|Year : 2015 | Volume
| Issue : 2 | Page : 381-387
Prospective study of special stage II (T 2b-3 N 0 M 0 ) non-small-cell lung cancer treated with hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy
Wei Zhang1, Chengxin Liu2, Haiqun Lin2, Yipeng Song2, Wei Huang2, Hongsheng Li2, Miaomiao Li2, Baosheng Li2
1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin; Department of Radiation Oncology, Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Zhifu Area, Yantai, Shandong province; Department of Radiation Oncology VI, Shandong Cancer Hospital, 440 Jiyan Road, Huaiyin Area, Jinan, Shandong province, China
2 Department of Radiation Oncology VI, Shandong Cancer Hospital, 440 Jiyan Road, Huaiyin Area, Jinan, Shandong province, China
|Date of Web Publication||7-Jul-2015|
Department of Radiation Oncology VI, Shandong Cancer Hospital, 440 JiYan Road, Jinan, Shandong province, 250117
Source of Support: None, Conflict of Interest: None
Clinical trial registration ChiCTR-ONC-13003383
Purpose: To analyze the effects of hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy (Hypo-SIB-IMRT) on medically inoperable patients with special stage II (T 2b-3 N 0 M 0 ) non-smallcell lung cancer (NSCLC).
Materials and Methods: Twenty-eight qualified patients were included. Hypo-SIB-IMRT was delivered with internal gross tumor volume (iGTV) 75Gy, clinical target volume (CTV) 60Gy, and planning target volume (PTV) 45Gy on weekdays in 3 weeks.
Results: The 1-, 2-, and 3-year overall survivals (OSs) were 93, 85, and 61%, respectively, with a median survival of 46.5 months; while progression-free survivals (PFSs) were 92, 79, and 64%; and distant metastasis-free survivals (DMFSs) were 92, 84, and 77%, respectively. The cancer-specific survivals (CSS) were 93, 88, and 74%, and local control (LC) were 92, 83, and 74%, respectively. 7.1% (2/28) of patients occurred local pain, 28.6% (8/28) were with Grade 1or 2 radiation pneumonitis (RP), and 7.1% (2/28) with Grade 1 esophagitis. Of the eight patients with RP, 17.9% (5/28) developed Grade 1 radiation pulmonary fibrosis (RPF).
Conclusion: Due to the favorable long-term survivals, LC, and minimal toxicities, Hypo-SIB-IMRT presented in this prospective study may be considered an option for patients with special stage II (T 2b-3 N 0 M 0 ) NSCLC who were medically inoperable.
Keywords: Hypofractionated, intensity modulated radiation therapy, non-smallcell lung cancer, overall survival, simultaneous integrated boost
|How to cite this article:|
Zhang W, Liu C, Lin H, Song Y, Huang W, Li H, Li M, Li B. Prospective study of special stage II (T 2b-3 N 0 M 0 ) non-small-cell lung cancer treated with hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy. J Can Res Ther 2015;11:381-7
|How to cite this URL:|
Zhang W, Liu C, Lin H, Song Y, Huang W, Li H, Li M, Li B. Prospective study of special stage II (T 2b-3 N 0 M 0 ) non-small-cell lung cancer treated with hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy. J Can Res Ther [serial online] 2015 [cited 2022 Aug 17];11:381-7. Available from: https://www.cancerjournal.net/text.asp?2015/11/2/381/157332
| > Introduction|| |
Lung cancer is increasing globally and still the leading cause of cancer death worldwide.  Surgical resection is the standard therapy for stage II non-small cell lung cancer (NSCLC). ,, Unfortunately, some patients with stage II NSCLC are associated with comorbid medical illnesses and not suitable for surgical resection. , Moreover, some clinical data suggest that the relapse or progression percentage of unresected stage II NSCLC patients with lymph node involved is probably higher, who were primarily referred to concurrent chemoradiotherapy (CCRT);  patients with T 2-3 N 0 M 0 tumors have higher cure rate and overall survival (OS) than those with T 1-2 N 1 M 0 ones, and may prefer RT alone rather than CCRT. ,, However, local control (LC) and OS at 3 years of conventionalRT have historically been poor, which are30-66% and 34-42%, respectively. ,, In order to implement right treatments and avoid the effect of chemotherapy on the results, we chose patients with T 2-3 N 0 M 0 tumors who were medically inoperable.
