N.E. Verstegen A.P.W.M. Maat F.J. Lagerwaard M.A. Paul M.I. Versteegh J.J. Joosten W. Lastdrager E.F. Smit B.J. Slotman J.J.M.E. Nuyttens S.Senan Submitted
10 Salvage surgery for local failures after stereotactic ablative radiotherapy for lung malignancies
Chapter 10 Abstract Introduction The literature on surgical salvage for potentially resectable recurrences following stereotactic radiotherapy (SABR) is limited. We describe our experience with salvage surgery in 17 patients who developed a local recurrence. Methods Patients who underwent surgical salvage for a local recurrence following SABR for pulmonary malignancies were identified from two Dutch institutional databases. Complications were scored using the Dindo-Clavien-classification. Results Seventeen patients who underwent surgery for a local recurrence were identified. Patients were treated with SABR for either primary non-small cell lung cancers (N=9) or solitary metastasis (N=8). Four patients with solitary metastasis had two surgeries for separate recurrences. Median time to local recurrence was 15.6 months. Recurrences were diagnosed with CT- and/or 18FDG-PET-imaging, with 5 patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during 5 resections, requiring conversion from a thoracoscopic procedure to thoracotomy in 3 procedures. Four patients experienced complications post-surgery; grade 2 (N=2) and grade 3a (N=2), respectively. All had viable tumor cells in the resection specimens. Median length of hospital stay was 7 days (range 4-15 days) and 30-day mortality was 0%. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. Median follow-up after surgery was 41 months and median overall survival was 38 months. Conclusions Experience with 21 surgical procedures for local recurrences post-sabr revealed only two grade IIIa complications, and a 30-day mortality of 0%. Median overall survival after surgery was 38 months. Our results suggests that salvage surgery can be safely performed after SABR.
Surgical salvage for local failures following SABR 151 Introduction While surgery remains the treatment of choice for operable patients with early stage, resectable, non-small cell lung cancer (NSCLC), stereotactic ablative radiotherapy (SABR) is the recommended therapy for unfit patients, and for those who decline surgery 1,2. Although randomized controlled trials comparing surgery and SABR have failed to complete accrual 3, several studies using propensity score matching, matched pair analysis, Markov modeling and meta-analytic methodologies for patients with early stage NSCLC reveal comparable outcomes for both treatment modalities 4,5. Increasingly, fitter and potentially operable patients are being referred for SABR 6,7. Consequently, careful follow-up and early recognition of local recurrences has become increasingly important for such patients. There is limited literature on salvage surgery following SABR for pulmonary malignancies 8-10, reporting on a total of 16 such patients. We report on the feasibility and outcomes in the largest series to date of patients who underwent surgical salvage for local failure after SABR. Materials and methods We retrospectively identified patients who were suspected of having a local recurrence following SABR, and who underwent surgical salvage from institutional databases in both the VU University Medical Center and the Erasmus Medical Center. In addition, surgeons from other centers were contacted individually. The conduct of this study was approved by the institutional medical ethics committee. SABR was delivered in an outpatient setting. In the VUmc, patients were treated as previously described, with individualized target volumes encompassing all motion on four-dimensional CT scans, with no active motion management 11. In the Erasmus MC, patients were treated with Cyberknife with real-time tumor tracking 12. All fractionation schemes had a biologically effective dose of >100 Gy 10 described to the planning target volume (PTV). In each case we retrospectively calculated the maximum dose delivered to the ipsilateral proximal bronchial tree. Post-treatment follow-up generally consisted of a contrast-enhanced CT-scan of the thorax and abdomen carried out at 2-3 months after treatment, 6-monthly for 2 years, and annually thereafter. In the event patients were not followed up at our centers, attending lung physicians and surgeons were contacted for all details related to the diagnosis of
Chapter 10 local recurrence, and any subsequent surgery. Local failure was defined as a suspected recurrence in, or adjacent to, the PTV. The diagnosis of local recurrence was based on CT and/or 18 FDG PET scans. All patients were referred for surgical salvage of the local recurrence. Complications following surgery were classified using the Dindo-Clavien classification 13. Follow-up was calculated using the reverse Kaplan-Meier method 14. Time-to-event outcomes were analyzed using the Kaplan Meier method. Results Twenty patients with a suspected local recurrence for which they underwent surgery were identified. Three patients were excluded from further analysis. One patient was excluded as details of the surgical procedure and the post-operative course were unavailable; However this patient died of unrelated causes, 39 months after undergoing surgery. Another patient excluded had a pre-operative diagnosis of mediastinal lymph node metastasis, and a third had previous large-field conventional thoracic radiotherapy in addition to SABR. Details of the remaining seventeen patients, comprising 21 resections, are summarized in table 1. Four patients who were treated for oligo-lung metastases of a colorectal carcinoma, each underwent two resections for local recurrences of separate lesions. Nine patients underwent resection for a local recurrence of early stage NSCLC, and eight patients for a local recurrence of a treated pulmonary metastasis. Fifteen of seventeen patients presenting with a local recurrence of an early stage NSCLC had an isolated local recurrence. In addition, one patient had a solitary adrenal gland metastasis, and the other had a histologically confirmed recurrence in a single 18 FDG-PET positive hilar node. All patients had peripheral tumors with a mean diameter of 19.6 mm (SD±10.3), and the median PTV was 16.5 mm3 (range 4.1 243mm3). The maximum dose in the ipsilateral proximal bronchial tree structures was below 30Gy in all patients and below 20Gy in all but one patient.
