carboplatin and thoracic radiotherapy in patients with stage III non-small cell lung cancer

Lung Cancer 77 (2012) 89–96

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Randomized phase II study of concurrent cisplatin/etoposide or paclitaxel/carboplatin and thoracic radiotherapy in patients with stage III non-small cell lung cancer夽 Luhua Wang a,∗ , Shixiu Wu b , Guangfei Ou a , Nan Bi a , Wenfeng Li b , Hua Ren a , Jianzhong Cao a , Jun Liang a , Junling Li c , Zongmei Zhou a , Jima Lv a , Xiangru Zhang c a

Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Department of Radiation Oncology, First Affiliate Hospital of Wenzhou Medical College, Wenzhou, Zhejiang Province, China c Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China b

a r t i c l e

i n f o

Article history: Received 21 September 2011 Received in revised form 7 February 2012 Accepted 14 February 2012 Keywords: NSCLC Locally advanced Concurrent chemoradiation Cisplatin Etoposide Paclitaxel Carboplatin

a b s t r a c t Objective: To evaluate the activity and safety of concurrent thoracic radiotherapy (TRT) plus weekly paclitaxel/carboplatin (PC) regimen compared with widely used cisplatin/etoposide (PE) regimen in patients with unresectable stage III non-small cell lung cancer (NSCLC). Patients and methods: Patients were randomly assigned to receive the following treatments: PE arm, cisplatin (50 mg/m2 ) on days 1, 8, 29, and 36 and etoposide (50 mg/m2 ) on days 1–5 and 29–33 plus 60 Gy of TRT; PC arm, weekly concurrent carboplatin (AUC = 2) and paclitaxel (45 mg/m2 ) plus 60 Gy of TRT. Results: A total of 65 patients were randomized (PE arm, n = 33; PC arm, n = 32). The 3-year overall survival (OS) was significantly better in the PE arm than in the PC arm (33.1% vs. 13%, P = .04). The incidence of Grade 3/4 neutropenia was 78.1% in the PE arm and 51.5% in the PC arm (P = .05). The rate of Grade 2 or greater radiation pneumonitis was 25% in the PE arm and 48.5% in the PC arm (P = .09). Conclusions: Compared to PE regimen, weekly PC regimen cannot be recommended since it failed to achieve an improvement in either OS or PFS. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer remains the leading cause of cancer-related deaths in the world. In China, approximately 500,000 lung cancer patients were diagnosed and 428,000 individuals were estimated to die from the cancer in 2005. Non-small cell lung cancer (NSCLC) accounts for more than 80% of primary lung cancers, and about one third of NSCLC patients are diagnosed at a locally advanced stage. Concurrent chemoradiation (ChRT) is the standard of care for unresectable stage III NSCLC patients with good performance status [1]. The combination of chemotherapy and thoracic radiotherapy (TRT) could decrease distant micrometastases and improve local control with a survival benefit. In the phase III trial performed by the Radiation Therapy Oncology Group (RTOG) 9410 [2], a cisplatin/etoposide

夽 This study was accepted for oral presentation at the 52nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, San Diego, CA, Oct 31–Nov 4, 2010. ∗ Corresponding author at: Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China. Tel.: +86 10 87716559; fax: +86 10 87716559. E-mail address: [email protected] (L. Wang). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2012.02.011

(PE) regimen plus concurrent TRT significantly prolonged the overall survival compared with the sequential arm. Although advances have been made, the clinical results for unresectable stage III NSCLC remain inadequate, which indicates the need for improvement [3]. During the last decade, the use of new agents in combination with the platinum agents, which are called third-generation regimens, has been proven to increase survival in patients with advanced NSCLC compared with conventional chemotherapy agents. Among the third-generation regimens, a weekly paclitaxel plus carboplatin (PC) regimen is one of the most commonly used regimens, and there is considerable interest in the combination of PC with TRT for the treatment of locally advanced NSCLC. Since the 1990s, several clinical trials [2,4–20] have demonstrated a mean survival time (MST) ranging from 14 to 35 months for the PE regimen plus TRT and a MST of 12–28 months for the weekly PC regimen plus TRT in unresectable IIIA/IIIB NSCLC. However, to the best of our knowledge, no head-to-head study has been reported to compare the clinical results of these two regimens. Herein, we conducted a bi-centric phase II trial to assess the activity and safety in weekly PC vs. PE-based ChRT for patients with unresectable IIIA/IIIB NSCLC.

