Stereotactic Ablative Radiotherapy for stage I histologically proven non-small cell lung cancer: An Italian multicenter observational study

Objectives

Aim of this retrospective multicenter observational study was to provide data on outcomes and prognostic factors in patients affected with stage I histologically confirmed NSCLC treated with Stereotactic Ablative Radiotherapy (SABR, or Stereotactic Body Radiotherapy, SBRT) outside clinical trials.

Materials and Methods

We analyzed a cohort of 196 patients with histological/cytological diagnosis of NSCLC. Median age at treatment was 75 years old; median tumor diameter was 2.48 cm, and median GTV 13.3 cc. One hundred fifty-five patients had stage IA disease (79.1%) and 41 patients stage IB disease (20.9%). Total doses ranged from 48 to 60 Gy in 3–8 fractions. Primary endpoints of the study were safety (acute and late toxicity) and efficacy (Local Control, Disease-Free Survival, Overall and Cancer-Specific Survival).

Results

Median follow-up time was 30 months. The percentage of grade ≥2 pulmonary toxicity was 3%, and the 30 and 60 days mortality rate was 0%. Local Recurrence-Free Survival was 89.7% at 3 years. Fifty-nine patients (30.1%) had at least one failure (local and/or nodal and/or distant), with a Disease-Free Survival (DFS) rate at 3 years of 65.5%. Overall Survival (OS) and Cancer-Specific Survival (CSS) rates were 68% and 82.1% at 3 years, respectively. Median time to any recurrence was 15 months, while median overall survival time was 54 months. At multivariate analysis, stage IB was the only variable associated to a decrease in DFS, OS and CSS (HR 2.77, p = 0.006; HR 2.38, p = 0.009; HR 4.06, p ≤ 0.001, respectively). A difference in survival according to stage was also evident at the log-rank test (p ≤ 0.0001 for CSS and OS).

Conclusion

The results of the present study support the routine use of SABR for stage I NSCLC in a daily practice environment. The only prognostic factor that has been confirmed by our analysis was tumor stage (IA vs. IB).     

Stereotactic ablative radiotherapy for early stage non-small cell lung cancer: A critical literature review of predictive factors of relapse

Stereotactic ablative radiation therapy (SABR) has become the standard treatment for peripheral medically non-operable patients with early stage non-small cell lung cancer (NSCLC). Previous attempts of trials to compare SABR and surgery have failed and new randomized studies (SABRtooth, STABLEMATES, and VALOR) are ongoing. While predictive factors of relapse have been extensively studied in patients receiving surgery, there is scarce data on such putative factors in SABR patients. The purpose of this review is to analyze such predictive factors through a critical review of the literature.     

Radiotherapy in inoperable stage I lung cancer

In 38 cases of Stage I lung cancer, for which surgery was not indicated because of poor cardiopulmonary function or other reason, radical irradiation yielded excellent results. The five year survival rate was 42.1%, the 10-year survival rate 28.4% and the 15-year survival rate 17.1%. Postradiation complications which can be life-threatening, were acceptably low in incidence, and there was no radiation-related death. The results support the concept of radical irradiation being acceptable as a treatment modality for Stage I lung cancer if the patients concerned cannot have surgery because of poor cardiopulmonary function or some other reason.     

Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome

Purpose

To report the clinical outcome of treatment using real-time tumor tracking for 70 patients with inoperable stage I non-small cell lung cancer (NSCLC).

Materials and methods

Seventy inoperable patients with peripherally located early-stage NSCLC were treated with 45 or 60 Gy in three fractions using CyberKnife. Pathology was available in 51% of patients. Thirty-nine patients had a T1-tumor and 31 had a T2-tumor. Markers were placed using the vascular, percutaneous intra-, or extra-pulmonary approach, depending on the risk of pneumothorax.

Results

The actuarial 2-year local control rate for patients treated with 60 Gy was 96%, compared to 78% for patients treated with a total dose of 45 Gy (p = 0.197). All local recurrences (n = 4) occurred in patients with T2-tumors. Overall survival for the whole group at two years was 62% and the cause specific survival was 85%. The median follow-up was 15 months. Grade 3 toxicity occurred in two patients (3%) after marker placement. Treatment-related late grade 3 toxicity occurred in 7 patients (10%). No grade ?4 toxicity occurred.

Conclusion

Excellent local control of 96% at 1- and 2-years was achieved using 60 Gy in three fractions for NSCLC patients treated with the real-time tumor tracking. Toxicity was low.     

