Abstract
Purpose
This study aimed to analyze the outcome of low and medium doses of hypofractionated stereotactic body radiotherapy (SBRT) in early stage lung cancer.
Methods
Thirty-five early stage lung cancer patients were treated with SBRT. Initially, SBRT was administered with a low dose of 5 x 8Gy in all cases. Subsequently, a medium dose of 5 x 10Gy for peripherally located lesions was given, continuing to prescribe 5 x 8Gy in centrally located ones. Study endpoints were local control (LC), LC duration, survival and toxicity.
Results
Patients had a good performance status, and T1-2 stage cancer. The SBRT doses of 5 x 8Gy and 5 x 10Gy were administered to 57% and 43% of patients, respectively. At first evaluation after SBRT, local control was obtained in all cases but only 15 (43%) had a complete response. Median duration of LC was 41 months and there was a trend in favor of 5 x 10Gy with respect to 5 x 8Gy in 2- and 3-year LC rates (93% and 69%, versus 60% and 50%, p = 0.1). Four of the 15 (27%) complete responders had local relapse after a quite long median time of 31.5 months. Median overall survival was 40 months. No examined variables (i.e., dose, volume, T stage, and site) significantly conditioned LC, duration of LC, failure rate and survival. Both SBRT schedules were well tolerated.
Conclusion
Outcome of low and medium SBRT doses in terms of LC, duration of LC, patterns of failure and survival was suboptimal compared with recently reported results of SBRT in early stage lung cancer patients.
Keywords: Stereotactic body radiotherapy, lung cancer, hypofractionated radiotherapy, dose schedules.
INTRODUCTION
Surgical resection is the standard of care for early stage lung cancer, with less than 20% of local failure and a 5 year overall survival rate of 71-77% and 49-58% for pT1 and pT2 stages, respectively (1,2). However, patients who are medically inoperable for significant comorbidities can receive conventional conformal radiotherapy as an alternative treatment option, which unfortunately gives unsatisfactory results in terms of local control and survival (local failure varies from 6 to 70%, and median 5 year survival is less than 20%) (3). Moreover, this conventional technique cannot be used in patients with lung cancer and respiratory insufficiency because of the difficulty in avoiding symptomatic radiation-induced bronchopneumonia and fibrosis (3).
Hypofractionated stereotactic body radiotherapy (SBRT), a recent approach that allows the safe delivery high-doses of radiation in single fractions or in three to five fractions, can give suitable clinical outcome with a low incidence of toxicity (4-6). Consequently, lung SBRT is becoming the treatment of choice for medically inoperable early stage lung cancer patients or for operable ones who refuse surgery (7,8).
The optimal dose and fractionation of lung SBRT had not yet been already established. Phase I/II trials assessing the SBRT approach have reported local progression-free survival rates between 85% and 100% (5,9-12). Various fractionation schedules and dose prescriptions have been applied, with a dose–response relationship generally in favor of a biologic effective dose (BED) equivalent to more than 100 Gy in 2-Gy fractions (13-15). BED is calculated by using the standard formula D = [1+d/(α/β)], where D represents total dose, d represents dose per fraction, and α/β is assumed to be 10 for tumors.
An important notion of warning was issued by Timmerman et al. with respect to the use of SBRT for centrally located lesions which are those tumors within or touching the zone of the proximal bronchial tree, defined as a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi); also tumors that are immediately adjacent to mediastinal or pericardial pleura (PTV touching the pleura) are considered central tumors (9). Because excessive late toxicity was sometimes seen in treating central tumors with SBRT, a lower level of dose is generally suggested for centrally located lesions with respect to peripherally located ones.
In our Center, lung SBRT was initially administered with a low prescription dose of 5 x 8Gy (BED = 72Gy), in all cases. Considering the favorable safety profile obtained with this regimen and the need to improve the outcome, we passed to a medium prescription dose of 5 x 10Gy (BED = 100Gy) only for peripherally located lesions, continuing to prescribe 5 x 8Gy in centrally located ones. The analysis of our experience in SBRT for early stage lung cancer is described.