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2. Patients and methods 2.1. Eligibility criteria Patients were required to have cytologically or histologically confirmed NSCLC by biopsy. The eligible patients were also to meet the following criteria: between 18 and 70 years of age; Eastern Cooperative Oncology Group (ECOG) performance status ≤1; ≤10% weight loss in the 3 months before inclusion; inoperable AJCC stage IIIA, or IIIB; and neutrophils ≥1.5 × 109 /L, platelets ≥100 × 109 /L, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin ≤1.5 × the upper limit of the institutional normal range, and creatinine concentration ≤120 ␮mol/L. Ineligibility criteria included malignant pleural effusion; active uncontrolled infection; clinically significant cardiovascular disease; history of other malignancies; forced expiratory volume in 1 s < 40% of normal; and previous treatment with radiotherapy, chemotherapy, or immunotherapy. The protocol of this trial was approved by the institutional ethics committees of the two participating institutions. All patients provided written informed consent prior to enrollment. 2.2. Pretreatment evaluation All patients provided their full medical histories and underwent physical examination. Laboratory investigations included complete and differential blood counts (CBC) and assays of electrolytes, glucose, calcium, albumin, transaminases, alkaline phosphatases, total bilirubin, and creatinine. The following examinations had to be performed within the month preceding entry into the study: electrocardiograph (ECG), chest X-ray, bronchoscopy, chest and abdominal CT, brain MRI, radionuclide bone scan, as well as the adjunctive use of chest MRI or FDG positron emission tomography (FDG-PET) when available. 2.3. Treatment Radiotherapy. Thoracic radiotherapy (TRT) started with a linear accelerator (6 MV-X) on the first day of chemotherapy. All of the patients underwent a three-dimensional conformal radiotherapy (3D-CRT). The gross tumor volume (GTV) included the primary disease as well as any involved regional lymph nodes, which were defined as those with a short-axis diameter of at least 1 cm on CT scan or with a short-axis diameter of less than 1 cm but with high fluorodeoxy-glucose (FDG) uptake on PET-CT scan. The primary tumor was contoured using pulmonary window CT settings and nodal GTV using the mediastinal window. The clinical tumor volume (CTV) included primary tumor plus a 0.6–0.8 cm margin, ipsilateral hilum, subcarinal, and the ipsilateral mediastinal to the highest lymph node stations involved. A minimum dose of 60 Gy (2 Gy per fraction, Monday–Friday) was delivered, and a range of 60–66 Gy in 2 Gy fractions was allowed. The maximum spinal cord dose should not exceed 45 Gy at any point. The lung volume receiving >20 Gy (V20), which was calculated by using total lung volume minus GTV, was limited to no more than 30%. Radiotherapy should be interrupted for Grade 4 toxicity, including severe esophagitis or pulmonary toxicity. Protocol treatment was discontinued if treatment was interrupted for more than 2 weeks. Concurrent chemotherapy. Patients were randomly assigned to receive one of two chemotherapy regimens. Fig. 1A showed the schedule of the ChRT programs. The PE arm consisted of 50 mg/m2 /d of cisplatin on days 1, 8, 29, and 36 and 50 mg/m2 /d of etoposide on days 1–5 and 29–33. A protocol-mandated hydration and antiemetic regimen was used for all patients. The PC arm consisted of carboplatin administered at 2 mg/mL/min, which is the area under the plasma concentration time curve (AUC), and

