Omitting elective nodal irradiation and irradiating postinduction versus preinduction chemotherapy tumor extent for limited-stage small cell lung cancer

Interim analysis of a prospective randomized noninferiority trial

Authors

  • Xiao Hu MD,

    1. Department of Radiation Oncology, Cancer Center, Sun Yat Sen University, Guangzhou, People's Republic of China
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    • The first 3 authors contributed equally to this article.

  • Yong Bao MD,

    1. Department of Radiation Oncology, Cancer Center, Sun Yat Sen University, Guangzhou, People's Republic of China
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    • The first 3 authors contributed equally to this article.

  • Li Zhang MD,

    1. Department of Medical Oncology, Cancer Center, Sun Yat Sen University, Guangzhou, People's Republic of China
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    • The first 3 authors contributed equally to this article.

  • Ying Guo MD,

    1. Good Clinical Practice, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat Sen University, Guangzhou, People's Republic of China
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  • Yuan Yuan Chen MD,

    1. Department of Radiation Oncology, Cancer Center, Sun Yat Sen University, Guangzhou, People's Republic of China
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  • Kai Xin Li MD,

    1. Department of Radiation Oncology, People's Liberation Army 180 Hospital, Quanzhou, People's Republic of China
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  • Wei Hua Wang MD,

    1. Radiation Therapy Center, Kiang Wu Hospital, Macau, People's Republic of China
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  • Yuan Liu MD,

    1. Department of Radiation Oncology, Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, People's Republic of China
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  • Han He MD,

    1. Department of Radiation Oncology, The First People's Hospital of Foshan City, Foshan, People's Republic of China
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  • Ming Chen MD

    Corresponding author
    1. Department of Radiation Oncology, Cancer Center, Sun Yat Sen University, Guangzhou, People's Republic of China
    • Department of Radiation Oncology, Cancer Center, Sun Yat Sen University, 651 Dongfeng Rd E, Guangzhou 510060, People's Republic of China

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Abstract

BACKGROUND:

Controversies exist with regard to thoracic radiotherapy volumes for limited-stage small cell lung cancer (SCLC). This study compared locoregional progression and overall survival between limited-stage SCLC patients who received thoracic radiotherapy to different target volumes after induction chemotherapy.

METHODS:

Chemotherapy consisted of 6 cycles of etoposide and cisplatin. After 2 cycles of etoposide and cisplatin, patients were randomly assigned to receive thoracic radiotherapy to either the postchemotherapy or prechemotherapy tumor extent as study arm or control. Elective nodal irradiation was omitted for both arms. Forty-five Gy/30Fx/19 days thoracic radiotherapy was administered concurrently with cycle 3 chemotherapy. Prophylactic cranial irradiation was administered to patients who achieved complete remission. An interim analysis was planned when the first 80 patients had been followed for at least 6 months, for consideration of potential inferiority in the study arm.

RESULTS:

Forty-two and 43 patients were randomly assigned to a study arm and a control, respectively. The local recurrence rates were 31.6% (12 of 38) and 28.6% (12 of 42), respectively (P = .81). The isolated nodal failure rates were 2.6% (1 of 38) and 2.4% (1 of 42), respectively (P = 1.00). All isolated nodal failure sites were in the ipsilateral supraclavicular fossa. Mediastinal N3 was the only factor to predict isolated nodal failure (P = .004; odds ratio [OR], 29.33; 95% CI, 2.94-292.38). One-year and 3-year overall survival rates were 80.6%, 36.2%, and 78.9%, 36.4%, respectively (P = .54).

CONCLUSIONS:

Preliminary results indicated that irradiated postchemotherapy tumor extent and omitted elective nodal irradiation did not decrease locoregional control in the study arm, and the overall survival difference was not statistically significant between the 2 arms. Further investigation is warranted. Cancer 2012;. © 2011 American Cancer Society.

