Cardiopulmonary Toxicity Following Intensity-Modulated Proton Therapy (IMPT) Versus Intensity-Modulated Radiation Therapy (IMRT) for Stage III Non-Small Cell Lung Cancer

IntroductionIntensity-modulated proton therapy (IMPT) has the potential to reduce radiation dose to normal organs when compared to intensity-modulated radiation therapy (IMRT). We hypothesized that IMPT is associated with a reduced rate of cardiopulmonary toxicities in patients with Stage III NSCLC when compared with IMRT.MethodsWe analyzed 163 consecutively treated patients with biopsy-proven, stage III NSCLC who received IMPT (n = 35, 21%) or IMRT (n = 128, 79%). Patient, tumor, and treatment characteristics were analyzed. Overall survival (OS), freedom-from distant metastasis (FFDM), freedom-from locoregional relapse (FFLR), and cardiopulmonary toxicities (CTCAE v5.0) were calculated using the Kaplan-Meier estimate. Univariate cox regressions were conducted for the final model.ResultsMedian follow-up of surviving patients was 25.5 (range, 4.6-58.1) months. Median RT dose was 60 (range, 45-72) Gy [RBE]. OS, FFDM, and FFLR were not different based on RT modality. IMPT provided significant dosimetric pulmonary and cardiac sparing when compared to IMRT. IMPT was associated with a reduced rate of grade more than or equal to 3 pneumonitis (HR 0.25, P = .04) and grade more than or equal to 3 cardiac events (HR 0.33, P = .08). Pre-treatment predicted diffusing capacity for carbon monoxide less than equal to 57% (HR 2.8, P = .04) and forced expiratory volume in the first second less than equal to 61% (HR 3.1, P = .03) were associated with an increased rate of grade more than or equal to 3 pneumonitis.ConclusionsIMPT is associated with a reduced risk of clinically significant pneumonitis and cardiac events when compared with IMRT without compromising tumor control in stage III NSCLC. IMPT may provide a safer treatment option, particularly for high-risk patients with poor pretreatment pulmonary function.     

Single Institution Experience of Proton and Photon-based Postoperative Radiation Therapy for Non–small-cell Lung Cancer

IntroductionPostoperative radiation therapy (PORT) for non–small-cell lung cancer remains controversial with studies showing no overall survival (OS) benefit in the setting of excessive cardiopulmonary toxicity. Proton beam therapy (PBT) can potentially reduce toxicity with improved organ-at-risk sparing. We evaluated outcomes of PORT patients treated with PBT and intensity-modulated radiation therapy (IMRT).Materials and MethodsThis is a retrospective review of 136 PORT patients (61 PBT, 75 IMRT) treated from 2003 to 2016. A Kaplan-Meier analysis was performed to assess oncologic outcomes. A Cox regression was conducted to identify associated factors. Total toxicity burden (TTB) was defined as grade ≥ 2 pneumonitis, cardiac, or esophageal toxicity.ResultsMedian OS was 76 and 46 months for PBT and IMRT with corresponding 1- and 5-year OS of 85.3%, 50.9% and 89.3%, 37.2% (P = .38), respectively. V30 Gy heart (odds ratio [OR], 144.9; 95% confidence interval [CI], 2.91-7214; P = .013) and V5 Gy lung (OR, 15.8; 95% CI, 1.22-202.7; P = .03) were predictive of OS. Organ-at-risk sparing was improved with PBT versus IMRT; mean heart 2.0 versus 7.4 Gy (P < .01), V30 Gy heart 2.6% versus 10.7% (P < .01), mean lung 7.9 versus 10.4 Gy (P = .042), V5 Gy lung 23.4% versus 42.1% (P < .01), and V10 Gy lung 20.4% versus 29.6% (P < .01). TTB was reduced with PBT (OR, 0.35; 95% CI, 0.15-0.83; P = .017). Rates of cardiac toxicity were 14.7% IMRT and 4.9% PBT (P = .09). Rates of ≥ grade 2 pneumonitis were 17.0% IMRT and 4.9% PBT (P = .104).ConclusionPBT improved cardiac and lung sparing and reduced toxicity compared with IMRT. Considering the impact of cardiopulmonary toxicity on PORT outcomes, PBT warrants prospective evaluation.     

