Meng-Hao Wu

Safety and efficacy of semiextended field intensity-modulated radiation therapy and concurrent cisplatin in locally advanced cervical cancer patients: An observational study of 10-year experience

Abstract Patients with locally advanced cervical cancer (LACC) are at risk of para-aortic lymph node (PALN) metastasis. Pelvic concurrent chemoradiotherapy, the current standard treatment for LACC, has a PALN failure rate of 9% according to the Radiation Therapy Oncology Group Trial 90–01, suggesting that it may not completely eliminate all microscopic tumors in the PALNs. To minimize the toxicities associated with conventional prophylactic extended-field radiotherapy, our institute use prophylactic semiextended field radiotherapy that includes only the PALNs below the level of the renal vessels. Use of intensity-modulated radiotherapy (IMRT) is another means of reducing the incidence of toxicity. This study evaluated the safety and efficacy of prophylactic semiextended field IMRT (SEF-IMRT) and concurrent cisplatin chemotherapy in patients with LACC. We retrospectively assessed survival and toxicity in 76 patients with stage IB2–IVA cervical cancer and negative PALNs who received prophylactic SEF-IMRT and concurrent weekly cisplatin (40u200amg/m2) between 2004 and 2013. The region targeted by SEF-IMRT included the PALNs below the level of the renal vessels, and the prescribed dose was 50.4 Gy in 28 fractions. Brachytherapy was administered at a dose of 30 Gy in 6 fractions. Survival outcomes were calculated by using the Kaplan–Meier method, and acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All patients completed the planned SEF-IMRT, as well as brachytherapy. Acute grade ≥3 gastrointestinal, genitourinary, and hematologic toxicities were observed in 2, 0, and 41 patients, respectively. The median follow-up time after SEF-IMRT was 55 (range, 11–124) months. Eight patients developed out-field distant recurrences without PALN failure, and 1 patient experienced out-field PALN failure with simultaneous distant metastasis. No patients had late genitourinary toxicities, and 3 patients had late grade 3 gastrointestinal toxicities. The 5-year overall survival, disease-free survival, local failure-free survival, regional failure-free survival, PALN failure-free survival, and distant metastasis-free survival rates were 85.0%, 84.4%, 96.0%, 97.3%, 98.6%, and 88.4%, respectively. For patients with LACC, prophylactic PALN irradiation up to the level of the renal vessels reduced PALN recurrence and resulted in favorable outcomes with few severe toxicities.

Prophylactic lower para-aortic irradiation using intensity-modulated radiotherapy mitigates the risk of para-aortic recurrence in locally advanced cervical cancer: A 10-year institutional experience

OBJECTIVEnTo evaluate the effects of prophylactic sub-renal vein radiotherapy (SRVRT) using intensity-modulated radiotherapy (IMRT) for cervical cancer.nnnMETHODSnA total of 206 patients with FIGO stage IB2-IVA cervical cancer and negative para-aortic lymph nodes (PALNs) who underwent pelvic IMRT (PRT) or SRVRT between 2004 and 2013 at our institution were reviewed. SRVRT cranially extended the PRT field for PALNs up to the left renal vein level. The prescribed dose was consistent 50.4Gy in 28 fractions.nnnRESULTSnOverall, 110 and 96 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage and positive pelvic lymph nodes (PLNs). The median follow-up time was 60months (range, 7-143). For the total study population, the 5-year PALN recurrence-free survival (PARFS) and overall survival (OS) for PRT vs. SRVRT were 87.6% vs. 97.9% (p=0.03) and 74.5% vs. 87.8% (p=0.04), respectively. In patients with FIGO III-IVA or positive PLNs, the 5-year PARFS and OS for PRT vs. SRVRT were 80.1% vs. 96.4% (p=0.02) and 58.1% vs. 83.5% (p=0.012), respectively. However, there were no significant differences in these outcomes for patients with FIGO IB-IIB and negative PLNs. In a multivariate analysis, only SRVRT was associated with better PARFS (HR, 0.21; 95% CI, 0.06-0.78; p=0.02). The SRVRT did not significantly increase severe late toxicities.nnnCONCLUSIONnProphylactic SRVRT using IMRT reduced PALN recurrence with tolerable toxicities, supporting the application of risk-based radiation fields for cervical cancer.

