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Three-dimensional conformal radiotherapy for locoregionally recurrent lung carcinoma after external beam irradiation: A prospective phase I–II clinical trial
Int. J. Radiation Oncology Biol. Phys., Vol. 57, No. 5, pp. 1345–1350, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter
doi:10.1016/S0360-3016(03)00768-5
CLINICAL INVESTIGATION
Lung
THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR LOCOREGIONALLY RECURRENT LUNG CARCINOMA AFTER EXTERNAL BEAM IRRADIATION: A PROSPECTIVE PHASE I–II CLINICAL TRIAL KAI-LIANG WU, M.D., GUO-LIANG JIANG, M.D., HAO QIAN, M.D., LI-JUAN WANG, M.D., HUAN-JUN YANG, M.D., XIAO-LONG FU, M.D., AND SHEN ZHAO, M.D. Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China Objective: To observe in a clinical trial the feasibility, tolerance, and efficacy of reirradiation by threedimensional conformal radiotherapy (3D-CRT) for locoregionally recurrent lung carcinoma after external beam radiotherapy (EBRT). Methods and Materials: Between June 1999 and March 2001, 23 lung carcinoma patients with locoregional recurrence after EBRT were enrolled in this study. Of the 23 patients, 21 were men and 2 were women (median age 68 years, range 43–79). At the first course of RT, 9 patients had squamous cell carcinoma, 7 adenocarcinoma, and 7 small cell carcinoma. The interval between the first course of RT and recurrence varied from 6 to 42 months (median 13). The median dose of the first course of RT was 66 Gy (range 30 –78). Reirradiation was carried out using 3D-CRT and only covered the radiographic lesions. The median dose of reirradiation was 51 Gy (range 46 – 60), which was delivered by a conventionally fractionated schedule (i.e., 1.8 –2.0 Gy/fraction, 5 fractions/wk). The toxicity was assessed according to the Radiation Therapy Oncology Group criteria. Results: The median follow-up time was 15 months (range 2–37). Acute radiation esophagitis occurred in 9% of patients (Grade 1–2). Acute radiation pneumonitis developed in 22% of patients (Grade 1–2). No cases of acute Grade 3 or greater toxicity had been recorded at last follow-up. Pulmonary fibrosis was observed in 26% of patients (Grade 2–3); no other severe late complications have been observed. The 1- and 2-year survival rate was 59% and 21%, respectively. The locoregional progression-free rate at 1 and 2 years was 51% and 42%, respectively. Conclusion: Reirradiation using 3D-CRT was tolerated by this group of recurrent lung carcinoma patients without severe complications. The 2-year outcome was encouraging. Reirradiation with 3D-CRT can be considered an option for the management of locoregionally recurrent lung carcinoma. © 2003 Elsevier Inc. Lung carcinoma, Radiotherapy, Recurrence, Reirradiation, Three-dimensional conformal radiotherapy.
Locoregional failure after thoracic irradiation for lung carcinoma presents a clinical challenge to oncologists. In 1982, the Radiation Therapy Oncology Group reported an incidence of 34% for locoregional recurrence and 16% for locoregional plus distant failure for non–small-cell carcinoma (NSCLC) after irradiation (1). When the status of local control was evaluated by all methods, including clinical, radiologic, endoscopic, and histologic examinations, the local failure rate may be as great as 85% (2). Although tumor control has improved since then with improvement in radiotherapy (RT) techniques and increases in the dose delivered, local failure after RT still has a high incidence. The choice of treatment for locoregionally recurrent lung
carcinomas is very limited. In the English-language medical literature, only five papers described reirradiation for thoracic failure of lung carcinoma. Furthermore, those were all retrospective studies (3–7). This reflected the controversy on reirradiation, mainly owing to concerns regarding the risk of toxicity and complications after reirradiation. Now we are in the era of three-dimensional conformal RT (3D-CRT). The results of clinical investigations have shown that 3D treatment planning has significant potential for improving RT planning for lung carcinoma, both for adequate tumor coverage to high doses and for minimizing normal tissue dosage. Therefore, we believe that reirradiation at high doses delivered by 3D-CRT for thoracic recurrence of lung carcinoma would be possible. Nevertheless,
Reprint requests to: Guo-Liang Jiang, M.D., Department of Radiation Oncology, Cancer Hospital, Fudan University, 399 Ling Ling Rd., Shanghai 200032 China. Tel: 86-021-641-75-590; Fax: 86-021-641-74-774. E-mail: [email protected] Supported by Grant 994119005 from Shanghai Science and Technology Committee and grant 20011626 for the 2000’ Key
Project of Clinical Investigation from the Ministry of Public Health. Acknowledgments—The authors thank Dr. Taifu Liu for his assistance in the editing of the English. Received Jan 17, 2003, and in revised form May 21, 2003. Accepted for publication May 27, 2003.