Factors Associated With Acute Toxicity in Pediatric Patients Treated With Proton Radiation Therapy: A Report From the Pediatric Proton Consortium Registry

PurposeLimited prospective information regarding acute toxicity in pediatric patients receiving proton therapy (PT) exists. In this study, Pediatric Proton Consortium Registry (PPCR) data was analyzed for factors associated with development of acute toxicity in children receiving passively scattered or pencil beam scanning PT.Methods and MaterialsPediatric patients treated with PT and enrolled on the PPCR from 2016 to 2017 at 7 institutions were included. Data were entered on presence versus absence of acute general, cardiac, endocrine, eye, gastrointestinal, genitourinary, hematologic, mouth, musculoskeletal, neurologic, psychological, respiratory, and skin toxicities before (baseline) and at the end of PT (acute). Associations between patient and treatment variables with development of acute toxicity were assessed with multivariable modeling.ResultsOf 422 patients included, PT technique was passively scattered in 241 (57%), pencil beam scanning in 180 (43%), and missing in 1 (<1%) patient. Median age was 9.9 years. Daily anesthesia for treatment was used in 169 (40%). Treatments were categorized as craniospinal irradiation (CSI; n = 100, 24%), focal central nervous system PT (n = 157, 38%), or body PT (n = 158, 38%). Passively scattered PT was associated with increased risk of hematologic toxicity compared with pencil beam scanning PT (odds ratio [OR]: 3.03; 95% confidence interval [CI], 1.38-6.70; P = .006). There were no other differences toxicities between PT techniques. Uninsured patients had increased risk of GI (OR: 2.71; 95% CI, 1.12-6.58; P = .027) and hematologic toxicity (OR: 10.67; 95% CI, 2.68-42.46; P <.001). Patients receiving concurrent chemotherapy were more likely to experience skin (OR: 2.45; 95% CI, 1.23-4.88; P = .011), hematologic (OR: 2.87; 95% CI, 1.31-6.25; P = .008), GI (OR: 2.37; 95% CI, 1.33-4.21; P = .003), and mouth toxicities (OR: 2.03; 95% CI, 1.10-3.73; P = .024). Patients receiving 49 to 55 Gy were more likely to experience skin (OR: 2.18; 95% CI, 1.06-4.44; P = .033) toxicity than those receiving <49 Gy.ConclusionsThe PPCR registry highlights broad differences in acute toxicity rates in children receiving PT, and identifies opportunities for improvements in prevention, monitoring, and treatment of toxicities.     

Toxicity Related to Radiotherapy Dose and Targeting Strategy: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Locally Advanced Non–Small Cell Lung Cancer

Objective

Concurrent chemoradiotherapy (CRT) was the standard treatment for locally advanced NSCLC (LA-NSCLC). This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on adverse events (AEs).

Hypofractionated Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost and Simultaneous Integrated Protection in Pancreatic Ductal Adenocarcinoma

AimsTo evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) and simultaneous integrated protection (SIP) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma.Materials and methodsPatients receiving SBRT following induction chemotherapy from January 2017 to December 2018 were included in this observational analysis. SBRT was delivered in five consecutive daily fractions by administering 30 Gy to the planning target volume while simultaneously delivering a 50 Gy SIB to the tumour–vessel interface. SIP was created by lowering the dose to 25 Gy on the overlap area between the planning target volume and the planning organ at risk volume. The primary end point was acute and late gastrointestinal grade ≥3 toxicity. Secondary end points were freedom from local progression, overall survival and progression-free survival (PFS).ResultsFifty-nine consecutive patients (27 borderline resectable and 32 locally advanced) were included. Fifty-eight patients (98.3%) completed the SBRT planned treatment and 35 patients (59.4%) received surgical resection following SBRT. No acute or late grade ≥3 SBRT-related adverse events were observed. The median follow-up time was 15.1 months in the overall cohort and 18.1 months in censored patients. One- and 2-year freedom from local progression rates were 85% and 80% versus 79.7% and 60.6% in resected and unresected patients, respectively (P = 0.33). The median overall survival and PFS were 30.2 months and 19 months from diagnosis and 19.1 months and 10.7 months from SBRT in the entire cohort. Resected patients had improved 2-year overall survival rates (72.5% versus 49%, P = 0.012) and median PFS (13 months versus 5 months; P < 0.001) relative to unresected patients. There was no survival difference between borderline resectable and locally advanced patients.ConclusionsSBRT with SIB/SIP had an excellent toxicity profile and could be administered safely on pancreatic ductal adenocarcinoma patients, even in a total neoadjuvant setting.     