Impact of para-aortic recurrence risk-guided intensity-modulated radiotherapy in locally advanced cervical cancer with positive pelvic lymph nodes

OBJECTIVESnA previous study has suggested the benefit of sub-renal vein radiotherapy (SRVRT) for pelvic lymph node (PLN)-positive cervical cancer. In order to better select patients for SRVRT, this study aimed to evaluate the value of a risk-based radiation field based on PLN location and number in PLN-positive cervical cancer.nnnMETHODSnWe reviewed 198 patients with FIGO stage IB2-IVA cervical cancer, positive PLNs, and negative para-aortic lymph nodes (PALNs) from 2004 to 2015 at two tertiary centers. All patients underwent pelvic radiotherapy (PRT) or SRVRT with IMRT. The SRVRT extended the PRT field cranially to the level of the left renal vein. The prescribed doses were 45-50.4Gy in 1.8Gy per fraction.nnnRESULTSnOverall, 118 and 80 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage, common iliac PLNs, and number of PLNs. The median follow-up was 63months (range: 7-151months). PALN failure was experienced by 28 patients (23.7%) in the PRT group and 1 patient (1.3%) in the SRVRT group (p<0.001). Compared with PRT, SRVRT significantly improved 5-year PALN recurrence-free survival (56.8% vs. 100%, p<0.001) and cancer-specific survival (56.5% vs. 93.9%, p<0.001) among patients with common iliac PLNs or ≥3 PLNs. No significant differences were observed in these outcomes among patients with PLNs below the common iliac bifurcation and 1-2 PLNs. The SRVRT did not increase severe toxicities.nnnCONCLUSIONSnRisk-based radiation field based on PLN location and number could optimize outcomes for PLN-positive cervical cancer.

Development of delineation for the left anterior descending coronary artery region in left breast cancer radiotherapy: An optimized organ at risk

BACKGROUND AND PURPOSEnThe left anterior descending coronary artery (LAD) and diagonal branches (DBs) are blurred on computed tomography (CT). We aimed to define the LAD region (LADR) with adequate inclusion of the LAD and DBs and contouring consistency.nnnMETHODS AND MATERIALSnThe LADR was defined using coronary CT angiograms. The inclusion ratio was used to assess the LAD and DBs inclusion by the LADR. Four radiation oncologists delineated the LAD and LADR, using contrast-enhanced CT of 15 patients undergoing left breast radiotherapy. The Sørensen-Dice similarity index (DSI), Jaccard similarity index (JSI), and Hausdorff distance (HD) were calculated to assess similarity. The mean dose (Dmean) and maximum dose (Dmax) to the LAD and LADR were calculated to compare consistency. Correlations were evaluated using Pearsons correlation coefficient.nnnRESULTSnThe inclusion ratio of the LAD by the LADR was 96%. The mean DSI, JSI, and HD values were respectively 27.9%, 16.7%, and 0.42mm for the LAD, and 83.1%, 73.0%, and 0.18mm for the LADR. The Dmean between the LAD and LADR were strongly correlated (r=0.93).nnnCONCLUSIONnDelineation of the LADR significantly improved contouring similarity and consistency for dose reporting. This could optimize dose estimation for breast radiotherapy.

Dosimetric predictors of acute haematological toxicity in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy.

