Stereotactic body radiation therapy for the treatment of locally recurrent pancreatic cancer after surgical resection

BackgroundTo report on a cohort of radiation-naïve patients with pancreatic cancer who developed isolated local recurrence following surgical resection and were subsequently treated with stereotactic body radiation therapy (SBRT).MethodsPatients with pancreatic cancer who were treated with SBRT for isolated local recurrence after surgical resection were retrospectively reviewed. Clinical outcomes were calculated from completion of SBRT and included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS). Univariate (UVA) analysis was performed to identify variables associated with clinical outcomes. Kaplan-Meier method was used for survival outcomes. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0.ResultsFrom September 2012 to November 2018, a total of 19 patients with localized pancreatic cancer were treated with SBRT for isolated local recurrence after initial surgical resection. No patients had prior radiation. The median biologically effective dose (BED₁₀) was 54.8 Gy (range, 37.5–54.8 Gy). Median OS was 17.1 months, with 6-month and 1-year OS rates of 94.4% and 69.6%, respectively. Nine patients (47.4%) developed local failure after SBRT. Pattern of first failure after SBRT was distant in 7 patients (46.7%), local in 5 patients (33.3%), and synchronous distant and local in 3 patients (20.0%). One patient developed local failure after developing distant disease first. Of the 9 local failures, 3 (33.3%) were out-of-field. Median LPFS was 22.2 months, with 6-month and 1-year LPFS rates of 86.9% and 63.2%, respectively. A BED₁₀ <54.8 Gy was associated with inferior LPFS (1-year, 25.0% vs. 80.2%, P<0.009). Median DMFS and PFS were 15.6 months. There was 1 case (5.3 %) of grade 3 gastric perforation. There were no cases of grade 4–5 toxicity events.ConclusionsSBRT for locally recurrent pancreatic cancer after initial curative resection is safe and feasible. A BED₁₀ <54.8 Gy was significantly associated with inferior local control. Further studies investigating dose escalation and optimal treatment volumes in the locally recurrent setting are warranted.     

Advances of stereotactic body radiotherapy in pancreatic cancer

Pancreatic cancer (PCA) is one of the most aggressive tumors with few effective treatment modalities. It is the 4th and 7th leading cause of cancer death in the United States and China, respectively. At the time of diagnosis, only 20% of cases present with a resectable tumor, and about 40% with a locally advanced tumor that is considered unresectable. Even resected patients still have a poor prognosis, with an incidence of local recurrence ranging from 20% to 60%. It is also reported that up to 30% of PCA patients die from locally obstructive disease with few or no distant metastases. These findings have highlighted the importance of local radiation therapy in the treatment of PCA. As the role of conventional chemoradiotherapy remains controversial, the dawn of the pancreas stereotactic body radiation therapy (SBRT) era represents a potential paradigm shift in the management of PCA. SBRT delivers a higher biological effective dose to the tumor with sharp dose escalation in a shorter treatment time course. Pancreas SBRT is a novel therapeutic option to achieve local tumor control with minimal toxicity. Herein, we review the advancement of SBRT for PCA patients with different stages of pancreatic adenocarcinoma.     

A prospective trial of stereotactic body radiation therapy for unresectable pancreatic cancer testing ablative doses

BackgroundWe explored the safety and efficacy of ablative doses of stereotactic body radiation therapy (SBRT) for unresectable pancreatic cancer.MethodsThis phase I/II trial included patients with unresectable pancreatic cancer previously treated with any number of cycles of induction chemotherapy. Patients were enrolled according to a 3+3 dose escalation design at 10, 12.5, and 15 Gy ×3, with subsequent patients at the maximally tolerated dose (MTD). Treatment was delivered to gross tumor delineated with MRI fusion using image-guidance to fiducial markers. Dose-limiting toxicity (DLT) was defined as grade 3+ toxicity within 30 days. Secondary endpoints included late gastrointestinal (GI) toxicity, freedom from local failure (FFLF), and survival.ResultsFifteen patients received a median 10 cycles of chemotherapy. There were no DLTs, and the MTD was 15 Gy ×3. Thirty-day toxicity included grade 2 nausea (46%) and grade 2 diarrhea (7%). Median survival after SBRT was 12.8 months (23 months after diagnosis) and median relapse-free survival was 7 months. At 1-year, FFLF was 80%. Four patients had grade 3+ GI bleeding after 30 days (median 6 months). Grade 3+ GI bleeding was associated with tumor volume (P=0.01), heterogeneity of dose within the planning target volume (PTV) (V120, P=0.03), and duodenal dose (V26–30 Gy, P<0.2).ConclusionsThis aggressive SBRT regimen demonstrated limited 30-day morbidity, a moderate degree of local control, and a moderate risk for late GI bleeding. Further work is necessary to define the most appropriate hypofractionated radiation therapy (RT) regimen in the ablative dose range.     

Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer

Background

While clinical outcomes following induction chemotherapy and stereotactic body radiation therapy (SBRT) have been reported for borderline resectable pancreatic cancer (BRPC) patients, pathologic response has not previously been described.

Methods

This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by SBRT and surgical resection. Each surgical specimen was assigned two tumor regression grades (TRG), one using the College of American Pathologists (CAP) criteria and one using the MD Anderson Cancer Center (MDACC) criteria. Overall survival (OS) and progression free survival (PFS) were correlated to TRG score.

Results

We evaluated 36 patients with a median follow-up of 13.8 months (range, 6.1-24.8 months). The most common induction chemotherapy regimen (82%) was GTX (gemcitabine, docetaxel, capecitabine). A median SBRT dose of 35 Gy (range, 30-40 Gy) in 5 fractions was delivered to the region of vascular involvement. The margin-negative resection rate was 97.2%. Improved response according to MDACC grade trended towards superior PFS (P=061), but not OS. Any neoadjuvant treatment effect according to MDACC scoring (IIa-IV vs. I) was associated with improved OS and PFS (both P=0.019). We found no relationship between CAP score and OS or PFS.

Conclusions

These data suggest that the increased pathologic response after induction chemotherapy and SBRT is correlated with improved survival for BRPC patients.     

盐酸吉西他滨联合伽玛射线立体定向体部放疗治疗局部晚期胰腺癌的临床研究

目的:观察盐酸吉西他滨联合伽玛射线立体定向体部放疗治疗不能手术的局部晚期胰腺癌的疗效及安全性。方法:205例不能手术切除的胰腺癌患者按治疗方法分为3组:A组67例为盐酸吉西他滨联合立体定向放射治疗组,B组72例为单用立体定向放射治疗组,C组66例为单用盐酸吉西他滨治疗组。盐酸吉西他滨1000mg/m2,第1、8天静脉输注,21-28天为1个周期,治疗4-6周期。联合治疗组第一周期化疗的第1天同步行伽玛射线立体定向体部放疗,等剂量曲线为55%-70%,肿瘤≤5cm的单次周边剂量4.0-5.5Gy,肿瘤>5cm的单次周边剂量3.0-4.0Gy,治疗总剂量为32-48Gy,治疗次数8-12次,5次/周。结果:2个月后增强CT复查肿瘤病灶。A组肿瘤病灶治疗有效率(RR)为32.8%(22/67),疾病控制率(DCR)为86.6%(58/67),临床受益反应为86.6%(58/67),中位生存时间(MST)为12.3个月(范围4-42个月),1年生存率为49.3%(33/67),治疗期间常见毒副反应为白细胞、血小板下降及消化道反应;B组RR为18.1%(13/72),DCR为68.1%(49/72),临床受益反应为66.7%(48/72),MST为8.6个月(范围4-30个月),1年生存率为31.9%(23/72),治疗期间常见毒副反应为恶心及呕吐;C组RR为13.6%(9/66),DCR为66.7%(44/66),临床受益反应为48.5%(32/66),MST为7.8个月(范围3-22个月),1年生存率为28.8%(19/66),治疗期间常见毒副反应为白细胞、血小板下降。盐酸吉西他滨联合立体定向放射治疗组的近期疗效(RR)及远期疗效(1年生存率)均优于单用立体定向放射治疗组(P=0.045;P=0.038)或单用盐酸吉西他滨(P=0.009;P=0.016)。结论:盐酸吉西他滨单药联合伽玛射线立体定向体部放疗治疗不能手术的局部晚期胰腺癌具有较好的疗效和安全性。     

Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy

Purpose Prospective pilot study to assess patient outcome after stereotactic body radiation therapy (SBRT) for limited metastases from breast cancer. Methods Forty patients with ≤5 metastatic lesions received curative-intent SBRT, while 11 patients with >5 lesions, undergoing SBRT to ≤5 metastatic lesions, were treated with palliative-intent. Results Among those treated with curative-intent, 4-year actuarial outcomes were: overall survival of 59%, progression-free survival of 38% and lesion local control of 89%. On univariate analyses, 1 metastatic lesion (versus 2–5), smaller tumor volume, bone-only disease, and stable or regressing lesions prior to SBRT were associated with more favorable outcome. Patients treated with palliative-intent SBRT were spared morbidity and mortality from progression of treated lesions, though all developed further metastatic progression shortly (median 4 months) after enrollment. Conclusions SBRT may yield prolonged survival and perhaps cure in select patients with limited metastases. Palliative-intent SBRT may be warranted for symptomatic or potentially symptomatic metastases.     

立体定向放疗联合免疫治疗晚期恶性肿瘤进展

晚期肺转移癌或黑素瘤中放疗联合免疫检测点抑制剂,封闭免疫抑制通路,增强抗肿瘤免疫应答,在临床上明显改善生存。体部立体定向放疗大剂量精准照射到肿瘤靶区,最大程度避免周围正常组织损伤,同时还诱导相关细胞因子和免疫分子表达,较常规放疗更能诱导强烈的免疫反应及远隔效应,更适合与免疫联合。已有研究表明总剂量和分割模式是调节放疗免疫反应的重要参数;放疗与免疫序贯时机显著影响疗效,肿瘤浸润淋巴细胞、PD-L1表达水平和MMR缺陷可能是预测放疗免疫治疗的重要指标。采用合理的放疗剂量和分割模式,选择最佳序贯时机和有效的预测标记物,SBRT联合免疫可以最大程度激活全身免疫反应,发挥远隔效应协同作用晚期恶性肿瘤。     

Stereotactic body radiation therapy (SBRT) for early-stage lung cancer in the elderly

Early-stage non-small cell lung cancer (NSCLC) is on the rise due to the implementation of screening guidelines for patients at risk for developing lung cancer. It is anticipated that as the US population continues to age, there will be a higher percentage of medically inoperable early-stage lung cancer patients. For this reason, noninvasive ablative therapies are necessary. Stereotactic body radiation therapy (SBRT) is an effective modality in addressing early-stage NSCLC. SBRT consists of high-dose radiation delivered over 3–5 treatments. Several randomized trials comparing surgery to SBRT in early-stage operable patients have unfortunately closed early due to poor accrual. However, a recent pooled analysis from 2 randomized trials (StereoTActic Radiotherapy and Radiosurgery Or Surgery for operable Early-stage non–small cell Lung cancer) comparing surgery to SBRT did show comparable local control and overall survival rates between surgery and SBRT, offering a very effective, noninvasive modality for older adult patients with early-stage NSCLC. In this review, we summarize the role of SBRT in early-stage NSCLC, in particularly applied to the older adult population.     

Preoperative neutrophil-to-lymphocyte ratio as a prognosticator in early stage pancreatic ductal adenocarcinoma

Background

The neutrophil-to-lymphocyte ratio (NLR), which reflects the cancer-induced systemic inflammation response, has been proposed as a risk factor for poor long-term prognosis in cancer. We investigated the prognostic role of the NLR and the relationship between the NLR and TNM stage in pancreatic ductal adenocarcinoma (PDAC) patients following curative resection.

