Abstract
Aim: This is a retrospective analysis of a selected series of high-risk non-small cell lung cancer (NSCLC) patients with post-surgical loco-regional relapse treated with salvage stereotactic body radiotherapy (SBRT). Outcome and toxicity profiles were assessed. Patients and Methods: Twenty-eight patients (unfit for surgery or systemic therapy) with 30 lesions underwent salvage SBRT as an alternative therapy because of advanced age, co-morbid conditions or no response obtained from other treatments. Results: Complete and partial responses were 16% and 70%, respectively. Local progression was observed in 3 patients. Regional relapse occurred in 5 patients. Distant progression occurred in 10 patients. The 2-year overall survival (OS) and disease-free survival (DFS) were 57.5% and 36.6%, respectively. Radiation acute pneumonitis occurred as follows: three patients developed grade 1, two patients experienced grade 2 and one patient experienced grade 3 toxicity. Conclusion: Stereotactic body radiotherapy could have an alternative role in isolated loco-regional relapse in patients unfit or resistant to other therapies.
Surgery is the standard treatment for non-small cell lung cancer (NSCLC) patients with early stage and some patients with stage III disease at diagnosis. Although, a complete resection is often performed, reported loco-regional recurrence rates range from 10% to 50% depending on the pathological stage (1-2). More than 80% of relapses occur within 24 months from curative surgery (3). Isolated local recurrence occurs in 10-40% of radically resected patients, principally in the bronchial stump or hilar-mediastinal area (4).
There is no standard definition of postoperative local recurrence. Different sites of relapse are included, such as the bronchial stump, the ipsilateral mediastinum, the ipsilateral hilum, the ipsilateral lung, the whole mediastinum, the staple line or anywhere inside the thorax (5-7). Local recurrence in resected patients is, also, defined as any site of relapse within the bronchial stump, staple line, ipsilateral hilum, ipsilateral mediastinum as described by Trodella et al. (7); this definition is restricted only to the areas encompassed inside the adjuvant irradiated volume and is limited to patients where radiation is indicated as complementing treatment.
In clinical practice, patients with postoperative recurrent NSCLC often presented with related-symptoms, advanced age and associated co-morbid conditions. Furthermore, recurrent disease could be resistant to chemotherapy for patients receiving systemic treatment in the preoperative or postoperative setting (8). For this reason, a considerable percentage of patients are unfit for repeated surgical treatment or systemic anti-cancer agents.
In the literature, there exist several studies regarding salvage radiotherapy as a treatment option for inoperable recurrent NSCLC (9-12). Different radiation schedules, timing, irradiated volumes and associated chemotherapy are reported in inhomogeneous populations of patients.
Stereotactic body radiation therapy (SBRT) is widely used for inoperable early stage NSCLC and isolated metastases. Nevertheless, ablative doses can increase local control and may improve survival in completely resected recurrent NSCLC patients. High biologically effective doses can be delivered to the tumor minimizing the surrounding normal tissue dose and treatment-related toxicities, particularly when image-guidance is associated to SBRT to verify the correct position (13). However, SBRT could have an alternative role in isolated loco-regional relapse in patients unfit or resistant to other therapies.
This is a retrospective analysis of a selected series of high-risk NSCLC patients with postoperative loco-regional relapse treated with salvage SBRT in our Institute of Radiation Oncology. Response, local control, toxicity rates and survivals were evaluated. To our knowledge, this is the first report of salvage SBRT performed for postoperative recurrent NSCLC, including the mediastinal lymph nodes.
Patients and Methods
Patients' characteristics. The postoperative loco-regional recurrence was defined as any site of relapse within the ipsilateral lung, bronchial stump, staple line and in the N1-N3 nodal groups as described by Varlotto et al. (14).