OBJECTIVEnHaematological toxicity (HT) is common in patients with oesophageal cancer (EC) treated with chemoradiotherapy (CRT). The Quantitative Analysis of Normal Tissue Effects in the Clinic guidelines provide no dose constraints for the bone marrow (BM) to avoid HT. We aimed to determine dosimetric factors associated with HT during CRT for EC.nnnMETHODSn41 patients with EC treated with neoadjuvant cisplatin and 5-fluorouracil-based CRT were retrospectively reviewed. Associations between the dose-volume histogram parameters of thoracic bones and blood cell count changes during CRT were assessed using logistic regression analyses. Receiver-operating characteristic curves were used to derive optimal dosimetric planning constraints. Vx indicates the total organ volume percentage exceeding a radiation dose of x (Gy).nnnRESULTSnGreater thoracic vertebrae and rib irradiation doses, including mean vertebral dose (MVD), thoracic vertebrae V5-30 (TVV5-30), mean rib dose and rib V5-20, were associated with increased leukopenia (gradeu2009≥u20093) risk. Additional BM sites (sternum, scapulae and clavicles) did not influence HT. White blood cell and absolute neutrophil count nadirs were associated with increased irradiation doses to the thoracic vertebrae, ribs and sternum. Chemotherapy cycle number was not significantly associated with severe neutropenia or leukopenia. Cut-off values with the highest likelihood of avoiding leukopenia were MVDu2009<u200925.9u2009Gy, TVV20u2009<u200970% and TVV10u2009<u200977%.nnnCONCLUSIONnThoracic bone irradiation dose was significantly associated with HT after adjusting for chemotherapy effects. Efforts to maintain MVDu2009<u200925.9u2009Gy, TVV10u2009<u200977% and TVV20u2009<u200970% could reduce HT.nnnADVANCES IN KNOWLEDGEnThis is the first study addressing issues concerning HT in patients with neoadjuvant CRT-treated EC.

Delineation guideline for the para-aortic lymph node region in cervical cancer

https://doi.org/10.1016/j.radonc.2018.05.010 0167-8140/ 2018 Elsevier B.V. All rights reserved. Dear Editor, We read with great interest the paper entitled, ‘‘An atlas to aid delineation of para-aortic lymph node region in cervical cancer: Design and validation of contouring guidelines,” which addresses guidelines for delineating the para-aortic lymph node (PAN) clinical target volume (CTV) in patients with cervical cancer [1]. The authors evaluated 21 patients with 39 pathological PANs identified via positron emission tomography–computed tomography (PET-– CT) and used asymmetrical margins to expand the aorta and inferior vena cava (IVC) and create a CTV with more favourable PAN coverage. The proposed CTV was validated in 10 additional patients with 29 PANs. The final proposed PAN CTV involved a generally 10-mm circumferential expansion (with 15-mm lateral expansion) from the aorta and 8-mm anteromedial and 6-mm posterolateral expansion from the IVC. The left renal vein marked the superior extent of the PAN CTV. The variability in the upper extent of prophylactic para-aortic irradiation among centres likely reflects the lack of evidence and delineation guidelines [2]. We recently published sub-renal vein radiotherapy (SRVRT) findings to address the effects of prophylactic para-aortic irradiation with an upper extent of the left renal vein and the role of the risk-based radiation field in cervical cancer [3,4]. SRVRT with intensity-modulated radiotherapy reduced PAN recurrence without increasing severe toxicities, especially among patients with positive pelvic lymph nodes or FIGO III–IVA disease. However, prospective trials must validate the applicability of PAN guidelines and our findings in clinical practice. The EMBRACE II study may resolve this important issue. Takiar et al. also proposed delineation of the PAN CTV based on the anatomical PET–CT distribution in their figure rather than providing a detailed definition, as in the authors’ paper [5]. However, we observed some differences and identified questions for which the resolution would facilitate the use of this important guideline in clinical practice. First, Takiar et al. suggested an anterior margin close to the aorta and IVC, while the authors suggested 10and 8mm margin expansions from the aorta and IVC, respectively. Although the left para-aortic and aorto-caval areas appear to be most risky; more information is needed regarding the PANs anterior to these major vessels. As the riskiest area may be just anterior to major vessels, a limited anterior margin might reduce radiation doses to the bowel. Second, the 15-mm left lateral margin, rather than the iliopsoas muscle, was used as a lateral anatomical landmark. This margin raises concerns because of the risk of false-negative findings for micro-metastatic PANs on PET–CT [6]. Consistent with this, Ramirez et al. found that patients with positive pelvic lymph nodes and negative PANs on PET–CT had a histopathologically positive PAN rate of 22% [7]. We congratulate the authors on their work and hope that continued efforts such as theirs will ultimately lead to an evidencebased consensus regarding the international recommendations for CTV design in cervical cancer radiotherapy.

