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Efficacy and Toxicity of Chemoradiotherapy with Carboplatin and Irinotecan Followed by Consolidation Docetaxel for Unresectable Stage III Non-small Cell Lung Cancer

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Efficacy and Toxicity of Chemoradiotherapy with

Carboplatin and Irinotecan Followed by Consolidation

Docetaxel for Unresectable Stage III Non-small Cell

Lung Cancer

Bruno R. Bastos, MD,* Georges F. Hatoum, MD,† Gail R. Walker, PhD,‡ Khaled Tolba, MD,*

Christiane Takita, MD,† Jorge Gomez, MD,* Edgardo S. Santos, MD, FACP,* Gilberto Lopes, MD,*

and Luis E. Raez, MD, FACP, FCCP*

Introduction: In 2003, consolidation docetaxel was a promising concept for unresectable stage IIIA/B nonsmall cell lung cancer (NSCLC). To test the hypothesis that chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel would be feasible and clinically active, we conducted a phase II study.

Methods: Thirty-two patients with unresectable stage IIIA/B NSCLC received irinotecan (30 mg/m2

) and carboplatin dosed to a target area under the concentration curve of 2, each administered weekly for 7 weeks. Concurrent radiotherapy was administered more than 7 weeks to a total dose of 63 Gy in 35 fractions. Consolidation docetaxel (75 mg/m2

) was administered every 3 weeks for 3 doses 4 weeks after chemoradiotherapy. The primary end point was objective response rate by RECIST.

Results: Complete responses occurred in 4 patients and partial responses occurred in 14, for an objective response rate of 56.3% (95% confidence interval [CI], 37.7–73.6%). Median progression-free survival was 6.5 months (95% CI, 4.6 –13.5); median duration of survival was 14.8 months (95% CI, 6.9 –27.3). The most common hematologic toxicity was leukopenia, which were grade 3 or 4 in 16 patients (50%). Radiation pneumonitis (gradeⱖ2) occurred in 13 of 31 treated patients (42%).

Conclusions: These findings suggested that concurrent chemoradio-therapy with carboplatin and irinotecan followed by consolidation docetaxel is clinically active based on median survival in patients with unresectable stage III NSCLC; however, the 42% incidence of clinical radiation pneumonitis was unexpected and warrants further investigation to determine the mechanism and preventive strategies. (J Thorac Oncol. 2010;5: 533–539)

T

herapeutic advances have led to improved survival in patients with unresectable stage III nonsmall cell lung cancer (NSCLC), but the optimal treatment remains in flux. Current recommendations include platinum-based doublets with concurrent radiotherapy to the involved lung field.1–3

Platinum agents have the advantage of being suitable for delivery at full doses during concurrent radiotherapy. Che-moradiotherapy with cisplatin and etoposide is an established approach and led to a median survival of 15 months in a phase II study conducted by the Southwest Oncology Group (SWOG 9019).4 To improve this outcome, SWOG added

docetaxel as consolidation after the same concurrent chemo-radiotherapy schema from SWOG 9019, which yielded an impressive median survival of 26 months in a phase II study (SWOG 9504).5 This median survival result was validated

again in a phase III study (SWOG 0023)6 in which patients

received the SWOG 9504 schema followed by randomization to receive placebo or maintenance gefitinib; median survival was 35 months. Although consolidation with docetaxel did not improve survival in another phase III study (HOG LUN 01-24/USO-023), the median survival remained in the same range (23 months).7

Thus far, no single platinum-based doublet regimen has emerged as being superior in randomized studies.1–3

Carbo-platin is attractive because it is less toxic than cisCarbo-platin, when either is combined with etoposide.8Newer agents are being

evaluated in combination with platinum analogues for their ability to improve survival beyond that achieved with estab-lished regimens. Irinotecan is an attractive alternative be-cause of its properties as a radiosensitizer9; widespread use

for lung cancer, especially in Asia; and favorable safety

From the *Division of Hematology/Oncology, †Department of Radiation Oncology, and ‡Division of Biostatistics, Sylvester Comprehensive Can-cer Center, University of Miami Miller School of Medicine, Miami, Florida.

