Background
For early-stage non-small cell lung cancer (NSCLC), surgery remains the standard of care with a 5-year survival rate of 46–63%.Reference van Rens, de la Riviere, Elbers and van Den Bosch 1 However, many patients are not surgical candidates due to significant medical comorbidities. Stereotactic body radiation therapy (SBRT) is a non-invasive treatment approach that offers an alternative to surgery in medically inoperable patients. SBRT has been shown to provide local control (LC) rates of 90%, with survival rates comparable with those with surgery alone.Reference Onishi, Shirato and Nagata 2 – Reference Zhang, Yang and Li 5
The toxicity of SBRT may differ based on tumour location relative to the proximal bronchial tree.Reference Timmerman, McGarry and Yiannoutsos 6 Previous studies have shown that for peripherally located tumours (>2 cm from the proximal bronchial tree), single-fraction (SF) SBRT is well tolerated with relatively low toxicity.Reference Videtic, Stephans and Woody 7 – Reference Fritz, Kraus and Muhlnickel 11 Centrally located tumours (<2 cm from the proximal bronchial tree) treated with multiple-fraction SBRT are perhaps similarly well tolerated compared to peripheral lung tumours,Reference Fakiris, McGarry and Yiannoutsos 12 whereas SF-SBRT for central lung tumours have been evaluated in relatively fewer studies.Reference Osti, Carnevale and Valeriani 13 , Reference Le, Loo and Ho 14
Over a 5-year period at Roswell Park Cancer Institute (RPCI), 42 patients received either SF or five-fraction (FF-) SBRT for centrally located lung tumours. In this retrospective review, we evaluate the clinical outcome of these patients, including survival rates and toxicities.
Methods
Patients
A retrospective chart review was conducted on patients who underwent definitive treatment using SF- and FF-SBRT for central lung tumours at RPCI between January 2009 and October 2014. All information was collected and maintained in a database approved by the institutional review board at RPCI.
Before SBRT treatment, all patients underwent initial consultation for complete history and physical examination. Imaging included computed tomography (CT) and/or fluorodeoxyglucose positron emission tomography (FDG-PET) in most cases.
Treatment planning
CT simulation for all patients was performed with patients in the supine position, using a Body Fix (Elekta, Stockholm, Sweden) immobiliser. Respiratory motion was assessed using Real-Time Position Management by Varian Medical System (Palo Alto, CA, USA). All patients underwent 4D CT to evaluate tumour movement with respiration and to generate an internal target volume (ITV).
Treatment planning was per RTOG 0915 for SF-SBRT and per RTOG 0813 for FF-SBRT,Reference Videtic, Gomez and Stephans 9 , Reference Videtic, Hu and Singh 10 , Reference Bezjak, Paulus and Gaspar 15 using a 3D-conformal approach with 11 non-coplanar fields on all patients, except for five patients in the FF-SBRT group who underwent volumetric-modulated arc therapy. No intensity-modulated radiation therapy was used. Gross tumour volume (GTV) was identified and outlined on each CT slice by an appropriately trained physician. Tumours were identified using lung windows, as well as soft tissue windows as necessary to distinguish tumour from adjacent atelectasis or vessels. The clinical target volume was defined as equal to GTV. An ITV surrounding the GTV was generated as described above using 4D CT to account for tumour motion. The planning target volume (PTV) was created by adding a uniform 0·5 cm margin to the ITV.
Of 11 patients who received SF-SBRT, 10 patients received 30 Gy (without heterogeneity corrections), and the remaining one patient received 26 Gy (with heterogeneity corrections). All FF-SBRT patients were planned without heterogeneity correction. Dose was prescribed to the prescription line at the edge of the PTV. Dose conformality and normal tissue constraints were as per RTOG 0915 for SF-SBRT and per RTOG 0813 for FF-SBRT. The prescription isodose surface was required to be greater than or equal to 60%, and <90% of the maximum dose. In all, 99% of the PTV was required to receive ≥90% of the prescription dose.
Follow-up
Patients were scheduled for follow-up at 1·5, 3, and 6 months post-treatment. Subsequent follow-ups were performed every 6 months for 2 years. Tumour response to treatment was assessed with a PET/CT at the 1-year follow-up and surveillance CT imaging of the chest at all other follow-up visits.
