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CT-guided interstitial brachytherapy of inoperable non-small cell lung cancer
Lung Cancer 74 (2011) 253–257
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
CT-guided interstitial brachytherapy of inoperable non-small cell lung cancer Zhong-Min Wang a,b,1 , Jian Lu b,1 , Tao Liu c , Ke-Min Chen d , Gang Huang e , Fen-Ju Liu a,∗ a
School of Radiation Medicine and Public Health, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China Department of Radiology, Shanghai Ruijin Hospital Luwan Branch, 149 Chongqing South Road, Shanghai 200020, China c Department of General Surgery, Shanghai Ruijin Hospital Luwan Branch, 149 Chongqing South Road, Shanghai 200020, China d Department of Radiology, Shanghai Ruijin Hospital, 197 Ruijin Er Road, Shanghai 200025, China e Nuclear Medicine, School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai 200025, China b
a r t i c l e
i n f o
Article history: Received 10 December 2010 Received in revised form 17 February 2011 Accepted 4 March 2011 Keywords: Interstitial brachytherapy CT-guided intervention 125 I seed Inoperable non-small cell lung cancer (NSCLC)
a b s t r a c t Purpose: The aim of this study was to assess the technical feasibility, efficacy, and complications of CTguided interstitial brachytherapy for treating inoperable non-small cell lung cancer (NSCLC). Materials and methods: Twenty one patients were included in this prospective study. The median age was 72.6 years (57–85). Tumors were treated with brachytherapy that was positioned under CT-fluoroscopy. The treatment planning system (TPS) was used preoperatively to reconstruct three dimensional images of the tumor and to calculate the estimated seed number and distribution. The median matched peripheral dose (MPD) was 130 Gy (range, 100–160 Gy). All procedures were performed under local anesthesia. A follow-up CT was performed 6 weeks later and every 3 months post implantation. Results: Follow-up period was 2–30 months. The mean diameter of the 21 lung tumors was 4.6 cm (range, 2.8–6.5 cm). The response rate of pain relief was 83.3% (10/12). The pain-free duration was 0–12 months (median: 6 months; 95% CI: 3–9 months). Overall responding rate (CR + PR) for this group of patients was 71.4%. Local tumor control rate was 85.7%. Six (28.6%) patients died as a result of primary tumor progression; thirteen (61.9%) patients died of multi-organ failure or other metastases. Two (9.5%) patients survived to follow-up. At the time of analysis, the median survival time for all patients was 10 months (95% CI: 6.6–13.4 months), with 1 year and 2 year survival rates were 42.4% and 6.5%, respectively. Median survival time for stage II, stage III, and stage IV was 20 months, 9 months, and 8 months, respectively. No major complications were observed. Minor complications (19%) included mild pneumothorax (n = 1), hemosputum (n = 1), pleural effusion (n = 1), and localized skin erythema (n = 1). None of these complications required further treatment, although hospital discharge was delayed. No 125 I seeds migrated to other tissues or organs. Conclusion: Minimally invasive CT-guided interstitial brachytherapy is safe, useful, less complicated and considered as a palliative treatment option for inoperable non-small cell lung cancer. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is among the most commonly occurring malignancies in the world and one of the few that continue to show an increasing incidence [1,2]. Non-small cell lung carcinoma (NSCLC) treatments are determined by the type and stage of cancer and include surgery, external beam radiation therapy (EBRT), chemotherapy, and high-dose-rate endobronchial brachytherapy (HDR-EBBT).
∗ Corresponding author. Tel.: +86 512 65880060; fax: +86 512 65880060. E-mail addresses: [email protected] (Z.-M. Wang), [email protected] (J. Lu), [email protected] (T. Liu), [email protected] (K.-M. Chen), [email protected] (G. Huang), [email protected] (F.-J. Liu). 1 These authors contributed equally to this work and should be considered as co-first authors. 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.03.006
Surgery is usually the treatment of choice for localized cancers, but only approximately 20% of all patients with NSCLC are candidates for potentially curative resection [3]. Also, chemotherapy and external beam radiation have not greatly affected outcomes in patients with unresectable disease, and the gain often comes with substantial toxicity, especially for those who already have other comorbidities [4]. As part of a multimodality treatment of advanced lung cancer, HDR-EBBT may influence survival in patients with malignant central airway obstruction [5]. HDR-EBBT has been used alone and with EBRT or interventional pulmonology in various palliative protocols [6–8]. Minimally invasive therapies have attained increasing attention for the treatment of cancer patients. CT-guided percutaneous implantation of permanent seeds can be used in peripherally located tumors and has the obvious advantage of avoiding an open thoracotomy. We utilize 125 I seeds interstitial brachytherapy for routine use in malignant tumors at various sites.