Skeletal Muscle Loss Is an Imaging Biomarker of Outcome after Definitive Chemoradiotherapy for Locally Advanced Cervical Cancer

Purpose: This study investigates the association between body composition change during concurrent chemoradiotherapy (CCRT) and outcome in patients with locally advanced cervical cancer (LACC). Experimental Design: Pre- and posttreatment CT images of 245 patients with LACC who were treated between 2004 and 2015 were analyzed. Skeletal muscle index (SMI) and density (SMD), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) were measured from two sets of CT images at the level of the L3 vertebra. Sarcopenia and a low SMD were defined using published cut-off points. Predictors of overall survival (OS) and cancer-specific survival (CSS) were analyzed using Cox regression models. Results: The median follow-up was 62.7 (range, 7.3–152.3) months. Among the 245 patients, 127 (51.8%) had pretreatment sarcopenia, and 154 (62.9%) had a low SMD. SMI did not decrease significantly during CCRT, 0.6%/150 days [95% confidence interval (CI), −1.8–0.6; P = 0.35]. However, SMI loss during CCRT of >10.0%/150 days was independently associated with poorer OS (HR, 6.02; 95% CI, 3.04–11.93; P < 0.001) and CSS (HR, 3.49; 95% CI, 1.44–8.42; P = 0.006) when adjusted for FIGO stage, pathology, and treatment. Pretreatment sarcopenia and change of SMD, SATI, and VATI during CCRT were not associated with survival. Conclusions: Skeletal muscle measurements could be imaging biomarkers to predict outcomes for patients with LACC in clinical practice. Further studies are needed to determine whether multimodal interventions can preserve skeletal muscle mass and thereby improve survival. Clin Cancer Res; 24(20); 5028–36. ©2018 AACR.

Comparison of Dosimetry for Left Anterior Descending Coronary Artery in Left Breast Irradiation by Intensity-Modulated and 3-Dimentional Conformal Radiotherapy

Purpose: The intent of this study was to compare the dosimetry of the left anterior descending coronary artery (LAD) and organs at risk (OARs) in left breast cancer patients in two treatment techniques, intensity-modulated radiation therapy (IMRT) and 3-dimentional conformal radiotherapy (3DCRT). Materials and Methods: Fourteen patients with left breast cancer who had received post-operative radiotherapy (RT) to the breast between October 2012 and November 2013 were enrolled in the study. All patients were irradiated with 6- or 10-MV photon beams using 3-dimentional conformal tangential technique to the left whole breast. For dosimetric comparison, two sets of six-field IMRT plans, with or without LAD constraint of V20 Gy＜50%, on each patient were performed. These three RT plans were named tangential field (TF), non-LAD constraint (NLC) and LAD constraint (LC), respectively. Five patients also received supraclavicular fossa (SCF) irradiation, but only whole breast dosimetry parameters were analyzed. The conformity index (CI), homogeneity index (HI) and dose-volume histogram (DVH) for the LAD, heart and ipsilateral lung were calculated for analysis. Repeated measures of one-way ANOVA with Bonferroni post hoc test (software SPSS 21.0) was used for statistics. Results: For the 14 patients given left breast irradiation, there was an obvious statistical benefit for HI (average 12.67%) and CI (average 92.95%) by IMRT (both p＜0.0001). According to the data, it was found that an LAD mean dose (Dmean), V20 Gy, V30 Gy and LAD area mean dose (LAD of 10 mm in all directions) were reduced by using the LC arm (average 20.28 Gy, 41.19%, 29.60% and 21.46 Gy, respectively) if using IMRT technique (all p＜0.05). However, there was no statistical difference between TF and LC arms (p＞0.05). Additionally, although the low dose bath (LAD V5 Gy average 82.81%) was a drawback in IMRT (p＜0.05), the LC arm was still better than the NLC arm if the LAD constraint was used (p=0.013). There was no statistical significance between the 3 arms in regard to LAD maximum dose (Dmax) (3-arm average 47.21 Gy). 3DCRT had lower heart Dmean (average 3.77 Gy), ipsilateral lung Dmean (average 7.14 Gy) and V5 Gy (average 19.21%) than with IMRT (average 6.10 Gy, 9.31 Gy and 38.57%, respectively) (all p＜0.0001), and there was no statistical difference between IMRT arms (p＞0.05). Conclusion: In the light of our dosimetric data, IMRT may offer much better HI and CI than conventional tangential-field RT. In order to decrease the high-dose area of LAD, we had to select an appropriate LAD constraint (in this study, LAD V20 Gy ＜50% was used), if IMRT planning was done. IMRT technique results in a low dose bath (V5 Gy) and we should use this treatment option carefully. Further investigation for LAD constraint is needed.