Outcome assessment
Local failure was defined as recurrence within the involved lobe or PTV. Nodal failure was defined as recurrence in regional lymph nodes along the natural lymphatic drainage based on the location of primary tumour. Distant failure was defined as recurrence in uninvolved lobes or other organs, including new sites of distant failure for patients with oligometastasis in lungs.
Toxicity was analysed retrospectively from the clinical database using the Common Terminology Criteria for Adverse Events version 4·0. Patients with multiple toxicities were counted once using the highest toxicity grade only. All severe adverse events following treatment were reported regardless of presumed aetiology. Only toxicities directly attributable to radiation therapy were included for analysis. Other adverse events that were deemed to be caused by preceding respiratory comorbidities (e.g., pneumonia, chronic obstructive pulmonary disease (COPD) exacerbation and other respiratory infections) were excluded from this analysis.
Statistical methods
Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan–Meier method, and treatment groups were compared using log-rank tests. Local failure, nodal failure and distant failure were calculated using the competing risks method, and treatment groups were compared using Gray’s tests. Differences in grade 3+ toxicity were calculated using Fisher’s exact test. Differences between treatment groups were evaluated with Fisher’s exact test for categorical variables and Mann–Whitney U test for continuous variables. All p values were two-sided, and p values <0·05 were considered significant. R software version 3·3·1 (R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analysis.
Results
Baseline characteristics
A total of 42 patients with central lung tumours, including NSCLC (n=35), limited-stage small cell lung cancer (SCLC, n=1), or lung oligometastases (n=6) were evaluated. Patient characteristics are described in Table 1. The median age was 75·5 (range 50–89), median Karnofsky Performance Status was 80 (range 60–100), and the median smoking in pack-year was 50 (range 3–150). The median tumour diameter was 2·3 cm (range 0·1–4). The majority of lung tumours were adenocarcinoma and squamous cell carcinoma, stage I, and clinical T1N0. Five patients in SF- and 19 patients in FF-SBRT regimen groups had no history of chemotherapy, surgery or radiation treatment affecting their lungs, whereas all other patients had previous cancer treatments, including prior lung resections and systemic chemotherapy for cancer in other organs.
Baseline characteristics of patients and tumours
Abbreviations: Fx, fraction; NS, not significant; KPS, Karnofsky performance status; NA, not available or not specified; SBRT, stereotactic body radiation therapy; AJCC, American Joint Committee on Cancer.
In the SF-SBRT treatment group, 11 patients received 26–30 Gy (median 30 Gy). In the FF-SBRT group, 31 patients received 50–60 Gy (median 55 Gy). Two patients in the SF-SBRT group and five patients in the FF-SBRT group declined surgery, whereas the remaining patients were medically inoperable due to poor performance status and limited pulmonary or cardiac function.
Malignancy was confirmed with biopsy in all but one SF-SBRT patient, for whom the lesion was determined to be malignant by PET/CT scan showing a new 1-cm lesion with a standardised uptake value (SUV) of 3·4.
Outcomes
After a median follow-up of 12 months (range 1·4–41·2) for the SF-SBRT and 17 months (range 0–60·7) for the FF-SBRT groups (p=0·64), median OS was 27 and 25 months, respectively. One-year OS rates for the SF- and FF-SBRT groups were 82 and 87%, respectively. The 1-year LC rate was 100% for the SF-SBRT group, and 96% for FF-SBRT group. There was no statistically significant difference in OS (p=0·061), PFS (p=0·47), local failure (p=0·43), nodal failure (p=0·42), and distant failure (p=0·45) at 18 months (Figures 1–4).
Overall survival based on treatment group. p Value: 0·061.
Progression-free survival based on treatment group. p Value: 0·47.
Local failure based on treatment group. p Value: 0·43.
Distant only failure based on treatment group. p Value: 0·45.
Toxicity
Two patients from each treatment group exhibited multiple grade 3–4 toxicities. These patients were counted once using the highest grade of toxicity only. Five out of 11 patients in the SF-SBRT group experienced grade 3–4 toxicities, such as bronchopulmonary haemorrhage,Reference Ma, Mix, Rivers, Hennon, Gomez and Singh 16 left vocal cord palsyReference Syed, Ma and Gomez 17 and pneumonia. Eight out of 32 patients in the FF-SBRT group reported grade 3 toxicities only, including pneumonia, COPD exacerbation, pleural effusion, pulmonary embolism and non-specified respiratory infection.