Impact of low skeletal muscle mass on non-lung cancer mortality after stereotactic body radiotherapy for patients with stage I non-small cell lung cancer

Purpose

The purpose of the present study was to retrospectively evaluate impact of pre-treatment skeletal muscle mass (SMM) on overall survival and non-lung cancer mortality after stereotactic body radiotherapy (SBRT) for patients with stage I non-small cell lung cancer (NSCLC).

Double-scattered proton-based stereotactic body radiotherapy for stage I lung cancer: A dosimetric comparison with photon-based stereotactic body radiotherapy

Purpose

Stereotactic body radiotherapy (SBRT) has gained popularity in the treatment of early-stage non-small-cell lung cancer (NSCLC) because of its ability to deliver conformal radiation doses to small targets. However, photon-based SBRT (xSBRT) is associated with significant grade 3+ toxicities. In this study, we compare xSBRT treatment plans with proton-based SBRT (pSBRT) to determine whether dose to normal structures could be reduced if SBRT was delivered with protons.

Materials and methods

Eight patients with medically inoperable, peripherally located stage I NSCLC were treated with xSBRT to 48 Gy in 4 12-Gy fractions. These patients were retrospectively re-planned using the same treatment volumes with 3-dimensional conformal double-scatter proton therapy. A Wilcoxon paired test compared dosimetric parameters between the plans for each patient.

Results

Compared with xSBRT there was a dosimetric improvement with pSBRT for these volumes: lung V5 (median difference [MD] = 10.4%, p = 0.01); V10 (MD = 6.4%, p = 0.01); V20 (MD = 2.1%, p = 0.01); V40 (MD = 1.5%, p = 0.05); and mean lung dose (MD = 2.17 Gy, p = 0.01). There were also benefits (p = <0.05) in D0.1cm3 and D5cm3 with pSBRT to the heart, esophagus, and bronchus.

Conclusions

In a dosimetric comparison between photon and proton-based SBRT, protons resulted in lower doses to critical organs at risk and a smaller volume of non-targeted normal lung exposed to radiation (V5, V10, V20, and V40). The clinical significance and relevance of these dosimetric improvements remain unknown.     

Stereotactic body radiotherapy for bilateral primary lung cancers: the Indiana University experience

PURPOSE: To review the outcomes of 10 patients treated with stereotactic body radiotherapy for bilateral primary medically inoperable lung cancer. METHODS AND MATERIALS: Between July 2001 and February 2005, 10 patients were treated at Indiana University with stereotactic body radiotherapy for bilateral multiple primary lung cancers using a stereotactic body frame (Elekta, Stockholm, Sweden). Nine patients had cancers that were deemed inoperable secondary to multiple medical comorbidities. One patient refused surgery. All patients had biopsy proven non-small-cell lung carcinoma of at least one of their masses and presented with either metachronous or synchronous pulmonary nodules. Positron emission tomography scans were done for all patients before treatment. Radiation dose varied between 4800 and 6600 cGy given in 3 fractions prescribed to the 80% line covering at least 95% of the planning target volume. We performed a retrospective review of the outcome of these patients. RESULTS: The mean follow-up time was 20.7 months and the median time was 18.5 months (range, 7-42 months). At the time of this review, all 10 patients were living. Eight (80%) of 10 patients had no evidence of disease progression. One patient developed distant metastasis 5 months after treatment and a second patient developed a local recurrence within the radiation field 11 months after treatment. Six patients had either acute or late pulmonary toxicity, but all toxicity was < or =Grade 2 as defined by the Radiation Therapy Oncology Group toxicity criteria. CONCLUSION: Our preliminary results indicate that stereotactic body radiotherapy is a possibly safe and potentially effective treatment option for patients with bilateral multiple primary lung cancers that are deemed medically inoperable.     