Evaluation of Dose to Heart and Left Anterior Descending Coronary Artery during Left Breast Irradiation

Purpose: The aim of this retrospective study is to quantify dose irradiated to the heart and the left anterior descending coronary artery (LADCA) in left breast cancer patients treated with adjuvant breast radiotherapy and analyse the probable causes of high dose to the heart and LADCA. Methods and Materials: Twenty-one consecutive patients with left-sided breast cancer who underwent adjuvant radiotherapy to the breast between August 2012 and October 2013 are enrolled in our study. All patients were irradiated with 6- or 10-MV tangential beams to the breast and seven patients of them also received supraclavicular fossa (SCF) irradiation with IMRT technique. For each dose plan, dose-volume histograms (DVHs) for the heart and LADCA were calculated and analyzed. Pearson correlation coefficient was calculated to assess the relationship between average heart D_(mean) (mean dose), LAD D_(mean) and LAD_(max) (maximum dose) and between LAD D_(mean) and volume of LADCA in the radiation fields (i.e., it received ＞25 Gy). Students t test was used to assess the statistical significance of differences in radiation dose to LADCA and heart between patients who received SCF IMRT or not. Results: For the 21 patients given left breast irradiation, the average mean [range] dose was 4.04 [1.75-11.15] Gy to the heart and 21.29 [6.99-35.28] Gy to the LADCA, and the average maximum dose was 54.31 [50.55-58.42] Gy to the LADCA. There is significant correlation between D_(mean) to the heart and LADCA (r= 0.80, p ＜ 0.01). The D_(mean) to LADCA was postulated to increase 3.44 Gy for each increase of 1 Gy in the mean radiation dose delivered to the heart in our study. There is significant correlation between Dmean to LADCA and the volume of LAD in the radiation fields (i.e., it received ＞25 Gy) (r= 0.94, p＜ 0.0001). The D_(mean) to LADCA was postulated to increase 0.77 Gy for each increase of 1 ml of LADCA volume in the radiation field. For 7 patients who received left-tangential radiotherapy and SCF IMRT, the average mean dose was 4.15 [2.58-8.9] Gy to the heart and 21.93 [16.49-35.21] Gy to the LADCA, and the average maximum dose was 55.21 [52.63-57.79] Gy to the LADCA. SCF IMRT contributed to average mean dose 0.15 [0.05-0.35] Gy and average maximum dose 0.43 [0.15-0.68] Gy to the LADCA. There is no significant difference in Dmean to the LADCA and heart between patients who received SCF IMRT or not (p= 0.38, p= 0.45, respectively). Conclusion: For patients receiving left-tangential radiotherapy, the higher Dmean to the LADCA was strongly correlated to the larger volume of LADCA in the radiation fields. There is significant correlation between D_(mean) to the heart and LADCA. The patients with the higher mean heart dose had the higher mean LADCA dose. We may suggest to limit mean dose to LADCA by avoiding volume of LADCA in the treatment fields if well visualized LADCA on CT scan or limiting the mean heart dose to lower mean LADCA dose if poor visualization of LADCA on CT scan.