Disclosure: Edgardo S. Santos, MD, FACP, has received compensation for speaking engagements by Sanofi Aventis. Gilberto Lopes, MD, was paid an honorarium from Pfizer and Sanofi Aventis, and has received grant support from Pfizer and Sanofi Aventis for clinical research. Luis E. Raez, FACP, FCCP, is a speaker for Sanofi Aventis and has received research support for Sanofi Aventis and Pfizer.

Address for correspondence: Bruno R. Bastos, MD, Department of Hema-tology and Oncology, Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard; Weston, FL 33331. E-mail: bastosb@ccf.org

Gilberto Lopes is currently at Johns Hopkins Singapore, Singapore. Preliminary results of this study were presented at the American Society of

Clinical Oncology (ASCO) Meetings in Atlanta in 2006 and Chicago in 2008.

Copyright © 2010 by the International Association for the Study of Lung Cancer

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profile compared with other agents. Weekly irinotecan with concurrent radiotherapy was feasible in phase I studies, first as monotherapy10,11and, subsequently, in combination with

carboplatin.12–14 The dose-limiting toxicities of

chemoradio-therapy with weekly irinotecan and carboplatin were nausea, vomiting, and esophagitis.12 These early studies provided

preliminary evidence of clinical activity, with objective re-sponse rates of 60 to 72%.12–14

Based on the evidence available in 2003, when consol-idation chemotherapy was a promising concept because of the results of the SWOG 9504 study,5 we hypothesized that

chemoradiotherapy with weekly carboplatin and irinotecan followed by consolidation docetaxel would be feasible and clinically active. To test this hypothesis, we conducted an open-label, investigator-initiated, single-arm phase II study of patients with unresectable stage III NSCLC. The primary objective was to determine the response rate; secondary objectives were to determine the safety of this new combi-nation regimen and to estimate progression-free and overall survival.

MATERIALS AND METHODS Eligibility

Adults (ⱖ18 years) were eligible if they had histolog-ically or cytologhistolog-ically confirmed NSCLC that had not been treated with systemic chemotherapy, thoracic radiotherapy, or surgical resection. Patients had to have clinical evidence of unresectable stage IIIA or IIIB disease confirmed by radio-logic studies, which include computed tomography (CT) scans. Positron emission tomography scans were not required but were allowed to be used per investigator discretion; patients with malignant pleural or pericardial effusion were excluded. Patients also had to have measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, adequate blood cell counts (absolute neutrophil count ⬎1500/␮l, platelet count ⬎100,000/␮l, and hemoglobin ⱖ8.0 g/dl), total bilirubin less than the institution’s upper normal limit, and creatinine less than twice the institution’s upper normal limit. Baseline pulmonary function test was not a required test to entry the study, but it was extremely encouraged to be performed. Exclusion criteria were major surgery within 3 weeks, New York Heart Association class 3 or 4 heart disease, myocardial infarction within 6 months, congestive heart failure, unstable angina, clinically significant pericardial effusion or arrhythmia, peripheral neuropathy grade more than 1, another malignancy within 5 years, and hypersensitivity to study drug components. Women could not be pregnant or lactating; patients of childbearing potential had to use contraception. All patients provided written in-formed consent. The University of Miami Institutional Re-view Board approved the study, which was conducted in accordance with federal and institutional regulations.