METHODS
From May 2004 to December 2011, 35 early stage lung cancer patients were treated with SBRT. All cases considered inoperable by thoracic surgeons, were discussed in a multidisciplinary meeting with radiation oncologists, surgeons, radiologists, medical oncologists, and pathologists to share SBRT indication. After the clinical evaluation, all patients underwent a chest and abdomen CT scan. About half of the patients (fifteen, 43%) received 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan.
The SBRT schedules adopted were 5 x 8Gy and 5 x 10Gy. The dose was always prescribed to the isocenter and the minimal coverage accepted dose was 90% with a maximum dose not exceeding 110%. Patients were placed in the supine position with both arms above their head, with a personally thermoplastic mask for immobilization. Abdominal compression was used to reduce breathing excursion. A stereotactic body frame with a rigid body fixation system and a fiducial box was used. In this condition, the localization was obtained using a multi-slice CT, with a 500 mm of field of view (FOV), 512 x 512 pixel of matrix size, 2.5 mm of slice thickness, and 0 mm of distance between slices. The use of contrast was evaluated case by case, and CT was done in free quiet respiration after adequate patient education (i.e., the radiation oncologist made recommendations to each patient to remain calm and to breath avoiding deep inspirations and/or expiration) (16).
Gross tumor volume (GTV) was defined as the radiologically visible tumor using lung or mediastinal windowing for peripherally or centrally located lesions, respectively. Clinical target volume (CTV) was coincident with GTV and planned target volume (PTV) was designed as GTV/CTV plus an additional margin of 8-10 mm in the craniocaudal and 4-5 mm in the axial directions. After dosimetric and physic calculations, the GTV/CTV was re-contoured in the image slices obtained with a verification CT. This last exam was administered to verify the adequate coverage of target volume (i.e., PTV must include both GTVs/ CTVs) using the image fusion of the first CT and the verification CT. If necessary, before starting treatment, a dosimetric re-elaboration was carried out.
Coplanar dynamic arcs (generally, differently weighted 8 arcs) were conformed around PTV, typical field-shape margin was 2 mm, and micro-multileaves (MLC) set-up changed every 10 degrees to follow the possible variations on target profile through the beam eye view system. Treatment was delivered with a 5-MV X-rays Elekta linear accelerator with external dynamic 3D-line MLC. Before each SBRT fraction, accuracy of treatment was evaluated with daily MV portal imaging.
Response was assessed 2-3 months after the end of treatment with a CT scan. Further follow-up was done using total body CT and clinical evaluation every 3-4 months.
Local control (LC) was defined as an absence of primary tumor progression (i.e., any response or stable disease). In accord with the Response Evaluation Criteria in Solid Tumors (17), complete response (CR) was defined as complete resolution of enhancing lesion, partial response (PR), ≥ 30% reduction in size of the lesion, stable disease (SD), no change in dimension of the lesion or <50% reduction, and progression of disease (PD), > 20% increase in size of the lesion.
Acute toxicity was scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3 (18). Late toxicity was recorded according to the Radiation Therapy Oncology Group-RTOG/ European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring. Pulmonary function tests were performed before the start of treatment and repeated at first follow up and 1 year.
Study endpoints were LC, duration of LC, survival and toxicity. Dose of SBRT, tumor volume, T stage, and tumor site were the variables analyzed to study which factors were prognostic for duration of LC and survival. At the time of the analysis, all 35 patients were evaluable for LC, and 33 patients for survival because two were lost to follow-up.
Statistical analysis was performed using a software package (MedCalc 11.1 Broekstraat 52, B-9030 Mariakerke Belgium). Overall survival, duration of LC was estimated for the entire population and for each subgroup using the Kaplan-Meier product-limit method (19).
Evidence of statistically significant differences in duration of LC and survival between subgroups was assessed with the log-rank test. A value of p < 0.05 (two tailed) was considered statistically significant.
RESULTS
Patient characteristics are shown in Table 1. The SBRT schedules of 5 x 8Gy and 5 x 10Gy were given to 57% and 43% of patients, respectively. The majority of patients were males (92%) with a median age of 71 years, a good performance status, and T1-2 stage (the only T3 tumor registered was so defined because of two lesions in the same lobe). Biopsy was performed and confirmed the pathological diagnosis of non-small cell lung cancer in 28 (80%) patients. In the remaining 7 (20%) patients, biopsy was not done because of concern for pneumothorax. All these seven patients were assessed with a PET-CT scan. Of the tumors, 25 (72%) were characterized as peripheral and 10 (38%) were centrally located.