Lesser toxicities considered to be caused by respiratory comorbidities were excluded from this analysis. After the exclusion of such toxicities, two out of 11 patients in the SF-SBRT group and two out of 32 patients in the FF-SBRT group experienced grade 3–4 toxicities. Characteristics of these four cases are described in Table 2. No grade 4–5 toxicities were observed in the FF-SBRT group. The only grade 4 toxicity (n=1) occurred in SF-SBRT group, whereas no grade 5 toxicity was observed. All toxicities resolved, except for one case of grade 4 bronchopulmonary haemorrhage necessitating pneumonectomy, which resulted in surgical complications leading ultimately to death.Reference Ma, Mix, Rivers, Hennon, Gomez and Singh 16 SF- and FF-SBRT groups showed no significant difference in grade 3+ toxicity (n=2 for SF-SBRT, n=2 for FF-SBRT, p=0·28). Median time to radiation-induced toxicity was 14·6 months and all toxicities occurred at least 12 months after SBRT.
Characteristics of patients with grade 3+ toxicity
Abbreviations: Fx, fraction; M, male; F, female; mets, pulmonary oligometastasis; SBRT, stereotactic body radiation therapy; NSCLC, primary non-small cell lung cancer; LUL, left upper lobe; RML, right middle lobe; LLL, left lower lobe; RUL, right upper lobe.
Discussion
This retrospective review of 42 patients with central lung tumours compares clinical outcomes for those treated with SF-SBRT versus those treated with FF-SBRT. To our knowledge, this is the first such comparison that has been reported in the literature.
Our SF- and FF-SBRT groups showed no significant difference in OS and LC. The 1-year OS and LC rate in our SF-SBRT cohort was comparable with those reported elsewhere.Reference Osti, Carnevale and Valeriani 13 , Reference Le, Loo and Ho 14 Similarly, OS and LC rates in our FF-SBRT cohort were consistent with past studies.Reference Modh, Rimner and Williams 18 , Reference Mangona, Aneese and Marina 19
In our patients, SF- and FF-SBRT had no statistically significant difference in the prevalence of grade 3+ toxicity. However, a single case of grade 4 toxicity was reported in the SF-SBRT group, whereas grade 3 toxicities only were reported in the FF-SBRT group. Other multi-fraction regimens, showed low overall toxicity,Reference Modh, Rimner and Williams 18 – Reference Chaudhuri, Tang and Binkley 21 however, there area few cases of high toxicity.Reference Corradetti, Haas and Rengan 22 – Reference Bezjak, Paulus and Gaspar 24 The median time to grade 3 or higher toxicity in our study was 14·6 months from treatment, which is consistent with other studies.Reference Timmerman, McGarry and Yiannoutsos 6 , Reference Corradetti, Haas and Rengan 22 , Reference Bezjak, Paulus and Gaspar 24 When treating patients with central lung tumours, some degree of mortality risk seems to be inevitable regardless of whether SBRTReference Senthi, Haasbeek, Slotman and Senan 25 or pneumonectomyReference Shapiro, Swanson and Wright 26 is performed.
In addition to the inherent limitations of any retrospective review, our patient cohort was very small. Although not statistically significant, both cohorts had heterogeneous tumour types (including early-stage NSCLC and oligometastases) and different length of follow-up.
Several prospective, multicentric phase I–II studies are in progress to further examine multi-fraction SBRT for central lung tumours, including RTOG 0813Reference Bezjak, Paulus and Gaspar 15 and European Organization for Research and Treatment of Cancer 22113-08113. 27 These studies may further elucidate OS, patterns of failure and toxicities seen in the treatment of central lung tumours.
Conclusion
Central SF- and FF-SBRT had comparable OS and LC. Though not currently being studied in prospective trials, SF-SBRT may have some utility for patients unable to have multi-fraction SBRT.
Acknowledgements
The authors would like to acknowledge Jennifer Meyer for her numerous efforts in collecting and maintaining clinical information.
Financial support
This research received no specific grant from any funding agency or from commercial or not-for-profit sectors.
Conflicts of Interest
None.
Ethical Standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by Clinical Research Services and Office and Office of Research Subject Protection at Roswell Park Cancer Institute. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guides on the care and has been approved by Clinical Research Services and Office and Office of Research Subject Protection at Roswell Park Cancer Institute under the study number EDR 171710.
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