INTRODUCTION
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the principle of reirradiation is for palliation to relieve symptoms that result from recurrent tumors or to prevent or delay the appearances of symptoms that will occur if the recurrences continue to grow. The present study was designed as a clinical Phase I-II prospective trial to observe the feasibility, tolerance, and efficacy of reirradiation by 3D-CRT for locoregionally recurrent lung carcinomas. METHODS AND MATERIALS Patient eligibility Patients were enrolled if they satisfied all the following requirements: patient age 18 – 80 years; Karnofsky performance status ⱖ70; histologic or cytologic diagnosis at first course of irradiation confirmed as NSCLC or small-cell lung carcinoma (SCLC); lung cancer recurrence after definitive, palliative irradiation or postoperative external beam radiotherapy (EBRT); and the recurrence had developed ⱖ6 months after irradiation. In addition, recurrences were confirmed whenever possible by histologic or cytologic examination. If not, they had to be verified by observation through bronchial endoscopy and/or evidence seen on CT, MRI, or positron emission tomography showing the reappearance or enlargement of the tumor shadow within the original irradiation volume. The diagnosis of recurrence was determined by a group of physicians, including diagnostic radiologists and oncologists. The recurrences had to be limited to the thorax without evidence of distant metastases and identified on CT or MRI in three dimensions. Finally, the liver, kidney, and bone marrow function had to be within normal limits. Patients had forced expiratory volume in 1 s of ⬎1L and did not have severe cardiovascular disease (e.g., repeated onset of heart attack) or other medical contraindications for irradiation. Pretreatment evaluation Patients underwent physical examination, CT and/or MRI of the thorax and brain, ultrasound examination of the abdomen, including liver, spleen, kidneys, suprarenal glands, retroperitoneal nodes, and pelvis, and radionuclide bone scanning. Electrocardiography and pulmonary function tests (forced expiratory volume in 1 s) were performed. A complete blood count and biochemistry survey were also required. The corresponding tests or measurements were taken if the patients had special symptoms and syndromes suggestive of distant metastases. The data of the first course of irradiation were retrospectively reviewed, including the beam arrangement, field size and shape, and doses to the tumor and critical structures. 3D-CRT technique Reirradiation was carried out by 6-MV photons using 3D-CRT. All patients underwent simulation in the supine position with a vacuum polystyrene immobilization device, and the lesion motion during breathing was observed under simulator fluoroscopy. The planning CT scan was undertaken with 1-cm slices, but with 0.5 cm within the target
Volume 57, Number 5, 2003
volume. The CT data were registered in the treatment planning system (Cadplan, version 6.0.3, Varian). The gross tumor volume as shown on CT/MRI was delineated by a group of physicians using the International Commission on Radiation Units and Measurements Report 50 (8). A margin of 1.5–2.0 cm was extended from the gross tumor volume to the planning target volume (PTV) to cover the subclinical invasion and to offset the setup uncertainty. In addition, the motion of the lesions observed under fluoroscopy was taken into account when the margin was determined. No elective nodal irradiation was given. The principle for designing the reirradiation plan was to minimize the dose to normal structures, which had already been irradiated, and at the same time to deliver to the tumor doses as high as possible. Therefore, avoidance of the same beam pathway of the first course of RT became the first priority. With the help of beam’s eye view, multiple noncoplanar field arrangements were often used, generally four to five portals, as well as the dynamic arc technique. The dynamic arc fields consisted of 15–30 coplanar fields, which were modified by 15–30° wedges, when necessary. The dose was normalized to the isocenter of the PTV with no correction for inhomogeneity. Conventional fractionation (i.e., 2.0 Gy/fraction, 5 fractions/wk) was used with a total dose of 46 – 60 Gy, depending on the doses given at the first course of RT. If the dose at the first course had been ⬍50 Gy, 60 Gy was given at reirradiation, and if ⬎50 Gy, 46 –50 Gy was given at reirradiation. The optimization of the plan was based on dose–volume histograms and the following criteria: (1) In terms of the heterogeneity of the radiation dose in the PTV, the maximal dose did not exceed the prescription by ⬎7%. (2) A 95% isodose volume encompassed the PTV. (3) The maximal point dose to critical normal structures outside the PTV could not exceed the prescription dose. (4) The doses to critical organs were limited to within tolerances and were kept to the lowest. The dose to the spinal cord was restricted to ⬍25 Gy at the second RT course. (5) The lung volume receiving ⬎20 Gy was kept to the minimum. After the 3D-CRT plan was finished, the fields were checked under simulator fluoroscopy to ensure full coverage of the lesions before reirradiation. On the first day of reirradiation and weekly thereafter, portal films were obtained to verify the correction for RT. The verification for the dynamic arc technique was as follows. If, for example, there were 10 fields in an arc of 90° with 10° between, the treatment planning system would print 10 digitally reconstructed radiographs with different field shapes. The linear accelerator then implemented the plan without the patient on the treatment coach, and the machine was set to stop at every 10° angle. The field shape on that angle was compared with corresponding digitally reconstructed radiograph to verify consistency. The dynamic arc fields were implemented automatically. Technicians set up the first field, and for the rest of the fields, the gantry of the linear accelerator continuously rotated, with the multileaf collimator changing its
Recurrent lung cancer after irradiation
shape as planned for every 8 –10° rotation, all under computer control.
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Table 1. Clinical characteristics of 23 patients with recurrent lung carcinoma Characteristic
Chemotherapy Chemotherapy was optional. If the patient’s condition was good, one cycle of chemotherapy was administered before reirradiation. Additional cycles were given afterward if the patient could tolerate it. The chemotherapy was delivered sequentially with the reirradiation. The chemotherapy regimen was mitomycin C (5– 6 mg/m2, Day 1), vindesine (3– 4 mg/m2/d, Days 1 and 8), and cisplatinum (25–30 mg/m2, Days 1–3) for NSCLC and etoposide (50 – 60 mg/m2/d, Days 1–3) and cisplatinum (25–30 mg/ m2/d, Days 1–3) for SCLC. Toxicity criteria and follow-up Acute toxicity, that occurring within ⬍90 days after reirradiation, was evaluated using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria (9). Late toxicity (⬎90 days) was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scale (9). All patients were evaluated weekly during reirradiation, every 3 months for the first year, and every 6 months for the next 3 years. Chest CT was required at 3, 6, and 12 months after reirradiation for the first follow-up year. Thereafter, chest CT or chest X-ray films were required, and, once progression of lesions was suspected on chest X-ray films, chest CT/MRI was mandatory. Survival and locoregional control The overall survival and locoregional progression-free rates after reirradiation were estimated using the KaplanMeier method. Locoregional progression free was defined as no lesions on CT/MRI in the thorax and the lesions shown on CT/MRI remained shrunken or unchanged in size. Once the shadow of lesions reappeared or enlarged, it was considered progression. RESULTS Clinical characteristics Between June 1999 and March 2001, 23 patients (21 men and 2 women) with locoregional recurrence were enrolled in this study. Their clinical characteristics are shown in Tables 1 and 2. The median age at the time of reirradiation was 68 years (range 43–79). Sixteen patients had NSCLC and seven SCLC. At the first course of RT, 7 patients had Stage II (International Union Against Cancer, 1997) and 16 patients had Stage III. The recurrences were diagnosed by histologic or cytologic examination in 15 patients (65%) and by CT, MRI, or positron emission tomography and endoscopy in 8 patients (35%). In the 15 cases confirmed by histologic or cytologic evaluation, the histologic types of the recurrent tumor were the same as those of the original tumors.