Critical review of nonsurgical treatment options for stage I non-small cell lung cancer

Surgery has traditionally been regarded as the treatment of choice for patients with stage I non-small cell lung cancer. However, the morbidity and mortality associated with surgery in elderly patients with considerable comorbidity remains of concern, as are the poor 5-year survival rates. Until recently, conventional radiation therapy was the only alternative curative treatment option for patients who were unfit for surgery, but with lower local control rates that were inferior to those with surgery. However, a growing body of clinical data on outcomes with newer nonsurgical treatment options such as stereotactic radiation therapy (SRT) and radiofrequency ablation (RFA) is now available. SRT is a noninvasive method showing a 2-year local control rate in excess of 85% in both T1 and T2 tumors after three to eight fractions of high-precision radiotherapy. Despite the use of very high radiation doses, high-grade toxicity is limited to approximately 5% of patients. Percutaneous RFA is an invasive method showing 2-year local control rates of approximately 64% in smaller tumors, but results are poorer in lesions > or =3 cm. Compared with SRT, a higher procedure-related morbidity and mortality rate has been reported, mainly caused by pneumothorax and hemorrhage. Although data from randomized trials of conventional radiotherapy versus SRT or RFA are not available, the use of SRT is becoming widespread for patients who are unfit for surgery. Reported 2-year local control rates after SRT are comparable with those achieved with surgery, and prospective randomized trials comparing surgery with SRT in patients who are fit to undergo surgery are now being planned.     

早期非小细胞肺癌的体部立体定向放射治疗进展

体部立体定向放射治疗（stereotactic body radiotherapy,SBRT）成为医学上不能手术的早期非小细胞肺癌（non-small cell lung cancer,NSCLC）的标准治疗方式。近十年的临床证据表明SBRT替代手术治疗效果可观。由于毒副作用小,SBRT同样适用于肺功能差、患有某些严重并发症的老年患者。最近针对可手术早期NSCLC患者的对比研究中发现SBRT可能同样适用于这一群体,但这些可观的结果仍需要长期随访的前瞻性实验的验证。本文就SBRT治疗早期非小细胞肺癌的临床进展做一综述。     

Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease

Introduction

As a finding of benign disease is uncommon in Dutch patients undergoing surgery after a clinical diagnosis of stage I NSCLC, patients are also accepted for stereotactic ablative radiotherapy (SABR) without pathology. We studied outcomes in patients who underwent SABR after either a pathological (n = 209) or clinical diagnosis (N = 382).

Materials and methods

Five hundred and ninety-one patients with a single pulmonary lesion underwent SABR after either a pathological- or a clinical diagnosis of stage I NSCLC based on a ¹⁸FDG-PET positive lesion with CT features of malignancy. SABR was delivered to a total dose of 60 Gy in 3, 5 or 8 fractions, and outcomes were compared between groups with and without pathological diagnosis.

Results

Patients with pathology had significantly larger tumor diameters (p < .001) and higher predicted FEV1% values (p = .025). No significant differences were observed between both groups in overall survival (p = .99) or local control (p = .98). Regional and distant recurrence rates were also similar.

Conclusions

In a population with a low incidence of benign ¹⁸FDG-PET positive lung nodules, clinical SABR outcomes were similar in large groups of patients with or without pathology. The survival benefits reported after the introduction of SABR are unlikely to be biased by inclusion of benign lesions.     

早期非小细胞肺癌立体定向放疗的相关研究

目前临床上确诊的早期非小细胞肺癌患者中,约20%因自身原因不能手术。立体定向放射治疗具有治疗时间短、治疗相关性损伤轻及肿瘤局控率高的优势,当前国际上已经将其作为早期不能手术非小细胞肺癌的一线治疗方案。在早期能手术非小细胞肺癌的治疗中,立体定向放疗也达到了令人鼓舞的治疗效果,但也存在部分亟待解决的问题。本文将对立体定向放射治疗在早期非小细胞肺癌治疗中的剂量分割、临床适应症及放疗损伤进行综述。     

Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy

PURPOSE: To investigate the clinical outcomes of patients with pathologically proven, peripherally located, Stage I non-small-cell lung cancer who had undergone stereotactic body radiotherapy using real-time tumor tracking radiotherapy during the developmental period. METHODS AND MATERIALS: A total of 41 patients (25 with Stage T1 and 16 with Stage T2) were admitted to the study between February 2000 and June 2005. A 5-mm planning target volume margin was added to the clinical target volume determined with computed tomography at the end of the expiratory phase. The gating window ranged from +/-2 to 3 mm. The dose fractionation schedule was 40 or 48 Gy in four fractions within 1 week. The dose was prescribed at the center of the planning target volume, giving more than an 80% dose at the planning target volume periphery. RESULTS: For 28 patients treated with 48 Gy in four fractions, the overall actuarial survival rate at 3 years was 82% for those with Stage IA and 32% for those with Stage IB. For patients treated with 40 Gy in four fractions within 1 week, the overall actuarial survival rate at 3 years was 50% for those with Stage IA and 0% for those with Stage IB. A significant difference was found in local control between those with Stage IB who received 40 Gy vs. 48 Gy (p = 0.0015) but not in those with Stage IA (p = 0.5811). No serious radiation morbidity was observed with either dose schedule. CONCLUSION: The results of our study have shown that 48 Gy in four fractions within 1 week is a safe and effective treatment for peripherally located, Stage IA non-small-cell lung cancer. A steep dose-response curve between 40 and 48 Gy using a daily dose of 12 Gy delivered within 1 week was identified for Stage IB non-small-cell lung cancer in stereotactic body radiotherapy using real-time tumor tracking radiotherapy.     