准直器角度对肺癌SBRT-VMAT治疗计划的影响

目的:研究准直器角度对中央型非小细胞肺癌(NSCLC)患者体部立体定向放射治疗(SBRT)容积旋转调强(VMAT)计划剂量学影响。方法:选取10名中央型NSCLC患者进行VMAT计划设计。使用Varian Eclipse系统,6 MV FFF X射线,最大剂量率1400 MU/min。机架角度:CCW 179°~181°、CW 181°~179°,双弧准直器角度互组,0°~90°每间隔10°设置准直器角度,即为(0°,0°)、(10°,350°)、(20°,340°)、(30°,330°)、(40°,320°)、(50°,310°)、(60°,300°)、(70°,290°)、(80°,280°)和(90°,270°)制定十个计划。在处方剂量相同并且处方剂量线包绕相同靶区体积的前提下(归一至80%),比较计划靶区参数:D 95%、V 90%、适形度指数(CI)、梯度指数(GI)、D 2 cm以及机器跳数(MU),危及器官参数:双肺(D 1500 cm³、D 1000 cm³)、心脏(D 15 cm³)、脊髓(D 1.2 cm³、D 0.35 cm³)。用SPSS软件对每个分析指标做Wilcoxon符号秩检验,判断差异是否具有统计学意义。结果:在有统计学意义的基础上,10组计划中,准直器角度为60°时(P<0.05),靶区D 95%剂量最高,准直器角度为50°时(P<0.05),靶区V 90%最高。CI和GI在0°最佳。危及器官双肺(D 1500 cm³、D 1000 cm³)、心脏(D 15 cm³)、脊髓(D 1.2 cm³)受照剂量均在0°最低,脊髓D 0.35 cm³在整个角度范围内不具有统计学差异。此外,所有计划中危及器官受照剂量均远远低于计划规定值,其中双肺(D 1500 cm³)在50°的剂量与最低值仅相差4.1%(P<0.05),心脏(D 15 cm³)在60°的剂量与最低值仅相差3.4%(P<0.05)。结论:改变准直器角度对肺癌SBRT-VMAT计划剂量有明显的影响。选择合适的准直器角度,正常组织受照剂量远远低于计划限量时,靶区体积剂量明显提高,但计划复杂度也略有提升。在临床计划设计过程中,应充分考虑准直器角度的影响,制定更合适的治疗计划。     

Interinstitutional variations in planning for stereotactic body radiation therapy for lung cancer

PURPOSE: The aim of this study was to assess interinstitutional variations in planning for stereotactic body radiation therapy (SBRT) for lung cancer before the start of the Japan Clinical Oncology Group (JCOG) 0403 trial. METHODS AND MATERIALS: Eleven institutions created virtual plans for four cases of solitary lung cancer. The created plans should satisfy the target definitions and the dose constraints for the JCOG 0403 protocol. RESULTS: FOCUS/XiO (CMS) was used in six institutions, Eclipse (Varian) in 3, Cadplan (Varian) in one, and Pinnacle3 (Philips/ADAC) in one. Dose calculation algorithms of Clarkson with effective path length correction and superposition were used in FOCUS/XiO; pencil beam convolution with Batho power law correction was used in Eclipse and Cadplan; and collapsed cone convolution superposition was used in Pinnacle3. For the target volumes, the overall coefficient of variation was 16.6%, and the interinstitutional variations were not significant. For maximal dose, minimal dose, D95, and the homogeneity index of the planning target volume, the interinstitutional variations were significant. The dose calculation algorithm was a significant factor in these variations. No violation of the dose constraints for the protocol was observed. CONCLUSION: There can be notable interinstitutional variations in planning for SBRT, including both interobserver variations in the estimate of target volumes as well as dose calculation effects related to the use of different dose calculation algorithms.     

A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases

PURPOSE: To determine the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) for liver metastases. METHODS AND MATERIALS: A multicenter Phase I clinical trial was conducted. Eligible patients had one to three liver metastases, tumor diameter <6 cm, and adequate liver function. The first cohort received 36 Gy to the planning target volume (PTV) in three fractions (F). Subsequent cohorts received higher doses up to a chosen maximum of 60 Gy/3F. At least 700 mL of normal liver had to receive a total dose <15 Gy. Dose-limiting toxicity (DLT) included acute Grade 3 liver or intestinal toxicity or any acute Grade 4 toxicity. The MTD was exceeded if 2/6 patients in a cohort experienced DLT. RESULTS: Eighteen patients were enrolled (10 male, 8 female): median age, 55 years (range, 26-83 years); most common primary site, colorectal (6 patients); median aggregate gross tumor volume, 18 ml (range, 3-98 ml). Four patients had multiple tumors. No patient experienced a DLT, and dose was escalated to 60 Gy/3F without reaching MTD. CONCLUSIONS: Biologically potent doses of SBRT are well tolerated in patients with limited liver metastases. Results of this study form the basis for an ongoing Phase II SBRT study of 60 Gy over three fractions for liver metastases.     