Gender Male Female Age (y) Stage at first RT course* IIa IIb IIIa IIIb Histologic type at first RT course Squamous cell carcinoma Adenocarcinoma Small cell carcinoma KPS before reirradiation ⬍70 ⱖ70 Weight loss in 6 mo ⱖ5% ⬍5%
21 2 68 (43–79) 2 5 6 10 9 7 7 0 23 5 18
* International Union Against Cancer, 1997. Abbreviations: RT ⫽ radiotherapy; KPS ⫽ Karnofsky performance score.
First course of RT and reirradiation For the initial treatment, 13 patients had received definitive RT, 6 patients palliative RT, and 4 patients postoperative RT. The four-field technique was used for RT planning for all 23 patients. For the 13 patients with definitive RT, parallel opposed AP and PA fields were applied to cover the primary tumor, as well as the mediastinal lymph nodes, then as a boost, parallel opposed oblique fields were used that were just large enough to treat the gross tumor as seen on CT/MRI. Doses were delivered by conventional fractionation (1.8 –2.0 Gy/fraction, 5 fractions/wk) with 42– 44 Gy by AP–PA fields and 14 –34 Gy by oblique fields. The median dose to gross tumors was 66 Gy (range 56 –78) for definitive RT. The dose to the spinal cord was limited to 42– 44 Gy. Lung tissue directly adjacent to tumor received
Table 2. Tumor characteristics
Recurrence in fields at field margins Recurrence diagnosed by histologic examination Histolic type Squamous cell carcinoma Adenocarcinoma Small cell carcinoma CAT/MRI/PET and endoscopy Gross tumor volume (cm3) Median Range
Patients (n)
%
16 7
70 30
15
65
8 3 4 8
35
80 30–138
Abbreviation: PET ⫽ positron emission tomography.
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Table 3. Acute toxicity RTOG grade Toxicity
1 ⫹ 2 (%)
ⱖ3 (%)
Esophagitis Pneunomitis Myelosuppression Skin Heart Myelitis
9 22 9 9 0 0
0 0 0 0 0 0
Abbreviation: RTOG ⫽ Radiation Therapy Oncology Group
56 –78 Gy and lung in the pathway of beams received 14 –22 Gy in 12 cases and 34 Gy in 1 case. For the 6 cases of palliative RT, only primary tumor was irradiated to a median dose of 40 Gy (range 30 –56) by the same technique. For postoperative RT, 40 – 44 Gy was delivered to the mediastinal node area by AP–PA fields, and then a boost dose was given to positive surgical margins or residual disease by a pair of oblique fields. For postoperative patients, doses ranged from 40 to 66 Gy (median 60). The doses to the spinal cord and lung in the palliative or postoperative setting were lower than those for definitive RT. For all 23 patients, the median dose at the first course was 66 Gy (range 30 –78). The median interval between the first RT course and reirradiation was 13 months (range 6 – 42). The median dose of reirradiation was 51 Gy (range 46 – 60). The technique of 3D-CRT was four to five fixed noncoplanar fields in 6 cases, four to five fixed coplanar fields in 6 cases, dynamic arc fields in 8 cases, and dynamic arc combined with fixed noncoplanar fields in 3 patients. Chemotherapy For the entire group, the median chemotherapy cycle was one (range one to three). Acute toxicity and tolerance The 23 patients tolerated reirradiation with 3D-CRT well. The incidence of acute toxicity is shown in Table 3. Grade 1–2 esophagitis occurred in 9% of patients, and Grade 1–2 pneumonitis in 22% of patients. No Grade 3 or greater acute toxicity had been recorded at last follow-up. Late toxicity The last follow-up evaluation was done in December 2002. The median follow-up from completion of reirradiation to the last follow-up visit was 15 months (range 2–37). At the last follow-up visit, 17 patients (74%) had either Grade 1 late toxicity or no toxicity at all. Six patients (26%) had pulmonary fibrosis on chest CT, of whom four had Grade 2 with no symptoms and two had Grade 3 with clinical symptoms. Survival and failure pattern Seven patients were alive at last follow-up without tumor progression in 5 cases and tumor recurrence again in 2
Fig. 1. Overall survival after reirradiation for 23 cases of recurrent lung carcinoma.