The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer

AimNew hormonal agents are available for treating metastatic castration-resistant prostate cancer (mCRPC). We aim to define the incidence and relative risk (RR) of cardiovascular events in mCRPC patients treated with these agents.MethodsProspective studies were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods.ResultsWe included six articles in this meta-analysis covering a total of 6735 patients who were used to evaluate cardiac toxicity. The use of new hormonal agents was associated with an increased risk of all grades of such toxicity (RR = 1.32, 95% CI, 1.08–1.60; p = 0.006) compared to a placebo, even if the absolute difference in terms of incidence was small at 14.8% versus 11.5%, respectively. No increased risk of grade 3–4 events (RR = 1.35, 95% CI, 0.90–2.03; p = 0.15) was observed.A total of 7830 patients were used to evaluate hypertension, and it was found that the use of new hormonal agents compared to a placebo was associated with an increased risk of all-grades (RR = 1.84, 95% CI, 1.37–2.46; p < 0.001) and grade 3–4 events (RR = 1.77, 95% CI, 1.13–2.77; p = 0.01). The absolute incidence was 12.5% versus 7.5% for all-grades and 3.7% versus 2.4% for grade 3–4.ConclusionsThis analysis revealed a significant increase in the incidence and RR of cardiovascular toxicity in mCRPC treated with new hormonal agents as opposed to a placebo, even though the occurrence of all- and grade 3–4 events rose only 14% and 4%, respectively. Follow-ups for the onset of treatment-related cardiovascular events should therefore be considered in these patients.     

An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer

BackgroundBoth sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib.MethodsTwo sequential prospective single arm phase II studies investigated either 12 weeks of sunitinib (n = 43) or pazopanib (n = 34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800 mg once daily (OD)) and sunitinib (50 mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12 weeks of therapy.ResultsThere was no significant difference in the overall number of toxic events (grade 1–4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p > 0.05). Increased grade 2–4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11–2.56] p < 0.03). Sunitinib was associated with an increased grade 2–4 mucositis (16% versus 0% p = 0.02) and fatigue (42% versus 15% p = 0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p = 0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p < 0.05). There was no difference in the occurrence of asymptomatic toxicity.ConclusionThis indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient’s choice. Further comparative data from randomised trials are awaited.     

Renal function,body surface area,and age are associated with risk of early-onset fluoropyrimidine-associated toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care

BackgroundThe objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care.Patients and MethodsA total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early – i.e. cycle one or two – severe (grade ≥ 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis.ResultsAmong 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade ≥3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio [OR] 0.85 per 10 ml/min/1.73 m², p = 0.0007), body surface area (BSA) (OR 0.33 per m², p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade ≥3 toxicity was 0.704 (95% confidence interval 0.666–0.743, optimism-corrected AUC 0.690).ConclusionRenal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care.     

Optimizing Palliative Focal Radiation Therapy Dose in Cutaneous T-Cell Lymphoma: How Low Can You Go?