Therapy

Chemotherapy was administered intravenously on an outpatient basis unless hospitalization was required for an-other reason. Irinotecan (30 mg/m2) and carboplatin dosed to

a target area under the concentration curve of 2 were

admin-istered weekly for 7 weeks on days 1, 8, 15, 22, 29, 36, and 43 with radiotherapy. The carboplatin dose was calculated using the Calvert formula (total dose in mg ⫽ target area under the concentration curve ⫻ [creatinine clearance in ml/min ⫹ 25]). Thirty minutes before chemotherapy, pre-medication consisted of a 5-hydroxytryptamine3receptor

an-tagonist, dexamethasone (10 mg), and atropine (0.25 mg). Epoetin alfa was started at standard doses when hemoglobin was less than or equal to 10 g/dl or hematocrit was less than or equal to 33%. Prophylactic granulocyte colony-stimulating factor was administered with subsequent cycles if a patient had afebrile grade 4 neutropenia for more than or equal to 5 days or neutropenic fever based on existing guidelines.15

Radiotherapy with 1.8 Gy/d was started within 24 hours of the first day of chemotherapy and was delivered Monday through Friday for 5 weeks. After 45 Gy, radiotherapy to the primary tumor and nodal metastases was boosted to 2 Gy/d (18 Gy in 9 fractions) for a total dose of 63 Gy in 35 fractions over 7 weeks. Three-dimensional treatment planning methods were used to delineate the treatment targets and normal structures, and heterogeneity corrections were used in dose calculation. Anteroposterior-posteroanterior fields were used initially to treat the primary lung and nodal tumor, and the elective mediastinal and ipsilateral hilar nodes to a dose of 45 Gy, followed by oblique off-cord beams to a dose of 18 Gy to minimize the spinal cord and the lung dose for the boost field treatment were used. Intensity-modulated radiation ther-apy was not allowed in this trial. Targets were defined in accordance with a report by the International Commission on Radiation Units and Measurements16as follows: gross tumor

volume encompassed all detectable tumors and lymph nodes with a short-axis diameter more than 1 cm observed on CT scans. Clinical target volume included gross tumor volume and noninvolved mediastinal and ipsilateral hilar nodes. Treatment planning target volume included clinical target volume plus a 10- to 15-mm margin. Contouring of target volumes and normal tissues (esophagus, spinal cord, and lung) was performed on each section. The lungs were treated as a single organ for radiation treatment planning and dose calculation.

In the absence of progressive disease, defined by RE-CIST criteria with CT or positron emission tomography scan, 3 to 4 weeks after completing chemoradiotherapy and after resolution of toxicity, consolidation docetaxel (75 mg/m2) was administered every 3 weeks on days 1, 21, and 42. Premedications consisted of 8 mg of dexamethasone orally for 6 doses and, at the discretion of the treating physician, 5-hydroxytryptamine3 receptor antagonist. Twenty-four

hours after completing docetaxel, pegfilgrastim (6 mg) was administered subcutaneously. Dose delays and reductions were specified for grade 3 or 4 toxicities during chemoradio-therapy and consolidation chemoradio-therapy and were generally consis-tent with existing guidelines.17–19

Follow-Up

Follow-up evaluation included physical examination with assessment of performance status, tumor staging, complete blood cell counts, and laboratory studies. Screen-ing studies with assessment of toxicity (and without tumor

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staging) were repeated weekly during chemoradiotherapy, 3 to 4 weeks after completing chemoradiotherapy, and 4 to 6 weeks after consolidation therapy. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0.20Response was determined 3

to 4 weeks after completing chemoradiotherapy and 4 to 6 weeks after consolidation therapy by RECIST with CT scans.21Complete and partial response had to be confirmed

in two assessments performed at least 4 weeks apart. Subsequent follow-up was every 3 months at the discretion of the treating physician.

Statistical Methods

Target sample size was a total of 32 patients based on the institution’s 18-month enrollment capacity and was ex-pected to yield 30 evaluable patients who completed at least 1 treatment cycle. Sample size was based on precision of a two-sided 95% confidence interval (CI) estimate of the over-all response rate. More specificover-ally, with 32 patients and a study response rate approximating the target response rate of 60%, the lower confidence bound using the exact method would rule out a null rate of 40%. Progression-free and overall survival were estimated by the Kaplan-Meier method, with corresponding two-sided 95% CIs for median times and survival proportions based on Greenwood’s variance and the log-transformation method, respectively.22 For

progression-free survival, follow-up was measured from study enrollment to documented evidence of disease progression or death, whichever occurred first, or last documented progression-free status (censored observations). Overall survival was mea-sured from study enrollment to date of death or last contact (censored observations).