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We investigated the feasibility of CT-guided interstitial brachytherapy for inoperable non-small cell lung cancer, and we herein report the results for 21 NSCLC patients following 125 I seeds interstitial brachytherapy. The indications, technique outcome, and complications are reported. 2. Patients and methods All patients provided written informed consent before the study and were informed of potential benefits and risks. The study protocol was approved by the Ethics Committee of the School of Medicine, Shanghai Jiao Tong University. 2.1. Criteria for enrollment All patients enrolled displayed contraindications to surgery or had rejected surgery due to personal reasons. The enrolled patients also needed to satisfy the following criteria: histological confirmation of NSCLC; lung masses suspected for lung cancer detected by CT; a single primary pulmonary tumor; neutrophil leukocyte 3 × 109 /L or higher, platelets 70 × 109 /L or higher, and hemoglobin 90 g/L or higher in peripheral blood; prothrombin index (PI) greater than 50% and partial thromboplastin time (PTT) less than 50 s; kidney function within normal range; Karnofsky physical scores (KPS) greater than or equal to 50; and absence of infection. 2.2. Instruments We used a Siemens CT scanner with chest imaging conditions of 130 kV, 300 mA s, and width of 5 mm. Dose distribution was calculated using a Fudan TPS2.00 brachytherapy planning system (Fudan University, Shanghai, China) based on the American Association of Physicists in Medicine TG43 brachytherapy formalism [9]. The 125 I sealed seed sources were supplied by XinKe Pharmaceutical Ltd, Shanghai. For the seed implantation we used 18-G implantation needles and turntable implantation gun (XinKe Pharmaceutical Ltd, Shanghai, China). The diameter of each seed was 0.8 mm, the length was 4.5 mm, and thickness of the wall of the titanium capsule was 0.05 mm. The 125 I produces gamma rays (5% of 35 keV, 95% of 28 keV) with a half-life of 59.6 days, half-value thickness of 0.025 mm of lead, penetration of 17 mm, incipient rate of 7 cGy/h, and activities of 0.5–0.7 mCi. 2.3. CT-guided implantation protocol The total volume of each tumor was calculated according to the CT image with the treatment planning system (TPS) before implantation [10]. In brief, the information from CT or MRI images was reconstructed into a three-dimensional form, and the precise margin of the tumor was outlined to facilitate the calculation of tumor matched peripheral dose (MPD). The expected number of implanted seeds was calculated according to the modified level formula [11]. In practice, to reach the maximum radiation effect, the number of seeds implanted was 15% more than needed. Implantation was guided by CT according to our TPS. The 125 I seed with a nominal activity of 0.5–0.7 mCi/seed and a diameter of less than 1 mm was used as a radiation source and implanted into NSCLC under fluoroscopy CT guidance, at a spacing of 1 cm, avoiding puncturing main vessels and other nearby organs. Implant parameters are listed in Table 1. All the brachytherapy implants were performed in a standard CT room under local anesthesia. Sufficient breath training was given to ensure steady breath movement during the procedure. CT imaging was taken at intervals of 5 mm. The distance between the adjacent implantation needles was approximately 1 cm each. Repeated CT with the implantation
Table 1 Implant parameters. Characteristic
Median 3
Volume implanted (cm ) MPD (Gy) Dose rate (Gy/h) Total activity (mCi) No. seeds Activity/seed (mCi)
43.2 130 0.07 29.2 59 0.6
Range 27.5–88.2 100–160 0.05–0.09 16.8–45.5 28–91 0.5–0.7
needles in place permitted adjustment of depth and angle of needle direction. Two to seven seeds per needle were loaded, and seeds were released every 0.5–1 cm apart upon withdrawing the needles. Afterwards the implantation puncture site was bandaged and compressed to achieve hemostasis. Patients were kept in our radiooncology/interventional ward for 1–2 full days. 2.4. Evaluation of curative effect Patients were examined by CT 2 months after the operation. The efficacy was determined according to the tumor response standards suggested by the World Health Organization [12]. Briefly, complete response (CR) was defined as the complete disappearance of the lesion lasting for more than 4 weeks. Partial response (PR) referred to the situation where the size (i.e., the longest dimension multiplied by maximal upright dimension) of the lesion decreased by more than 50% and then remained unchanged for 4 weeks. Stable disease (SD) was defined as the situation where the size of the tumor decreased by less than 50% or increased by less than 25%. Response rate was defined as the sum of CR and PR. Local tumor control after interstitial brachytherapy was defined as the absence of tumor progression in CT (SD + PR + CR). 2.5. Post implant chemotherapy and radiation therapy Four out of 21 patients who gave consent to chemotherapy received combined treatment with gemcitabine (GEM) and cisplatin (DDP) 1 week after implantation. The chemotherapy treatment consisted of gemcitabine 1000 mg/m2 on days 1 and 8, and low-dose fractionated cisplatin 20 mg/m2 on days 1, 2, 3 of a 21day cycle. The chemotherapy was repeated every 3 weeks for up to six cycles if tolerated. The remaining patients strongly refused systemic chemotherapy. Post implantation EBRT was generally recommended for previously unirradiated patients; however, 21 patients did not receive EBRT because they were unable to receive the planned EBRT or refused further therapy. 2.6. Follow-up All 21 patients entered the follow-up phase immediately after the implantation. The intended follow-up period was 30 months with visits at 1 month, 3 months, and every 3 months postintervention for clinical examination, blood sampling, and CT examination of the chest. No patients were lost to follow-up. Follow-up chest CT scans to evaluate response were obtained on all patients at various time intervals from implantation. Visual analog scale (VAS) pain score was recorded as level 0–10, in which 0 indicated no pain, 1–3 indicated mild pain, 4–7 meant moderate pain, and 8–10 severe pain [13]. Scoring began after 125 I seeds were implanted. Major and minor complications were defined according to Society of Interventional Radiology reporting standards [14]. 2.7. Statistical analysis With SPSS 13.0 software, quantitative indicators before and after the operation were compared using paired t-test or nonparametric