Hypofractionated regimens consist of fewer fractions with higher dose per fraction, which was an effective way of killing tumor cells and showed advanced results. Recent studies showed that stereotactic body radiotherapy (SBRT) improved LC for patients with stage IINSCLC, compared with those after surgery or conventional RT. , However, increased normal tissue toxicities due to higher doses per fraction in SBRT should be paid attention. Risk adaptive SBRT, which was applied to both peripheral and central early-stage NSCLC, improved the incidence of radiation induced complication with acceptable outcomes. , The hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy (Hypo-SIB-IMRT) technique conducted a higher dose to primary tumor; whereas, lower doses to subclinical disease and planning treated regions at the same time, which was in accordance with radiation biology.  In another word, different tumor burdens need different doses to cure. To gain the balance between outcomes and normal tissue toxicities, we performed this prospective study, and first applied Hypo-SIB-IMRT for patients with special stage II (T 2b-3 N 0 M 0 ) NSCLC who were medically inoperable. The primary endpoint in this study was OS, and secondary end points were progression-free survivals (PFSs), cancer-specific survivals (CSS), distant metastasis-free survivals (DMFSs), LC, and toxicities.
| > Patients and methods|| |
We performed this study after approval by three Institutional Review Boards. It was scheduled for 30 patients with special stage II (T2b-3 N0M0) NSCLC; who were medically inoperable, were included. No patients received chemotherapy before and after Hypo-SIB-IMRT until recurrence. Study enrollment was restricted to patients at high risk for complications evaluated by thoracic surgeons (for suitability for lobectomy), and referred to the RT department via multidisciplinary conferences. Most of them did not have surgery due to severe underlying cardiopulmonary dysfunction. Patients without cardiopulmonary dysfunction were eligible if they were deemed to have high-risk features of comorbid medical illness making them unsuitable for surgical resection. The study was approved by the ethical committees of our hospitals according to the Declaration of[TAG:2][/TAG:2]
Helsinki II. All patients signed an informed consent. Patients were excluded from this study if progressive disease, including distant organ or lymph node metastases, had been noted after the previous treatment.
Diagnosis and staging
Morphologic confirmation of the primary tumors by computed tomography (CT)-guided puncture or bronchoscopic biopsy was requested. If the shorter diameters of mediastinal lymph nodes were larger than 1.0 cm on pretreatment chest CT, a transbronchial needle aspiration was recommended. However, if patients refused biopsy or accompanied with unsuitable conditions, and there was no cytological or histologic verification, CT with an interval of 3 months showing tumor progression, or abnormal concentration of 18F-fluorodeoxyglucose (18F-FDG) uptake in the lesions on positron emission tomography (PET) images were acceptable. The staging procedure included chest and upper abdomen CT (included visualization of the liver and adrenal glands), brain magnetic resonance (MR), nuclear scanning of bone, or whole body 18 F-FDG PET.
The gross tumor volume (GTV) consisted of the primary lung tumor as defined on the lung windows of the planning CT. The internal GTV (iGTV) was based on slow CT, conventional CT with active breath control (ABC), 18 F-FDG PET scan, or four dimensional CT (4DCT), which were not routinely available when the trial was designed. Clinical target volume (CTV) was defined by expanding the iGTV with 5 mm for squamous cell carcinoma and 7mm for the others to account for the microscopic extension. Furthermore, the CTV contour should be edited off bone, pleura, fissures, etc., for that subclinical infiltration was unlikely occurred in such anatomy structures. To define the planning target volume (PTV), the CTV was then expanded by 5 mm set-up margin. Elective irradiation of lymph node regions was not performed.
Five to seven multileaf collimated beams were used. Beams' distributions were generally partial to one side of the lung with tumors, sparing of the spinal cord and contralateral lung as far as possible. To meet the planning goal, the beam numbers, directions, configurations, and fluence were optimized according to the positions and shapes of the targets with heterogeneity correction for lung, soft tissue, and bone using Pinnacle or Eclipse systems.
