Abstract
Background: We conducted long-term follow-up analysis of the outcomes for patients affected by advanced-stage non-small cell lung cancer (NSCLC) treated with hypofractionated radiotherapy (RT). Materials and Methods: Sixty patients with advanced-stage NSCLC (IIIA-IV) treated with hypofractionated radiotherapy (60Gy/20 fractions) were analyzed. Radiation was delivered using an image-guided RT technique to verify the correct position. Toxicities were graded according to the Common Toxicity Criteria for Adverse Effects v4.0 scale. Results: Overall, six patients achieved a complete response and 46 patients had a partial response (tumor response rate 86%). After a median follow-up of 30 months, locoregional progression occurred in 23 patients and distant progression occurred in 38. The 1-year and 2-years overall survival were 57% and 40%, respectively. The 1-year and 2-years progression-free survival (PFS) were 47.1% and 33.5%, respectively. The median duration of OS and PFS was 13 months and 12 months, respectively. The 2-year local PFS and metastases-free survival (MFS) were 53% and 40.3%, respectively. On univariate analysis, the T-size (≥5 cm), and type of response to RT (non-response/progressive disease) were significantly associated with worse OS. Type of response was identified as significant prognostic factors for PFS (p<0.01) local PFS (p=0.015) and MFS (p<0.01). Acute grade 3 esophagitis and pneumonitis occurred in three patients (5%) and four patients (6%), respectively. Late grade 3 esophagitis and pneumonitis occurred in 2% (one patient) and 3% (two patients), respectively. No patient experienced grade 4 acute or late RT-related toxicities. Conclusion: Hypofractionated RT offers good disease control for patients with advanced-stage NSCLC with acceptable toxicity rates. Phase III randomized trials are necessary to compare hypofractionated RT with conventional RT.
Most of the patients with non-small cell lung cancer (NSCLC) present with disease at advanced stage and have a poor prognosis (1). The standard treatment of locally advanced NSCLC remains conventional fractionated radiotherapy (RT) of 60-66Gy and concurrent platinum-based chemotherapy (2, 3), obtaining a median survival of 16-17 months.
Attempts have been made to intensify systemic treatment due to the high propensity of the locally advanced disease to recur distantly. In recent years, efforts have also been made to intensify radiotherapy regimens in order to improve locoregional control and survival rates (4-6). As previous studies demonstrated that repopulation of tumor cells occurs after 4 weeks from the start of therapy, in particular for highly proliferative cancer (7), reducing overall treatment time could increase response rates and disease control.
A higher biological effective dose (BED) can be delivered to the tumor with hypofractionated RT also taking into account the repopulation time of tumor cells (8). The efficacy of RT was evaluated based on the prescribed total dose converted to the BED in patients with NSCLC who received standard RT, continuous hyperfractionated accelerated radiotherapy (CHART) or hypofractionated radiotherapy; better outcomes were reported for hypofractionated RT in terms of 2-years disease-free survival (9).
Moreover, hypofractionated RT could be indicated for the population of patients not eligible for the concurrent approach because of limited metastatic disease or who are not fit for combined treatment (10), in order to control tumor-related symptoms especially of centrally located tumors, and improve quality of life and even survival in selected categories (11, 12).
Concerns remain due to the increase of severe adverse effects such as esophagitis and pneumonitis for patients treated with altered RT regimens, because of the large target volume and the usual compromised general condition of the patients at baseline. Furthermore, less is known regarding the association of chemotherapy with hypofractionation. Phase I-II studies reported that hypofractionated RT and concomitant chemotherapy was feasible with good outcomes but severe toxicities appeared (13). On the other hand, good disease control with acceptable toxicity rates when modern RT techniques were used has been described by several studies (14, 15).
We conducted a prospective study including patients affected by inoperable advanced-stage NSCLC treated with hypofractionated RT demonstrating encouraging results and acceptable toxicity profile (15). At our center, this regimen has been routinely offered as an alternative treatment to patients not eligible for the standard combined therapy. The aim of the present study was to report outcomes and tolerance after long-term follow-up.