cases. The remaining 16 patients died of locoregional failures (8 patients), distant metastases (3 patients), both locoregional and distant failure (4 patients), and intercurrent disease (1 patient). After reirradiation, the median survival time was 14 months (range 2–37). The overall survival rate after reirradiation (Fig. 1) was 59% and 21% at 1 and 2 years, respectively. The 1- and 2-year locoregional progression-free rate was 51% and 42%, respectively. DISCUSSION Lung carcinoma is an extremely aggressive neoplasm. Although RT has been widely used for NSCLC, the outcome has been disappointing, with 5-year survival rates of 5–10% and locoregional control rates of 10 –20% (10 –13) after definitive irradiation of 60 Gy. For SCLC, distant metastases accounted for most failures, but locoregional failure was still an important cause. As the efficacy of systemic chemotherapy has improved in decreasing distant metastases, locoregional control of SCLC has become more important in prolonging patients’ lives. However, even given combined chemotherapy and thoracic RT, about onehalf of SCLC patients will have locoregional recurrence. For lung carcinoma recurrence, few treatment modalities have been reported to be effective in the literature. Reirradiation has seldom been considered a treatment choice, especially when recurrence occurred within previously heavily irradiated areas because of concerns about radiation-induced morbidity and mortality. It was believed that reirradiation was associated with problems of radiation injury that prevented delivery of adequate doses. Moreover, increased use of more intensive combined therapy of chemoradiation has reduced patients’ ability to tolerate retreatment with chemotherapy and RT (14). Recently, some papers have reported on reirradiation for recurrent tumors in other sites. The usefulness of
Recurrent lung cancer after irradiation
such therapy has begun to be recognized (15), especially when 3D-CRT has been widely applied and demonstrated its effectiveness in the sparing of normal tissues. However, only a few reports have been published on reirradiation for recurrent lung carcinoma. We believe that reirradiation can be considered when recurrence in the thorax has resulted in severe symptoms that would worsen a patient’s quality of life. From our experience in NSCLC treated by 3D-CRT, it is possible to deliver a second course of RT without causing undue complications (16). A balance is needed so that the doses to the recurrent tumor inhibit tumor growth, but do not produce unacceptable complications. Montebello et al. (6) retrospectively evaluated the efficacy of reirradiation with EBRT for 30 patients with recurrent lung carcinoma. The median dose of the initial irradiation was 60 Gy in 6 weeks. The median interval between the initial RT and recurrence was 12 months. The median dose of reirradiation was 30.3 Gy in 3 weeks. Of the symptomatic patients, 70% of patients subjectively responded to reirradiation. Its toxicity included esophagitis, dry desquamation, and symptomatic pneumonitis. Green and Melbye (4) reported that a 74% favorable objective response rate was attained in 29 patients with recurrent lung carcinoma after reirradiation. The median total dose delivered at the first and second course of RT equaled 82 Gy, and the median dose of reirradiation was 35 Gy (range 6 –54). Only 1 patient developed symptomatic radiation pneumonitis, and 1 patient had rib sclerosis and fracture. The median survival time was 5 months (range 1–54). Although the above two publications suggested the possibility of reirradiation for recurrent lung carcinoma, the most troublesome complication was radiation-induced myelopathy due to overdosage to the spinal cord. Generally, for most lung carcinoma patients, the spinal cord has been irradiated to its tolerance dose at the first course, and, at the second course, more doses would have to be imposed on it because of difficulties in totally avoiding radiation to the spinal cord by the conventional RT technique. Jackson and Ball (5) reported 1 patient with transverse myelopathy after receiving 43 Gy to the spinal cord at initial RT and an additional 3.3 Gy from scatter radiation at reirradiation. For the present study, we carried out the treatment plan with great caution and paid much attention to the doses to the critical structures. When designing the plan for the second course of RT, we considered the tolerance of the spinal cord and lung. In terms of the tolerance of the spinal cord for reirradiation after a high first dose, it has been demonstrated that the spinal cord has a large capacity to recover from occult radiation injury induced by a commonly prescribed dose. Therefore, it could tolerate another course of RT according to studies on the monkey spinal cord (17) and reirradiation of human tumors. However, no precise quantitative data were available in that series regarding to what extent the occult injury had been
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repaired and what was the tolerance for reirradiation. It was estimated by Ang et al. (17) that 65– 68 Gy would be well tolerated when the dose of the first course did not exceed 45 Gy in 2-Gy fractions. At the first RT course in this study, the dose to the spinal cord had been 42– 44 Gy for most patients. Therefore, we restricted the dose to the spinal cord to ⬍25 Gy for reirradiation. However, the constraint lacked firm evidence. In respect to the doses to the lung during reirradiation, we speculated that the lung, as a late responding tissue similar to the spinal cord, also possessed the long-term capability to repair occult radiation damage. We also believed that the magnitude of the long-term recovery depended on the size of the initial dose and the elapsed time. In the first RT course, except for the portion of lung adjacent to pulmonary lesions, most of the lung involved received quite a low dose (14 –22 Gy). Hence, we thought the irradiated lung had partially recovered from occult injury and retained a part of pulmonary function to varying extents. On the basis of the above considerations, we designed the fields to avoid the same beam path used in the first RT course. Because we used virtual simulation with a 3D-CRT planning system, this could be accomplished after repeated trial and error. A range of doses (46 – 60 Gy) to the tumor was used, which was decided on the basis of two considerations: the total dose at the first RT course and the DVH of the lung. Because the purpose of reirradiation was palliative, the avoidance of severe acute and late complications should be the first priority, but the tumor dose should be as high as possible to obtain better palliation. Therefore, a balance between complications and efficacy was critical. Ours was a trial study to reach this goal. Although the median follow-up was only 15 months, the toxicity and complications were acceptable with no severe consequences. The 2-year overall survival rate of 21% and 2-year locoregional progression-free survival rate of 42% were quite encouraging. This group of patients was highly selected. The biologic behavior of their tumors was not believed to be highly malignant, because they did not develop distant metastases when tumor recurred in the thorax at a median of 13 months after the first RT course. Thus, their prognoses should be better than those with distant metastases. Despite this favorable prognostic factor, the results were still quite good in general. However, more patients and longer follow-up are needed to evaluate finally the effectiveness of 3D-CRT for recurrent lung carcinoma. CONCLUSION On the basis of our findings, the high dose of reirradiation by 3D-CRT can be given safely and successfully to this group of patients with locally recurrent lung carcinoma. The outcome is promising. Longer follow-up and more patients are needed to confirm the safety and efficacy of reirradiation. Nevertheless, reirradiation can be considered an option for the management of locally recurrent lung carcinoma after RT.