PurposePrimary cutaneous T-cell lymphomas (CTCLs) are radiosensitive tumors with variable and often relapsing courses. Local disease can be treated with low-dose focal palliative radiation therapy (RT), though little data supports the use of a specific dose. This study assesses clinical outcomes after focal RT to a total dose of 4 Gy, 8 Gy, or 12 Gy.Methods and MaterialsAn International Review Board-approved, retrospective, single-institution study was performed of 225 lesions in 41 patients with primary CTCL treated with low-dose focal RT from 2015 to 2020. Patient, tumor, and treatment characteristics were reviewed. The primary outcome was freedom from treatment failure (FFTF), defined as time to requiring local retreatment, and secondary outcomes included response rates and toxicities.ResultsOf the 225 lesions, 90 received 4 Gy, 106 received 8 Gy, and 29 received 12 Gy. Lesions treated with 12 Gy (96%) or 8 Gy (92%) had a significantly higher 1-year FFTF compared with 4 Gy (77%) (P = .034). Overall response rate and complete response rate were not significantly different between different doses (P = .117), though there was a trend toward higher overall response rate at initial assessment with 8 Gy versus 4 Gy (91.5% vs 82.2%, P = .057). Toxicity was low, with 7.1% of lesions having grade 2 or higher radiation dermatitis.ConclusionsIn primary CTCL lesions treated with focal palliative RT, a dose response was noted favoring 8 to 12 Gy, with 1-year FFTF rates over 90%. However, 4 Gy resulted in substantially better outcomes than previously reported, with 77% requiring no further treatment at 1 year and comparable response rates to higher doses. While our data substantiates 8 to 12 Gy as the standard of care, it also suggests that 4 Gy should be considered an acceptable alternative in situations with concern for radiation toxicities, such as with fragile or heavily pretreated skin.     

Heart Dose Is an Independent Dosimetric Predictor of Overall Survival in Locally Advanced Non–Small Cell Lung Cancer

IntroductionIn the randomized trial of standard- versus high-dose chemoradiotherapy for locally advanced (LA) NSCLC (Radiation Therapy Oncology Group 0617), overall survival (OS) was worse in the high-dose arm. Although heart dose was suggested as a contributing factor, actionable parameters have not been established. We present an analysis of clinical and dosimetric parameters affecting OS in this patient population, focusing on heart dose.MethodsClinical data were collected on 416 patients with LA NSCLC treated at a single institution, with a subset of 333 available treatment plans recontoured using Radiation Therapy Oncology Group 0617 normal tissue guidelines. Toxicity and dosimetry data were analyzed for 322 patients; multivariate analysis was performed on 251 patients. Dosimetric parameters of radiation to tumor and organs at risk were analyzed with clinical data pertaining to OS, disease-free survival, and toxicity.ResultsPatients were treated with radiation therapy to prescribed doses of 50.0 to 84.9 Gy (median 66.0 Gy). Median follow-up was 14.5 months. Median OS was 16.8 months. The 1- and 2-year OS rates were 61.4% and 38.8%, respectively. On multivariate analysis, factors independently associated with worse OS were increasing heart V₅₀ (volume receiving ≥50 Gy), heart volume, lung V₅ (proportion of the lung structure [excluding the target volume]) receiving at least 5 Gy), bilateral mediastinal lymph node involvement, and lack of concurrent chemotherapy. When stratified by heart V₅₀ less than 25% versus 25% or greater, the 1-year OS rates were 70.2% versus 46.8% and the 2-year OS rates were 45.9% versus 26.7% (p < 0.0001). Median heart V₅₀ was significantly higher (20.8% versus 13.9%, p < 0.0001) for patients with cardiac toxicity with a Common Terminology Criteria for Adverse Events grade of 1 or higher.ConclusionsHeart dose is associated with OS and cardiac toxicity for patients with LA NSCLC treated with chemoradiotherapy.     

Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Antiangiogenic Agents

IntroductionSevere pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFis). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.MethodsWe evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any-grade and grade 3 plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR plus VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.ResultsTreatment with VEGFi plus SABR was associated with higher rates of G3+ pulmonary hemorrhage compared with those treated with SABR alone for the overall cohort (3-y incidence: 7.9% versus 0.6%, p < 0.01) and those with central tumors (19.1% versus 3.3%, p = 0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% versus 45.0%, p = 0.044), but not central nonabutting tumors (0.0% versus 1.3%, p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi plus SABR compared with VEGFi alone (9.6% versus 1.3%, p = 0.04).ConclusionsThe combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.     

Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial

Background

This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT).

Methods

Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost.

Results

Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54–0.86, and 65%, 95% CI, 0.52–0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78–17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT.

Conclusions

PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.     

Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology

BackgroundConcurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years.Patients and methodsHoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D.ResultsMedian survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction.ConclusionsConsolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity.     

Early clinical outcomes of helical tomotherapy/intensity‐modulated proton therapy combination in nasopharynx cancer

This study aimed to evaluate the feasibility of combining helical tomotherapy (HT) and intensity‐modulated proton therapy (IMPT) in treating patients with nasopharynx cancer (NPC). From January 2016 to March 2018, 98 patients received definitive radiation therapy (RT) with concurrent chemotherapy (CCRT). Using simultaneous integrated boost and adaptive re‐plan, 3 different dose levels were prescribed: 68.4 Gy in 30 parts to gross tumor volume (GTV), 60 Gy in 30 parts to high‐risk clinical target volume (CTV), and 36 Gy in 18 parts to low‐risk CTV. In all patients, the initial 18 fractions were delivered by HT, and, after rival plan evaluation on the adaptive re‐plan, the later 12 fractions were delivered either by HT in 63 patients (64.3%, HT only) or IMPT in 35 patients (35.7%, HT/IMPT combination), respectively. Propensity‐score matching was conducted to control differences in patient characteristics. In all patients, grade ≥ 2 mucositis (69.8% vs 45.7%, P = .019) and grade ≥ 2 analgesic usage (54% vs 37.1%, P = .110) were found to be less frequent in HT/IMPT group. In matched patients, grade ≥ 2 mucositis were still less frequent numerically in HT/IMPT group (62.9% vs 45.7%, P = .150). In univariate analysis, stage IV disease and larger GTV volume were associated with increased grade ≥ 2 mucositis. There was no significant factor in multivariate analysis. With the median 14 month follow‐up, locoregional and distant failures occurred in 9 (9.2%) and 12 (12.2%) patients without difference by RT modality. In conclusion, comparable early oncologic outcomes with more favorable acute toxicity profiles were achievable by HT/IMPT combination in treating NPC patients.     

Local Control and Toxicity of a Simultaneous Integrated Boost for Dose Escalation in Locally Advanced Esophageal Cancer: Interim Results from a Prospective Phase I/II Trial

IntroductionApproximately 50% of recurrences after standard-dose chemoradiation for locally advanced esophageal cancer occur within the gross tumor volume (GTV). In this prospective phase I/II clinical trial, we explored the use of a simultaneous integrated boost (SIB) dose to the GTV.MethodsForty-four patients with unresectable esophageal cancer received chemoradiation with an SIB of 58.8 to 63 Gy to the GTV and 50.4 Gy to the planning target volume, all in 28 fractions, with 5 weeks of concurrent docetaxel and fluorouracil or capecitabine. The end points were maximum tolerated dose, time to local failure, and clinical response.ResultsExcluding those with less than 6 months of follow-up, 38 patients were evaluated at the time of analysis. The median age was 65 years (range 37–84). Most patients (71%) were men; 84% had T3 disease, 37% had N1 disease, 26% had N2 disease, 13% had M1 disease, and 50% had adenocarcinoma. The maximum tolerated SIB dose was 63 Gy. None experienced Common Terminology Criteria for Adverse Events grade 4 or 5 toxicity. At a median follow-up time of 13.3 months (range 1.2–36.2), 11 (29%) had local failure (median time to local failure 2.5 months [range 1.5–23.9]). A comparison with 97 similar patients who received 50.4 Gy without an SIB showed that the SIB reduced the local failure rate for patients with node-positive disease (13% versus 56%, p = 0.04), adenocarcinoma (26% versus 59%, p = 0.02), or stage III–IV disease (29% versus 55%, p = 0.04).ConclusionsSIB intensity-modulated radiation therapy to gross primary disease may improve local control for patients with unresectable locally advanced esophageal cancer, especially those with adenocarcinoma.     