Materials and Methods
Patient characteristics. A prospective database was designed to register data regarding patient, tumor and treatment characteristics between 2009 and 2014 at our Department of Radiation Oncology. Sixty patients treated with hypofractionated RT affected by advanced-stage NSCLC were analyzed. All patients had histologically confirmed NSCLC of advanced stage according to the American Joint Committee Oncology Group for Cancer Staging System 2010 (16). Inclusion criteria were: unresectable locally advanced NSCLC (IIIA/IIIB); patients with stage IV presenting ≤2 metastatic sites (brain, adrenal gland, bone, lung) were included when local control was judged to be important for quality of life, tumor-related symptoms and prognosis; performance status (Eastern Cooperative Oncology Group Criteria) ≤2; minimum follow-up time of 6 months. There were no restrictions on previous chemotherapy regimens. Patients unfit for chemotherapy because of comorbidities or advanced age or patients who rejected chemotherapy were also included. No associated full-dose chemotherapy was allowed. Exclusion criteria were malignant pleural or pericardial effusion. Patient characteristics are summarized in Table I.
Pre-treatment evaluation included total body computed tomography (CT), bronchoscopy with histological examination, lung function tests, 18-fluorodeoxyglucose positron-emission tomography (FDG-PET/CT). The Internal review Board approved the study. Written informed consent was obtained by all patients.
Treatment. Treatment details were previously described. Briefly, all patients underwent pre-treatment CT planning in the supine position, which was matched with diagnostic CT and PET-CT for the target volume delineation (gross tumor volume – GTV, clinical target volume – CTV). The GTV1 and the GTV2 included the primary tumor and the clinically positive lymph nodes with a short-axis diameter ≥1 cm and/or positive at PET-CT. The GTVs were expanded 4-5 mm in all directions to create the CTVs. A margin of 5 mm was added in all directions to generate the planning target volumes (PTVs). Radiation therapy was delivered by a linear accelerator using 6 MV photon beams with 3D conformal technique. Image guidance was performed with kilovoltage on-board cone-beam CT that was matched to the planning CT prior to each treatment. The RT regimen utilized consisted of 60Gy in 20 fractions of 3 Gy/each for five times a week for 4 weeks. The calculated BED was 79.4Gy, whereas the α/β ratio for lung cancer is 10 (17). The overall treatment time was 26 days. The dose constraints were (α/β=3Gy): spinal cord ≤36Gy, heart V33 <25%, esophagus V42 <32%, lung V20 <25-30%, mean lung dose ≤15Gy.
Induction chemotherapy was administered to 45 (75%) patients. The majority received platinum-based chemotherapy regimen (n=36). In addition, 15 (25%) patients were unfit for chemotherapy because of age (n=8) or co-morbidity (n=6) or rejection (n=1) (Table II).
Follow-up and statistics. Follow-up was performed every three months for the first two years after RT and every six months afterwards. Treatment related-toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (18) and were classified as acute (within 3 months from RT) or late (after 3 months from RT). A total body CT with contrast medium was performed at 1 month after RT and every 6 months afterwards. FDG/PET-CT was performed at 4 months after RT and for suspected radiological progression.
The Response Evaluation Criteria in Solid Tumors (RECIST) measurement was used to determine response rates distinguished as complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) (19). Metabolic response was also evaluated to consider functional response. Survival was calculated from the date of initial RT and were estimated using the Kaplan–Meier method. The overall survival (OS) was defined as the time to death from any cause or last follow-up. Progression-free survival (PFS) and the local PFS were defined as the time to local/systemic progression or death and the time to locoregional progression, respectively. Metastases-free survival (MFS) was defined as the time to distant progression. Univariate and multivariate analyses were performed using the Cox regression model. Statistical analysis was performed using the SPSS statistical software package version 22.0 (SPSS, Inc., Chicago, IL, USA). A p-value of less than 0.05 was considered as statistically significant.
Results
Response and disease progression. All patients completed RT receiving the total prescribed dose. Out of the 60 patients, six patients achieved a CR (10%) and 46 patients had a PR (76%), with a tumor response rate of 86%. After 6 months from RT, seven patients (12%) continued to be non-responders (NR) with stable disease and only one patient (2%) developed local progression during treatment.