Table 1: Patient Characteristics Surgical salvage for local failures following SABR 153 Patients treated for primary NSCLC (N=9) N(%) / median (range) Patients treated for solitary metastasis (N = 8 / N = 12) N(%) / median (range) Age (years) 65 (54-71) 62 (44-74) Gender - M - F Tumor location - LUL - LLL - RUL - RML - RLL Fractionation scheme - 1x30Gy - 3x20Gy - 3x17Gy - 5x11Gy - 5x12Gy - 8x7,5Gy Diagnosis of LR - CT + PET + PA - CT + PET - CT only 6 (67%) 3 (33%) 4 (44% 3 (33%) - - - 4 (44%) 5 (56%) 4 (44%) - 7 (88%) 1 (13%) 3 (25%) 3 (25%) 3(25%) 1(8%) 2 (17%) 3 (25%) 4 (33%) 3 (25%) 1 (8%) - 1 (8%) - 7 (88%) 1 (13% Time to local recurrence 22 (9 34) 13 (6-48) Tumor stage - T1aN0M0 - T1bN0M0 - T2aN0M0 - T2bN0M0 Pathology before SABR - Adenocarcinoma - Squamous cell - NSCLC - No 4 (44%) 3 (33%) LUL: Left upper lobe. RML: Right middle lobe. LLL: left lower lobe. RUL: Right upper lobe. LR: local recurrence. CT: Computed tomography imaging. PET: Positron emission tomography imaging. PA: Pathology. All 17 patients who were initially considered to be medically operable and surgically resectable at the time of diagnosis, but were referred for SABR following discussions in a multidisciplinary tumor board and with patients themselves. Similarly, all patients who underwent salvage surgery were discussed in multidisciplinary tumor boards. The
Chapter 10 median Charlson co-morbidity index was 1 (range 0-7) 15. Lung function tests before SABR and surgery were available in 10 patients, including all patients who were treated for a local recurrence of a primary NSCLC. The mean predicted FEV1% of before SABR was 76% ± 26%, whereas it was 72% ±20% at the time of the diagnosis of a local recurrence (p=0.123). Median time to the diagnosis of local recurrence following SABR was 15.6 months (range 6-48 months). All patients had a growing lesion on consecutive CT-scans. In all but one patient, the clinical diagnosis of a local recurrence was based on positive 18 FDG-PETscans. However, the diagnosis of local recurrence was pathologically confirmed before surgery in only four patients. In another patient, a cytology specimen obtained by endobronchial brushings was suggestive for malignancy. Details of the surgical procedures are summarized in Table 2. A lobectomy was performed during 15 resections, three of which were performed by video-assisted thoracoscopic surgery (VATS). In one patient, a planned VATS-lobectomy was converted to an open pneumonectomy due to extensive peritumoral and pleural adhesions. One patient underwent a sleeve-lobectomy as a pre-operative endobronchial ultrasound showed hilar lymph node metastasis. Three patients underwent a wedge-resection, one of which was performed with VATS, because of the small tumor size and in another patient a segmental resection was performed. Due to the prior SABR, special attention was paid to intra-operative findings. During nine out of the 21 resections, no noteworthy findings were observed, while in seven other resections, limited intra-thoracic adhesions were observed. Extensive adhesions were observed during five procedures, which necessitated conversion from a VATS to an open procedure in three patients, which led to an open pneumonectomy in one patient with extensive peritumoral and pleural adhesions. As intra-operative extensive tumor growth into the visceral pleura and pericardial fat was found, it is unclear whether these adhesions were caused only by tumor progression, or were due to the SABR treatment delivered using the largest PTV in this series. The remaining patient had a conversion from a VATS to an open-procedure due to tumor location. In only two patients the bronchial stump was covered with an intercostal muscle flap. A complete resection with free resection margins was obtained in all but one patient, who underwent a pneumonectomy with evidence of tumor growth into the pericardial fat.