Salvage SBRT was performed as an alternative therapy for patients unfit for surgery or systemic therapy or failure from other treatments. Patients were carefully reviewed and data were retrospectively analyzed. A performance status (Eastern Cooperative Oncology Group Criteria) ≤2 was required for all patients. High-risk patients presenting the following criteria were enrolled for salvage SBRT: i) maximum tumor diameter <50 mm; ii) advanced age (≥75 years) and/or co-morbid conditions; iii) no response obtained from other treatments (failure after chemotherapy, surgery) in patients with young age without co-morbidity; iv) no distant metastases; v) no previous adjuvant radiation treatment inside the thorax. The minimum follow-up time requested for the analysis was 6 months.
Pre-treatment evaluation included clinical examination, complete blood count, total body computed tomography (CT) scan, lung function tests and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET/CT) for all patients. Local relapse diagnosis was confirmed by histological examination in 4 patients. The current study was carried out according to the Declaration of Helsinki (1964) and the Internal Review Board approved the study. Written inform consent was obtained by all patients.
Treatment. All patients underwent a 4-dimensional CT pre-treatment planning (slice thickness of 2.5 mm) in the supine position. The maximum intensity projection image constitutes a visualization of the maximum extent of the target movement. An internal tumor volume (ITV) method was used to define the target volume, including the tumor position in all phases of the normal respiratory cycle. Planning CT images were matched with diagnostic PET-CT using point-to-point matching for the ITV delineation. The PTV was determined by adding 4mm in all directions to the ITV.
Total prescribed dose to the PTV encompassed the 90-95% isodose with normalization to the maximal dose. Position before treatment was checked using cone-beam (Kilo-Voltage) CT scan. Stereotactic body radiation therapy was delivered with a Varian Linear Accelerator, using 7 to 9 static non-opposing coplanar fields, with 6-MV photons (Varian Medical Systems, Inc., Palo Alto, CA).
The choice of radiation schedule was based on the target volume and the type/site of recurrence. The prescribed dose was 23 Gy in single fraction (minimal biologically effective dose 10 (BED10) 76 Gy) for mediastinal nodal recurrences. The total dose was 30Gy in single fraction (minimal BED10 120 Gy) for peripheral or small tumors (<30cc). The total dose was 45 Gy in 3 fractions (minimal BED10 112.5 Gy) for centrally located or large tumors (≥30 cc). The biological-effective dose for the present fractionated schedules was estimated using the formula: BED=nd (1 + d/(α/β)), where n is the number of fractions; d is the dose per fraction; and the α/β ratio for lung cancer is 10.
Follow-up and statistics. Follow-up was performed every three months for the first two years after radiotherapy and every six months afterwards. Physical examination, performance status, treatment-related adverse effects, blood count, liver and renal function tests, lung function tests, total body CT, FDG-PET/CT examinations were assessed at follow-up. A total body CT with contrast medium was performed at 1 month after RT completion and every 6 months afterwards. A post-treatment FDG/PET-CT was performed at 4 months after RT and for suspected progressive disease. Treatment-related toxicity was graded according to CTCAE v 4.0.
The Response Evaluation Criteria in Solid Tumors (RECIST) measurement was used to determine response rates distinguished in CR (complete response), PR (partial response), SD (stable disease) and PD (progression of disease). Statistical analysis was performed using the SPSS statistical software package version 19.0 (SPSS, Inc., Chicago, Illinois, USA). The overall survival (OS) was defined as the time to death from any cause or last follow-up. The disease-free survival (DFS) was defined as the time to local/regional/systemic progression. Local recurrence after salvage radiotherapy was defined as in-field or marginal re-growth of the disease. Regional recurrence was defined as new appearance of positive mediastinal or hilar lymph nodes. Metastasis-free survival (MFS) was defined as any site of distant metastasis including lung lesions in the same lobe or in the ipsilateral different lobe. Survivals were calculated from the date of initial radiotherapy and were estimated using the Kaplan–Meier method. Differences in OS, DFS, MFS and regional control were calculated between patients with mediastinal nodal relapse and patients with ipsilateral lung/chest wall/bronchial stump relapse.