45 mg/m2 of paclitaxel was administered on days 1, 8, 15, 22, 28, and 35. All the chemotherapy agents were administrated intravenously. Antiemetic drugs were administered as required. Consolidation treatment. The consolidation treatment after ChRT was delivered as per local protocol. The choice of either platinum-based doublet chemotherapy regimen or single agent chemotherapy regimen was acceptable. 2.4. Evaluation and follow-up CBCs and blood chemistry examinations were repeated every week during the treatment. Four weeks into the treatment, thoracic CT was performed. After discharge from the hospital, the patients were followed up every 3 months from hospital medical records and/or by phone. The follow-up evaluations consisted of a history, physical examination, and a thoracic CT at intervals of 3 months or earlier if clinically indicated. Other imaging examinations were obtained when recurrence was suspected. Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate treatment response by a senior radiologist and a radiation oncologist 4–6 weeks after the end of the ChRT. Treatment toxicities were evaluated according to the NCI CTC version 2.0 grading system. 2.5. Statistical analysis The primary endpoint of this trial was 3-year overall survival. SWOG 9504 reported a 3-year overall survival of 35% for the PEbased ChRT program [6]. In addition, a 3-year overall survival of 18% was reported to be achieved using the weekly paclitaxel-based ChRT program [25]. Based on the previous published data, assuming 10% of patients would be lost at follow-up, 35 patients for each treatment were needed to test whether the PC-based ChRT is inferior to the PE-based ChRT, with a 5% one-sided type I error and 80% power. Overall survival (OS) was calculated from the first day of treatment to death or the last follow-up, and progression-free survival (PFS) was calculated as the time to progression or death without progression from the date of diagnosis. Second endpoints included response and treatment-related toxicities. Student’s t-test, nonparametric Mann–Whitney u test, or 2 -test was used to evaluate the difference between patient clinical characteristics. Actuarial survival curves were generated using the Kaplan–Meier method. Survivals were compared by using the log-rank test. Fisher’s exact test was used to compare treatment groups with respect to toxicity rates, as well as overall response rates. A value of P < .05 was considered statistically significant. 3. Results 3.1. Patients From December 2004 to September 2007, 71 patients were initially registered (Fig. 1B) in the trial. Eventually, 65 patients were randomly assigned to the PE arm (33 patients) or the PC arm (32 patients). The patient characteristics were listed in Table 1, which showed that all prognostic factors were well balanced between two treatment arms. The median GTV in the PE arm was 136.5 cm3 (range, 75.3–265.3 cm3 ), and the median GTV in the PC arm was 124.6 cm3 (range, 64.8–297.8 cm3 ). 3.2. Treatment delivery The treatment delivery for 65 patients was listed in Table 1. A total of 48 patients (73.8%) received all planned concurrent chemoradiation. In the PE arm, 25 of 33 patients (75.8%)

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91

Fig. 1. (A) Treatment schema and (B) flowchart of participant’s recruitment and trial design.

completed all the treatment, which were not significantly differ from those in the PC arm (23 of 32 patients, 71.9%, P = .72). Concurrent chemotherapy was not completed in the 13 patients (eight in the PE arm and five in the PC arm) as a result of toxicity in four patients (6.2%), progressive disease in three patients (4.6%), and patient refusal not due to toxicity in six patients (9.2%). Thirty patients (90.7%) in the PE arm and 24 patients (72.8%) in the PC arm received ≥ 60 Gy of radiotherapy (P = .12). The main reasons for the reduced radiation doses were acute severe toxicity (six patients from the PC arm, including one case of thrombocytopenia, one case of esophagitis, and two cases of pneumonitis; one patient from the PE arm because of esophagitis), as well as disease progression (one patient from the PC arm and one case from the PE arm). One patient in the PE arm received a reduced radiation dose because the lung dose was considered too high. One patient receiving the PC regimen refused radiotherapy on the fourth week. The percentage of patients receiving consolidation chemotherapy was 75.8% (the PE arm) vs. 59.4% (the PC arm) (P = .25). Regimens of consolidation chemotherapy included: gemcitabine plus cisplatin (GP), paclitaxel and carboplatin (PC), and single agent of gemcitabine or, docetaxel. The median number of cycles given for the PE arm was 3, while that for the PC arm was 4, 3.3. Toxicity Treatment-related acute toxicities are listed in Table 2. The incidence of Grades 3 and 4 neutropenia was higher in the PE arm than