Exclusive radiotherapy for primary squamous cell carcinoma of the vagina

PurposeTo retrospectively analyze results of external beam therapy (EBT) with brachytherapy (BT) for primary vaginal squamous cell carcinoma (PVSCC).Materials and methodsFrom 1970 to 2001, 91 patients were included. FIGO stages were: I (29%), II (38%), III (29%) and IVa (4%). EBT delivered a median total dose of 50 Gy to the pelvis. BT was performed with a customized intra-vaginal applicator and in 36% of applications combined endocavitary and interstitial BT. ICRU Report 38 parameters were reported.ResultsThe 5-year cause specific survival (CSS) rates were: 83% for stage I, 76% for stage II, 52% for stage III, and 2 of the 4 stage IVa patients died 9 and 36 months after treatment. The 5-year pelvis control rates were: 79% for stage I and II and 62% for stage III. Recurrences as a first event were local only in 68% of cases, nodal only in 10%, metastatic only in 13% and combined in 9%. In multivariate analysis: stage (I and II versus II and IV), response to EBT (evaluated at BT), and the number of BT applications were statistically significant for CSS. Grade 2–3 toxicities were as follows (Franco-Italian Glossary): rectum (n = 3), sigmoid colon and small bowel (n = 8), bladder (n = 5), ureter (n = 4) and vagina (n = 13). Anterior location of the tumor increased bladder toxicity (p = 0.01) and total reference air kerma was higher in patients who experienced grade 2–3 urinary or digestive toxicity (p = 0.03).ConclusionEBT with BT is an effective treatment for patients with stage I–II PVSCC. The incidence and severity of late toxicity were relatively low. Recent advances in the treatment of cervix carcinoma emphasize the need for concomitant radio-chemotherapy in stages III–IV and the use of MRI for treatment planning.     

Lung Metastases Treated with Image-guided Stereotactic Body Radiation Therapy

AimsTo evaluate outcomes after treatment with image-guided stereotactic body radiation therapy (SBRT) using daily online cone beam computed tomography for malignancies metastatic to the lung.Materials and methodsForty-seven lung metastases in 32 patients were treated with volumetrically guided SBRT. The median age was 62 years (21–87). Primaries included colorectal (n = 10), sarcoma (n = 4), head and neck (n = 4), melanoma (n = 3), bladder (n = 2), non-small cell lung cancer (n = 2), renal cell (n = 2), thymoma (n = 2), thyroid (n = 1), endometrial (n = 1) and oesophageal (n = 1). The number of lung metastases per patient ranged from one to three (68% single lesions). SBRT was prescribed to the edge of the target volume to a median dose of 60 Gy (48–65 Gy) in a median of four fractions (four to 10). Most lesions were treated using 12 Gy fractions (92%) to 48 or 60 Gy.ResultsThe median follow-up was 27.6 months (7.6–57.1 months). The 1, 2 and 3 year actuarial local control rates for all treated lesions were 97, 92 and 85%, respectively. Two patients with colorectal primaries (four lesions in total) had local failure. The median overall survival was 40 months. The 1, 2 and 3 year overall survival from the time of SBRT completion was 83, 76 and 63%, respectively. There were no grade 4 or 5 toxicities. Grade 3 toxicities (one instance of each) included pneumonitis, dyspnoea, cough, rib fracture and pain.ConclusionSBRT with daily online cone beam computed tomography for lung metastases achieved excellent local tumour control with low toxicity and encouraging 2 and 3 year survival.     

Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation

AimMERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC).MethodsIn this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m² on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary end-points were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-A_high populations.ResultsOf 481 patients randomised (242 placebo–paclitaxel; 239 bevacizumab–paclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51–0.91; log-rank p = 0.0007) in the intent-to-treat population (median 8.8 months with placebo–paclitaxel versus 11.0 months with bevacizumab–paclitaxel) and 0.64 (96% confidence interval, 0.47–0.88; log-rank p = 0.0038) in the pVEGF-A_high subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade ≥3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade ≥3: 11% versus 4%).ConclusionThe significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab.Clinical trials registrationClinicalTrials.gov NCT01663727.