Stereotactic, high single-dose irradiation of stage I non-small cell lung cancer (NSCLC) using four-dimensional CT scans for treatment planning

We reviewed response rates, local control, survival and side effects after non-fractionated stereotactic high single-dose body radiation therapy for lung tumors.

Forty patients with stage I non-small cell lung cancer (NSCLC) underwent radiosurgery involving single-dose irradiation. The standard dose prescribed to the isocenter was 30 Gy with an axial safety margin of 10 mm and a longitudinal safety margin of 15 mm. The planning target volume (PTV) was defined using three CT scans with reference to the phases of respiration so that the movement span of the clinical target volume (CTV) was enclosed.

The volume of the bronchial carcinomas varied from 4.2 to 130 cm³ (median: 19.5 cm³), and the PTV derived from four-dimensional CT (4D-CT) scans using image fusion ranged from 15.6 to 390.5 cm³ (median: 101 cm³). Tumor size ranged from 1.7 to 10 cm at largest focuses. Follow-up periods varied from 6.0 to 61.5 months (median: 20 months). We observed three local tumor recurrences, resulting in an actuarial local tumor control of 81% at 3 years. With the exception of two rib fractures, no serious late toxicity was observed. The overall survival probability rates were: 2 years: 66%, 3 years: 53% (median overall survival: 37 months). Cancer-specific survival probability was: 2 years: 71%, 3 years: 57%.

Non-fractionated high single-dose SBRT for NSCLC is more convenient for the patient and less time-consuming than hypofractionated SBRT, but data dealing with this method are still scanty. This alternative treatment results in favourable local control and acceptable toxicity.     

Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer

PURPOSE: High local control rates can be achieved using stereotactic radiotherapy in Stage I non-small-cell lung cancer (NSCLC), but reports have suggested that toxicity may be of concern. We evaluated early clinical outcomes of "risk-adapted" fractionation schemes in patients treated in a single institution. METHODS AND MATERIALS: Of 206 patients with Stage I NSCLC, 81% were unfit to undergo surgery and the rest refused surgery. Pathologic confirmation of malignancy was obtained in 31% of patients. All other patients had new or growing 18F-fluorodeoxyglucose positron emission tomography positive lesions with radiologic characteristics of malignancy. Planning four-dimensional computed tomography scans were performed and fractionation schemes used (3 x 20 Gy, 5 x 12 Gy, and 8 x 7.5 Gy) were determined by T stage and risk of normal tissue toxicity. RESULTS: Median overall survival was 34 months, with 1- and 2-year survivals of 81% and 64%, respectively. Disease-free survival (DFS) at 1 and 2 years was 83% and 68%, respectively, and DFS correlated with T stage (p = 0.002). Local failure was observed in 7 patients (3%). The crude regional failure rate was 9%; isolated regional recurrence was observed in 4%. The distant progression-free survival at 1 and 2 years was 85% and 77%, respectively. SRT was well tolerated and severe late toxicity was observed in less than 3% of patients. CONCLUSIONS: SRT is well tolerated in patients with extensive comorbidity with high local control rates and minimal toxicity. Early outcomes are not inferior to those reported for conventional radiotherapy. In view of patient convenience, such risk-adapted SRT schedules should be considered treatment of choice in patients presenting with medically inoperable Stage I NSCLC.     