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Table 2 Patient characteristics. Patient No./Age (y)/Sex
Histologye
Stage
Tumor size (cm)
Prior treatment
Location
Reasons of unresectability
1/65/M 2/71/M 3/57/F 4/79/M 5/68/M 6/72/F 7/79/F 8/81/M 9/73/M 10/78/F 11/67/M 12/64/M 13/68/M 14/62/F 15/73/F 16/75/M 17/76/F 18/85/M 19/75/M 20/73/M 21/83/F
SCC SCC AC SCC AC LCC SCC SCC AC SCC AC SCC SCC SCC AC SCC AC AC SCC AC AC
IIA IIA IIB IIB IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIB IIIB IV IV IV IV IV IV IV IV
2.8 4.1 5.8 5.5 4.0 3.8 3.5 4.6 4.8 5.3 4.0 4.6 4.0 5.8 6.5 5.1 4.2 4.1 5.6 5.2 4.8
None None None None Chemotherapy Radiotherapy None None None None None Chemotherapy None None Chemotherapy None Chemotherapy None Radiotherapy Chemotherapy None
Peripheral RLLa Peripheral RULb Peripheral LLLd Peripheral LLL Central RUL Peripheral LULc Peripheral RLL Peripheral RUL Central RUL Peripheral RLL Peripheral RLL Central RUL Peripheral LUL Peripheral RUL Central LLL Peripheral LUL Central LUL Peripheral LLL Peripheral RLL Central RUL Peripheral LLL
Poor pulmonary functional reserve Reject surgery Reject surgery Poor pulmonary functional reserve ARDS Heart failure Poor pulmonary functional reserve ARDS Poor pulmonary functional reserve Reject surgery Reject surgery Tumor growing Reject surgery Reject surgery Tumor growing Reject surgery Reject surgery Reject surgery ARDS Tumor growing Reject surgery
a b c d e
Right lower lobe. Right upper lobe. Left upper lobe. Left lower lobe. AC: adenocarcinoma, SCC: squamous cell carcinoma, LCC: large cell carcinoma, ARDS: acute respiratory distress syndrome.
methods. The median survival time of survival analysis was evaluated by the Wilcoxon test and Kaplan–Meier methods. A P value of less than 0.05 was defined as statistically significant.
3. Results 3.1. Patient characteristics Between December 2006 and May 2009, 21 consecutive patients with NSCLC (13 men and 8 women, mean age 72.6 years, range 57–85) were included in this prospective, nonrandomized study. The tumors ranged in diameter from 2.8 to 6.5 cm (mean, 4.6 cm). There were one, twelve, and eight tumors sized <3 cm, 3–5 cm, and >5 cm, respectively. Four patients (19.0%) had stage II lung cancer and 17 patients (80.9%) had unresectable stage III or IV lung cancer. Patient characteristics are listed in Table 2. Four central lung cancer patients had concomitant subcarinal and mediastinal node metastases. Six patients with non-small cell lung cancer had invasion of the chest wall and/or diaphragm. Patients were first diagnosed by using computed tomography (CT) or magnetic resonance imaging (MRI). Histological confirmation of the diagnosis was achieved in all 21 patients by CT-guided fine needle aspiration (FNA) and bronchoscopic biopsy 1 week before implantation. All of the twenty-one patients received CT-guided radioactive 125 I seed interstitial brachytherapy, one lesion for each. Seven patients had suffered from severe pain (Visual Analog Scale, VAS 8–10); five patients had suffered from moderate pain (VAS 4–7).
3.2. Pain relief Seven patients had severe chest wall pain before interstitial brachytherapy (Visual Analog Scale, VAS 8–10); five patients had moderate pain (VAS 4–7) before seed implant. The pain intensity decreased from severe pain to mild pain for six patients, from moderate pain to mild pain for four patients. The response rate of pain relief was 83.3% (10/12). The pain-free duration was 0–12 months (median: 6 months; 95% CI: 3–9 months).
3.3. Response to treatment Tumor response, which was demonstrated on repeated CT film 2 month post-treatment, revealed complete response (CR) in 6 cases, partial response (PR) in 9 cases (Figs. 1–3), stable disease (SD) in 3 cases, and progressive disease (PD) in 3 cases. Overall responding rate (CR + PR) for this group of patients was 71.4%. Local tumor control rate was 85.7%.
3.4. Overall survival Median diameter of the tumor was 4.6 cm. Follow-up period was 2–30 months. Six (28.6%) patients died as a result of primary tumor progression; thirteen (61.9%) patients died of multi-organ failure or other metastases. Two (9.5%) patients survived to follow-up. At the time of analysis, the median survival time for all patients was 10 months (95% CI: 6.6–13.4 months), with 1 year and 2 year survival rates were 42.4% and 6.5%, respectively (Fig. 1). Median survival time for stage II, stage III, and stage IV was 20 months, 9 months, and 8 months, respectively. When analyzed according to tumor stage, the cumulative survival rates for patients with stage II, stage III and stage IV at the end of 12 months and 24 months were 100%, 33.3%, 25.0% and 50.0%, 0%, 0%, respectively (Figs. 2 and 3).
3.5. Adverse reactions There were no major complications detected during our followup period. Minor complications are reported in Table 3. Minor complications (4 of 21, 19%) included mild pneumothorax (n = 1) requiring no tube drainage, hemosputum (n = 1) requiring no treatment, pleural effusion (n = 1), and localized skin erythema (n = 1). Pneumothorax with the lung compressed by less than 30% was improved after conservative treatment. None of these complications required further treatment, although hospital discharge was delayed. No 125 I seeds migrated to other tissues or organs.