Results
Response and disease progression. The median time-to-recurrence from primary surgical treatment was 24 months (range=6-72 months). Five patients received previous therapy before SBRT. Three patients underwent surgery as salvage therapy for the first local recurrence. Two patients received chemotherapy but no response was obtained. The median time from initial treatment for these patients was 34 months (range=8-54 months). Twenty-three patients were unfit for surgery or systemic therapy due to advanced age and/or co-morbid conditions.
Between 2010 and 2013, 28 patients with 30 lesions were treated with salvage SBRT for postoperative loco-regional recurrence from NSCLC. There were 23 male and 5 female. The mean and the median age were 74 and 75 years, respectively. The median PTV was 19 cc (range=3.6-74.6 cc). The patients' characteristics are summarized in Table I.
Out of the 30 treated lesions, CR occurred in 5 cases (16%) and PR occurred in 21 cases (70%) with a tumor response rate of 86%. After 6 months from radiotherapy, 4 patients (14%) presented local SD.
Patients' characteristics (n=28).
In-field local progression was observed in 3 (10%) patients: two of them presented previous PR and one patient presented initial SD, respectively. Regional relapse occurred in 5 patients (18%). Distant progression occurred in 10 (35%) patients: in the lung three patients, diffuse three patients, in the bone two patients and the brain two patients.
Survivals and local control. Overall, the median follow-up time was 18 months (range=6-48 months). At the time of the analysis, 19 patients were alive. One patient was alive with PD, while 18 patients had no evidence of disease or SD. The median follow-up of the survivors was 18 months (range=6-48 months). Death occurred in 9 patients: 6 patients died from systemic progression of disease and 3 patients died from other causes.
Local control was 96.6% (95% confidence interval (CI)=90.1-100%) at 1 year and 84.7% (95% CI=69.1-100%) at 2 years, respectively (median time to local progression not reached) (Figure 1a). Regional control was 92.9% (95% CI=83.8-100%) at 1 year and 69.8% (95% CI=46.9-100%) % at 2 years (median time to regional progression not reached), respectively (Figure 1b). Most of regional recurrences occurred at the first year after radiation therapy. The 1- and 2-year OS were 92.4% (95% CI=82.9-100%) and 57.5% (95% CI=37.5-88.2%), respectively (median time to death, 31 months) (Figure 2a). The 1- and 2-year DFS were 74.3% (95% CI=59.6-92.8%) and 36.6% (95% CI=17.7-75.8%), respectively, with a median time to progression of 20 months (Figure 2b). The 1- and 2-year MFS were 77.9% (95% CI=63.7-95.3%) and 60% (95% CI=43.3-83.2%), respectively (median time to distant progression not reached).
No significant differences in OS, DFS, MFS or loco-regional control was found between patients with mediastinal nodal relapse and patients with ipsilateral lung/chest wall/bronchial stump relapse. Even though, in the group of patients affected by nodal relapse, the 2-year OS (41.5% vs. 65.3%), the 2-year DFS (26.7% vs. 42.1%) and the 2-year MFS (53.3% vs. 62%) were lower compared to the group of patients with ipsilateral lung/chest wall/bronchial stump recurrence. The 2-year regional control (88% vs. 35.6%) was higher for the group of patients affected by ipsilateral lung/chest wall/bronchial stump relapse.
Toxicities. Overall, the treatment was well-tolerated. Radiation pneumonitis was the most common acute toxicity after treatment. Pneumonitis occurred as follows: three patients (10%) developed grade 1, two patients (7%) experienced grade 2 and only one patient (3.5%) experienced grade 3 toxicity. One patient (3.5%) developed grade 2 treatment-related cough. Grade 3 esophagitis was observed in only one patient (3.5%). No patient experienced grade 1-2 esophagitis at 3 months from SBRT. Six patients (21%) experienced grade 1 lung fibrosis after 6 months. Only 2 patients (7%) developed grade 2 fibrosis. No patient experienced esophagitis or other RT-related late effects as plexopathy or rib fractures.