X刀立体定向放射治疗非小细胞肺癌的临床研究

目的观察X刀立体定向放射治疗非小细胞肺癌(NSCLC)的近期、远期疗效及其并发症,探讨X刀立体定向放疗在非小细胞肺癌治疗中的应用价值。方法75例符合条件的NSCLC患者随机分为两组,X刀治疗组38例,应用X刀立体定向放疗,剂量4~6Gy/次,每日或隔日1次,共治疗8~10次,使GTV边缘剂量达45~55Gy。常规放疗组37例,常规分割放疗,每次1.8~2.0Gy,每日1次,每周5次,总照射剂量60~65Gy。结果X刀组总有效率(CR PR)为86.8%,明显优于常规放疗组的62.1%,两组差异有非常显著性(P<0.05)。X刀组1,2,3年生存率分别为87.5%、60.0%和35.0%;常规放疗组分别为58.3%、27.8%和16.7%,两组间1,2,3年生存率比较差异均有显著性。结论与常规放疗相比,X刀立体定向放疗可以在较好保护周围正常组织的同时,提高肿瘤照射区的放射剂量,从而增加非小细胞肺癌的局部控制率,提高远期生存率。     

Comparison of accelerated hypofractionation and stereotactic body radiotherapy for Stage 1 and node negative Stage 2 non-small cell lung cancer (NSCLC)

Purpose

Stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) have favorable local control (LC) relative to conventional fractionation in the treatment of stage I non-small cell lung cancer (NSCLC). We report the results of our single institution experience with the treatment of early stage NSCLC with SBRT or AHRT in cases where SBRT was felt to be suboptimal.

Methods

One hundred and sixty patients with Stage 1 and node negative Stage 2 NSCLC were treated with SBRT or AHRT from 2003 to 2011. Median follow-up was 29.4 and 19 months (mo), respectively. The median dose was 54 Gy in 3 fractions (fx) (SBRT) and 70.2 Gy in 26 fx (AHRT). Acute and late toxicities (tox) were graded (G) per CTCAE v4. Time to local (LF), regional (RF) and distant (DF) failure were estimated using the Kaplan–Meier method. The impact of patient and tumor related factors on LF were estimated by multivariate Cox proportional hazard model.

Results

Three-year LC rates were 87.7% (SBRT) and 71.7% (AHRT). The 3-year freedom from DF was 73.3% and 68.1%. Median OS was 38.4 (95% CI 29.7–51.6) and 35 (95% CI 22–48.3) mo. No G3 or 4 tox were observed. At 1 year, 30% and 50% of complications resolved, while (5–6%) had persistent chest wall pain.Multivariate analysis demonstrated that increasing dose per fraction and tumor size (>5.5 vs. 4 cm) in the AHRT and SBRT group were found to be associated with a reduced (HR 0.33 95% CI 0.13–0.84, p = 0.021) and increased (HR: 6.372 95% CI 1.23–32.92, p = 0.027) hazard for local failure respectively.

Conclusions

Our results compare favorably with other reports of treatment for early stage NSCLC. AHRT patients had comparable LC despite increased size and central disease. Toxicity was limited and overall survival, regional and distant recurrences were similar between groups.     

Pulmonary function and quality of life after VMAT-based stereotactic ablative radiotherapy for early stage inoperable NSCLC: a prospective study

ObjectivesTo analyze changes in pulmonary function and quality of life (QoL) at different time points after Stereotactic Ablative Radiotherapy (SABR) for early stage inoperable lung cancer, and potential correlations between radiation dose-volume parameters and pulmonary toxicity or changes in pulmonary function tests (PFT) and QoL.Materials and methodsFrom July 2012 to October 2013, 30 patients were enrolled in this prospective observational study. Complete PFT were performed and Lung Cancer Symptoms Scale (LCSS) questionnaire administered prior to SABR; all patients then underwent Computed Tomography (CT) scan and PFT at 45, 135, 225 and 315 days after SABR, together with LCSS questionnaire. Clinical lung toxicity and radiological toxicity (acute and late) were prospectively recorded by using the Radiation Therapy Oncology Group (RTOG) scoring system.ResultsA decline in Slow Vital Capacity (SVC), Forced Expiratory Volume in 1 s (FEV₁), Single-breath lung diffusing capacity (D_LCO) and blood partial pressure of oxygen (PaO₂) was seen at 135 days post-SABR. PaO2 values rescued to normal levels at 315 days. None of the baseline PFT parameters resulted to be associated with the occurrence of pulmonary toxicity or with late radiological changes. Mean V5, V10, and V20 and MLD_2Gy were higher in patients who developed radiation pneumonitis, even if not significantly associated at Cox regression analysis. LCSS QoL showed a significant worsening of the single item fatigue at 135 days after SABR.ConclusionsA small (mean 10%) but significant decline in lung volumes and D_LCO was recorded after SABR, with clinical impact of such change difficult to estimate in individual patients. Global QoL was not significantly impaired. Dose-volume parameters did not emerge as significantly predictive of any clinical, radiological or functional toxicity.