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Fig. 1. 73-year-old NSCLC patient with metastases to mediastinal lymph nodes. (A) Preoperative contrast-enhanced CT scan shows a 5.2 cm × 4.3 cm tumor in the right upper lobe of central NSCLC (arrow). (B) Intraoperative unenhanced CT scan shows that 125 I seeds are implanted into the tumor via 18G implantation needles (arrow). (C) Two weeks after seeds implantation for lung cancer, contrast-enhanced CT scan shows a marked shrinkage in tumor size and brachytherapy seeds in place (arrow). Also, CT scan shows metastases in lymph nodes in the mediastinum (arrow). (D) An 18G implantation needle was inserted into the metastatic mediastinal lymph nodes through the intercostal space during operation. (E) 2 month follow-up. Contrast-enhanced CT scan shows metastatic lymph nodes significantly decreased and 125 I seeds gathered together (arrow).
Table 3 Major and minor complications post implantation. Event
No.
Major complications Minor complications Pneumothorax (no required tube drainage) Mild hemosputum Pleural effusion (no drainage) Localized skin erythema
0 1 1 1 1
4. Discussion
Fig. 2. Overall survival curve for twenty one patients with NSCLC after interstitial brachytherapy.
125
I seed
Fig. 3. Cumulative survival curve for patients with stage II, stage III and stage IV at the end of 12 months and 24 months.
Radioactive seeds implanted at thoracotomy have been used for the treatment of unresectable NSCLC of the lung since the 1940s. Interstitial radiation (brachytherapy) allows the administration of high dose radiation to a tumor, with minimal irradiation to adjacent normal structures [15,16]. Therefore, image-guided radioactive seeds interstitial brachytherapy which can be performed without surgery or general anesthesia has attracted increasing attention because of its ability to increase the radiation dose to malignant tumors without damaging neighboring organs [17,18]. Minimally invasive, percutaneous techniques require more accurate image guidance by fluoroscopy, CT, ultrasound, or MRI. Currently, only CT facilitates the appropriate image guidance for the treatment of lung tumors [19–21]. Sider et al. [22] reported a case of CT guidance implantation of 125 I seeds for an unresectable carcinoma of the lung and achieved a successful distribution of seeds without complications. We used 125 I seed as the most common isotope, and 125 I seed placement has become a routine treatment for malignant tumors at various sites. We describe here the results of 21 inoperable NSCLC patients following 125 I seeds interstitial brachytherapy, which offered local control of the tumor and relief of symptoms. The advantages of this technique over other interventional procedures result from its accurate dosage and fewer complication. When the low-energy 125 I seeds are implanted, the gamma rays are concentrated in the immediate surrounding tissues, sparing adjacent normal structures and medical personnel [23,24]. Additionally, the relatively long half-life (59.4 days for 125 I seeds) provides prolonged radiation exposure to the implanted tumor volume, with a shorter treatment time. The complication rates were also lower compared with other interventional ablation procedures; no major complications were seen in this study group. Minor complications
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such as pneumothorax, hemosputum, pleural effusion, and localized skin erythema were treated medically. Heelan et al. [25] reported seven patients with lung tumors who underwent percutaneous implantation of 125 I sources into the tumor under CT guidance. Follow-up radiologic evaluations were available for six patients, demonstrating complete or incomplete tumor shrinkage. Martínez-Monge et al. [26] reported seven patients with early stage T1N0M0 NSCLC who had medical contraindications for surgical resection and were treated with CTguided percutaneous implantation of 103 Pd or 125 I seeds. After a median follow-up of 13 months, no patient has developed local or regional failure. In our group we obtained even distribution of the radioactive seeds with overall response rate of 71.4%, local control rate of 85.7%, and pain relief rate of 83.3%. Median survival time for all patients was 10 months. Based on these data it appeared that 125 I seed interstitial brachytherapy offered substantial control of inoperable NSCLC and significant palliation of symptoms. After these promising results, we plan to further evaluate interventional interstitial brachytherapy as an additional tool in multimodal oncologic therapy. Our study had certain limitations. First, because of the time limitation and inclusion criteria, the sample size was small, although our results reached statistical significance. Further study with a larger sample size might yield more accurate results. Second, we did not manage to include quality of life, which is one of the important parameters of outcomes for palliative treatment such as inoperable NSCLC. Finally, radioactive 125 I seed interstitial brachytherapy is considered an alternative approach for the treatment of inoperable NSCLC, with its curative effect, minimal surgical trauma, and minimal complications. 5. Conclusion This study suggested that CT-guided interstitial brachytherapy using 125 I seeds implantation appeared to be safe, effective, uncomplicated, and could produce adequate pain relief for treating inoperable NSCLC. Further research directed at decreasing the adverse reactions and utilizing combination therapy is being carried out in an attempt at improving survival and quality of life. Conflict of interest statement The authors declare no any conflicts of interest in this research. Acknowledgements We thank Trerotola, SO, MD (Department of Radiology, Division of Interventional Radiology (S.O.T.), University of Pennsylvania Medical Center, 1 Silverstein, 3400 Spruce Street, Philadelphia, Pennsylvania 19104) for editorial assistance in checking and revising the manuscript. This work is supported by the National Natural Science Foundation of China (30870585, 81071244 and 81071281) and the fund of Science and Technology Commission of Shanghai Municipality (10ZR1419800, 1052nm01000, 10441902002 and 10JC1410900).