RESULTS

Thirty-two patients were enrolled between January 2004 and April 2007. Baseline patient characteristics and demographics are listed in Table 1. The median duration of treatment was 16 weeks (range, 1–26 weeks). Only 17 pa-tients (53%) completed chemoradiotherapy and were able to proceed to consolidation with docetaxel (median duration, 18 weeks; range, 8 –26 weeks). Reasons for not receiving con-solidation chemotherapy were disease progression during chemoradiotherapy (n⫽ 7), radiation pneumonitis (n ⫽ 2), pneumonia (n ⫽ 2), neutropenic fever (n ⫽ 1), myocardial infarction resulting in removal from the study (n ⫽ 1), withdrawal of patient consent (n⫽ 1), and poor performance status (n⫽ 1).

Response and Survival

The best overall response during the study was 4 complete and 14 partial responses for an objective response rate of 56.3% (95% CI, 37.7–73.6%; Table 2).

The estimated median progression-free survival was 6.5 months (95% CI, 4.6 –13.5; Figure 1). Six patients remained progression free after a median follow-up of 33.5 months (range, 2.0 – 45.5 months), including 1 patient who had stable disease at time of last follow-up at 2 months and subsequently died because of toxicity at 7.1 months. Twenty-six patients had disease progression or

disease-related death after a median follow-up of 5.3 months (range, 0.3–19.5 months), including 1 patient who died because of disease progression at 4.2 months and 1 without disease progression who died because of toxicity at 5.3 months. Kaplan-Meier estimates of progression-free sur-vival were 36% (95% CI, 20 –52%) at 1 year and 16% (95% CI, 6 –31%) at 2 years.

The estimated median duration of survival in all patients was 14.8 months (95% CI, 6.9 –27.3; Figure 2). Ten patients remained alive after a median follow-up of 24.0 months (range, 2.6 – 45.5 months); 22 patients died TABLE 1. Patient Demographics in 32 Patients with Unresectable Non-small Cell Lung Cancer

Characteristics N (%), Unless Otherwise Stated

Age (yr) ⬍50 6 (19) 50–59 11 (34) 60–69 9 (28) ⱖ70 6 (19) Median (range) 57.5 (42–78) Sex Male 21 (66) Female 11 (34) Race White 26 (81) Black 6 (19) Ethnicity Hispanic 20 (63) Non-Hispanic 12 (38)

ECOG performance status

0 16 (50) 1 16 (50) Stage IIIA 16 (50) IIIB 16 (50) Pathology Squamous cell 10 (31) Adenocarcinoma 11 (34) Poorly differentiated 11 (34)

ECOG, Eastern Cooperative Oncology Group.

TABLE 2. Best Overall Response by RECIST in 32 Patients Treated with Chemoradiotherapy with Carboplatin and Irinotecan Followed by Consolidation Docetaxel

RECIST Category N (%) 95% Confidence Interval

Complete response* 4 (12.5)

Partial response 14 (43.8)

Complete and partial response 18 (56.3) 37.7–73.6%

Stable disease 4 (12.5)

Progressive disease 9 (28.1)

Not assesseda 1 (3.1)

* Division of Hematology/Oncology–Sylvester Comprehensive Cancer Center, Univeristy of Miami, Leonard M. Miller School of Medicine, Miami, FL.

a

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after a median follow-up of 7.0 months (range, 0.4 –30.0 months). Kaplan-Meier estimates of overall survival (Fig-ure 2) were 54% (95% CI, 35–70%) at 1 year, 38% (95% CI, 21–56%) at 2 years, and 19% (95% CI, 6 –39%) at 3 years.