Lung cancer is a common malignancy of the chest. In clinical practice, small cell lung cancer (SCLC) accounts for 15% of all lung cancer. Among all diagnosed SCLC patients, about 30% are of limited-stage. Despite high sensitivity to both radiotherapy and chemotherapy, the locoregional recurrence rate could reach 75%-90% when patients were treated with chemotherapy alone.1 Thoracic irradiation reduced the recurrence rate and increased the long-term survival rate of limited-stage SCLC patients by 5%.2, 3 For patients who achieved complete remission of tumor after treatment, a significant survival benefit to prophylactic cranial irradiation (PCI) was observed with a 3-year survival absolute benefit of 5.4%.4 Chemotherapy combined with radiotherapy is the standard treatment modality for limited-stage SCLC at present.

To date, the standard chemotherapy regimen for limited-stage SCLC remains etoposide and cisplatin (EP).5 Although an optimal result with a 5-year survival rate was 26%, and a median survival time of 26 months was achieved in a prospective phase 3 trial, conducted by Turrisi et al6 with 45Gy/30F/19 days hyperfractionated accelerated radiotherapy combined with EP chemotherapy at the first day of radiotherapy, study designs in many prospective trials regarding radiochemotherapy for limited-stage SCLC include induction chemotherapy combined with TRT.7-14 Controversies still exist with regard to TRT target volumes of limited-stage SCLC after chemotherapy, and few prospective studies were designed to solve this issue in the past 2 decades.15 Only data from prospective, nonrandomized studies were available, not withstanding a trial performed 20 years ago, which is obviously not up-to-date now.

Therefore, we have initiated this prospective randomized study on TRT target volumes for limited-stage SCLC since June 2002, with a primary objective of comparing the locoregional progression and overall survival (OS) between limited-stage SCLC patients who received TRT to postchemotherapy or prechemotherapy tumor extent after induction chemotherapy while omitting elective nodal irradiation (ENI).

MATERIALS AND METHODS

Inclusion Criteria

Patients were eligible when they had histologic or cytologic verification of SCLC and were radiographically confirmed with limited-stage with no pleural effusion (including brain computed tomography/magnetic resonance imaging [CT/MRI], contrast-agent CT chest and abdomen, and bone scintigraphy whereas positron-emission tomography and CT was not mandatory). Limited-stage was defined according to the Veterans Administration Lung Cancer Group.16 Patients with contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy were also included. The patients were aged between 18 and 75 years without previous thoracic radiotherapy, chemotherapy, or biotherapy. Karnofsky performance status was ≥80 forced expiratory volume at 1 second (FEV1) ≥1 L, had measurable or assessable disease, neutrophilic granulocyte ≥1.5 × 109/L, hemoglobin ≥100 g/L, and platelet count ≥100 × 109/L. Serum creatine and bilirubin were <1.5 × the upper normal limit (UNL). Aminotransferase was <2 × UNL. Weight loss was less than 10% within 6 months before diagnosis. Written informed consent was required from all patients.

Exclusion Criteria

Patients were ineligible when they had a history of other malignant diseases except for nonmelanomatous skin cancer, carcinoma in situ of the cervix, or any contraindications for chemoradiotherapy, malignant pleural and/or pericardial effusion.

Interventions

Chemotherapy

Chemotherapy consisted of etoposide (100 mg/m2 on days 1 to 3) and cisplatin (80 mg/m2 on day 1) administered intravenously at 21-day intervals for 6 cycles. TRT was administered concurrently with cycle 3 chemotherapy.

Radiotherapy

All patients were immobilized in a supine position on a vacuum bag with both arms above the head; a contrast-enhanced CT simulation was performed from the fourth cervical vertebra to the second lumbar vertebra, using a maximal slice thickness of 5 mm. A three-dimensional treatment planning system was applied to the radiotherapy plan. The targets were contoured in accordance with the International Commission on Radiation Units and Measurements (ICRU 50) guidelines. Gross tumor volume (GTV) included the primary tumor (GTV-T), prechemotherapy positive lymph nodes (GTV-N) with lymph nodes in the mediastinum with a short diameter ≥1 cm, or lymph nodes with positive tumor cell sampling, or clusters of small lymph nodes of short diameter <1 cm within 1 region, or 18F-FDG standard uptake value ≥2.5 on PET/CT at initial staging. For patients who were randomized to a study arm (ie, to irradiate the postchemotherapy tumor extent), the clinical target volume-tumor (CTV-T) included the postchemotherapy GTV-T with a margin of 0.8 cm. For patients who were randomized to a control arm (ie, to irradiate the prechemotherapy tumor extent), the CTV-T included the prechemotherapy GTV-T with a margin of 0.8 cm. The clinical target volume-node (CTV-N) included the prechemotherapy positive lymph nodes with a margin of 1.5 cm. The prechemotherapy volumes were contoured on simulation CT images by referring to corresponding diagnostic CT images performed before induction chemotherapy. The simulation CT images were matched with diagnostic CT images by referring to anatomic structures such as vertebrae, fissures, vessels, and bronchus. The diameter of the contoured tumor extent should be consistent with preinduction chemotherapy tumor extent on corresponding diagnostic CT slices. The lymph node regions originally involved before induction chemotherapy, however, were included in the radiation fields for both arms even when the lymph node disappeared after induction chemotherapy. But there was no additional ENI to cover the uninvolved lymphatics for both arms. CTVs (include CTV-T and CTV-N) were edited according to anatomy. Planning target volumes (PTV) involved CTVs with a margin of 1 cm-1.5 cm.