Locoregional progression occurred in 23 patients (38%), with a median time to local progression of 12 months (range=3-27months). Distant progression occurred in 38 patients (63%) with a median time to progression of 16 months (range=3-56 months): stage IIIA 17 months, stage IIIB 16 months, stage IV 8 months (p=0.329). Most of the patients developed multiple simultaneous distant localizations (13 patients) principally in the lung, liver, brain and bone. Other sites of distant progression were lung (eight patients), followed by brain (six patients), bone (three patients), lymph nodes (three patient), liver (two patients) and pleural effusion (two patients).
Patients' characteristics (n=60).
Survival and variables. Overall, the median follow-up time was 30 months (range=3-63 months). At the time of analysis,18 patients (30%) were still alive. Death occurred in 35 (58%) patients due to distant or local progression of NSCLC and in seven (12%) due to other causes. The 1-year and 2-year OS were 57% (95% CI=45.4-71.2%) and 40% (95% CI=28.9-55.3%), respectively (Figure 1a). The median OS was 13 months (95% CI=6.9-19.2 months) for all stages: IIIA 20 months, IIIB 13 months, IV 12 months (p=0.435). The 1-year and 2-years PFS were 47.1% (95% CI=35.6-62.3%) and 33.5% (95% CI=22.6-5.0%), respectively (Figure 1b). The median time-to-progression was 12 months (95% CI=6.9-17.1 months) for all stages: IIIA 13 months, IIIB 16 months, IV 8 months (p=0.42). Recurrences occurred mostly within the first 2 years after RT. The local PFS was 68.8% (95% CI=56.9-83.1%) at 1-year and 53% (95% CI=39.3-71.6%) at 2-years (Figure 2a). The 1- and 2-years MFS were 50.2% (95% CI=38.5-65.4%) and 40.3% (95% CI=28.7-56.7%), respectively (Figure 2b).
Patterns of treatment.
On univariate analysis the T-size (≥5 cm) and type of response (NR/PD) were associated with worse OS (p=0.04, and p<0.01, respectively). Type of response was identified as a significant prognostic factor for PFS(p<0.01), local PFS (p=0.015) and MFS (p<0.01). For the other variables, no impact on survival was found (Table III).
On the multivariate analysis T-size (<5 cm) and type of response (CR/PR) were associated with better OS [(Hazard ratio–HR)=0.49 (95% CI=0.26-0.96; p=0.04]; and PR (HR=0.30, 95% CI=0.13-0.67; p≤0.01), CR (HR=0.08, 95% CI=0.02-0.37; p≤0.01) (data not shown).
Toxicity. Radiation pneumonitis and esophagitis were the most common acute toxicities. No acute or late grade 4 adverse effects were observed (Table IV).
Discussion
The 5-year OS for patients with NSCLC ranges from 5% to 10% (2, 3). The low survival may be explained by common occurrence of metastases and also by low response to local treatment. Local progression is also an important issue because of the appearance of related symptoms and compromised quality of life.
Improving outcomes for patients with stage III disease remains a challenge, despite multiple decades of clinical trials. In order to improve survival, better local and systemic control is required (20). Attempts have been made to intensify chemotherapy and radiation total dose to the tumor, but poor outcomes were obtained. A randomized phase III study (21) compared standard RT (60Gy/2Gy) versus high-dose RT (74Gy/2Gy) with concurrent carboplatin and paclitaxel with or without cetuximab in patients with stage IIIA/IIIB NSCLC. After 23 months of follow-up, lower median OS was described for patients who received high-dose RT (p=0.004) or cetuximab (p=0.29). There were more treatment-related deaths in the high-dose chemoradiotherapy- and the cetuximab-treated groups, but no differences in grade 3 or more effects between RT groups.
Overall survival (OS) (a) and progression-free survival (PFS) (b).
Local progression-free survival (LPFS) (a) and metastasis-free survival (MFS) (b).
Altered fractionation RT regimens (hypofractionated RT or CHART) had a significant benefit on OS (p=0.009), reducing death from cancer (p=0.02) compared to conventional RT as demonstrated by a recent meta-analysis (22). Moreover, a BED of 55 Gy or more was significantly associated with better survival (p<0.001), but higher rates of acute esophagitis were registered for modified RT regimens compared to conventional schedules (p<0.001).