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Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
CT-guided interstitial brachytherapy of inoperable non-small cell lung cancer Zhong-Min Wang a,b,1 , Jian Lu b,1 , Tao Liu c , Ke-Min Chen d , Gang Huang e , Fen-Ju Liu a,∗ a
School of Radiation Medicine and Public Health, Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou 215123, Jiangsu, China Department of Radiology, Shanghai Ruijin Hospital Luwan Branch, 149 Chongqing South Road, Shanghai 200020, China c Department of General Surgery, Shanghai Ruijin Hospital Luwan Branch, 149 Chongqing South Road, Shanghai 200020, China d Department of Radiology, Shanghai Ruijin Hospital, 197 Ruijin Er Road, Shanghai 200025, China e Nuclear Medicine, School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai 200025, China b
a r t i c l e
i n f o
Article history: Received 10 December 2010 Received in revised form 17 February 2011 Accepted 4 March 2011 Keywords: Interstitial brachytherapy CT-guided intervention 125 I seed Inoperable non-small cell lung cancer (NSCLC)
a b s t r a c t Purpose: The aim of this study was to assess the technical feasibility, efficacy, and complications of CTguided interstitial brachytherapy for treating inoperable non-small cell lung cancer (NSCLC). Materials and methods: Twenty one patients were included in this prospective study. The median age was 72.6 years (57–85). Tumors were treated with brachytherapy that was positioned under CT-fluoroscopy. The treatment planning system (TPS) was used preoperatively to reconstruct three dimensional images of the tumor and to calculate the estimated seed number and distribution. The median matched peripheral dose (MPD) was 130 Gy (range, 100–160 Gy). All procedures were performed under local anesthesia. A follow-up CT was performed 6 weeks later and every 3 months post implantation. Results: Follow-up period was 2–30 months. The mean diameter of the 21 lung tumors was 4.6 cm (range, 2.8–6.5 cm). The response rate of pain relief was 83.3% (10/12). The pain-free duration was 0–12 months (median: 6 months; 95% CI: 3–9 months). Overall responding rate (CR + PR) for this group of patients was 71.4%. Local tumor control rate was 85.7%. Six (28.6%) patients died as a result of primary tumor progression; thirteen (61.9%) patients died of multi-organ failure or other metastases. Two (9.5%) patients survived to follow-up. At the time of analysis, the median survival time for all patients was 10 months (95% CI: 6.6–13.4 months), with 1 year and 2 year survival rates were 42.4% and 6.5%, respectively. Median survival time for stage II, stage III, and stage IV was 20 months, 9 months, and 8 months, respectively. No major complications were observed. Minor complications (19%) included mild pneumothorax (n = 1), hemosputum (n = 1), pleural effusion (n = 1), and localized skin erythema (n = 1). None of these complications required further treatment, although hospital discharge was delayed. No 125 I seeds migrated to other tissues or organs. Conclusion: Minimally invasive CT-guided interstitial brachytherapy is safe, useful, less complicated and considered as a palliative treatment option for inoperable non-small cell lung cancer. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is among the most commonly occurring malignancies in the world and one of the few that continue to show an increasing incidence [1,2]. Non-small cell lung carcinoma (NSCLC) treatments are determined by the type and stage of cancer and include surgery, external beam radiation therapy (EBRT), chemotherapy, and high-dose-rate endobronchial brachytherapy (HDR-EBBT).
∗ Corresponding author. Tel.: +86 512 65880060; fax: +86 512 65880060. E-mail addresses: [email protected] (Z.-M. Wang), [email protected] (J. Lu), [email protected] (T. Liu), [email protected] (K.-M. Chen), [email protected] (G. Huang), [email protected] (F.-J. Liu). 1 These authors contributed equally to this work and should be considered as co-first authors. 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.03.006
Surgery is usually the treatment of choice for localized cancers, but only approximately 20% of all patients with NSCLC are candidates for potentially curative resection [3]. Also, chemotherapy and external beam radiation have not greatly affected outcomes in patients with unresectable disease, and the gain often comes with substantial toxicity, especially for those who already have other comorbidities [4]. As part of a multimodality treatment of advanced lung cancer, HDR-EBBT may influence survival in patients with malignant central airway obstruction [5]. HDR-EBBT has been used alone and with EBRT or interventional pulmonology in various palliative protocols [6–8]. Minimally invasive therapies have attained increasing attention for the treatment of cancer patients. CT-guided percutaneous implantation of permanent seeds can be used in peripherally located tumors and has the obvious advantage of avoiding an open thoracotomy. We utilize 125 I seeds interstitial brachytherapy for routine use in malignant tumors at various sites.