TRT consisted of 1.5 Gy twice a day in 30 fractions over a 3-week period to a total dose of 45 Gy treated with a linear accelerator using 6-15-MV photons. The minimal interval between fractions was 6 hours. Patients who achieved complete remission (CR) of tumor after the completion of chemoradiotherapy were offered PCI, which was delivered daily to a total dose of 30 Gy over a period of 3 weeks or 25 Gy over 2 weeks.

Follow-up

Patients were reviewed 4-6 weeks after treatment, and every 3 months in the first 2 years, and every 6 months thereafter. Physical examination and CT scans of the thorax and upper abdomen were performed routinely.

Response and Toxicity Criteria

Tumor response was evaluated with thoracic CT scans when induction chemotherapy, TRT, and consolidate chemotherapy were completed, in accordance with Response Evaluation Criteria in Solid Tumors Group (RECIST). During radiotherapy, acute radiation-induced pneumonitis and esophagitis as well as body weight change of each patient was recorded, and a complete blood count was performed at least once a week. Acute hematologic toxicities and weight loss were classified in accordance with the National Cancer Institute Common Toxicity Criteria (CTCAE version 3.0). Acute and late toxicities of lung and esophagus were evaluated according to RTOG criteria.17 Late toxicities were graded 6 months after TRT.

Study Design and Statistical Analysis

This study was designed as a prospective, randomized, noninferiority trial. The primary endpoint was local progression. We hypothesized that the 3-year local control rates for both arms were 80%; sample sizes of 252 in each group achieved 80% power to detect a noninferiority margin difference between the group proportions of −10%. The study arm proportion was assumed to be 70% under the null hypothesis of inferiority. The power was computed for the case when the actual study arm proportion was 80%. The test statistic used was the 1-sided z test (unpooled). The significance level of the test was targeted at .025. An interim analysis was designed when the first group of 80 patients had completed all therapies and were followed for at least 6 months. The object of this interim analysis was for consideration of potentially substantial inferiority of locoregional control in the study arm.

Survival time was calculated from time of induction chemotherapy to the date of death or last follow-up. A statistical software package SPSS 13.0 (IBM, Somers, New York) was applied, and the Kaplan-Meier method was used to estimate survival data. The distribution of survival time between arms was tested by log-rank method; a Student t test was used for comparison of means. Fisher exact test was used for comparisons of categorical data. Binary logistic regression analysis was used to assess the impact on outfield recurrence of tumor location (upper, middle, or lower lobe), tumor type (central or peripheral), T category, N category, and mediastinal N3 disease. All P values were based on a 2-sided test, and the differences were regarded as statistically significant when P < .05.

The protocol was approved by the clinical ethics committee of Sun Yat Sen University Cancer Center before study activation.

RESULTS

Patient Characteristics

Between June 2002 and January 2010, a total of consecutive 86 patients with limited-stage SCLC were enrolled onto the study. One patient was ineligible because of a second primary small cell lung cancer. The characteristics of the 85 eligible patients were well balanced in 2 arms (Table 1).

Table 1. Characteristics of Patients According to Treatment Arm: Eligible Patients
CharacteristicStudy Arm (n=42)Control Arm (n=43)P
 No. of Patients%No. of Patients% 
  1. Abbreviations: AJCC, American Joint Commission on Cancer; CT, computed tomography; FEV1(L), forced expiratory volume at 1 second; KPS, Karnofsky performance score; PET, positron emission tomography.