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REFERENCES 1. Perez CA, Stanley K, Grundy G, et al. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: Report by the Radiation Therapy Oncology Group. Cancer 1982;50:1091–1099. 2. Arriagada R, Le Chevalier T, Quoix E, et al. ASTRO plenary: Effect of chemotherapy on locally advanced non-small cell lung cancer—A randomized study of 353 patients. Int J Radiat Oncol Biol Phys 1991;20:1183–1190. 3. Eric LG, Maria WW, John C, et al. Thoracic reirradiation for symptomatic relief after prior radiotherapeutic management for lung cancer. Am J Clin Oncol 2000;23:160–163. 4. Green N, Melbye RW. Lung cancer: Retreatment of local recurrence after definitive irradiation. Carcinoma 1982;49: 865–868. 5. Jackson MA, Ball DL. Palliative retreatment of locally recurrent lung carcinoma after radical radiotherapy. Med J Aust 1987;147:391–394. 6. Montebello JF, Aron BS, Manatunga AK, et al. The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol 1993;16:482–488. 7. Okamoto Y, Murakami M, Yoden E, et al. Reirradiation for locally recurrent lung cancer previously treated with radiotherapy. Int J Radiat Oncol Biol Phys 2002;52:390–396. 8. International Commission of Radiation Units and Measurements. Prescribing, recording and reporting photon beam therapy, Report No. 50. Bethesda: ICRU, 1993. 9. Cox JD, Stetz J, Pajak TF, et al. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the Euro-
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pean Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. Hazuka MB, Bunn PA, Jr. Controversies in the nonsurgical treatment of stage III non-small cell lung cancer. Am Rev Respir Dis 1992;145:967–977. Perez CA, Pajak TF, Rubin P, et al. Long-term observation of the patterns of failure in patients with unresectable non-oat cell carcinoma of lung treated with definitive radiotherapy: Report by the Radiation Oncology Group. Cancer 1987;59: 1874–1881. Blanke C, Ansari R, Mantravadi R, et al. Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: A Hoosier Oncology Group protocol. J Clin Oncol 1995;13:1425–1429. Schaake-Koning C, Van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung carcinoma. N Engl J Med 1992;326: 524–530. John PC, Michael JK, David V, et al. Retreatment of patients surviving carcinoma-free 2 or more years after initial treatment of small cell lung cancer. Chest 1996;110:165–171. Morris DE. Clinical experience with retreatment for palliation. Semin Radiat Oncol 2000;10:210–221. Wu KL, Jiang GL, Liao Y, et al. Three-dimensional conformal radiation therapy for non-small cell lung carcinoma (unpublished data). Ang KK, Jiang GL, Feng Y, et al. Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys 2001;50:1013–1020.
doi:10.1016/S0360-3016(03)00768-5
CLINICAL INVESTIGATION
Lung
THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR LOCOREGIONALLY RECURRENT LUNG CARCINOMA AFTER EXTERNAL BEAM IRRADIATION: A PROSPECTIVE PHASE I–II CLINICAL TRIAL KAI-LIANG WU, M.D., GUO-LIANG JIANG, M.D., HAO QIAN, M.D., LI-JUAN WANG, M.D., HUAN-JUN YANG, M.D., XIAO-LONG FU, M.D., AND SHEN ZHAO, M.D. Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China Objective: To observe in a clinical trial the feasibility, tolerance, and efficacy of reirradiation by threedimensional conformal radiotherapy (3D-CRT) for locoregionally recurrent lung carcinoma after external beam radiotherapy (EBRT). Methods and Materials: Between June 1999 and March 2001, 23 lung carcinoma patients with locoregional recurrence after EBRT were enrolled in this study. Of the 23 patients, 21 were men and 2 were women (median age 68 years, range 43–79). At the first course of RT, 9 patients had squamous cell carcinoma, 7 adenocarcinoma, and 7 small cell carcinoma. The interval between the first course of RT and recurrence varied from 6 to 42 months (median 13). The median dose of the first course of RT was 66 Gy (range 30 –78). Reirradiation was carried out using 3D-CRT and only covered the radiographic lesions. The median dose of reirradiation was 51 Gy (range 46 – 60), which was delivered by a conventionally fractionated schedule (i.e., 1.8 –2.0 Gy/fraction, 5 fractions/wk). The toxicity was assessed according to the Radiation Therapy Oncology Group criteria. Results: The median follow-up time was 15 months (range 2–37). Acute radiation esophagitis occurred in 9% of patients (Grade 1–2). Acute radiation pneumonitis developed in 22% of patients (Grade 1–2). No cases of acute Grade 3 or greater toxicity had been recorded at last follow-up. Pulmonary fibrosis was observed in 26% of patients (Grade 2–3); no other severe late complications have been observed. The 1- and 2-year survival rate was 59% and 21%, respectively. The locoregional progression-free rate at 1 and 2 years was 51% and 42%, respectively. Conclusion: Reirradiation using 3D-CRT was tolerated by this group of recurrent lung carcinoma patients without severe complications. The 2-year outcome was encouraging. Reirradiation with 3D-CRT can be considered an option for the management of locoregionally recurrent lung carcinoma. © 2003 Elsevier Inc. Lung carcinoma, Radiotherapy, Recurrence, Reirradiation, Three-dimensional conformal radiotherapy.
Locoregional failure after thoracic irradiation for lung carcinoma presents a clinical challenge to oncologists. In 1982, the Radiation Therapy Oncology Group reported an incidence of 34% for locoregional recurrence and 16% for locoregional plus distant failure for non–small-cell carcinoma (NSCLC) after irradiation (1). When the status of local control was evaluated by all methods, including clinical, radiologic, endoscopic, and histologic examinations, the local failure rate may be as great as 85% (2). Although tumor control has improved since then with improvement in radiotherapy (RT) techniques and increases in the dose delivered, local failure after RT still has a high incidence. The choice of treatment for locoregionally recurrent lung
carcinomas is very limited. In the English-language medical literature, only five papers described reirradiation for thoracic failure of lung carcinoma. Furthermore, those were all retrospective studies (3–7). This reflected the controversy on reirradiation, mainly owing to concerns regarding the risk of toxicity and complications after reirradiation. Now we are in the era of three-dimensional conformal RT (3D-CRT). The results of clinical investigations have shown that 3D treatment planning has significant potential for improving RT planning for lung carcinoma, both for adequate tumor coverage to high doses and for minimizing normal tissue dosage. Therefore, we believe that reirradiation at high doses delivered by 3D-CRT for thoracic recurrence of lung carcinoma would be possible. Nevertheless,
Reprint requests to: Guo-Liang Jiang, M.D., Department of Radiation Oncology, Cancer Hospital, Fudan University, 399 Ling Ling Rd., Shanghai 200032 China. Tel: 86-021-641-75-590; Fax: 86-021-641-74-774. E-mail: [email protected] Supported by Grant 994119005 from Shanghai Science and Technology Committee and grant 20011626 for the 2000’ Key
Project of Clinical Investigation from the Ministry of Public Health. Acknowledgments—The authors thank Dr. Taifu Liu for his assistance in the editing of the English. Received Jan 17, 2003, and in revised form May 21, 2003. Accepted for publication May 27, 2003.
