities were ≤grade 2. Eight patients (38%) presented grade 1—2 haematologic toxicity and only one patient presented grade 4 granulocytopenia. Five patients (24%) presented grade 1—2 gastrointestinal toxicity (mainly nausea and vomiting). B. Chemoradiotherapy: The most common locoregional toxicity was epithelitis (>90%). This did not exceed grade 3. Oesophagitis occurred in 18 patients (86%);13 patients (61%) presented grade 1—2 oesophagitis and seven grade 3—4. Pneumonitis occurred in 13 patients (62%): grade 1—2 in nine patients (43%) and grade 3—4 in four (19%). One patient died due to a radiation-associated pneumonitis. Most

Stage

T1

T2

T3

N0 N1 N2 N3

5 (24%) 1 (5%)

Total

5

1

Number of patients (%)

Complete response Partial response Stable disease Progressive disease Overall response

5 (24%) 11 (52%) 1 (5%) 4 (19%) 16 (76%)

patients with pneumonitis improved after steroid treatment. All toxicities are shown in Table 3. No long-term toxicities were observed.

3.4. Response Response was evaluated by chest X-ray or CT scan after the induction chemotherapy and by CT scan after chemoradiation therapy. Complete and partial response rates after the concurrent treatment were 24 and 52%, respectively, for an overall response rate of 76%. Stable disease and progressive disease occurred in four (19%) and one patient (5%), respectively. The response rate is shown in Table 4. Tumour response rate with induction chemotherapy was 52% (11 patients) and only one patient had progressive disease. After chemoradiation treatment seven of the initial partial responses were maintained and four patients achieved complete response. Four patients with stable disease after induction chemotherapy achieved partial response after chemoradiotherapy. Three patients progressed during chemoradiation treatment. The relationship between response rate with induction chemotherapy and after the combination treatment is shown in Table 5.

3.5. Patterns of failure At 5-year follow up, recurrence was observed in 16 patients. Local recurrence was observed in 12 patients (57%). Dis-

Table 5 Response rate after chemotherapy vs. after chemoradiotherapy

Distribution of T and N stages T0

Response

All patients (n = 21).

treatment were classified as having progressive disease during chemoradiation treatment (one patient showed locoregional progression and the other developed bone metastases). Median radiation dose of the 19 patients who completed the planned radiotherapy schedule was 60.7 Gy. Radiotherapy was stopped for 1 week in two patients. The first patient presented pneumonia and required hospitalisation. Interruption of treatment in the case of the second patient was due to technical problems with the lineal accelerator.

Table 2

Response rate

T4 3 (14%) 1 (5%) 7 (33%) 4 (19%) 15

Total 3 1 7 10 21

Complete response Partial response Stable disease Progression Overall response

Induction chemotherapy

Chemoradiotherapy

0 11 (52%) 9 (43%) 1 (5%) 11 (52%)

5 (24%) 11 (52%) 1 (5%) 4 (19%) 16 (76%)

242 Table 6

C. Pallar´ es et al.

4. Discussion

Patterns of failure

Sites of failure

Patients No.

%

Local Distant Local + distant Only local Only distant

12 10 6 6 4

57 48 28 28 19

No. of patients without local relapse

9 (5 patients disease-free + 4 patients with distant mets)

43

Fig. 1

Progression-free survival curve for 21 patients.

tant metastases were documented in 10 patients (48%). Six patients (28%) presented locoregional progression and died without distant metastases. Four patients (19%) died due to distant metastases without local failure. Locoregional tumour control was obtained in nine patients (43%) (Table 6).

3.6. Time to progression and survival analysis With a median follow-up of 60 months the median overall survival time was 15 months. The 1-year, 2-year and 5-year overall survival rates were 57, 33, and 24%, respectively. The disease progression rate at 1-year was 43% and the median progression-free survival was 8 months. The survival curves are shown in Figs. 1 and 2.

Fig. 2

Overall survival curve.