Age, y     
 Median5756.20
 Range40-7534-75 
Sex     
 Male3481.03683.7.78
 Female819.0716.3 
KPS     
 902661.93479.1.09
 801638.1920.9 
Mean FEV1(L)2.242.31.78
Weight loss     
 <5%3685.74195.3.15
 5%-10%614.324.7 
Tumor type     
 Central2457.12660.5.82
 Peripheral1842.91739.5 
AJCC stage     
 I0012.3.51
 II24.837.0 
 IIIA1126.21534.9 
 IIIB2969.02455.8 
PET/CT examination716.7614.0.77

Chemotherapy

All patients received 2 cycles of induction chemotherapy. After that, 4 patients of the study arm and 1 patient of the control arm developed distant metastasis and received palliative radiotherapy and chemotherapy. For the remaining patients, the average total cycles of chemotherapy administered in the study arm and control arm were 5.3 ± 0.7 and 5.3 ± 0.8, respectively (P = .94). Table 2 shows the actual mean dose-intensity (mg/m2/w) in each treatment stage.

Table 2. Actual Mean Dose-Intensity (mg/m2/w) in Each Treatment Stage According to Treatment Arm: Eligible Patients
VariableStudy Arm (n=38)Control Arm (n=42)P
  1. Abbreviations: CT, chemotherapy; CRT, concurrent chemoradiotherapy.

Etoposide   
Induction CT92.492.2.96
Concurrent CRT92.593.5.84
Consolidation CT83.182.0.86
Cisplatin   
Induction CT25.225.6.65
Concurrent CRT24.522.5.17
Consolidation CT22.122.7.69

Radiotherapy

All the remaining patients received 45 Gy/30 Fx TRT as planned. For the study arm and control arm, the average overall treatment time of TRT was 22.8 days ± 3.1 days (19 days-31 days) and 22.0 days ± 2.7 days (19 days-29 days) (P = .22). The average volume of CTV was 199.7 mL ± 113.1 mL and 222.8 mL ± 134.8 mL (P = .42). Fourteen and 16 patients received PCI (P = 1.00), while the numbers of patients who received 30 Gy/15 Fx or 25 Gy/10 Fx were 9 (23.7%) and 5 (13.2%) in the study arm and 9 (21.4%) and 7 (16.7%) in the control arm, respectively (P = .72).

Toxicity

Hematologic and nonhematologic acute and late toxicities are summarized in Table 3. Hematologic toxicity was mild to moderate in both arms; severe hematologic toxicity was infrequent. There were no significant differences in acute nonhematologic toxicity between the arms except for weight loss, although it was mild. Late toxicities of radiotherapy were mainly mild to moderate pulmonary and esophageal injury. Six (15.8%) patients developed grade II-III pulmonary injury in the control arm, and 1 (2.8%) patient in the study arm (P = .10). Late spinal cord toxicity was not observed.

Table 3. Incidence of Acute and Late Toxic Effects According to Treatment Arm
Toxic Effect/GradeStudy Arm (n=38)Control Arm (n=42)P
No. of Patients%No. of Patients%
  1. Patients with progressive disease after induction chemotherapy were not included in statistical analysis for toxic effects. Two patients of the study arm and 4 of the control arm were not appropriate for late toxic effects evaluation because of early death within 6 months after thoracic radiotherapy.

Acute toxic     
Hematologic toxicity ≥grade 3     
Leucopenia     
 III1026.31229.3.76
 IV513.237.3 
Thrombocytopenia     
 III615.837.3.48
 IV615.837.3 
Anemia     
 III821.1819.5.95
 IV25.312.4 
Weight loss     
 I1128.92354.8.04
 II25.337.1 
Pneumonitis     
 I1744.71945.2.51
 II37.912.4 
Esophagitis     
 0-I2463.23173.8.34
 II-III1436.81126.2 
Late toxic     
Pulmonary injury     
 0-I3597.23284.2.10
 II-III12.8615.8 
Esophageal injury     
 03391.73592.11.00
 I-II38.337.9 

Tumor Response

Table 4 shows tumor response after every stage of treatment according to treatment arm. The overall response rate was 92.1% (47.4% complete response rate and 44.7% partial response rate) in the study arm and was 88.1% (50% complete response and 38.1% partial response) in the control arm. There was no significant difference between the arms.