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the principle of reirradiation is for palliation to relieve symptoms that result from recurrent tumors or to prevent or delay the appearances of symptoms that will occur if the recurrences continue to grow. The present study was designed as a clinical Phase I-II prospective trial to observe the feasibility, tolerance, and efficacy of reirradiation by 3D-CRT for locoregionally recurrent lung carcinomas. METHODS AND MATERIALS Patient eligibility Patients were enrolled if they satisfied all the following requirements: patient age 18 – 80 years; Karnofsky performance status ⱖ70; histologic or cytologic diagnosis at first course of irradiation confirmed as NSCLC or small-cell lung carcinoma (SCLC); lung cancer recurrence after definitive, palliative irradiation or postoperative external beam radiotherapy (EBRT); and the recurrence had developed ⱖ6 months after irradiation. In addition, recurrences were confirmed whenever possible by histologic or cytologic examination. If not, they had to be verified by observation through bronchial endoscopy and/or evidence seen on CT, MRI, or positron emission tomography showing the reappearance or enlargement of the tumor shadow within the original irradiation volume. The diagnosis of recurrence was determined by a group of physicians, including diagnostic radiologists and oncologists. The recurrences had to be limited to the thorax without evidence of distant metastases and identified on CT or MRI in three dimensions. Finally, the liver, kidney, and bone marrow function had to be within normal limits. Patients had forced expiratory volume in 1 s of ⬎1L and did not have severe cardiovascular disease (e.g., repeated onset of heart attack) or other medical contraindications for irradiation. Pretreatment evaluation Patients underwent physical examination, CT and/or MRI of the thorax and brain, ultrasound examination of the abdomen, including liver, spleen, kidneys, suprarenal glands, retroperitoneal nodes, and pelvis, and radionuclide bone scanning. Electrocardiography and pulmonary function tests (forced expiratory volume in 1 s) were performed. A complete blood count and biochemistry survey were also required. The corresponding tests or measurements were taken if the patients had special symptoms and syndromes suggestive of distant metastases. The data of the first course of irradiation were retrospectively reviewed, including the beam arrangement, field size and shape, and doses to the tumor and critical structures. 3D-CRT technique Reirradiation was carried out by 6-MV photons using 3D-CRT. All patients underwent simulation in the supine position with a vacuum polystyrene immobilization device, and the lesion motion during breathing was observed under simulator fluoroscopy. The planning CT scan was undertaken with 1-cm slices, but with 0.5 cm within the target
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volume. The CT data were registered in the treatment planning system (Cadplan, version 6.0.3, Varian). The gross tumor volume as shown on CT/MRI was delineated by a group of physicians using the International Commission on Radiation Units and Measurements Report 50 (8). A margin of 1.5–2.0 cm was extended from the gross tumor volume to the planning target volume (PTV) to cover the subclinical invasion and to offset the setup uncertainty. In addition, the motion of the lesions observed under fluoroscopy was taken into account when the margin was determined. No elective nodal irradiation was given. The principle for designing the reirradiation plan was to minimize the dose to normal structures, which had already been irradiated, and at the same time to deliver to the tumor doses as high as possible. Therefore, avoidance of the same beam pathway of the first course of RT became the first priority. With the help of beam’s eye view, multiple noncoplanar field arrangements were often used, generally four to five portals, as well as the dynamic arc technique. The dynamic arc fields consisted of 15–30 coplanar fields, which were modified by 15–30° wedges, when necessary. The dose was normalized to the isocenter of the PTV with no correction for inhomogeneity. Conventional fractionation (i.e., 2.0 Gy/fraction, 5 fractions/wk) was used with a total dose of 46 – 60 Gy, depending on the doses given at the first course of RT. If the dose at the first course had been ⬍50 Gy, 60 Gy was given at reirradiation, and if ⬎50 Gy, 46 –50 Gy was given at reirradiation. The optimization of the plan was based on dose–volume histograms and the following criteria: (1) In terms of the heterogeneity of the radiation dose in the PTV, the maximal dose did not exceed the prescription by ⬎7%. (2) A 95% isodose volume encompassed the PTV. (3) The maximal point dose to critical normal structures outside the PTV could not exceed the prescription dose. (4) The doses to critical organs were limited to within tolerances and were kept to the lowest. The dose to the spinal cord was restricted to ⬍25 Gy at the second RT course. (5) The lung volume receiving ⬎20 Gy was kept to the minimum. After the 3D-CRT plan was finished, the fields were checked under simulator fluoroscopy to ensure full coverage of the lesions before reirradiation. On the first day of reirradiation and weekly thereafter, portal films were obtained to verify the correction for RT. The verification for the dynamic arc technique was as follows. If, for example, there were 10 fields in an arc of 90° with 10° between, the treatment planning system would print 10 digitally reconstructed radiographs with different field shapes. The linear accelerator then implemented the plan without the patient on the treatment coach, and the machine was set to stop at every 10° angle. The field shape on that angle was compared with corresponding digitally reconstructed radiograph to verify consistency. The dynamic arc fields were implemented automatically. Technicians set up the first field, and for the rest of the fields, the gantry of the linear accelerator continuously rotated, with the multileaf collimator changing its
Recurrent lung cancer after irradiation
shape as planned for every 8 –10° rotation, all under computer control.