The prescription doses were specified at the International Commission on Radiation Units and Measurements Reports 50 and 62 reference points. The time dose fractionations were as followings: iGTV 75Gy, CTV 60Gy, and PTV 45Gy in 15 fractions once daily on consecutive weekdays. The biologically equivalent doses (BEDs) of iGTV, CTV, and PTV were 112.5, 84, and 58.5Gy, respectively, using linear-quadratic (LQ) model with α/β ratio of 10Gy.  Constraints placed on the risk organs were according to our experience and standard for hypofractionated RT in our centers, including V20 (volume of lung irradiated to doses above 20Gy) of bilateral lung <30%and volume of heart receiving 25Gy <50%, respectively.  Moreover, it was considered acceptable that mean dose of bilateral lung was <16.7Gy; maximum dose of spinal cord was limited to 37.5Gy; maximum dose of esophagus, trachea, and main bronchus were all <45Gy, respectively. Central review of treatment plans was mandated before initiating therapy. A representative beam arrangement and dose-volume histogram is illustrated in [Figure 1] and [Figure 2].
|Figure 1: (a) Peripheral tumor, six fields, 4DCT simulation. (b) Central tumor, five fields, PET simulation. 4DCT = Four-dimensional computed tomography, PET = positron emission tomography|
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The Hypo-SIB-IMRT was delivered with 6-MV X-rays from a linear accelerator after immobilizing the patients in a vacuum bag. During the treatment, electrical port imaging device (EPID) or cone-beam CT (CBCT) were performed at least three times per week to verify the reproducibility of the target.
Patients were assessed after completion of Hypo-SIB-IMRT every 2 months for the 1 st year, 3-4 months during the 2 nd year, and 6 months thereafter. Tumor response was evaluated using response evaluation criteria in solid tumors (RECIST) considering the best response at any time from Hypo-SIB-IMRT.  Clinical examinations with grading of toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0) and chest CT or X-ray were performed at every follow-up. , PET was optional and mainly performed when tumor relapse was suspected. Performance status was recorded at every follow-up according to Karnofsky Performance Status (KPS). Local failure was defined as more than 20% increase or emergence in the summation of the maximum diameters at the treated region of the primary tumor after RT. Distant relapses were considered to be metastases of any distant lymph node or organs, such as contralateral lung, bone, brain, and so on.
The primary endpoint in this study was OS; and secondary end points were PFSs, CSSs, DMFSs, LC, and toxicities.
Statistical tests were carried out using Statistical Package for Social Sciences (SPSS) version 17.0 (SPSS Inc, IBM Company). All tests with a P-value less than0.05 considered to be statistically significant. OS, CSS, and LC curves were calculated by Kaplan-Meier algorithms with the day of first treatment as starting point and patients were censored at the time of corresponding events occurred. PFS was censored at the time of tumor progression as well as death (all causes), and DMFS was censored at the time of emergence of distant metastasis as well as death (all causes). The log-rank test was used to calculate the associations between outcome parameters (survivals or LC) and clinical factors, including gender, age, class, histologic type, tumor location (right vs left), type (peripheral vs central), stage (II A vsII B ), and volume (>60 cm 3 vs ≤60 cm 3 ).
| > Results|| |
From February 2007 to June 2012, a total of 28 patients with special stage II (T2b-3N0M0) NSCLC restaged by the 7 th edition of the Tumor Node Metastasis (TNM) classification for lung cancer were recruited at three centers in China. Until March 2013, 28 patients were recruited, and no patient met the inclusion criteria in previous 6 months. Therefore, we decided to carry on the statistical analysis of the 28 patients. They were referred to the RT Department via multidisciplinary conferences. All the patients did not have surgery due to existing comorbidity.