Table 2: Surgical outcome Type of resectionl - Lobectomy - VATS - Lobectomy - Sleeve-lobectomy - Pneumonectomy - Segment resection - Wedge resection - VATS - wedge resection Intra-operative findings - No adhesions - Limited adhesions - Extensive adhesions ptnm (NSCLC patients only) - T1N0 - T2N0 - T1N2 - T2N2 - T3N0 - T3N2 - T4N0 Radicality of resection - R0 - R2 Surgical complications - No - Grade 2 - Grade 3a Surgical salvage for local failures following SABR 155 N(%) or Median (range) 15 (71%) 3 (14%) 1 (5%) 1 (5%) 1 (5%) 3 (14%) 1 (5%) 9 (43%) 7 (33%) 5 (24%) 20 (95%) 1 (5%) 17 (81%) 2 (10%) 2 (10%) Length of hospital stay 7 (4-15) Four patients experienced complications grade 2 or higher following surgery, which in two cases was due to an infection treated with oral antibiotics (grade II complication). Two other patients, one of whom underwent a sleeve-lobectomy, developed persistent airway leakage, which was treated with a new thoracic tube (grade IIIa complication). There was no bronchopleural fistula present in these patients. The median length of hospital stay was 7 days (range 4-15 days) and 30-day mortality was 0%. In all patients, viable tumor cells were identified on pathological examination. Necrosis was described by the pathologists in eleven cases and fibrosis in six. Five patients had disease upstaging during surgery; one patient had a T3 tumor, three patients had mediastinal lymph node metastases, and one patient had direct extension in the visceral pleura and pericardial fatty tissue. All patients who were upstaged received adjuvant therapy consisting of chemotherapy (n=4) and radiotherapy (n=1).
Chapter 10 Median follow-up after surgery was 40.6 months. Five patients developed further diseaseprogression after surgery. Of these, three patients, all treated for oligo-metastases, developed further metastatic disease. Two patients treated for a local recurrence of a NSCLC developed further disease progression, one of whom had regional failure and subsequent distant failure, the other patient developed distant metastasis. Median overall survival after surgery was 38 months. Estimated actuarial survival at 1-year was 100%, and was 80% at 2-years post-surgery. Five patients died during follow-up, three patients due to unrelated causes, two patients died due to disease progression. Figure 1: Example of a patient with a local recurrence following SABR for NSCLC. A: CT-scan at the time of diagnosis of the primary tumor. B: CT-scan one year post SABR. C: CT-scan at the time of local recurrence. D: histological specimen of this patient showing poorly differentiated tumor cells (100x enlarged)
Surgical salvage for local failures following SABR 157 Discussion In this report, we present the largest series to date of patients who underwent surgical salvage for a resectable local recurrence following SABR treatment for a pulmonary malignancy. Our findings demonstrate that local failures following SABR can be successfully and safely salvaged in selected patients, as 95% of the resections were R0 and only two resections were complicated by > grade 2 toxicity (10%). The median length of hospital stay was within the normal range and 30-day mortality was 0% 16. Furthermore, median overall survival following surgery was 38 months. Previous reports on surgery for local recurrence after SABR have mainly originated from Japan, where pioneering work on SABR has been performed 8 10. Even though both Japanese and Western studies report using SABR doses to a BED of >100Gy, actual doses delivered differ as European guidelines recommend that this dose encompasses the PTV [17], while the Japanese practice had been to prescribe this dose the tumor isocenter 18. While delivering higher tumor doses to our patients, there is also a risk of higher doses to normal organs in the proximity, with potentially more problems with wound-healing after surgical procedures. This problem was not evident in our patients, which can be attributed to the fact that all our patients were treated for peripheral lung tumors using conformal treatment plans, resulting in low dose received by the proximal bronchial tree. During five resections (24%), extensive adhesions were seen causing conversion from a VATS procedure to an open procedure in three patients. The conversion rate in four of our eight thoracoscopic procedures is higher than generally reported 19,20. However, all but one resection could be safely and completely performed without the need for more extensive resection. Although only five patients had pathological confirmation of local recurrence before they underwent surgery, it should be pointed out that recent ESMO guidelines have recommend that all such cases should ideally have a pathological diagnosis before proceeding to surgery 1, especially given the difficulties in distinguishing fibrosis from recurrences 21. Our findings support the recommendation of periodic thoracic CT-scans after SABR for pulmonary malignancies, to detect local recurrence in a timely fashion 1. Our experience suggests surgical salvage can be safely performed in selected patients. However, as the number of patients in our report is still relatively limited and restricted to specialist centers, our findings need to be confirmed in additional series.