Table 1.
Patients Characteristics.
| Characteristic | Number of patients | Percent |
|---|---|---|
| Total cases | 35 | |
| Radiotherapy schedule | ||
| 5 x 8Gy | 20 | 57 |
| 5 x 10Gy | 15 | 43 |
| Sex | ||
| Male | 32 | 92 |
| Female | 3 | 8 |
| Age | ||
| Median | 71 years | |
| Range | 44-87 years | |
| Karnofsky performance status | ||
| Median | 100 | |
| Range | 70-100 | |
| T Stage AJCC 7thedition: | ||
| T1a | 22 | 63 |
| T1b | 10 | 28 |
| T2a | 2 | 6 |
| T3 | 1 | 3 |
| Histology: | ||
| Non-small cell lung cancer | 28 | 80 |
| Squamous | 12 | 34 |
| Adenocarcinoma | 15 | 43 |
| Anaplastic | 1 | 3 |
| Unknown | 7 | 20 |
| Tumor location: | ||
| Central | 10 | 28 |
| Peripheral | 25 | 72 |
| Follow up: | ||
| Median | 19 months | |
| Range | 6-81 months | |
Abbreviation: AJCC = American Joint Committee on Cancer
For all cases, median PTV was 38 cc (range, 11.6-134) and median diameter was 4 cm (range, 2-6.5). Considering patients according to the SBRT schedule adopted, median PTVs were 53 cc (range, 17.6-134) and 36 cc (range, 11.6-71.3 ) for patients treated with 5 x 8Gy and 5 x 10Gy, respectively.
Median follow-up was 19 months (range, 6-81). At first evaluation after SBRT, local control was obtained in all cases but only 15 (43%) had a complete response, 10 (50%) and 5 (33%) in 5 x 8Gy and 5 x 10Gy schedules, respectively (Table 2). This difference did not reach a statistical significance. Complete plus partial response rates were similar in both schedules (85% and 86% in 5 x 8Gy and 5 x 10Gy schedules, respectively)
Table 2.
Local control by radiotherapy schedule adopted.
| Local control | Radiotherapy schedules | All cases | |
|---|---|---|---|
| 5 x 8Gy | 5 x 10Gy | ||
| Complete response | 10 (50%) | 5 (33%) | 15 (43%) |
| Partial response | 7 (35%) | 8 (53%) | 15 (43%) |
| Stable disease | 3 (15%) | 2 (14%) | 5 (14%) |
| Progression | 0 | 0 | 0 |
Median duration of LC was 41 months (3-81 range), and LC rate was 87 +/- 6%, 71 +/- 10%, 56 +/- 12% at 1, 2 and 3 years, respectively. For 5 x 8Gy schedule median duration of LC was 53 months (6-81 range) and LC rate was 84 +/- 8%, 60 +/- 13%, 50 +/- 14% at 1, 2 and 3 years, respectively. For 5 x 10Gy schedule median duration of LC was 47 months (3-59 range) and LC rate was 93 +/- 7%, 93 +/- 7%, 69 +/- 20% at 1, 2 and 3 years, respectively. No statistically significant differences were found between the two SBRT schedules in duration of LC. However, there was a trend in favor of 5 x 10Gy in 2- and 3-year LC rates (93%, 69% for 5 x 10Gy and 60%, 50% for 5 x 8Gy with p = 0.1).
Patterns of failure among study patients are shown in Table 3. Of 22 (63%) patients who progressed, sixteen (45%) developed a local failure plus or minus nodal and/or metastatic diffusion. Considering patients with complete and partial response, four (27%) complete responders had local relapse of the treated lesion after a median time of 31.5 months and four (27%) partial responders had a local progression after a shorter median time of 8.5 months. Examining patients who have not a histologically proven diagnosis, 4 of 7 (57%) developed local or distant failure (i.e., one only local failure, one local plus nodal, one local plus distant and one metachronous lung failure).
Table 3.