Table 4. Tumor Response After Each Stage Treatment According to Treatment Arm
Tumor Response After Each Stage TreatmentStudy Arm (n=42)Control Arm (n=43)P
 No. of Patients%No. of Patients% 
  1. Abbreviations: CR, complete remission; PD, progressive disease; PR, partial response; SD, stable disease.

  2. Patients with PD after induction chemotherapy were not included in further statistical analysis for treatment efficacy.

Induction chemotherapy     
 CR24.8511.6.37
 PR2559.52660.5 
 SD1126.21125.6 
 PD49.512.3 
Thoracic radiotherapy     
 CR1026.31126.2.57
 PR2565.82559.5 
 SD37.949.5 
 PD0024.8 
Consolidation chemotherapy     
 CR1847.42150.0.89
 PR1744.71638.1 
 SD25.337.1 
 PD12.624.8 

Patterns of Failure

Patients who developed distant metastasis after induction chemotherapy were not included in analysis for local but for distant failure. At last follow-up, 12 (31.6%) patients in the study arm and 12 (28.6%) patients in the control arm experienced locoregional recurrence (P = .81). Among them, isolated outfield recurrence was observed in 1 (2.6%) and 1 (2.4%) patient in each arm (P = 1.00). Outfield recurrence in combination with distant metastasis were present in 2 (5.3%) and 1 (2.4%) patients. All outfield recurrences occurred in the nonirradiated ipsilateral supraclavicular fossa. Four (10.5%) and 6 (14.3%) patients had isolated infield recurrence as their first site of failure. Infield failure along with distant metastasis developed in 5 (13.2%) and 4 (9.5%) patients, respectively (P = .84). In the study arm, 21 (50.0%) patients experienced distant metastases, and 9 cases among them had multisite metastases. The metastatic sites were brain (12 of 21, 57.1%), bone (6 of 21, 28.6%), liver (4 of 21, 19.0%), lung (1 of 21, 4.8%), adrenal gland (1 of 21, 4.8%), and others (6 of 21, 28.6%). In the control arm, 20 (46.5%) patients experienced distant metastasis, 6 of them with multisite metastases. The metastatic sites were brain (11 of 20, 55.0%), bone (4 of 20, 20.0%), liver (3 of 20, 15.0%), lung (2 of 20, 10%), adrenal gland (1 of 20, 5.0%), and others (5 of 20, 25.0%) (P = .82).

Survival

Thirty-one patients remained alive at the time of analysis, with a median follow-up of 29.5 months in survivors (6.4 months-97.9 months). Progression-free survival (PFS) and OS were calculated on an intention-to-treat basis. The median PFS time was 15.5 months in the study arm (95% confidence interval [CI], 10.6 months-20.3 months) and 19.4 months (95% CI, 10.8 months-27.9 months) in the control arm. The 1-, 2-, and 3-year PFS rates were 58.8%, 35.7%, and not achieved, respectively, in the study arm, versus 66.8%, 42.0%, and 31.5% in the control arm (P = .69 by log-rank test) as shown in Figure 1. The median survival time was 22.1 months in the study arm (95% CI, 16.6-27.6 months) and 25.4 months (95% CI, 20.4-30.4 months) in the control arm. The 1-, 2-, and 3-year OS rates were 80.6%, 42.2%, and 36.2%, respectively, in the study arm, versus 78.9%, 52.2%, and 36.4% in the control arm (P = .54 by log-rank test) as shown in Figure 2.

Figure 1.

Prechemotherapy and postchemotherapy progression-free survival (percentage of patients).

Figure 2.

Prechemotherapy and postchemotherapy overall survival (percentage of patients).

Risk Factor for Outfield Recurrence

Table 5 shows the pretreatment tumor characteristics of the 5 patients who experienced outfield recurrence. Among them, 4 patients had mediastinal N3 nodal disease without supraclavicular nodes on physical examination and on CT scan at the time of staging. Possible factors that may relate to outfield recurrence, such as primary tumor location, tumor type, T category, N category, and whether the patient had mediastinal N3 nodal disease, were selected for logistic regression analysis. Mediastinal N3 was the only factor that was found to predict outfield recurrence (P = .004; odds ratio [OR] = 29.33; 95% CI, 2.94 to 292.38).