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Table 1. Clinical characteristics of 23 patients with recurrent lung carcinoma Characteristic
Chemotherapy Chemotherapy was optional. If the patient’s condition was good, one cycle of chemotherapy was administered before reirradiation. Additional cycles were given afterward if the patient could tolerate it. The chemotherapy was delivered sequentially with the reirradiation. The chemotherapy regimen was mitomycin C (5– 6 mg/m2, Day 1), vindesine (3– 4 mg/m2/d, Days 1 and 8), and cisplatinum (25–30 mg/m2, Days 1–3) for NSCLC and etoposide (50 – 60 mg/m2/d, Days 1–3) and cisplatinum (25–30 mg/ m2/d, Days 1–3) for SCLC. Toxicity criteria and follow-up Acute toxicity, that occurring within ⬍90 days after reirradiation, was evaluated using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria (9). Late toxicity (⬎90 days) was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scale (9). All patients were evaluated weekly during reirradiation, every 3 months for the first year, and every 6 months for the next 3 years. Chest CT was required at 3, 6, and 12 months after reirradiation for the first follow-up year. Thereafter, chest CT or chest X-ray films were required, and, once progression of lesions was suspected on chest X-ray films, chest CT/MRI was mandatory. Survival and locoregional control The overall survival and locoregional progression-free rates after reirradiation were estimated using the KaplanMeier method. Locoregional progression free was defined as no lesions on CT/MRI in the thorax and the lesions shown on CT/MRI remained shrunken or unchanged in size. Once the shadow of lesions reappeared or enlarged, it was considered progression. RESULTS Clinical characteristics Between June 1999 and March 2001, 23 patients (21 men and 2 women) with locoregional recurrence were enrolled in this study. Their clinical characteristics are shown in Tables 1 and 2. The median age at the time of reirradiation was 68 years (range 43–79). Sixteen patients had NSCLC and seven SCLC. At the first course of RT, 7 patients had Stage II (International Union Against Cancer, 1997) and 16 patients had Stage III. The recurrences were diagnosed by histologic or cytologic examination in 15 patients (65%) and by CT, MRI, or positron emission tomography and endoscopy in 8 patients (35%). In the 15 cases confirmed by histologic or cytologic evaluation, the histologic types of the recurrent tumor were the same as those of the original tumors.
Gender Male Female Age (y) Stage at first RT course* IIa IIb IIIa IIIb Histologic type at first RT course Squamous cell carcinoma Adenocarcinoma Small cell carcinoma KPS before reirradiation ⬍70 ⱖ70 Weight loss in 6 mo ⱖ5% ⬍5%
21 2 68 (43–79) 2 5 6 10 9 7 7 0 23 5 18
* International Union Against Cancer, 1997. Abbreviations: RT ⫽ radiotherapy; KPS ⫽ Karnofsky performance score.
First course of RT and reirradiation For the initial treatment, 13 patients had received definitive RT, 6 patients palliative RT, and 4 patients postoperative RT. The four-field technique was used for RT planning for all 23 patients. For the 13 patients with definitive RT, parallel opposed AP and PA fields were applied to cover the primary tumor, as well as the mediastinal lymph nodes, then as a boost, parallel opposed oblique fields were used that were just large enough to treat the gross tumor as seen on CT/MRI. Doses were delivered by conventional fractionation (1.8 –2.0 Gy/fraction, 5 fractions/wk) with 42– 44 Gy by AP–PA fields and 14 –34 Gy by oblique fields. The median dose to gross tumors was 66 Gy (range 56 –78) for definitive RT. The dose to the spinal cord was limited to 42– 44 Gy. Lung tissue directly adjacent to tumor received
Table 2. Tumor characteristics
Recurrence in fields at field margins Recurrence diagnosed by histologic examination Histolic type Squamous cell carcinoma Adenocarcinoma Small cell carcinoma CAT/MRI/PET and endoscopy Gross tumor volume (cm3) Median Range
Patients (n)
%
16 7
70 30
15
65
8 3 4 8
35
80 30–138
Abbreviation: PET ⫽ positron emission tomography.
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Table 3. Acute toxicity RTOG grade Toxicity
1 ⫹ 2 (%)
ⱖ3 (%)
Esophagitis Pneunomitis Myelosuppression Skin Heart Myelitis
9 22 9 9 0 0
0 0 0 0 0 0
Abbreviation: RTOG ⫽ Radiation Therapy Oncology Group
56 –78 Gy and lung in the pathway of beams received 14 –22 Gy in 12 cases and 34 Gy in 1 case. For the 6 cases of palliative RT, only primary tumor was irradiated to a median dose of 40 Gy (range 30 –56) by the same technique. For postoperative RT, 40 – 44 Gy was delivered to the mediastinal node area by AP–PA fields, and then a boost dose was given to positive surgical margins or residual disease by a pair of oblique fields. For postoperative patients, doses ranged from 40 to 66 Gy (median 60). The doses to the spinal cord and lung in the palliative or postoperative setting were lower than those for definitive RT. For all 23 patients, the median dose at the first course was 66 Gy (range 30 –78). The median interval between the first RT course and reirradiation was 13 months (range 6 – 42). The median dose of reirradiation was 51 Gy (range 46 – 60). The technique of 3D-CRT was four to five fixed noncoplanar fields in 6 cases, four to five fixed coplanar fields in 6 cases, dynamic arc fields in 8 cases, and dynamic arc combined with fixed noncoplanar fields in 3 patients. Chemotherapy For the entire group, the median chemotherapy cycle was one (range one to three). Acute toxicity and tolerance The 23 patients tolerated reirradiation with 3D-CRT well. The incidence of acute toxicity is shown in Table 3. Grade 1–2 esophagitis occurred in 9% of patients, and Grade 1–2 pneumonitis in 22% of patients. No Grade 3 or greater acute toxicity had been recorded at last follow-up. Late toxicity The last follow-up evaluation was done in December 2002. The median follow-up from completion of reirradiation to the last follow-up visit was 15 months (range 2–37). At the last follow-up visit, 17 patients (74%) had either Grade 1 late toxicity or no toxicity at all. Six patients (26%) had pulmonary fibrosis on chest CT, of whom four had Grade 2 with no symptoms and two had Grade 3 with clinical symptoms. Survival and failure pattern Seven patients were alive at last follow-up without tumor progression in 5 cases and tumor recurrence again in 2
Fig. 1. Overall survival after reirradiation for 23 cases of recurrent lung carcinoma.