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We investigated the feasibility of CT-guided interstitial brachytherapy for inoperable non-small cell lung cancer, and we herein report the results for 21 NSCLC patients following 125 I seeds interstitial brachytherapy. The indications, technique outcome, and complications are reported. 2. Patients and methods All patients provided written informed consent before the study and were informed of potential benefits and risks. The study protocol was approved by the Ethics Committee of the School of Medicine, Shanghai Jiao Tong University. 2.1. Criteria for enrollment All patients enrolled displayed contraindications to surgery or had rejected surgery due to personal reasons. The enrolled patients also needed to satisfy the following criteria: histological confirmation of NSCLC; lung masses suspected for lung cancer detected by CT; a single primary pulmonary tumor; neutrophil leukocyte 3 × 109 /L or higher, platelets 70 × 109 /L or higher, and hemoglobin 90 g/L or higher in peripheral blood; prothrombin index (PI) greater than 50% and partial thromboplastin time (PTT) less than 50 s; kidney function within normal range; Karnofsky physical scores (KPS) greater than or equal to 50; and absence of infection. 2.2. Instruments We used a Siemens CT scanner with chest imaging conditions of 130 kV, 300 mA s, and width of 5 mm. Dose distribution was calculated using a Fudan TPS2.00 brachytherapy planning system (Fudan University, Shanghai, China) based on the American Association of Physicists in Medicine TG43 brachytherapy formalism [9]. The 125 I sealed seed sources were supplied by XinKe Pharmaceutical Ltd, Shanghai. For the seed implantation we used 18-G implantation needles and turntable implantation gun (XinKe Pharmaceutical Ltd, Shanghai, China). The diameter of each seed was 0.8 mm, the length was 4.5 mm, and thickness of the wall of the titanium capsule was 0.05 mm. The 125 I produces gamma rays (5% of 35 keV, 95% of 28 keV) with a half-life of 59.6 days, half-value thickness of 0.025 mm of lead, penetration of 17 mm, incipient rate of 7 cGy/h, and activities of 0.5–0.7 mCi. 2.3. CT-guided implantation protocol The total volume of each tumor was calculated according to the CT image with the treatment planning system (TPS) before implantation [10]. In brief, the information from CT or MRI images was reconstructed into a three-dimensional form, and the precise margin of the tumor was outlined to facilitate the calculation of tumor matched peripheral dose (MPD). The expected number of implanted seeds was calculated according to the modified level formula [11]. In practice, to reach the maximum radiation effect, the number of seeds implanted was 15% more than needed. Implantation was guided by CT according to our TPS. The 125 I seed with a nominal activity of 0.5–0.7 mCi/seed and a diameter of less than 1 mm was used as a radiation source and implanted into NSCLC under fluoroscopy CT guidance, at a spacing of 1 cm, avoiding puncturing main vessels and other nearby organs. Implant parameters are listed in Table 1. All the brachytherapy implants were performed in a standard CT room under local anesthesia. Sufficient breath training was given to ensure steady breath movement during the procedure. CT imaging was taken at intervals of 5 mm. The distance between the adjacent implantation needles was approximately 1 cm each. Repeated CT with the implantation
Table 1 Implant parameters. Characteristic
Median 3
Volume implanted (cm ) MPD (Gy) Dose rate (Gy/h) Total activity (mCi) No. seeds Activity/seed (mCi)
43.2 130 0.07 29.2 59 0.6
Range 27.5–88.2 100–160 0.05–0.09 16.8–45.5 28–91 0.5–0.7
needles in place permitted adjustment of depth and angle of needle direction. Two to seven seeds per needle were loaded, and seeds were released every 0.5–1 cm apart upon withdrawing the needles. Afterwards the implantation puncture site was bandaged and compressed to achieve hemostasis. Patients were kept in our radiooncology/interventional ward for 1–2 full days. 2.4. Evaluation of curative effect Patients were examined by CT 2 months after the operation. The efficacy was determined according to the tumor response standards suggested by the World Health Organization [12]. Briefly, complete response (CR) was defined as the complete disappearance of the lesion lasting for more than 4 weeks. Partial response (PR) referred to the situation where the size (i.e., the longest dimension multiplied by maximal upright dimension) of the lesion decreased by more than 50% and then remained unchanged for 4 weeks. Stable disease (SD) was defined as the situation where the size of the tumor decreased by less than 50% or increased by less than 25%. Response rate was defined as the sum of CR and PR. Local tumor control after interstitial brachytherapy was defined as the absence of tumor progression in CT (SD + PR + CR). 2.5. Post implant chemotherapy and radiation therapy Four out of 21 patients who gave consent to chemotherapy received combined treatment with gemcitabine (GEM) and cisplatin (DDP) 1 week after implantation. The chemotherapy treatment consisted of gemcitabine 1000 mg/m2 on days 1 and 8, and low-dose fractionated cisplatin 20 mg/m2 on days 1, 2, 3 of a 21day cycle. The chemotherapy was repeated every 3 weeks for up to six cycles if tolerated. The remaining patients strongly refused systemic chemotherapy. Post implantation EBRT was generally recommended for previously unirradiated patients; however, 21 patients did not receive EBRT because they were unable to receive the planned EBRT or refused further therapy. 2.6. Follow-up All 21 patients entered the follow-up phase immediately after the implantation. The intended follow-up period was 30 months with visits at 1 month, 3 months, and every 3 months postintervention for clinical examination, blood sampling, and CT examination of the chest. No patients were lost to follow-up. Follow-up chest CT scans to evaluate response were obtained on all patients at various time intervals from implantation. Visual analog scale (VAS) pain score was recorded as level 0–10, in which 0 indicated no pain, 1–3 indicated mild pain, 4–7 meant moderate pain, and 8–10 severe pain [13]. Scoring began after 125 I seeds were implanted. Major and minor complications were defined according to Society of Interventional Radiology reporting standards [14]. 2.7. Statistical analysis With SPSS 13.0 software, quantitative indicators before and after the operation were compared using paired t-test or nonparametric