Hypofractionated RT can increase the dose to the tumor and the BED, taking into account the tumor cell re-population effect, reducing the overall delivery time of the treatment. Therefore, a significant percentage of patients with advanced-stage NSCLC often present with advanced age, comorbidities, poor performance status and potentially poor tolerance of standard concurrent therapy. This category of patients may be candidate for hypofractionated RT as an alternative approach.
Univariate analysis of the variables with overall survival and progression-free survival.
Treatment-related toxicities based on Common Terminology Criteria for Adverse Effects scale.
Based on these assumptions, we conducted a study that included patients with inoperable advanced-stage NSCLC treated with hypofractionated RT to the macroscopic disease. After RT, six patients achieved CR (10%) and 46 patients had a PR (76%), with a tumor response rate of 86%. Locoregional progression occurred in 23 patients (38%) and distant progression occurred in 38 (63%), principally in the lung, liver, brain and bone.
The hypofractionated RT regimen of 55 Gy/20 fractions is now the most common hypofractionated schedule in the United Kingdom as demonstrated by a multicenter study conducted on 609 patients with stage I-IIIB NSCLC (23). A total of 27% of patients received also chemotherapy (concurrent or sequential). The median OS from time of diagnosis was 20 months for patients with stage III patients and 2-year OS was 40%.
In the literature, several retrospective and prospective studies demonstrated feasibility and good outcomes in terms of survival and disease control for patients with advanced-stage NSCLC who received hypofractionated RT. The reported median time-to-progression was 9-20 months, and the 2-year OS and local PFS were 28-53% and 20-58%, respectively (4, 6, 14, 24-27). Even though these studies have some limitations, including the small sample of patients, the inhomogeneous fractionation, the long overall treatment time, and timing of concomitant chemotherapy. The majority of these studies were retrospective and, sometimes, palliative doses were used (10, 28). The BED was not high enough for curative intent and the outcomes described for hypofractionated schedules are comparable to those reported from conventional RT or CHART (4, 28). Often, treatment duration is longer than 4 weeks and the dose per fraction is low, increasing the probability of tumor cell re-population.
Since distant metastasis is the major pattern of failure for locally advanced NSCLC, the addition of chemotherapy can improve efficacy. In preliminary reports, chemotherapy regimens were inhomogeneous and sometimes a single drug was used as concomitant treatment with hypofractionated RT due to high rates of predicted toxicities (27, 29).
A phase I-II Chinese study that included 26 patients with stage IIIA/IIIB NSCLC or recurrent disease treated with accelerated hypofractionated RT (3 Gy/fraction) and concurrent chemotherapy reported promising outcomes after short follow-up, but high toxicity rates were observed. There were five treatment-related deaths (1.6%) due to esophagitis/pneumonitis (13).
The SOCCAR phase II randomized trial, which compared sequential versus concurrent chemotherapy and hypofractionated RT (55 Gy/20 fractions) in 130 patients with inoperable stage III NSCLC, described similar toxicities between the two arms with 2-year OS rates of 46% and 50%, respectively (30). The median OS for sequential versus concurrent therapy was 24.3 and 18.4 months, respectively, and the locoregional DFS at 2 years was 45% in both groups. Treatment-related mortality was 2.9% and 1.7% for the concurrent and sequential group, respectively, suggesting that hypofractionated RT and concomitant chemotherapy should be better explored in large controlled trials.
Our study reports the largest cohort of inoperable advanced NSCLC treated with hypofractionated RT using 3 Gy fractions and short overall treatment time (<4 weeks). After a median follow-up of 30 months, 2-year OS was 40%, and median OS was 13 months for all stages (IIIA 20 months, IIIB 13 months, IV 12 months). The 2-years PFS and the median time-to-progression was 33.5% and 12 months (IIIA 13 months, IIIB 16 months, IV 8 months), respectively. The local PFS was 68.8% at 1 year and 53% at 2 years. Our outcomes were promising, with high rates of disease control and longer time to progression.
Indeed, the reported outcomes from other studies are encouraging and suggest that hypofractionated RT with short overall treatment time should be compared with conventionally fractionated RT in powered randomized phase III trials (20). Therefore, the optimal dose required for a satisfactory local control is unknown.