cases. The remaining 16 patients died of locoregional failures (8 patients), distant metastases (3 patients), both locoregional and distant failure (4 patients), and intercurrent disease (1 patient). After reirradiation, the median survival time was 14 months (range 2–37). The overall survival rate after reirradiation (Fig. 1) was 59% and 21% at 1 and 2 years, respectively. The 1- and 2-year locoregional progression-free rate was 51% and 42%, respectively. DISCUSSION Lung carcinoma is an extremely aggressive neoplasm. Although RT has been widely used for NSCLC, the outcome has been disappointing, with 5-year survival rates of 5–10% and locoregional control rates of 10 –20% (10 –13) after definitive irradiation of 60 Gy. For SCLC, distant metastases accounted for most failures, but locoregional failure was still an important cause. As the efficacy of systemic chemotherapy has improved in decreasing distant metastases, locoregional control of SCLC has become more important in prolonging patients’ lives. However, even given combined chemotherapy and thoracic RT, about onehalf of SCLC patients will have locoregional recurrence. For lung carcinoma recurrence, few treatment modalities have been reported to be effective in the literature. Reirradiation has seldom been considered a treatment choice, especially when recurrence occurred within previously heavily irradiated areas because of concerns about radiation-induced morbidity and mortality. It was believed that reirradiation was associated with problems of radiation injury that prevented delivery of adequate doses. Moreover, increased use of more intensive combined therapy of chemoradiation has reduced patients’ ability to tolerate retreatment with chemotherapy and RT (14). Recently, some papers have reported on reirradiation for recurrent tumors in other sites. The usefulness of
Recurrent lung cancer after irradiation
such therapy has begun to be recognized (15), especially when 3D-CRT has been widely applied and demonstrated its effectiveness in the sparing of normal tissues. However, only a few reports have been published on reirradiation for recurrent lung carcinoma. We believe that reirradiation can be considered when recurrence in the thorax has resulted in severe symptoms that would worsen a patient’s quality of life. From our experience in NSCLC treated by 3D-CRT, it is possible to deliver a second course of RT without causing undue complications (16). A balance is needed so that the doses to the recurrent tumor inhibit tumor growth, but do not produce unacceptable complications. Montebello et al. (6) retrospectively evaluated the efficacy of reirradiation with EBRT for 30 patients with recurrent lung carcinoma. The median dose of the initial irradiation was 60 Gy in 6 weeks. The median interval between the initial RT and recurrence was 12 months. The median dose of reirradiation was 30.3 Gy in 3 weeks. Of the symptomatic patients, 70% of patients subjectively responded to reirradiation. Its toxicity included esophagitis, dry desquamation, and symptomatic pneumonitis. Green and Melbye (4) reported that a 74% favorable objective response rate was attained in 29 patients with recurrent lung carcinoma after reirradiation. The median total dose delivered at the first and second course of RT equaled 82 Gy, and the median dose of reirradiation was 35 Gy (range 6 –54). Only 1 patient developed symptomatic radiation pneumonitis, and 1 patient had rib sclerosis and fracture. The median survival time was 5 months (range 1–54). Although the above two publications suggested the possibility of reirradiation for recurrent lung carcinoma, the most troublesome complication was radiation-induced myelopathy due to overdosage to the spinal cord. Generally, for most lung carcinoma patients, the spinal cord has been irradiated to its tolerance dose at the first course, and, at the second course, more doses would have to be imposed on it because of difficulties in totally avoiding radiation to the spinal cord by the conventional RT technique. Jackson and Ball (5) reported 1 patient with transverse myelopathy after receiving 43 Gy to the spinal cord at initial RT and an additional 3.3 Gy from scatter radiation at reirradiation. For the present study, we carried out the treatment plan with great caution and paid much attention to the doses to the critical structures. When designing the plan for the second course of RT, we considered the tolerance of the spinal cord and lung. In terms of the tolerance of the spinal cord for reirradiation after a high first dose, it has been demonstrated that the spinal cord has a large capacity to recover from occult radiation injury induced by a commonly prescribed dose. Therefore, it could tolerate another course of RT according to studies on the monkey spinal cord (17) and reirradiation of human tumors. However, no precise quantitative data were available in that series regarding to what extent the occult injury had been
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repaired and what was the tolerance for reirradiation. It was estimated by Ang et al. (17) that 65– 68 Gy would be well tolerated when the dose of the first course did not exceed 45 Gy in 2-Gy fractions. At the first RT course in this study, the dose to the spinal cord had been 42– 44 Gy for most patients. Therefore, we restricted the dose to the spinal cord to ⬍25 Gy for reirradiation. However, the constraint lacked firm evidence. In respect to the doses to the lung during reirradiation, we speculated that the lung, as a late responding tissue similar to the spinal cord, also possessed the long-term capability to repair occult radiation damage. We also believed that the magnitude of the long-term recovery depended on the size of the initial dose and the elapsed time. In the first RT course, except for the portion of lung adjacent to pulmonary lesions, most of the lung involved received quite a low dose (14 –22 Gy). Hence, we thought the irradiated lung had partially recovered from occult injury and retained a part of pulmonary function to varying extents. On the basis of the above considerations, we designed the fields to avoid the same beam path used in the first RT course. Because we used virtual simulation with a 3D-CRT planning system, this could be accomplished after repeated trial and error. A range of doses (46 – 60 Gy) to the tumor was used, which was decided on the basis of two considerations: the total dose at the first RT course and the DVH of the lung. Because the purpose of reirradiation was palliative, the avoidance of severe acute and late complications should be the first priority, but the tumor dose should be as high as possible to obtain better palliation. Therefore, a balance between complications and efficacy was critical. Ours was a trial study to reach this goal. Although the median follow-up was only 15 months, the toxicity and complications were acceptable with no severe consequences. The 2-year overall survival rate of 21% and 2-year locoregional progression-free survival rate of 42% were quite encouraging. This group of patients was highly selected. The biologic behavior of their tumors was not believed to be highly malignant, because they did not develop distant metastases when tumor recurred in the thorax at a median of 13 months after the first RT course. Thus, their prognoses should be better than those with distant metastases. Despite this favorable prognostic factor, the results were still quite good in general. However, more patients and longer follow-up are needed to evaluate finally the effectiveness of 3D-CRT for recurrent lung carcinoma. CONCLUSION On the basis of our findings, the high dose of reirradiation by 3D-CRT can be given safely and successfully to this group of patients with locally recurrent lung carcinoma. The outcome is promising. Longer follow-up and more patients are needed to confirm the safety and efficacy of reirradiation. Nevertheless, reirradiation can be considered an option for the management of locally recurrent lung carcinoma after RT.
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