Chapter 11 References 1. Vansteenkiste J, Crinò L, Dooms C, et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. Ann Oncol 2014;25:1462 74. 2. Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e278S 313S. 3. Louie AV, Senthi S, Palma DA. Surgery versus SABR for NSCLC. Lancet Oncol 2013;14:e491. 4. Louie AV, Palma DA, Dahele M, et al. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons. Radiother Oncol 2015;114:138-147 5. Zhang B, Zhu F, Ma X, et al. Matched-pair comparisons of stereotactic body radiotherapy (SBRT) versus surgery for the treatment of early stage non-small cell lung cancer: A systematic review and meta-analysis. Radiother Oncol 2014;112:250 5. 6. Lagerwaard FJ, Verstegen NE, Haasbeek CJA, et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2012;83:348 53. 7. Peguret N, Dahele M, Lagerwaard F, et al. A brief report of 10-year trends in the use of stereotactic lung radiotherapy at a dutch academic medical center. J Thorac Oncol 2014;9:114 7. 8. Chen F, Matsuo Y, Yoshizawa A, et al. Salvage lung resection for non-small cell lung cancer after stereotactic body radiotherapy in initially operable patients. J Thorac Oncol 2010;5:1999 2002. 9. Neri S, Takahashi Y, Terashi T, et al. Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers. J Thorac Oncol 2010;5:2003 7. 10. Allibhai Z, Cho BCJ, Taremi M, et al. Surgical salvage following stereotactic body radiotherapy for early-stage NSCLC. Eur Respir J 2012;39:1039 42. 11. Lagerwaard FJ, Haasbeek CJA, Smit EF, et al. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;70:685 92. 12. Nuyttens JJ, van de Pol M. The CyberKnife radiosurgery system for lung cancer. Expert Rev Med Devices 2012;9:465 75. 13. Dindo D, Demartines N, Clavien PA. Classification of Surgical Complications. Ann Surg 2004;240:205 13. 14. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996;17:343 6. 15. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373 83. 16. Whitson BA, Groth SS, Duval SJ, et al. Surgery for early-stage non-small cell lung cancer: a systematic review of the video-assisted thoracoscopic surgery versus thoracotomy approaches to lobectomy. Ann Thorac Surg 2008;86:2008 16 17. Vansteenkiste J, De Ruysscher D, Eberhardt WEE, et al. Early and locally advanced non-smallcell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and
Conclusions and future directions 159 follow-up. Ann Oncol 2013;24 Suppl 6:vi89 98. 18. Suzuki O, Mitsuyoshi T, Miyazaki M, et al. Dose-volume-response analysis in stereotactic radiotherapy for early lung cancer. Radiother Oncol 2014;112:262 6. 19. Lee PC, Nasar A, Port JL, et al. Long-term survival after lobectomy for non-small cell lung cancer by video-assisted thoracic surgery versus thoracotomy. Ann Thorac Surg 2013;96:951 60; 20. Whitson BA, Andrade RS, Boettcher A, et al. Video-assisted thoracoscopic surgery is more favorable than thoracotomy for resection of clinical stage I non-small cell lung cancer. Ann Thorac Surg 2007;83:1965 70 21. Huang K, Senthi S, Palma DA, et al. High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer. Radiother Oncol 2013;109:51 7.