Discussion
The five-year OS rates of NSCLC patients who underwent radical resection have improved in the past years. Recurrences occur mostly in the first two years after complete resection and continue to develop from 3% to 6% per year afterwards (3, 15). The loco-regional relapse is the first site of failure in 5-20% of the patients after radical surgery (16). The most common site of loco-regional relapse is the mediastinal lymph nodes and the ipsilateral lung (15). In the current study, the median time from surgery to loco-regional recurrence was 24 months and the most frequent sites of relapse were the ipsilateral lung (60%) and regional lymph nodes (30%).
a) Local control (LC) and b) loco-regional control (LRC).
a) Overall survival (OS) and b) disease-free survival (DFS).
Up to date, the salvage treatment for local recurrence includes several options, such as surgery, radiotherapy, chemotherapy or their combination (17). Hence, there is no clear definition regarding the most appropriate therapy choice. The NCCN guidelines indicate the concurrent chemoradiation for mediastinal relapse as an evidence level 2A or chemotherapy-alone as an evidence level 2B, while there is no specific indication about the isolated recurrence (18). A retrospective review of patients with primary NSCLC reported different treatment preferences for patients with the recurrent disease; therapy included surgery in 43 patients, chemotherapy in 59 patents, radiation in 73 patients and a combined therapy in 96 patients (19). The salvage surgical treatment could be adequate for patients in good clinical conditions that presented with recurrent NSCLC limited to the lung parenchyma, bronchial stump or thoracic wall; it is not a suitable alternative for mediastinal lymph nodes relapse and patients with co-morbid conditions or advanced age (20). From 0.9% to 4.4% of patients undergoing surgery with curative intent are candidates for repeated resection for isolated local recurrence (21-22). Median DFS and OS range from 2.6 to 24 months and from 27 to 40 months after repeated resection, respectively; the reported 5-year actuarial survival rates range from 8.3% to 40.0% (19, 23-24).
Sometimes loco-regional relapse is considered to have a poor prognosis comparable to a newly diagnosed locally advanced inoperable NSCLC. In the clinical practice, chemotherapy for recurrence is routinely administered based on the recommended regimen for unresectable advanced NSCLC. Consequently, chemotherapy with or without concomitant radiotherapy is recommended in fit patients with loco-regional relapse. In recent years, an improvement in outcome has been noticed compared with previous reports that likely reflects the effects of new anti-cancer agents, including epidermal growth factor receptor-tyrosine kinase inhibitors. Furukawa et al. reported a series of 141 patients with local and distant recurrent NSCLC treated with gefitinib obtaining a 2-year OS of 28.9% and median survival of 12 months (25). Bar et al. treated 30 patients affected by loco-regional relapse with platinum-based combined therapy (radiation therapy median dose 63Gy) and obtained a median survival of 27 months with a response rate of 70% suggesting a possible benefit from aggressive-curative intent treatment (26).
Several studies reported the use of radiation therapy as salvage treatment, even though there is still no large controlled trial in the literature. The exact patterns and benefits of radiation therapy in the salvage setting remain unknown. Most of the studies are retrospective and report standard fractionated regimens, sometimes associated to chemotherapy.
The elective regional nodal irradiation is unclear; however, low incidence (approximately 6.4%) of local failure in the non-irradiated lymph nodes is described (27). Tada et al. treated 31 patients affected by loco-regional recurrence with standard radiation therapy (60 Gy/30 fractions) omitting elective nodal irradiation. The observed response rate was 87%; the median survival time was 14 months and the 2-year OS was 30%. Loco-regional relapse occurred in 15 patients (7 in-field relapse, 7 marginal relapses, 1 out-field relapse) with or without distant metastasis, whereas distant progression alone was observed in 7 patients (28).