Among 28 patients, there were 18 men and 10 women with a median age of 75 years (ranging from 50 to 85 years), with 22 patients more than or equal to 70 years. Seventeen patients had peripheral tumors and 11 were central ones. Of the 23 morphologically verified tumors; 14 were adenocarcinoma and nine squamous cell carcinoma. Eleven patients had stage II A (T 2b N 0 M 0 ) tumors and 17 were stage II B (T 3 N 0 M 0 ) ones. The median iGTV was 62.5 cm 3 (ranging from 28.6 to 137.0 cm 3 ), and 16 of them were more than 60 cm 3 . The median KPS was 70 (ranging from 60 to 90) [Table 1]. Of the 28 patients, chronic obstructive pulmonary disease (COPD; 71.4%) with emphysema and pronounced reduction of the lung capacity, or cardiovascular disease (CVD; 21.4%) represented the majority of patients. Two patients (7.2%) without severe comorbid medical illnesses refused surgery. COPD was defined according to Global Initiative for Chronic Obstructive Lung Diseases (GOLD) criteria. 
| > Survivals|| |
The 1-, 2-, and 3-year OS were 93, 85, and61%, respectively, with a median survival of 46.5months and median follow-up time of 41 months (ranging from 10 to 58 months). The 1-, 2-, and 3-year PFS were 92, 79, and 64%; while DMFS were 92, 84, and 77%; and CSS were 93, 88, and 74%, respectively [Figure 3]. There were significant differences in OS, CSS between the subgroups of tumor volumes (>60 cm 3 vs ≤60 cm 3 ), while DMFS was significant between different stages (II A vs II B ) [Figure 4]a-c. There were no significant differences in OS, PFS, DMFS, and CSS between the subgroups; including genders, age classes (≥70 vs <70 years), pathologies, tumor locations (right vs left), and types (peripheral vs central). During the follow-up, seven patients died of lung cancer, while five patients died of chronic obstructive lung disease and cardiovascular disease.
|Figure 3: (a) Overall survival (OS). (b) Progression-free survival (PFS). (c) Distant metastasis-free survival (DMFS). (d) Cancer-specific survival (CSS)|
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|Figure 4: (a) OS compared tumor volume ≤60 cm3 with >60 cm3(P value = 0.001). (b) DMFS compared stage IIA with stage IIB tumors (P value = 0.012). (c) CSS compared tumor volume ≤60 cm3 with >60 cm3( P value = 0.004). (d) LC compared tumor volume ≤60 cm3 with >60 cm3(P value = 0.003)|
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Local tumor control and tumor response
The 1-, 2-, and 3-year LC were 92, 83, and 74%, respectively. Ten patients experienced complete response, 12 partial response, and six stable. During the follow-up period, 10 patients experienced local tumor progression including four stage II A and six stage II B . The mean iGTVsof relapsed patients were larger than those who did not (mean iGTV 88.1vs 52.0cm 3 ). There were significant differences in LC between the subgroups of tumor volumes (>60 cm 3 vs ≤60 cm 3 ) [Figure 4]d. No differences were seen in genders, pathologies, tumor locations (right vs left), tumor types (peripheral vs central), and stages (II A vs II B ) between patients with or without local failure.
All patients were well-tolerated to the treatment of Hypo-SIB-IMRT, and no one experienced the toxicities over than Grade 2. Toxicity appeared up to 3 months in this analysis was defined as early, and after 3 months as late. The most common acute toxicities were as follows: 7.1% (2/28) of patients occurred local pain, 28.6% (8/28) were with Grade 1or 2 radiation pneumonitis (RP), and 7.1% (2/28) with Grade 1 esophagitis. Of the six patients with RP, 17.9% (5/28) developed Grade 1 radiation pulmonary fibrosis (RPF). During the entire follow-up period, rib fracture and injury of brachial plexus were not found.