in the PC arm (78.1% vs. 51.5%, P = .05). Grade 2/3 acute esophagitis in the PE arm was comparable to that in the PC arm (37.5% vs. 39.9%, P = .94). Grade ≥2 radiation-induced pneumonitis (RP) tended to be less frequent in the PE arm (25% vs. 48.5%, P = .09). In the PC arm, Grades of 2, 3, and 4 RP were observed in 9 (28.1%), 6 (18.8%), and 1 (3.1%) patients, respectively. In the PE arm, Grades of 2 and 3 RP were observed in 6 (18.2%) and 2 (6.1%) patients, respectively. The acute esophagitis was a recoverable toxicity and no severe late esophageal toxicities such as severe stricture or perforation were identified. Among patients with ≥Grade 2 RP in the PE arm, 1 patient was survival without disease, 1 died of pulmonary infection, and the other 6 died of tumor progression. Among those in the PC arm, 2 patients was survival without disease, 1 died of pulmonary infection, and the other 13 died of tumor progression. 3.4. Response and survival The overall complete response rates (CR + PR) were 63.7% and 81.3% in the PE and PC arm, respectively, which were not significantly different (P = .11). Survival was analyzed after a median follow-up of 46 months for living patients. The MST was 20.2 months (95% CI, 10.8–29.6) in the PE group and 13.5 months (95% CI, 8.3–18.7) in the PC group. The 1-, 2-, and 3-year OS were 65.6% (95% CI, 57.2–74%), 36.4% (95% CI, 26.6–45%), and 33.1% (95% CI, 24.6–41.7%) in the PE group and 54.5% (95% CI, 45.8–63.2%), 16.2% (95% CI, 9.6–24.9%), and 13% (95% CI, 7–19%) in the PC group (log-rank test P = .04; Fig. 2A).

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Table 1 Patient characteristics and treatment schedule.

Median age Gender Male Female ECOG PS 0 1 Weight loss <5% 5–10% Hb level ≥12 g/L <12 g/L Clinical stage IIIA IIIB Pathology Squamous Non-squamous Chemotherapy PE < 1 cycle or PC < 3 wks PE = 1 cycle or PC 3–4 wks PE = 2 cycles or PC ≥ 5 wks Radiotherapy <50 Gy 50–60 Gy ≥60 Gy Treatment delay (days) ≤10 >10 Consolidation Chemotherapy No Median GTV (cm3 )

The PE arm

The PC arm

P value

55.4 (26–77)

60.9 (40–75)

0.31

25 (75.8%) 8 (24.2%)

26 (78.8%) 6 (21.2%)

0.54

13 (39.4%) 20 (60.6%)

18 (56.3%) 14 (44.7%)

0.22

19 (57.6%) 14 (42.4%)

20 (62.5%) 12 (37.5%)

0.19

27 (81.8%) 6 (18.2%)

24 (75%) 8 (25%)

0.27

13 (39.4%) 20 (61.6%)

16 (50%) 16 (50%)

0.27

23 (69.7%) 10 (30.3%)

20 (62.5%) 12 (37.5%)

0.15

1 (3.1%) 7 (21.9%) 25 (75%)

3 (9.1%) 2 (6.1%) 28 (84.9%)

0.63 0.14 0.49

1 (3.1%) 2 (6.2%) 30 (90.7%)

1 (3%) 8 (24.2%) 24 (72.8%)

0.49 0.09 0.12

25 (78.1%) 7 (21.9%)

25 (75.8%) 8 (24.2%)

0.77

25 (75.8%) 8 (24.2%) 136.5 (75.2–265.3)

19 (59.4%) 13 (40.6%) 124.6 (64.8–297.8)

Table 2 Treatment-related toxicities.

Neutropenia Grade 1/2 Grade 3/4 Hemoglobin Grade 1/2 Grade 3/4 PLT Grade 1/2 Grade 3/4 Esophagitis Grade 1 Grade 2/3 Radiation pneumonitis Grade 1 Grade ≥2

PE

PC

P value

7 (25%) 25 (78.1%)

16 (48.5%) 17 (51.5%)

0.05

28 (87.5%) 4 (12.5%)

29 (87.9%) 4 (12.1%)

0.74

27 (84.4%) 5 (15.6%)

29 (87.9%) 4 (12.1%)

0.26

20 (62.5%) 12 (37.5%)

20 (60.1%) 13 (39.9%)

0.94

24 (75%) 8 (25%)

17 (51.5%) 16 (48.5%)

0.09

Fig. 2. (A) The overall survival (OS) and (B) the progression-free survival (PFS) curves.