Toxicity

The most common hematologic toxicity was leukope-nia, which was grade 3 in 14 patients and grade 4 in only 2 (Table 3). The most important nonhematologic toxicity was radiation pneumonitis, which was grade 2 in five patients, grade 3 in seven, and grade 4 in one. It was detected during the follow-up period several weeks after radiation was com-pleted and did not necessitate stopping chemoradiotherapy. Radiation pneumonitis (gradeⱖ2) occurred in 3 patients who received chemoradiotherapy alone and in 10 who received

chemoradiotherapy followed by consolidation docetaxel. In patients with radiation pneumonitis, CT scans of the chest showed unilateral or bilateral interstitial or patchy infiltrates inside the radiation fields. All patients and their radiation ports were reviewed by our radiation oncologists to verify these findings. The median V20 for patients with radiation

pneumonitis was 29%. All patients received symptomatic therapy for radiation pneumonitis including steroids.

DISCUSSION

This phase II study was designed to evaluate the clin-ical activity and feasibility of a new multimodality regimen after the results of SWOG 95045were released and before the

results of HOG LUN01-24/USO-0237were available. In this

phase II study, chemoradiotherapy with carboplatin and iri-notecan followed by consolidation docetaxel seemed to be clinically active as evidenced by 18 (56.3%) objective re-sponses among 32 patients. By comparison, the response rate was 67% in SWOG 9504.5Although the null response rate of

40% was not ruled out by our reported 95% CI (37.7–73.6%), it was ruled out by our 90% CI (40.3–71.3%). The Kaplan-Meier estimate of 2-year survival was 38% (95% CI, 21– 56%), and 10 patients remain alive with median follow-up of 24 months. Median survival, estimated at 14.8 months, com-pared favorably with that reported in SWOG 90194but may

be lower than that in recent phase III studies.6,7

We also sought a feasible alternative to commonly used platinum-based doublets, which are associated with neutro-penia, anemia, alopecia, nephropathy, neuropathy, and other side effects. The rate of neutropenia was acceptable in our study. The observed rate of radiation pneumonitis, including FIGURE 1. Progression-free survival in 32 patients treated

with chemoradiotherapy with carboplatin and irinotecan fol-lowed by consolidation docetaxel. Censored patients with-out disease progression are shown with tick marks.

FIGURE 2. Overall survival in 32 patients treated with che-moradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel. Censored patients who remained alive are shown with tick marks.

TABLE 3. Most Common Adverse Events in 32 Patients

Treated with Chemoradiotherapy with Carboplatin and Irinotecan Followed by Consolidation Docetaxel

Adverse Event N (%) Grade 1 or 2 Grade 3 or 4* Hematologic events Leukopenia 12 (38) 16** (50) Neutropenia 13 (41) 8* (25) Anemia 26 (81) 5* (16) Thrombocytopenia 14 (44) 1 (3) Nonhematologic events Radiation pneumonitis 5 (16)a 8 (26)*a Fatigue 16 (50) 1 (3) Cough 14 (44) 1 (3) Dysphagia 11 (34) Vomiting 8 (25) Radiation dermatitis 7 (22) 1 (3) Alopecia 7 (22) Heartburn 5 (16) Dyspnea 3 (9) Hemoptysis 2 (6) Otherb 3 (9)

Each asterisk represents one patient with grade 4 toxicity.

aThe percentage was based on 31 patients who underwent radiotherapy. bOne case each of neuropathic pain, cardiac ischemia, and thrombosis.