| > Discussion|| |
So far, radiotherapy for early-stage NSCLC had been developed to hypofractionated RT (Hypo-RT) era. Some studies had documented the advantages of Hypo-RT [Table 2]. ,,, The 2-year OS ranged from 48.2 to 55.6%with median survival times from 23.5 to 25.4 months, while 2-yearLC ranged from 63.9 to 76.2%. SBRT (5-34Gy per fraction given as 1-10 fractions over a period of 1-2 weeks) for stage II NSCLC had provided exciting results these years. Reported 2-year OS and LC ranged from 10to 85% and50 to 100%, respectively. ,, The SIB technique offered the advantage in delivering a higher dose to the primary tumor simultaneously, whereas, conventional lower doses to treat subclinical disease. As we all know, SIB-IMRT represented an ideal technique for escalating the local dose and shortening the overall treatment time, especially for head and neck cancers or prostate cancer. , In a study with SIB-IMRT for stage III NSCLC patients, seven patients with the largest GTVs, SIB-IMRT was superior to IMRT with dose escalation of 11.9%.  By far, hypo-SIB-IMRT has never been reported for patients with medically inoperable stage II NSCLC. In this study, we first applied Hypo-SIB-IMRT and BEDs were 112.5, 84, and 58.5Gy for iGTV, CTV, and PTV, respectively, which may offer some radiobiological advantages in terms of a higher dose per fraction to the heavier burden tumor targets, while a lower dose per fraction to lighter burden area. Hypo-SIB-IMRT for special stage II NSCLC in our prospective study resulted in encouraging3-year LC and OS of 74 and 61%, respectively. During the follow-up period, five patients died of comorbid diseases other than lung cancer, such as COPD or cardiovascular disease. Our encouraging outcomes may suggest that different tumor burdens prescribed different doses meets the radiobiological principles. As these studies about SBRT contained stage I patients, it was possible that outcomes were overestimated. No matter what the BED 10 were in the above studies; median survival time, OS, and LC in our current study were more promising, and the toxicities were mild [Table 2]. Besides, the 6 th Edition stage classification system defines the T 2 descriptor as: Tumor with any of the following features of size or extent: >3 cm in greatest dimension; involving main bronchus >2 cm distal to the carina; involving the visceral pleura; associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung. However, the T 2 descriptor was decided into T 2a (>3to 5 cm) and T2 b (>5 to 7 cm) by the International Association for the Study of Lung Cancer (IASLC) staging committee in the new TNM classification of NSCLC.  Therefore, T 2b patients with no nodal involvement (N 0 ) originally belonging to stage I belong to stage II A now, which may affect the comparison of survivals.
Though SBRT had provided exciting results for peripheral stage II NSCLC, the corresponding proportions of grade 3-5 radiation side effects which was 20% in one study could not be neglected.  In addition, SBRT was limited to peripheral early-stage NSCLC, while 11 patients in our study with central tumor also achieved excellent results as well as mild toxicities. Therefore, though SBRT was recommended for stage II NSCLC patients who were medically inoperable by NCCN, more modestly hypofractionated regimens were alternatives.  In our small cohort of patients, the Hypo-SIB-IMRT treatment was well tolerated without ≥grade 3 toxicities. It may partly be because the SIB technique in our study offered the advantage of delivering a higher dose to the primary tumor, whereas simultaneously lower doses to CTV and PTV, so that normal tissues could be protected better. It might also be somewhat dependent on our precise RT techniques including CT with ABC, FDG-PET, or 4DCT in simulation, and EPID or CBCT image guiding during the treatment.
There were significant differences in OS, CSS, and LC between the subgroups of tumor volumes (>60 cm 3 vs ≤60 cm 3 ), while LC was with significance between different tumor types (peripheral vs central). Besides, DMFS was with significance between different stages (II A vs II B ). These inclinations were in favor of the previous arguments, such as local relapses are more frequent for larger GTVs. ,,34] A fairly high3-year LC rate of 74% may challenge SBRT as the primary treatment for inoperable special stage II (T 2b-3 N 0 M 0 ) NSCLC. So, this could be considered as preliminary and investigated in a randomized study.
Owing to the excellent long-term survivals, LC and minimal toxicities applied in current study, Hypo-SIB-IMRT may provide better results for special stage II (T 2b-3 N 0 M 0 ) NSCLC patients without lymph nodes metastasis who are medically inoperable. The advanced RT techniques; such as SIB-IMRT, immobilization, and image guiding; should not be neglected. Nevertheless, an absolute conclusion could not be drawn from the prospective study. It should beinvestigated in a randomized study.
| > Acknowledgements|| |
This study was supported by National Nature Science Foundation 81272501, Taishan Scholar of China and Shandong research fund for outstanding young scientist plan (No. BS2013YY057).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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