0.25 0.48

Table 3 Clinical trials of PE chemotherapy with concurrent radiotherapy. Author and trials

Patients (n)

Treatment schedule

RT dose (Gy)

Response

MST (months)

Survival (%)

Toxicities

50

IIIB

PE + XRT → PE

61

Nb

15

15 (5 yr OS)

Grade 4 neutropenia 32% Grade 3/4 esophagitis 20% Grade ≥2 radiation pneumonitis 0

RTOG 9106 Phase II [5]

76

IIIA/IIIB

PEa + HfxRT → PE

69.6

Nb

18.9

35 (2 yr OS)

Grade 4 hematologic toxicity 57% Grade 3/4 esophagitis 53% Grade ≥3 radiation pneumonitis 25%

SWOG 9504 Phase II [6]

83

IIIB

PE + XRT → Docetaxol

61

CR 7% PR 60%

26

37 (3 yr OS)

Grade 4 neutropenia 54% Grade 3/4 esophagitis 17% Grade ≥2 radiation pneumonitis 0%

Park et al. Phase II [7]

54

IIIA/IIIB

PE + XRT → oral PE

60

CR 22% PR 60%

15.3

16 (5 yr OS)

Grade 4 hematologic toxicity 53% Grade 3/4 esophagitis 11% Grade 3/4 radiation pneumonitis 7%

Mostafa et al. Phase II [8]

32

IIIA/IIIB

PE + XRT → Docetaxol

66

CR 9% PR 50%

17.5

56.3 (2 yr OS)

Grade 3/4 neutropenia 15.5% Grade 3/4 esophagitis 9% Grade 3/4 radiation pneumonitis 3%

81 (total)

IIIA/IIIB

Arm 1: PE + XRT → GEM

60

1: CR 6.3% PR 68.8% 2: CR 9.4% PR 71.9%

16.1

30.8 (3 yr OS)

29.5

39.5 (3 yr OS)

For all patients: Grade 4 neutropenia 37.6% Grade 3/4 esophagitis 18.8% Grade ≥ 2 radiation pneumonitis 12.6%

S182 Phase II [9]

Arm 2: PE + XRT → GEM + Docetaxol NPC95-01 Phase III [10]

100 (cm3 arm)

IIIA/IIIB

PE + XRT → NP

60

CR 6% PR 27%

16.3

20.7 (4 yr OS)

Grade 3/4 neutropenia 48% Grade 3/4 esophagitis 32% Grade ≥ 2 radiation pneumonitis 5%

HOG-USO Phase III [11]

203

IIIA/IIIB

Arm 1: PE + XRT → Docetaxol Arm 2: PE + XRT

59.4

Nb

21.2 23.2

26.1 (3 yr OS) 27.1 (3 yr OS)

For all pts after ChRT program: Grade 4 neutropenia 9.9% Grade 3/4 esophagitis 17.2% Grade ≥ 2 radiation pneumonitis 0%

Schild et al. Phase III [12]

234

IIIA/IIIB

Arm 1: PE + qdRT Arm 2: PE + bidRT

60 60

Nb

14 15

37 (2 yr OS) 40 (2 yr OS)

Arm 1: Grade 3/4 neutropenia 80% Grade 3/4 nonhematologic toxicity 53% Arm 2: Grade 3/4 neutropenia 81% Grade 3/4 nonhematologic toxicity 65%

RTOG 9410 Phase III [12]

592 (total)

IIIA/IIIB

Arm of CON-BID: PE + HfxRT

69.6

Nb

16

Nb

Grade 3/4 nonhematologic toxicity 63%

SWOG 0023 Phase III [13]

571

IIIA/IIIB

Arm 1: PE + XRT → Docetaxol + gefiti-nib Arm 2: PE + XRT → Docetaxol

61

Nb

23

46 (2 yr OS)

35

59 (2 yr OS)

For all patients: Grade 4 neutropenia 18 Grade 3/4 esophagitis 14% Grade ≥2 radiation pneumonitis 3%

Arm of radical RT: PE + XRT → PE

61

22.2

20 (5 yr OS)

Intergroup 0139 Phase III [14] a b

194 (cm3 arm)

IIIA

Nb

L. Wang et al. / Lung Cancer 77 (2012) 89–96

Stage

SWOG 90 l9 Phase II [4]

Grade 3/4 neutropenia 41% Grade 3/4 esophagitis 23% Radiation pneumonitis –

Oral etoposide. Data were not acquired.