Much progress has been made in recent decades in treating stage IIIB NSCLC. At present, no chemoradiotherapy schedule can be considered standard care in this setting. Several treatment schedules of chemotherapy have been studied. Their aim is to, first, reduce distant metastases, the major cause of failure, and second, achieve local control in a local bulky disease. A number of hypotheses justify the use of full doses with the best combination chemotherapy: platinum in combination with third generation cytotoxic agents. However, bone marrow recovery at 3 weeks compromises the radiosensitation effect of a concurrent chemoradiation scheme. Lower and more frequent doses of cytotoxics may provide a better radiosensitation in locoregional disease, keeping induction and/or consolidation treatment to control distant disease. In two recent studies [13,17], induction and consolidation treatment showed an acceptable toxicity and improved survival. The distinctive features of our study are the combination of a two-drug induction schedules followed by chemoradiation with a single radiosensitizer in order to minimise the side effects. The selection of patients with excellent performance status and the inclusion of stage IIIB NSCLC patients only are important features to demonstrate the real value of chemoradiation in this setting, as reflected in the 24% overall survival at 5 years. Although the study group was limited in size we observed a similar overall response to that seen in recently published studies [9,14,17—20]. Additionally, overall survival and time-to-progression outcomes were similar (Table 7). Our group of patients were homogeneous with stage IIIB disease, but most studies included patients with stage IIIA and IIIB disease (between 25 and 63% of stage IIIA). This difference should be taken into account when comparing results. The combination of chemoradiotherapy is more toxic than radiotherapy alone. To reduce this toxicity we used only one drug in combination with radiotherapy. Several studies [11,21] have also found that the combination of two drugs with radiotherapy was tolerable, with grade 3—4 oesophagitis around 40—46%. We obtained lower grade 3—4 oesophagitis and pneumonitis rates, 24 and 19%, respectively, with only one toxic dead and similar survival rates (see biblio). In another recently published trial [22], a low dose of daily chemotherapy given concurrently with radiotherapy improved survival and reduced severe adverse effects (grade 3—4 oesophagitis 17% and pneumonitis 13%) supporting the idea that administration of low doses of chemotherapy concurrently with radiotherapy are equivalent to combined regimens. The schedule was well tolerated and showed a 90% treatment compliance, higher than other studies that combined doublets of chemotherapy agents concurrently with radiotherapy (70% compliance) [18]. The use of cytotoxic (against micrometastasis) or cytostatic (radiosensitive) chemotherapy combined with radiotherapy is not well defined. Several trials have studied the role of hyperfractionated accelerated radiotherapy in the setting of combined-modality treatment. Saunders et al enrolled 563 patients with inoperable NSCLC to receive either standard radiotherapy or continuous hyperfractionated accelerated radiotherapy (CHART). Patients randomised to the CHART

Main trials with concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer setting

Study

Treatment schedule

N

Stage

RR (%)

3-year OS (%)

Grade 3—4 O and P (%)

CALGB 9431 phase II [19]

Three arms: induction CT with C + G or P or V with concurrent RT C + VP16 with concurrent RT followed by consolidation CT (D) Three arms: CB + P and sequential RT; CB + P and concurrent CT-RT; concurrent CT-RT and consolidation CT Two arms: induction CT with C + P followed by CT-RT (C + V); Concurrent CT-RT (C + V) followed by consolidation CT (C + P). RT plus concurrent CT with C+P Two arms: induction CT with C + V followed by RT vs. concurrent CT-RT with C + VP16. Consolidation CT (C + V) in two arms.

175

IIIA, IIIB

74/67/73

28/19/23

O: 52/39/25, P: 14/24/22

IIIB

67

37

O: 17, P: 7a

276

IIIA, IIIB

NA

17/15/17

O: 3/19/28, P: 7/4/16

128

IIIA, IIIB

55/48

47/43 (2-year OS)

O: 6/13, P: 0/1

135

IIIB

75

37 (2-year OS)

O: 4, P: 3

205

IIIA, IIIB

54/49

19/25

O: 3/32, P: 11/5b

SWOG 9504 phase II [17]

Belani phase II [14]

Fournel phase II [20]

Kim phase II [18] Fournel phase III [9]

83

Induction chemotherapy with paclitaxel plus carboplatin

Table 7

N: number of patients; RR: response rate; OS: overall survival; O: oesophagitis; P: pneumonitis; CT: chemotherapy; RT: radiotherapy; C: cisplatin; G: gemcitabine; P: paclitaxel; V: vinorelbine; VP16: etoposide; D: docetaxel; CB: carboplatin. a 2% toxic deaths. b 7.8% toxic deaths.

243

244 arm had a significantly higher local control rate (23% versus 15%) and 2-year overall survival rate (29% versus 20%) [23]. The Eastern Co-operative Oncology Group (ECOG 2597) conducted a phase III trial to compare induction chemotherapy followed by standard radiotherapy or CHART [24]. The authors found a trend of benefit with CHART arm (3-year overall survival 20% versus 15%), but the study was closed early because of slow accrual. These trials have demonstrated the better results of hyperfractionated accelerated radiotherapy compared with conventional radiotherapy, but suggest that logistic issues of delivering treatment more than twice daily may create barriers to further exploring hyperfractionated regimens. If the addition of chemotherapy to daily radiotherapy has improved the results of radiotherapy alone, then these results may approach those obtained with accelerated radiotherapy. When we analysed the effect of induction chemotherapy, we observed a correlation between the response rate achieved after the induction and combined treatments. Eleven patients (52%) who had a partial response after induction chemotherapy maintained this or reached a complete response after chemoradiotherapy. Ten patients did not respond to initial chemotherapy, but four (40%) progressed after chemoradiation treatment. Regarding tumour burden we obtained a better survival rate in patients with less lymph node involvement. Two of four patients with N0/N1 involvement were alive at 5-year follow-up (50%) compared with 3 of the 17 patients with N2/N3 (17%). This suggests a higher treatment efficacy in patients with less tumour volume. In conclusion, induction chemotherapy with carboplatin and paclitaxel followed by weekly paclitaxel with concurrent radiotherapy was found to be active and tolerable in selected stage IIIB NSCSL patients. Although the main drawback is still toxicity, this seems to be less when lower doses of chemotherapy are administered concurrently with radiotherapy, and no effectiveness is lost. Further studies are needed to determine the optimal scheduling of concurrent chemotherapy and radiotherapy, the chemotherapy agents to be used and the total dose of radiotherapy.