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eight patients with grade more than or equal to 3 (26%), however, was unexpected compared with previous reports (Table 4).5–7,10 –14,23–27Grade more than or equal to 3

pneu-monitis occurred in no more than 15% of patients in early Asian studies in which chemoradiotherapy with irinotecan was administered alone10,11or with carboplatin,12,13except in

one study. Yamada et al.14reported pneumonitis in 23% of

patients treated with irinotecan (30 to 60 mg/m2weekly) and carboplatin (20 mg/m2for 5 days/wk). Radiation pneumonitis

occurred in 7 to 10% of patients in large cooperative group studies of chemoradiotherapy with cisplatin and etoposide followed by consolidation docetaxel.5–7

Of 32 patients entered, only 53% completed concurrent chemoradiotherapy as opposed to 72.4% in the HOG LUN01-24/USO-0237and 88% in the SWOG95045trial. We believe

that the main reason for this lower rate of completion was the higher incidence of grade more than or equal to 3 radiation pneumonitis in our trial at 26%. The incidence of radiation pneumonitis was 7% in the SWOG9504 trial and 9.6% in the HOG trial. The incidence of radiation pneumonitis did not increase after the consolidation therapy in our study (data not shown). The incidence of radiation pneumonitis was higher in patients who were randomized to consolidation docetaxel in the HOG study. Because our study was not randomized and studied a smaller sample size, we can not conclude that docetaxel contributed to an increase incidence of radiation pneumonitis.

Radiation pneumonitis is an interstitial pulmonary in-flammation. The radiographic hallmark is a diffuse infiltrate corresponding to a previous treatment field. Two separate

mechanisms are involved in the pathogenesis of this acute clinical phenomenon.28The first, classic radiation

pneumoni-tis, involves direct toxicity to endothelial and epithelial cells from the radiation, resulting in acute alveolitis. This process leads to accumulation of inflammatory and immune cells within the alveolar walls and spaces. The second mechanism, sporadic radiation pneumonitis, results in an “out-of-field” response. This is thought to be an immunologically mediated process, resulting in bilateral lymphocytic alveolitis.28Acute

radiation pneumonitis occurs within 1 to 6 months after thoracic irradiation. Asymptomatic radiologic findings can be detected in as many as 50% of treated patients, and radiation pneumonitis develops in 5 to 35% of patients.29 –31 The

incidence is often underreported, because symptoms can be attributed to another cardiovascular or respiratory disorder.32

Symptoms can include low-grade fever, chest congestion, shortness of breath, and dry cough. Severe reactions can cause dyspnea, hemoptysis, pleuritic chest pain, acute respi-ratory distress, and even death.

Potential risk factors for clinical radiation pneumonitis include radiation dose expressed as mean lung dose,32–34

dosi-metric parameters,33–34,36,37 and chemotherapy agents,32,38 but

the evidence is not consistent among studies partly because of differences in variables considered in multivariate analyses, criteria for grading pneumonitis, and method of delivering radiotherapy and whether it was concurrent with chemother-apy. For example, grading criteria and radiotherapy delivery in SWOG 0023 were similar to ours, but they waited longer after completing chemoradiotherapy before initiating do-cetaxel (4 – 8 versus 3– 4 weeks). Gaspar et al.37 recently

TABLE 4. Studies of Patients with Non-small Cell Lung Cancer Treated with Chemoradiotherapy

Reference Response Rate, n/N (%) Median Survival, mo Pneumonitis Grade >3, n/N (%) Irinotecan alone Choy et al.10 7/12 (58) NR NR Takeda et al.11 20/26 (76.9) 15.7 74/26 (15)

Irinotecan and carboplatin

Chakravarthy et al.12 11/18 (61) NR NR

Uejima et al.13 21/30 (72) Not reached Grade 2, 3/29 (10)

Yamada et al.14 18/30 (60) 14.9 7/30 (23)

Irinotecan and cisplatin

Fukuda et al.23 40/48 (83) 21 5/48 (10)

Langer et al.24 11/15 (73) 28 1/15 (7)

Oka et al.25 16/23 (70) NR 0/23 (0)

Takiguchi et al.26 6/12 (50) 10.1 NR

Induction irinotecan3 chemoradiotherapy with cisplatin

Kawahara et al.27 NR (64.7) 16.5 6/49 (13)