Table 5. Tumor Characteristic of Outfield Recurrent Patients at Staging Tumor Characteristic
Primary tumor location (lung lobe)No. of Patients (n=5)
  • a

    All mediastinal N3 nodal disease.

Left upper3
 Left lower0
 Right upper1
 Right middle0
 Right lower1
Primary tumor type 
 Central4
 Peripheral1
T category 
 T42
 T23
N category 
 N34a
 N21

DISCUSSION

At present, the combined chemoradiotherapy has been established as a standard treatment modality for limited-stage SCLC. However, wide controversies exist with regard to radiation target volume as TRT is concerned.1, 18 Two main questions with regard to the design of irradiation volume for limited-stage SCLC after induction chemotherapy are prominent, namely, should we treat with the postchemotherapy or the prechemotherapy tumor volume? Is ENI necessary?

Up until now, there are only 2 prospective studies especially designed to solve these problems.19, 20 Whereas results from retrospective studies of the 2-dimensional radiotherapy and nonplatinum-based chemotherapy era were not consistent with each other.21-24

The only phase III Southwest Oncology Group (SWOG) trial randomized 191 patients who achieved partial response or stable disease after induction chemotherapy to receive either postinduction or preinduction tumor field radiation. The corresponding recurrence rates were similar in both arms: 32% and 28%, respectively, and the difference of median survival time was not statistically significant (51 weeks vs 46 weeks, P = .73). However, life threatening and lethal toxicities were more common in the wide-volume radiotherapy arm than in the reduced-volume radiotherapy arm (17 of 93 vs 8 of 98).19

De Ruysscher et al20 conducted a phase 2 study based on CT-simulated radiotherapy reporting isolated nodal relapse rates after omitting ENI in patients with limited-stage SCLC. A crude isolated nodal failure rate of 11% was reported, higher than the authors' expectation. But due to the small sample size in the study, no definitive conclusions could be drawn.

The above-mentioned prospective trials each studied 1 of the 2-sided issues regarding TRT volume. Comparing them, this clinical trial was designed prospectively to include both aspects of this issue, ie, to treat with the postchemotherapy or the prechemotherapy tumor volume and omit ENI for both arms. (Table 6).

Table 6. Comparison Between This Trial and Two Other Prospective Studies
No. of Simulation InvestigatorsPatientsMethodOverall Target Definition
  1. Abbreviations: 2D, 2-dimensional; 3D, 3-dimensional; ENI, elective nodal irradiation.

Hu et al853DPost- or prechemotherapy tumor extent, omission of ENI for both arms
Kies et al184942DPost- or prechemotherapy extent, “abnormal appearing lung,” mediastinal, “low” supraclavicular fossa
De Ruysscher et al19273DPrechemotherapy tumor extent, omission of ENI

In our study, isolated outfield recurrent rate was 2.6% (1 of 38) and 2.4% (1 of 42), respectively, in the study arm and control arm (P = 1.00). All outfield recurrent sites were exclusively in the ipsilateral supraclavicular fossa, which were the same as the results reported by De Ruysscher et al20

As for the anatomy in the supraclavicular fossa, is it possible that its complicated structures will result in omission of tiny metastatic lymph nodes and outfield recurrence? There is some evidence that indicates 18F-FDG-PET/CT provides more accurate staging and prognosis judgment for SCLC patients than ordinary contrasted CT scan.25-31 PET/CT was able to detect 5.0% to 12.5% supraclavicular lymph nodes, which were originally negative on ordinary contrasted CT scans.28-31 van Loon J et al31 first reported their prospective study evaluating the role of PET/CT guided selective nodal irradiation; only 2 (3%) patients experienced an isolated nodal recurrence, and 1 of them was in the supraclavicular region. However, further investigations of the value of PET/CT in detecting supraclavicular lymphadenopathy are warranted because of lacking of prospective, large-scale, pathologically proven studies.