Patterns of failure and cause of death.
| Number of patients | Percent | |
|---|---|---|
| Site of failure | ||
| Local | ||
| Local only | 6 | 27 |
| Local and nodal | 4 | 18 |
| Local and distant | 3 | 13.5 |
| Local, nodal and distant | 1 | 4.5 |
| Local, distant, metachronous lung | 1 | 4.5 |
| Local, nodal, distant, metachronous lung | 1 | 4.5 |
| Nodal | ||
| Nodal only | 1 | 4.5 |
| Nodal and distant | 2 | 9 |
| Distant | ||
| Distant only | 2 | 9 |
| Metachronous lung | 1 | 4.5 |
| Cause of death | ||
| Lung cancer | 12 | 70 |
| Local progression | 1 | 6 |
| Regional progression | 2 | 12 |
| Local and regional | 1 | 6 |
| Distant progression | 4 | 23 |
| Regional and distant | 4 | 23 |
| Not related to lung cancer/Unknown | 5 | 30 |
Median overall survival was 40 months (3-81, range). Probability to survive at 1, 2 and 3 years resulted 91% ± 5%, 62% ± 10% and 51% ± 10%, respectively (Fig.1). No examined variables (i.e., dose of SBRT, tumor volume, T stage, and tumor site) significantly conditioned LC, duration of LC, failure rate or survival.
Figure 1.
Kaplan-Meier plot of overall survival probability. The number of patients at risk is presented as well.
At the time of analysis, 17 (48%) patients had died, 12 (70%) because of progressive malignant disease, and 5 (30%) as a consequence of their underlying cardiovascular, renal or pulmonary comorbidities.
No acute > grade 2 symptomatic toxicity was found. Regarding grade 2 acute toxicity, in 2 (6%) patients CT imaging evidenced an asymptomatic radiation-induced bronchopneumonia limited to the volume covered by the 70-90% isodose. As documented by pulmonary function tests, consequent fibrosis did not imply a deterioration of respiratory capacity. The incidence of bronchopneumonia was similar in both schedules without statistically significant differences: 1 (5%) in the 5 x 8Gy and 1 (6%) in the 5 x 10Gy. Acute toxicity was registered with the same incidence in centrally- and peripherally-located lesions (1 and 1 patient, respectively).
Symptomatic grade 3 late toxicity was registered in only 1 of 35 (3%) treated patients who developed a radiation-induced rib fracture 13 months after the end of SBRT administration according to the 5 x 10Gy schedule. The lesion was peripheral and the rib received 100% of the dose. Patient had chest wall pain responsive to minor analgesic. About 6 months later, pain disappeared with a re-calcification of the rib fracture. Three patients (8%) developed radiation fibrosis and one (3%) a ground glass area 6 months after treatment. All these patients had peripheral tumors.
DISCUSSION
Stereotactic body radiotherapy is a non-invasive cancer treatment where small and accurate radiation beams are used to deliver high doses in a small number of fractions to tumor targets in extracranial sites. Lung SBRT is becoming the treatment of choice for medically inoperable early stage lung cancer patients or for operable ones who refuse surgery (7,8).
The optimal dose and fractionation of lung SBRT were not already established. Various fractionation schedules and dose prescriptions have been applied, with a dose–response relationship in favor of a biologic effective dose (BED) equivalent to more than 100 Gy in 2-Gy fractions with an α/β ratio equal to 10 (13-15, 22,23). However, because excessive late toxicity was seen in treating tumors within or touching the zone of the proximal bronchial tree, a lower level dose was suggested for centrally located lesions with respect to peripherally located ones (9,13,14,20,21).
Our experience in SBRT for early stage lung cancer started with a low prescription dose of 5 x 8Gy (BED = 72Gy), independently of the tumor location. Then, considering the feasibility of this schedule, and with the intention of improving outcome, we passed to a medium prescription dose of 5 x 10Gy (BED = 100Gy) for peripheral tumors, leaving 5 x 8Gy for central ones. Despite the increased dose, there was a favorable safety profile. In fact, no acute > grade 2 toxicity was found in patients who underwent 5 x 10Gy SBRT schedule, and in only one patient (7%) CT imaging evidenced an asymptomatic radiation-induced bronchopneumonia. Moreover, one (7%) patient suffered from a symptomatic grade 3 late toxicity (rib fracture) with chest pain lasting for 6 months and well controlled with minor analgesic.