93

94

Table 4 Clinical trials of PC chemotherapy with concurrent radiotherapy. Author and trials

Stage

Treatment schedule

RT dose (Gy)

Response

MST (months)

Survival (%)

Toxicities

Pallarés Phase II [15]

Patients (n) 21

IIIA/IIIB

PC → PCw + XRT

61

CR 24% PR 52%

15

24 (5 yr OS)

Grade 4 neutropenia 0% Grade 3/4 esophagitis 24% Grade ≥ 2 radiation pneumonitis 47%

CALGB 9534 Phase II [16]

40

IIIA/IIIB

PC → PCw + XRT

>60

–

27 (3 yr OS)

Nb

Wang et al. Phase II [17]

52

IIIA/IIIB

Arm 1: PC → XRT Arm 2: PC → PCw + XRT

60

CR 9.5% PR 71.4%

15.8 19

37 (2 yr OS for all Pts)

For concurrent arm: Grade ≥2 neutropenia 61.9% Grade ≥2 esophagitis 41.9%% Grade ≥2 radiation pneumonitis 23.8%

Stinchcombe et al.

23

IIIA/IIIB

Paclitaxel + CBP + Irinotecan → PCw + XRT + gefitinib

74

PRInd 24%

16

Nb

Grade ≥3 esophagitis 19.5%

Belani et al. Phase II [19]

74 92

IIIA/IIIB

Arm 2: PC → PCw + XRT Arm 3: PCw + XRT → PC

63 63

Nb

12.7 16.3

15 (3 yr OS) 17 (3 yr OS)

2: Grade 4 neutropenia 16% Grade 3/4 esophagitis 19% Grade ≥2 radiation pneumonitis 10% 3: Grade 4 neutropenia 26% Grade 3/4 esophagitis 28% Grade ≥2 radiation pneumonitis 16%

California Cancer Consortium trial Phase II [20]

34

IIIA/IIIB

PCw + XRT

61

CR 21%

17

40 (2 yr OS)

Grade 3/4 neutropenia 12%

Nb

Phase II [18]

219 (total)

IIIA/IIIB

Arm 1: PC → XRT

60

Arm 2: PC → PCw + XRT CALGB 39801 Phase III [22]

182

IIIA/IIIB

184

RTOG 9801 Phase III [23]

120

IIIA/IIIBa

122

WJTOG0105 Phase III [24]

146 147 147

AMO: amifostine; PCw : weekly PC regimen. a Included two stage IIB patients. b Data were not acquired.

IIIA/IIIB

Arm 1: PCw + XRT

66

Arm 2: PC → PCw + XRT

66

Arm 1: PC → PCw + HfxRT + AMO Arm 2: PC → PCw + HfxRT

69.6

Arm 1: MVP + XRT Arm 2: Irinotecan/CBPw + XRT Arm 3: PCw + XRT

60

Grade 3/4 esophagitis 38% Grade 3/4 radiation pneumonitis 3%

1: CR 0% PR 43.4% 2: CR 1% PR 45.5%

14.1

14 (3 yr OS)

18.7

33 (3 yr OS)

1: CR + PR + SD 67% 2: CR + PR + SD 61%

12

29 (2 yr OS)

14

31 (2 yr OS)

17.3

28 (3 yr OS)

17.9

28 (3 yr OS)

20.5

35 (3 yr OS)

19.8

24 (3 yr OS)

22.0

26 (3 yr OS)