In a prospective study including 117 lung cancer patients comparing the value of palpation, ultrasonography (US), and CT in diagnosing metastasis of supraclavicular lymph nodes, van Overhagen et al32 performed US-guided fine-needle aspiration cytological analysis in patients with supraclavicular nodes with a short-axis diameter of 5 mm or greater. Cytological diagnosis was used as the standard of reference. The authors reported that CT (P = .001) and US (P<.001) were significantly more sensitive than palpation for detecting supraclavicular metastasis, but there was no significant difference between CT and US (P = .06).

In the study conducted by De Ruysscher et al,20 patients experiencing supraclavicular fossa relapse were all unexceptionally with mediastinal N3 nodal disease. van Overhagen et al32 also reported in their study that 93% (28 of 30) of lung cancer patients with supraclavicular lymph nodes metastasis were found to have N2 or N3 nodes at chest CT. Moreover, supraclavicular lymph nodes metastases were seen more frequently in patients with N3 nodes at chest CT than in patients with N0 to N2 nodes (P < .001). In patients with enlarged N3 nodes at chest CT, there was a 51% chance that supraclavicular lymph nodes metastasis were present and could be proved cytologically. In our study, 80% (4 of 5) patients who experienced supraclavicular fossa failure had mediastinal N3 nodal disease (Table 6). This type of N3 disease was the only factor that was found to predict supraclavicular fossa outfield relapse.

In this study, no patients developed outfield recurrence of mediastinal lymph nodes. One of the reasons may lie in that when the primary tumor and metastatic lymph nodes were irradiated, mediastinal lymph drainage also received incidental irradiation for a certain amount of dosage. There are some dosimetric studies available on incidental nodal irradiation for nonsmall cell lung cancer (NSCLC).33-35 Ronsenzweig et al35 reported in a series of NSCLC patients of whom 86% had stage III disease. When 50.4 to 81 Gy were delivered using 3-dimensional conformal radiotherapy, more than 40 Gy of incidental irradiation to the ipsilateral superior mediastinum, inferior mediastinum, and subcarinal regions was observed in 34%, 64%, and 41% of patients, respectively. However, no similar study was reported in limited-stage SCLC, and further investigations are warranted.

As for infield recurrence, some studies indicated that higher irradiation doses may be suggested to enhance local control thus further improve long-term survival.6, 7, 11, 36 A CALGB phase III trial NCT 0063285337 is currently under development that compares a 45-Gy twice-daily dose with a 2 Gy once-daily to 70 Gy and 61.2 Gy dose in a concomitant boost approach, in combination with concurrent EP regimen chemotherapy. Another currently ongoing trial NCT 0043356338 also compares 45-Gy twice-daily dose with a 2 Gy once-daily to 66 Gy concomitantly with EP regimen chemotherapy. We look forward to seeing whether the higher dose yielded in the study arms could be translated into improved local control and survival.

We have realized the limitations of this study. First, we did not perform a CT-simulation scan for patients before induction chemotherapy; this may have introduced error when CTV-T was contoured for the control arm. As we have noticed this, after these first 85 patients were included, all newly accrued patients underwent CT simulation before induction chemotherapy. Second, the follow-up time was relatively short for some patients but was not likely to significantly alter the current results. Third, TRT was administered with cycle 3 of chemotherapy in this study. When the study was designed and initiated in 2002, the timing of TRT (early vs late) was not established and was still controversial. With recent evidence,39, 40 we realize that delayed initiation of TRT results in inferior response and survival in patients with SCLC. In future studies, we will administer TRT earlier with chemotherapy for limited-stage SCLC patients.

In summary, the preliminary results indicated that irradiation to the postchemotherapy tumor extent and omission of ENI did not decrease local control while significantly fewer patients suffered from grade 1 weight loss. However, patients in the control arm achieved better OS than in the study arm, although the difference was not statistically significant.

The current sample size has not met designed requirements, caution must be taken when adopt the conclusions. Because of the slow accrual, we are going to initiate a multicenter randomized trial designed much the same as this study, but the new trial will initiate TRT earlier with chemotherapy, and patients with mediastinal N3 disease will receive prophylactic irradiation to the ipsilateral supraclavicular fossa.

Acknowledgements

We thank our patients and their families for their willingness to take part in this study.

FUNDING SOURCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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