A high dose to the involved site of recurrence would be efficient, principally when the use of more accurate restaging with PET/CT and image-guided radiation technique is employed. Bae et al. reported a median survival of 18.5 months with a 2-year OS of around 48% in patients with local/regional recurrent NSCLC who underwent radiotherapy alone 44-66Gy (78%) or combined therapy (22%). Only the recurrent disease was included in the target volume; the in-field failure and the intra-thoracic failure at 2 years occurred in 52.3% and 33.9%, respectively. Thus, the low dose group (BED10 ≤70.2Gy) had 2-year survival rates of 36.2% compared to the high dose group (BED10 >70.2Gy) that presented survival rates of 59.2% (p=0.018) (29). These studies suggest that patients affected by postoperative local relapse from NSCLC could benefit from a site involved treatment and that high doses are required to obtain optimal control of the disease. Modern techniques and advances in radiotherapy, such as SBRT and IGRT, can facilitate the delivery of ablative doses to the tumor sparing the healthy surrounding tissues. Thus, high-risk patients who are unfit for surgery or chemotherapy may have advantages from a curative treatment achieving a good tolerance.
Chang et al. reported a small series of stage I and isolated postoperative recurrent NSCLC centrally located who underwent SBRT with dose escalation for a total dose of 40-50Gy/4 fractions to the tumor obtaining an overall local control at the treated site of 100%. Of the patients with recurrent disease, 21.4% developed mediastinal lymph node metastasis and 35.7% developed distant metastasis. Four patients with recurrent NSCLC experienced grade 2 pneumonitis (30).
In the present study, we observed 16% of CR and 70% of PR with a tumor response rate of 86% of the 30 treated lesions. In-field local progression was observed in three (10%) patients: two of them presented previous PR and one patient presented SD, respectively. Regional relapse occurred in 5 patients (18%). Distant progression occurred in 10 (35%) patients.
A recent study by Takeda et al. (31) is the only report of salvage stereotactic ablative radiotherapy with total prescribed dose of 40-60Gy/5-10 fractions in 23 postoperative local relapse NSCLC patients. Local control and overall survival rates at 1 and 2 years were 94.7% and 86.8%, and 84% and 76.4%, respectively. Local and regional recurrence occurred in 2 and 3 patients, respectively; distant metastasis occurred in 4 patients. At one month after treatment, grade 2, 3 and 5 pneumonitis was observed in 3, 1 and 1 patients, respectively.
In our study, the 1- and 2-year OS were 92.4% and 57.5%, respectively (median time to death, 31 months). Local control was 96.6% at 1 year and 84.7% at 2 years, respectively. Regional control was 92.9% at 1 year and 69.8% at 2 years. The most part of regional recurrences occurred at the first year after radiation therapy. The 1- and 2-year DFS were 74.3% and 36.6%, respectively with a median time to progression of 20 months. Radiation pneumonitis was the most common acute toxicity occurring as follows: 3 patients (10%) developed grade 1, 2 patients (7%) experienced grade 2 and only one patient (3.5%) experienced grade 3 toxicity. Six patients (21%) experienced grade 1 lung fibrosis after 6 months. No patient experienced esophagitis or other RT-related late effects like plexopathy or rib fractures.
In conclusion, there is no clear evidence of the exact treatment option for post-surgical loco-regional relapse from NSCLC. Radiotherapy with ablative doses may have a role to improve local control as an alternative treatment, predominantly in patients who cannot be submitted to a repeated surgical procedure or present with mediastinal lymph node relapse. High-dose radiotherapy may be efficient to control the disease but modern technique should be used to deliver therapy safely. Stereotactic body radiotherapy is a valid alternative for patients unfit to other treatment(s) delivering higher doses to the tumor and sparing surrounding normal tissue. Larger series and controlled trials are necessary to develop appropriate indications and regimens for loco-regional recurrent NSCLC.
- Received November 14, 2014.
- Revision received November 27, 2014.
- Accepted December 4, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.