Induction cisplatin and etoposide3 consolidation docetaxel

SWOG 95045 56/83 (67) 26 6/83 (7); 2 deaths

SWOG 00236a NR 23 vs 35 38/543 (7); 6 deaths

HOG LUN 01–24/USO-0237b NR 21 vs 23 NR (10 vs 1); 1 death

Irinotecan and carboplatin3 consolidation docetaxel

This study 18/32 (56.3) 14.8 8/31 (26)

aAfter induction, patients received consolidation docetaxel with or without gefitinib; survival results reflect gefitinib versus no gefitinib.

bAfter induction, patients received consolidation docetaxel or no consolidation; survival and pneumonitis results reflect docetaxel versus no docetaxel.

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reported that the incidence of grade more than or equal to 3 radiation pneumonitis was highly correlated with V20 more

than 35% (p⬍ 0.01) in SWOG 0023 and was an independent factor in Cox regression analysis adjusted for other variables. This does not totally explain our findings as V20was 29% in our patients with radiation pneumonitis. The chemotherapy used in combination with radiotherapy was paclitaxel or etoposide in most previously published clinical studies, whereas we chose irinotecan as a radiation enhancer. Yamada et al.38reported a significantly higher incidence of grade more

than or equal to 2 radiation pneumonitis among patients who received radiotherapy concurrently with irinotecan than among those who did not (56 versus 14%). Therefore, the increased incidence of radiation pneumonitis in our study is probably also because of the use of a novel chemotherapeutic agent (irinotecan).

Patients with forced expired volume in 1 second less than 2 L are at a higher risk of developing radiation pneu-monitis.39 In our study, baseline pulmonary function tests

were strongly encouraged but not mandatory, because the patients had an excellent overall performance status, absence of chronic obstructive pulmonary disease, and other clinical parameters that could negatively impact their pulmonary reserve. The patients who were able to receive docetaxel were younger and had better performance status at diagnosis, therefore, this may justify why these patient subgroup had a lower incidence of high-grade radiation pneumonitis. The main risk factors identified in our study for the development of radiation pneumonitis were age, performance status, and stage of the disease. As we previously mentioned, the irino-tecan was likely the cause for the higher incidence of radia-tion pneumonitis in our study based on the V20results.

Two randomized trials have been recently reported exploiting the concept of chemoradiotherapy followed by consolidation chemotherapy.7,40 One used weekly paclitaxel

and cisplatin followed by monthly paclitaxel and cisplatin for three additional cycles.40 HOG LUN01-24/USO-023 used

weekly cisplatin and etoposide followed by 3 cycles of docetaxel.7Both trials failed to demonstrate improvement in

overall survival with consolidation strategies.

In conclusion, the results of this phase II study sug-gested that concurrent chemoradiotherapy with carboplatin and irinotecan followed by consolidation with docetaxel is clinically active based on median survival in patients with unresectable stage III NSCLC. The 42% incidence of grade more than or equal to 2 radiation pneumonitis was unexpected and warrants investigation to determine the mechanism and preventive strategies before further clinical evaluation of this regimen. Furthermore, consolidation chemotherapy with do-cetaxel failed to demonstrate improvement in overall survival in HOG LUN 01-24/USO 02-0337; however, the median

survival with consolidation docetaxel in these studies is appealing and might represent a better approach to the con-cept of consolidation—possibly with less toxic chemotherapy regimens during radiation. Further clinical studies are needed to define the optimal chemotherapy regimen and the use of novel radiotherapy techniques, which may be less toxic and

can improve overall survival in patients with unresectable stage III NSCLC.

ACKNOWLEDGMENTS

Supported in part by Sanofi-Aventis, US, and a re-search grant from Pfizer Oncology.

The authors thank Sanofi-Aventis and Pfizer Oncology for the research support provided for the study, and Cindy Hamilton for editing the manuscript.

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References

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