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Table 2 Patient characteristics. Patient No./Age (y)/Sex
Histologye
Stage
Tumor size (cm)
Prior treatment
Location
Reasons of unresectability
1/65/M 2/71/M 3/57/F 4/79/M 5/68/M 6/72/F 7/79/F 8/81/M 9/73/M 10/78/F 11/67/M 12/64/M 13/68/M 14/62/F 15/73/F 16/75/M 17/76/F 18/85/M 19/75/M 20/73/M 21/83/F
SCC SCC AC SCC AC LCC SCC SCC AC SCC AC SCC SCC SCC AC SCC AC AC SCC AC AC
IIA IIA IIB IIB IIIA IIIA IIIA IIIA IIIA IIIA IIIA IIIB IIIB IV IV IV IV IV IV IV IV
2.8 4.1 5.8 5.5 4.0 3.8 3.5 4.6 4.8 5.3 4.0 4.6 4.0 5.8 6.5 5.1 4.2 4.1 5.6 5.2 4.8
None None None None Chemotherapy Radiotherapy None None None None None Chemotherapy None None Chemotherapy None Chemotherapy None Radiotherapy Chemotherapy None
Peripheral RLLa Peripheral RULb Peripheral LLLd Peripheral LLL Central RUL Peripheral LULc Peripheral RLL Peripheral RUL Central RUL Peripheral RLL Peripheral RLL Central RUL Peripheral LUL Peripheral RUL Central LLL Peripheral LUL Central LUL Peripheral LLL Peripheral RLL Central RUL Peripheral LLL
Poor pulmonary functional reserve Reject surgery Reject surgery Poor pulmonary functional reserve ARDS Heart failure Poor pulmonary functional reserve ARDS Poor pulmonary functional reserve Reject surgery Reject surgery Tumor growing Reject surgery Reject surgery Tumor growing Reject surgery Reject surgery Reject surgery ARDS Tumor growing Reject surgery
a b c d e
Right lower lobe. Right upper lobe. Left upper lobe. Left lower lobe. AC: adenocarcinoma, SCC: squamous cell carcinoma, LCC: large cell carcinoma, ARDS: acute respiratory distress syndrome.
methods. The median survival time of survival analysis was evaluated by the Wilcoxon test and Kaplan–Meier methods. A P value of less than 0.05 was defined as statistically significant.
3. Results 3.1. Patient characteristics Between December 2006 and May 2009, 21 consecutive patients with NSCLC (13 men and 8 women, mean age 72.6 years, range 57–85) were included in this prospective, nonrandomized study. The tumors ranged in diameter from 2.8 to 6.5 cm (mean, 4.6 cm). There were one, twelve, and eight tumors sized <3 cm, 3–5 cm, and >5 cm, respectively. Four patients (19.0%) had stage II lung cancer and 17 patients (80.9%) had unresectable stage III or IV lung cancer. Patient characteristics are listed in Table 2. Four central lung cancer patients had concomitant subcarinal and mediastinal node metastases. Six patients with non-small cell lung cancer had invasion of the chest wall and/or diaphragm. Patients were first diagnosed by using computed tomography (CT) or magnetic resonance imaging (MRI). Histological confirmation of the diagnosis was achieved in all 21 patients by CT-guided fine needle aspiration (FNA) and bronchoscopic biopsy 1 week before implantation. All of the twenty-one patients received CT-guided radioactive 125 I seed interstitial brachytherapy, one lesion for each. Seven patients had suffered from severe pain (Visual Analog Scale, VAS 8–10); five patients had suffered from moderate pain (VAS 4–7).
3.2. Pain relief Seven patients had severe chest wall pain before interstitial brachytherapy (Visual Analog Scale, VAS 8–10); five patients had moderate pain (VAS 4–7) before seed implant. The pain intensity decreased from severe pain to mild pain for six patients, from moderate pain to mild pain for four patients. The response rate of pain relief was 83.3% (10/12). The pain-free duration was 0–12 months (median: 6 months; 95% CI: 3–9 months).
3.3. Response to treatment Tumor response, which was demonstrated on repeated CT film 2 month post-treatment, revealed complete response (CR) in 6 cases, partial response (PR) in 9 cases (Figs. 1–3), stable disease (SD) in 3 cases, and progressive disease (PD) in 3 cases. Overall responding rate (CR + PR) for this group of patients was 71.4%. Local tumor control rate was 85.7%.
3.4. Overall survival Median diameter of the tumor was 4.6 cm. Follow-up period was 2–30 months. Six (28.6%) patients died as a result of primary tumor progression; thirteen (61.9%) patients died of multi-organ failure or other metastases. Two (9.5%) patients survived to follow-up. At the time of analysis, the median survival time for all patients was 10 months (95% CI: 6.6–13.4 months), with 1 year and 2 year survival rates were 42.4% and 6.5%, respectively (Fig. 1). Median survival time for stage II, stage III, and stage IV was 20 months, 9 months, and 8 months, respectively. When analyzed according to tumor stage, the cumulative survival rates for patients with stage II, stage III and stage IV at the end of 12 months and 24 months were 100%, 33.3%, 25.0% and 50.0%, 0%, 0%, respectively (Figs. 2 and 3).
3.5. Adverse reactions There were no major complications detected during our followup period. Minor complications are reported in Table 3. Minor complications (4 of 21, 19%) included mild pneumothorax (n = 1) requiring no tube drainage, hemosputum (n = 1) requiring no treatment, pleural effusion (n = 1), and localized skin erythema (n = 1). Pneumothorax with the lung compressed by less than 30% was improved after conservative treatment. None of these complications required further treatment, although hospital discharge was delayed. No 125 I seeds migrated to other tissues or organs.