Nb

1: CR 2.1% PR64.4% 2: CR 2.7% PR 53.7% 3: CR 2.7% PR 53.7%

1: Grade 4 neutropenia 2.1% Grade 3/4 esophagitis 13% Grade ≥2 radiation pneumonitis 12% 1: Grade 4 neutropenia 4% Grade 3/4 esophagitis 32% Grade ≥2 radiation pneumonitis 4% 2: Grade 4 neutropenia 7% Grade 3/4 esophagitis 36% Grade ≥2 radiation pneumonitis 10% 1: Grade 3/4 neutropenia 30% Grade 3/4 esophagitis 30% Grade ≥2 radiation pneumonitis 16% 2: Grade 3/4 neutropenia 34% Grade 3/4 esophagitis 34% Grade ≥2 radiation pneumonitis 9% 1: Grade 3/4 neutropenia 96% Grade 3/4 esophagitis 5.5% Grade ≥3 radiation pneumonitis 1.4% 2: Grade 3/4 neutropenia 61% Grade 3/4 esophagitis 2.7% Grade ≥3 radiation pneumonitis 4.1% 3: Grade 3/4 neutropenia 62% Grade 3/4 esophagitis 8.2% Grade ≥3 radiation pneumonitis 4.1%

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CTRT 99/97 Phase III [21]

PR 50%

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The 1-, 2-, and 3-year progression-free survival (PFS) were 46.9% (95% CI, 38.1–55.7%), 21.9% (95% CI, 14.6–29.2%), and 21.9% (95% CI, 14.6–29.2%) in the PE arm and 42.4% (95% CI, 33.8–51%), 13.6% (95% CI, 7.4–21%), and 10.2% (95% CI, 5.7–15.7%) in the PC arm (log-rank test P = .14; Fig. 2B). In a multivariate analysis, the treatment arm (PE vs. PC; P < .01) was the only factor significantly related to overall survival. Sex (female vs. male; P = .53), disease stage (IIIA vs. IIIB; P = .85), PS (0 vs. 1; P = .97), baseline hemoglobin level (≥12 g/dL vs. <12 g/dL; P = .42), pathological type (squamous vs. non-squamous; P = .93), and response to therapy (CR + PR vs. S + P; P = .22) were not significantly related to survival. Analyses of the patterns of initial relapse revealed that both isolated locoregional relapses (primary tumor and/or regional nodes) and distant metastases were more frequent in the PC arm than in the PE arm (37.5% vs. 24.2%, and 31.3% vs. 24.2%, respectively), but the differences were not statistically significant (P = .25 and P = .52).

4. Discussion To our knowledge, this is the first head-to-head study designed for direct randomization between PE- and PC-based ChRT in patients with unresectable stage III NSCLC. We have demonstrated a favorable OS and a different toxicity profile in the PE group compared with those in the weekly PC group. However, it should be noted that a slight imbalance existed between the two arms. Patients from the PC arm were older, with more frequent weight loss, and, more often anemia. In addition, more patients in the PE arm received ≥60 Gy of radiotherapy and more patients in the PE arm received consolidation chemotherapy, although these differences were not statistically significant. In the present study, the MST and 3-year OS were 20.2 months and 33.1% in the PE arm, and 13.5 months and 13% in the PC arm (log-rank test P = .04). These results were consistent with those in historical reports (Tables 3 and 4), suggesting a favorable survival for the PE regimen compared with the weekly PC regimen in ChRT programs for patients with IIIA/IIIB NSCLC. Recently, the WJTOG0105 trial was reported to compare CDDP + MMC + VDS (MVP), irinotecan/carboplatin, or paclitaxel/carboplatin regimens with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC [24]. A favorable MST of 22.0 months was reported in the PC arm. However, the outcome in the reference arm of this trial was also more favorable than that in conventional reports. The favorable survival for the PE regimen compared with the weekly PC regimen may be due to two possible reasons. First, cisplatin is thought to be one of the active drugs in non-small cell lung cancer, and is considered a better radiosensitizer when administered with radiation therapy [26]. Second, the reduced dose of paclitaxel and carboplatin agents may decrease the efficacy. Some studies, such as CALGB 39801 [22], have reported that reduced doses of chemotherapy agents may be related to poor survival. In our study and the previously described studies, carboplatin AUC 2 and paclitaxel 45–50 mg/m2 /week used for concurrent chemoradiotherapy were lower than the dose density of two cycles of the conventional 3-week based regimen used for chemotherapy. Intriguingly, the difference in overall survival, but not of progression free survival was observed in this trial, perhaps due to the more frequent non-administration of further therapy in the PC arm (40.6% vs. 24.2%). Treatment-related toxicities are limiting factors for increasing the radiation dose and chemotherapy intensity in ChRT programs for IIIA/IIIB NSCLC. In the present study, the incidence of Grade 3/4 neutropenia was higher in the PE arm than that in the PC arm (78.1% vs. 51.5%, P = .04, one patient showed Grade 4 neutropenia in the PE