Primary tumor control is an essential requirement for the cure of early stage lung cancer (24). Stereotactic body radiotherapy provides more than double the rate of primary tumor control than conventional radiotherapy (4-6,22-23). Unfortunately, our results in term of LC, duration of LC, patterns of failure and survival were suboptimal compared with recently reported results of SBRT in early stage lung cancer patients. In fact, comparing results of the majority of prospective and retrospective published trials with ours, complete response was documented in more than 80% of patients, local relapse rate in ≤12%, and 3-year overall survival in ≥60%, with respect to our findings that showed 43% of complete response, 45% of local relapse and 40% of 3-year overall survival rates (4-6,11,14,20-23,25). Our limited results can be a consequence of the dose prescription method adopted. In fact, we prescribed dose to the isocentre with a 110% hot spot rather than to the isodose encompassing the entire tumor volume with much greater hot spots in the mid-GTV volume. So, in our experience, overall BED to the GTV resulted lower than in most published studies which prescribe dose to the tumor volume.
Although both adopted SBRT schedules gave a similar outcome, the schedule of 5 x 10Gy was associated with better 2- and 3-year LC rates (93%, 69% for 5 x 10Gy and 60%, 50% for 5 x 8Gy with p = 0.1). It can be supposed that this trend in favor of 5 x 10Gy schedule did not reach a statistical significance because of the limited number of recruited patients in our series.
Worthy to note is that few (4/15, 27%) patients with complete response had local relapse of the treated lesion and that relapse occurred after a quite long interval from SBRT (median time of 31,5 months). Therefore, in patients with early-stage lung cancer, complete response is a crucial end point to improve duration of response and outcome (14,24). Moreover, as a steepdose response relationship exists, higher doses should be used in SBRT for lung cancer. Some papers describe higher rates of complete response with BED > 100 (13,14,21,25-27).
Although the applicability of BED calculations for treatments with a large dose per fraction is unclear (28,29), our results are consistent with previous reports of suboptimal outcome for BED ≤ 100 Gy (21,26,30). Onishi et al. used BED calculations to compare a wide variety of SBRT dose and fractionation schedules and found improved treatment efficacy for BED >100 Gy (30). The meta-analysis by Zhang et al. showed a higher overall survival rates with medium and medium to high BED doses (i.e., 83.2-106 Gy, and 106-146 Gy, respectively) (13).
Trakul et al. have recently described results of a protocol in which SBRT was administered according to a volume-adapted dosing strategy in which small tumors (GTV <12mL) received single-fraction regimen with BED < 100 Gy, and larger tumors (GTV ≥ 12 mL) received multifraction regimen with BED ≥ 100 Gy. Considering that oncology outcomes were equivalent in the two groups, authors concluded that SBRT with BED < 100 Gy is effective for small tumors (30). It is an interesting report, but in our experience there was no relationship between tumor volume and administered doses.
Considering our suboptimal outcome with SBRT given at 5 x 8Gy and 5 x 10Gy doses, we recently started a phase I-II trial in which 5 x 12Gy (BED = 132 Gy) are prescribed in early-stage peripherally located lung cancer. Regarding SBRT for central tumors, although there are not definitive data in this setting, doses higher than 5 x 8Gy can increase severe toxicity. For this reason, the ideal dose prescribed for a 5-fraction treatment was not yet established. The accruing RTOG 0813 trial will help determine the preferred dose for this particular situation by the initial prescription of 10 Gy per fraction, with escalation or de-escalation of the dose per fraction based on observed toxicity. Thus, we decided to wait for results of this trial and continue in the meantime with 5 x 8Gy schedule in centrally located tumors.
CONCLUSION
Although low (5 x 8Gy) and medium (5 x 10Gy) doses of hypofractionated SBRT to the lung were associated with a good safety profile, outcomes in terms of LC, duration of LC, patterns of failure and survival were suboptimal compared with recently reported results of SBRT in early stage lung cancer patients. A trend in favor of medium dose SBRT in 2- and 3-year LC rates was found. Considering the steep-dose response relationship, doses higher than those adopted in this study should be used in SBRT for lung cancer to improve the percentage of cure.
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