A phase I dose-finding study administered docetaxel and concurrent hypofractionated RT (60 Gy/25 fractions of 2.4 Gy) delivered with Intensity Modulated Radiotherapy (IMRT) and Image Guided Radiotherapy (IGRT) technique after induction chemotherapy, in 34 patients affected by inoperable stage IIIA/IIIB NSCLC (27). The treatment was feasible with docetaxel at 38 mg/m2/week without any limiting toxicity. The median PFS and OS were 20 and 24 months, respectively.
A recent prospective dose-escalation study (31) included 12 patients with inoperable NSCLC (stage II-III) treated with IMRT (48Gy/20 fractions) and concurrent chemotherapy. No dose-limiting toxicity was observed and the maximum tolerated dose was EQD2 of 92 Gy/46. The 1-year local PFS and OS were 81% and 58%, respectively. Another study by Zhu et al. that included 68 patients with advanced NSCLC comparing outcomes from sequential chemotherapy and accelerated hypofractionated RT (50Gy/20 fractions) versus concurrent chemotherapy and standard RT, reported no significant differences in terms of OS, PFS, locoregional PFS or distant metastasis-PFS; the median survival was 19 months for both groups with less toxicity for the concomitant treatment group (32). The main limit of these studies is the short follow-up in evaluating the locoregional control and often it is not even reported.
No clear correlation between the delivered dose and toxicity rates was observed. Even though feasibility and acceptable toxicity rates were reported, there were some deaths related to hypofractionated RT and concomitant chemotherapy (13). On the other hand, other studies showed that hypofractionated RT sequential to chemotherapy can be conducted safely and dose escalation is feasible (14-15, 26).
The maximum-tolerated dose for hypofractionation has not been defined yet. Seventy-nine patients with NSCLC were enrolled in a prospective phase I trial of dose-escalated RT (57 Gy up to 85.5 Gy/25 fractions) without concurrent chemotherapy (33). After longer follow-up, grade 4-5 toxicities occurred in six patients and were correlated with the total dose (p=0004). The maximum-tolerated dose was identified as 63.25Gy in 25 fractions; late severe toxicities were attributable to damage to central structures. Bral et al. reported 30% of grade 3-4 toxicity rates in 40 patients with stage IIIA/B NSCLC who underwent hypofractionated RT (70.5 Gy/30 fractions) without concurrent chemotherapy (34). This evidence suggests that constraints should be corrected for the hypofractionated schedules and the mean lung dose and V20% should be lower than for conventional RT. The risk of high rates of toxicities remains even with the use of modern techniques.
In the present study, the treatment was well-tolerated. Out of the 24 patients that developed esophagitis, three (5%) had grade 3. Of the 16 patients that developed pneumonitis, four (6%) had grade 3. Late grade 3 esophagitis and pneumonitis occurred in 2% and 3%, respectively. No patient experienced acute or late grade 4 toxicities.
On the univariate analysis, T-size of ≥5 cm, and NR/PD as response to RT were associated with worse OS. On the multivariate analysis, T-size of <5 cm and CR/PR were associated with better OS (p=0.04, and p≤0.01, respectively), suggesting that intensifying the dose to the tumor could obtain better response, and in turn less local or distant progression, improving survival.
Hypofractionated RT could be a valid treatment for advanced-stage NSCLC patients but overall treatment time should be ≤4 weeks and the effective dose should be higher as for conventional RT. Furthermore, associated chemotherapy is necessary to delay progression but attention should be paid on timing due to the risk of severe side-effects.
Conclusion
Our data support that hypofractionated RT offers good outcomes and disease control for advanced-stage NSCLC with acceptable toxicity rates. Dose escalation can be safely conducted but timing of associated chemotherapy remains to be defined. Larger prospective cohorts are necessary to better evaluate efficacy and local control but controlled studies using homogeneous therapy should be performed. Therefore, phase III randomized trials are necessary to compare conventional radiotherapy with hypofractionated RT.
Footnotes
Conflicts of Interest
None.
- Received June 29, 2015.
- Revision received July 22, 2015.
- Accepted July 24, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