95

arm). Conversely, the incidence of Grade 2 or greater radiationinduced pneumonitis was more frequent in the PC arm than in the PE arm (48.5% vs. 25%, P = .06). Grade 2/3 esophagitis was 37.5% and 39.9% in the PE and PC arm, respectively. These results were similar to other historical studies, which suggested a different toxicity profile between the PE-based ChRT and PC-based ChRT programs. The major objective of this phase II study was to the feasibility of the two chemotherapy regimens. Based on our results, compared to PE regimen, weekly PC regimen cannot be recommended since it failed to achieve an improvement in either OS or PFS. It appears that PE concurrent chemoradiotherapy is better tolerated (with less Grade 2 or greater RP) and full dose can be used. In addition, in the PE arm, the patient situation after chemo-radiotherapy allowed further consolidation therapy at a higher frequency (75.8% vs. 59.4%). There are some limitations of this study. First, because this is a phase II trial, the sample size is relatively small. Second, there was some imbalance between the two arms. It might also be noted that the total failure, locoregional relapses, and distant metastases were still high in both arms (57.6%, 33.3%, and 33.3% in the PE arm and 78.1%, 46.9%, and 40.7% in the PC arm), which were comparable to those in the literature. Treatment regimens need to be studied further to improve outcomes. Further studies could be performed to determine the optimal chemotherapy regimens (including new regimens or increased chemotherapy density), the integration of molecularly targeted agents, or radiation dose escalation. Conflict interest statement None declared. Acknowledgments Partial support by the CSCO Foundation: Y-20040007 and National 115 Project: Multimodality treatment for lung cancer, grant no: 2006BAI02A02 [1]-03. References [1] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology treatment of unresectable non-small cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330–53. [2] Curran Jr WJ, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011;103:1452–60. [3] Baggstrom MQ, Stinchcombe TE, Fried DB, Poole C, Hensing TA, Socinski MA. Third-generation chemotherapy agents in the treatment of advanced nonsmall cell lung cancer: a meta-analysis. J Thorac Oncol 2007;2:845–53. [4] Albain KS, Crowley JJ, Turrisi III AT, Gandara DR, Farrar WB, Clark JI, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic sage IIIB no-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 2001;20:3454–60. [5] Lee JS, Scott C, Komaki R, Fossella FV, Dundas GS, McDonald S, et al. Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06. J Clin Oncol 1996;14:1055–64. [6] Gandara DR, Chansky K, Albain KS, Leigh BR, Gaspar LE, Lara Jr PN, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB nonsmall-cell lung cancer: Phase II Southwest Oncology Group Study S9504. J Clin Oncol 2002;21:2004–10. [7] Park J, Ahn YC, Kim H, Lee SH, Park SH, Lee KE, et al. A phase II trial of concurrent chemoradiation therapy followed by consolidation chemotherapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancers. Lung Cancer 2003;42:227–35. [8] Mostafa E, Khatab A, Al-Adwy ER, Al-Assal GM. Limited field radiotherapy concomitant with cisplatin/etoposide followed by consolidation docetaxel for the treatment of inoperable stage III non-small cell lung cancer. J Egypt Nat Cancer Inst 2007;19:28–38. [9] Movsas B, Langer CJ, Ross HJ, Wang L, Jotte RM, Feigenberg S, et al. Randomized phase II trial of cisplatin, etoposide, and radiation followed by gemcitabine alone or by combined gemcitabine and docetaxel in stage III A/B unresectable non-small cell lung cancer. J Thorac Oncol 2010;5(5):673–9. [10] Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung

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