Conflict of interest

C. Pallar´ es et al.

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

The authors indicated no potential conflicts of interest.

References [1] Glassberg AB, Cornett P. Lung. Non-small-cell. In: Dollinger M, Rosenbaum EH, Cable G, editors. Everyone’s guide to cancer therapy. Kansas City, MO: Somerville House Books Limited; 1994. p. 469—75. [2] Perez CA, Bauer M, Emami BN, Byhardt R, Brady LW, Doggett RL, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986;12:539—47. [3] Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: sevenyear follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210—5. [4] Sause W, Sacott C, Taylor S. Preliminary results of a phase III trial in regional advanced non-respectable non-small-cell lung cancer: Radiation Therapy Oncology Group and Eastern

[15]

[16]

[17]

[18]

Cooperative Oncology Group. J Natl Cancer Inst 1995;87:198— 205. Le Chevalier T, Arriagada R, Quoix E. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non small cell lung cancer. Lung Cancer 1944;10:5239—44. Schaske-Koning C, Van der Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992;326(8):524—30. Curran WJ, Scott CB, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. Proc Am Soc Clin Oncol 2003;22 [abstract 2499]. Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, 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—9. Fournel P, Robinet G, Thomas P, Souquet PJ, L´ ena H, Vergnen´ egre A, et al. Randomized phase III trial of sequencial chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 2005;23(25):5910—7. Choy H, Devore RF, Hande KR, Porter LL, Rosenblatt P, Yunus F, et al. A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study). Int J Radiat Oncol Biol Phys 2000;47:931—7. Choy H, Akeley W, Safran H, Graziano S, Chung C, Williams T, et al. Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. J Clin Oncol 1998;16:3316—22. Belani CP, Aisner J, Day R, Ramanathan R, Jett J, Capozzoli MJ, et al. Weekly paclitaxel and carboplatin with simultaneous thoracic radiotherapy (TRT) for locally advanced non-smallcell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1997;16:448a [Abstract 1608]. Langer CJ, Movsas B, Hudes R, Schol J, Keenan E, Kilpatrick D, et al. Induction paclitaxel and carboplatin followed by concurrent chemoradiotherapy in patients with unresectable, locally advanced non-small cell lung carcinoma: report of Fox Chase Cancer Center study 94-001. Semin Oncol 1997;24(Suppl. 12):S12-89—95. Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005;23:5883—91. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. AJCC cancer staging manual. 6th ed. New York: SpringerVerlag; 2002. p. 167—177. Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748—56. Gandara DR, Chansky K, Albain KS, Leigh BR, Gaspar LE, Lara PN, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol 2003;21:2004—10. Kim YS, Yoon SM, Choi EK, Yi BY, Kim JH, Ahn SD, et al. Phase II study of radiotherapy with three-dimensional conformal boost concurrent with paclitaxel and cisplatin for stage IIIB non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2005;62:76—81.

Induction chemotherapy with paclitaxel plus carboplatin [19] Vokes EE, Herndon JE, Crawford J, Leopold KA, Perry MC, Miller AA, et al. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiation for satge IIIB non-small-cell lung cancer: cancer and leukemia group study 9431. J Clin Oncol 2002;20:4191— 8. [20] Fournel P, Vergnen´ egre A, Robinet G, L´ ena H, Gervais R, Le Caer H, et al. Induction (ICT) or consolidation chemotherapy (CT) with cisplatin (C) and paclitaxel (P) plus concurrent chemo-radiation (CT/TRT) with cisplatin and vinorelbine (V) for unresectable non-small cell lung cancer (NSCLC) patients (pts): randomized phase II trial GFPC-GLOT-IFCT 02-01. Proc Am Soc Clin Oncol 2006;24:18S [abstract 7048]. [21] Lau D, Leigh B, Gandara D, Edelman M, Morgan R, Israel V, et al. Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/paclitaxel

245 consolidation for stage III non-small-cell lung cancer: a California cancer consortium phase II. J Clin Oncol 2001;19:442—7. [22] Jeremic B, Milicic B, Acimovic L, Milisavljevic S. Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin and paclitaxel in patients with stage III non-small-cell lung cancer: long-term results of a phase II study. J Clin Oncol 2005;23:1144—51. [23] Saunders M, Dische S, Barret A, Harvey A, Griffiths G, Parmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: mature data from the randomized multicenter trial. Radiother Oncol 1999;52:137—48. [24] Belani CP, Wang W, Johnson DH, Wagner H, Schiller J, Veeder M, et al. Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 2005;23:3760—7.