Stereotactic body radiation therapy in pancreatic cancer: the new frontier

Pancreatic cancer (PCA) remains a disease with a poor prognosis. The majority of PCA patients are unable to undergo surgical resection, which is the only potentially curative option at this time. A combination of chemotherapy and chemoradiation (CRT) are standard options for patients with locally advanced, unresectable disease, however, local control and patient outcomes remains poor. Stereotactic body radiation therapy (SBRT) is an emerging treatment option for PCA. SBRT delivers potentially ablative doses to the pancreatic tumor plus a small margin over a short period of time. Early studies with single-fraction SBRT demonstrated excellent tumor control with high rates of toxicity. The implementation of SBRT (3–5 doses) has demonstrated promising outcomes with favorable tumor control and toxicity rates. Herein we discuss the evolving role of SBRT in PCA treatment.     

寡转移瘤患者体部立体定向放疗的疗效及安全性

目的 探讨小体积寡转移瘤患者局部立体定向放疗（SBRT）的疗效及安全性。方法收集2011年6月至2016年12月85例转移灶≤5个、预计生存期＞3个月、一般状况良好的Ⅳ期寡转移瘤患者,采用3个剂量的SBRT,主要研究终点是局部控制率和毒性反应,次要研究终点是总生存期（OS）和无疾病进展生存期（PFS）。疗效评价采用RECIST 1.1版标准;毒副反应采用RTOG评价标准;Kaplan-Meier法计算生存,Log-rank检验生存差异。结果 85例患者共187处转移灶,中位随访时间为25个月,局部控制率为66.8％（125／187）,其中24、30、36 Gy剂量组局部控制率分别为39.0％、79.0％、84.0％,差异有统计学意义（P＜0.05）。全组中位PFS为7.8个月（1～25个月）,1、2、3年无进展生存率分别为33.3％、25.0％、23.0％;中位OS为25个月,1、2、3年生存率分别为80.5％、75.6％、70.6％。4例患者发生3级以上急性毒副反应,其中2例是肺部转移瘤,2个月后证实为放射性肺炎;另外1例是肝脏转移瘤,放疗时发生严重呕吐、转氨酶升高需入院治疗;还有1例肝、肺、骨多发转移患者发生4级骨髓抑制（白细胞减少为主）。结论 寡转移瘤患者在安全治疗范围内可以从局部SBRT放疗中获得较好的局部控制率,不良反应可耐受。     

Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: Clinical implications

Purpose

To analyze the patterns of failure, the toxicity profile, and the factors influencing efficacy of stereotactic body radiation (SBRT) for early-stage non-small-cell lung cancer (NSCLC).

Methods and materials

A search was based on PubMed electronic databases. All searches were conducted in May, 2009.

Results

The local control ranged from 80% to 100% in most studies with adequate isocentric or peripheral biologically effective dose (BED). Recurrences were associated with increased tumor size. The main pattern of failure after SBRT was distant metastasis. Grades 3-5 toxicity occurred mostly in centrally located tumors, and adjuvant chemotherapy may further decrease all recurrences; possibly translating to a survival benefit in large or centrally located tumors where high BED cannot be safely reached.

Conclusion

SBRT is an excellent treatment option for early-stage, and mostly medically inoperable, NSCLC. BED at both the isocenter and the tumor periphery is very important for optimal tumor control; higher doses are required for large (?T2) lesions; SBRT for centrally located tumors can be feasible with a much less aggressive dose regimen than 60-66 Gy/3 fractions and adjacent critical structures excluded from the target volume; chemotherapy may optimize the clinical outcome in large or centrally located lesions.