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Fig. 1. 73-year-old NSCLC patient with metastases to mediastinal lymph nodes. (A) Preoperative contrast-enhanced CT scan shows a 5.2 cm × 4.3 cm tumor in the right upper lobe of central NSCLC (arrow). (B) Intraoperative unenhanced CT scan shows that 125 I seeds are implanted into the tumor via 18G implantation needles (arrow). (C) Two weeks after seeds implantation for lung cancer, contrast-enhanced CT scan shows a marked shrinkage in tumor size and brachytherapy seeds in place (arrow). Also, CT scan shows metastases in lymph nodes in the mediastinum (arrow). (D) An 18G implantation needle was inserted into the metastatic mediastinal lymph nodes through the intercostal space during operation. (E) 2 month follow-up. Contrast-enhanced CT scan shows metastatic lymph nodes significantly decreased and 125 I seeds gathered together (arrow).
Table 3 Major and minor complications post implantation. Event
No.
Major complications Minor complications Pneumothorax (no required tube drainage) Mild hemosputum Pleural effusion (no drainage) Localized skin erythema
0 1 1 1 1
4. Discussion
Fig. 2. Overall survival curve for twenty one patients with NSCLC after interstitial brachytherapy.
125
I seed
Fig. 3. Cumulative survival curve for patients with stage II, stage III and stage IV at the end of 12 months and 24 months.
Radioactive seeds implanted at thoracotomy have been used for the treatment of unresectable NSCLC of the lung since the 1940s. Interstitial radiation (brachytherapy) allows the administration of high dose radiation to a tumor, with minimal irradiation to adjacent normal structures [15,16]. Therefore, image-guided radioactive seeds interstitial brachytherapy which can be performed without surgery or general anesthesia has attracted increasing attention because of its ability to increase the radiation dose to malignant tumors without damaging neighboring organs [17,18]. Minimally invasive, percutaneous techniques require more accurate image guidance by fluoroscopy, CT, ultrasound, or MRI. Currently, only CT facilitates the appropriate image guidance for the treatment of lung tumors [19–21]. Sider et al. [22] reported a case of CT guidance implantation of 125 I seeds for an unresectable carcinoma of the lung and achieved a successful distribution of seeds without complications. We used 125 I seed as the most common isotope, and 125 I seed placement has become a routine treatment for malignant tumors at various sites. We describe here the results of 21 inoperable NSCLC patients following 125 I seeds interstitial brachytherapy, which offered local control of the tumor and relief of symptoms. The advantages of this technique over other interventional procedures result from its accurate dosage and fewer complication. When the low-energy 125 I seeds are implanted, the gamma rays are concentrated in the immediate surrounding tissues, sparing adjacent normal structures and medical personnel [23,24]. Additionally, the relatively long half-life (59.4 days for 125 I seeds) provides prolonged radiation exposure to the implanted tumor volume, with a shorter treatment time. The complication rates were also lower compared with other interventional ablation procedures; no major complications were seen in this study group. Minor complications
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such as pneumothorax, hemosputum, pleural effusion, and localized skin erythema were treated medically. Heelan et al. [25] reported seven patients with lung tumors who underwent percutaneous implantation of 125 I sources into the tumor under CT guidance. Follow-up radiologic evaluations were available for six patients, demonstrating complete or incomplete tumor shrinkage. Martínez-Monge et al. [26] reported seven patients with early stage T1N0M0 NSCLC who had medical contraindications for surgical resection and were treated with CTguided percutaneous implantation of 103 Pd or 125 I seeds. After a median follow-up of 13 months, no patient has developed local or regional failure. In our group we obtained even distribution of the radioactive seeds with overall response rate of 71.4%, local control rate of 85.7%, and pain relief rate of 83.3%. Median survival time for all patients was 10 months. Based on these data it appeared that 125 I seed interstitial brachytherapy offered substantial control of inoperable NSCLC and significant palliation of symptoms. After these promising results, we plan to further evaluate interventional interstitial brachytherapy as an additional tool in multimodal oncologic therapy. Our study had certain limitations. First, because of the time limitation and inclusion criteria, the sample size was small, although our results reached statistical significance. Further study with a larger sample size might yield more accurate results. Second, we did not manage to include quality of life, which is one of the important parameters of outcomes for palliative treatment such as inoperable NSCLC. Finally, radioactive 125 I seed interstitial brachytherapy is considered an alternative approach for the treatment of inoperable NSCLC, with its curative effect, minimal surgical trauma, and minimal complications. 5. Conclusion This study suggested that CT-guided interstitial brachytherapy using 125 I seeds implantation appeared to be safe, effective, uncomplicated, and could produce adequate pain relief for treating inoperable NSCLC. Further research directed at decreasing the adverse reactions and utilizing combination therapy is being carried out in an attempt at improving survival and quality of life. Conflict of interest statement The authors declare no any conflicts of interest in this research. Acknowledgements We thank Trerotola, SO, MD (Department of Radiology, Division of Interventional Radiology (S.O.T.), University of Pennsylvania Medical Center, 1 Silverstein, 3400 Spruce Street, Philadelphia, Pennsylvania 19104) for editorial assistance in checking and revising the manuscript. This work is supported by the National Natural Science Foundation of China (30870585, 81071244 and 81071281) and the fund of Science and Technology Commission of Shanghai Municipality (10ZR1419800, 1052nm01000, 10441902002 and 10JC1410900).
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