Late Treatment-related Toxicity Research Articles

Long-term health status of high-risk neuroblastoma survivors treated with high-dose chemotherapy and hematopoietic stem cell transplantation.

10054 Background: Current treatment strategies including high-dose chemotherapy with stem cell transplantation rescue (HDC-SCT) have improved 5-year event-free survival for high-risk neuroblastoma (HRNB) patients, but with an increased risk of late treatment-related toxicities. Methods: Between 1980 and 2012, 439 children were treated for HRNB with HDC-SCT in Gustave Roussy (GR), among which 145 were alive and disease-free at 5-year post-SCT. Long-term health data have been collected for those 145 patients, prospectively within the long-term follow-up clinic in GR or retrospectively from pediatric consultations. Results: With a median follow-up post-SCT of 15 years (range 5-34), we observed 6 late relapses, 11 second cancers (including 3 papillary thyroid carcinomas; median delay = 20 years post-SCT [18-22]) and 9 deaths. Event-free and overall survival at 20-year post-SCT were 82% (95%CI = 70–90) and 89% (95%CI = 78–95), respectively. A second health event was observed in 135 patients (median = 3/patient), including 103 patients with at least 1 severe event (median = 1/patient). Cumulative incidence at 15-year post-SCT for second cancers is 4%, cardiac diseases 8%, thyroid 11%, renal 7%, hepatic focal nodular hyperplasia 14%, dental mal-development 70%, and severe hearing loss 20%. Height-for-age z-score was ≤-2 for 30 patients (21%) and ≤-3 for 12 patients (8%). After Busulfan-Melphalan conditioning regimen, 40/43 females and 33/35 males had a gonadal insufficiency. Conclusions: Long-term consequences of HRNB treatment including HDC are frequent and disabling, mainly due to hearing loss and gonadal insufficiency.

Involved-Site Radiation Therapy for H. Pylori-Independent Gastric MALT Lymphoma: 26 Years of Experience with 178 Patients

Gastric mucosa associated lymphoid tissue lymphoma (GML) is often associated with Helicobacter pylori (H. pylori) infection. Eradication of H. pylori is effective for up to 80% of patients. For H. pylori-independent GML, treatment options include surgery, immunotherapy, chemotherapy and radiation therapy (RT). The purpose of this study is to investigate the efficacy and safety of involved site radiation therapy and routine endoscopic surveillance, hypothesizing that radiation is highly effective for H. pylori–independent GML and most patients are curable with RT alone. A single institution database at a tertiary referral cancer center was queried for patients with H. pylori-independent GML treated with radiation between 1991 and 2017. Prior to treatment, pathology was confirmed by hematopathology experts and patients underwent staging with either computed tomography scan, positron emission tomography, endoscopic ultrasound, or a combination of techniques. All patients received involved site radiation therapy to the stomach. The clinical treatment volume (CTV) included the stomach and first part of the duodenum. Perigastric lymph nodes and other parts of the duodenum were also included in CTV if involved with disease. Response was assessed by follow up endoscopies (EGDs) within 10-12 weeks following RT with multiple biopsies at frequent intervals, as well as appropriate radiographic imaging. Survival analysis was calculated using the Kaplan Meier estimator and toxicity was graded according to CTCAEv4 criteria. There were 178 patients identified (56% female). Median age was 63 years (range 25-91 years). Eighty-eight percent of patients presented with stage I disease; 6% were stage II and 6% were stage IV. Median RT dose was 3000 cGy over 20 fractions. Post treatment EGD with biopsy was obtained in 173 patients, of which 95% demonstrated a complete pathologic response. Intriguingly, 4 patients had abnormal posttreatment EGD biopsies that spontaneously resolved. One patient experienced grade 3 toxicity. Over a median follow up of 9 years, 8% experienced local failures and 10% developed distant sites of disease. Eighty-three percent of patients remained lymphoma free. Five and 10-year overall survival estimates from all causes were 97% and 84%, respectively. RT is a highly effective, safe treatment for GML with excellent overall survival and very rare acute or late treatment related toxicities. Spontaneous resolution of abnormal post treatment biopsies offers an intriguing window into histologic responses to radiation. Favorable outcomes from this large retrospective sample of patients provide credible and compelling support for the use of RT for H. pylori-independent GML as standard of care.

Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches.

Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) is a distinct clinical entity within the head and neck cancers, with a unique epidemiology and, in general, a favorable prognosis. Because of this favorable prognosis, researchers have considered de-intensifying the current standard treatment of HPV+ OPC in order to reduce acute and late treatment related toxicity without compromising outcome. Current ongoing trials can be divided in three main categories: de-intensification of the chemotherapy by replacing concomitant platinum-based chemotherapy with the EGFR-inhibitor cetuximab, or de-intensification of the radiation dose of either the primary radiotherapy of selected, good-responding patients after induction chemotherapy or of the adjuvant radiotherapy based on pathology features after primary surgery. Despite the good prognosis of the majority of HPV+ OPC patients, a proportion of them still have poor prognosis. This unmet need has led clinical research on new treatment strategies focused on influencing the unique micro-environment of HPV+ OPC with for example immunotherapy. This article summarizes the current understanding regarding the optimal treatment of non-metastatic HPV+ OPC. Ongoing and published clinical trials regarding de-intensification strategies, immunotherapy and proton therapy are described focusing on the rationale and underlying evidence of these emerging treatment strategies. Nevertheless, until the results of the ongoing trials are known, the treatment of HPV+ OPC in clinical practice should remain identical to the treatment of HPV negative OPC.

The efficacy of radiotherapy for muscle invasive bladder cancer and its associated factors analysis

Objective To analyze the efficacy and its impacting factors of pelvic confined muscle invasive bladder cancer (MIBC) treated with radiotherapy, also including the preservation of functional bladders and the treatment related late toxicity. Methods Forty-five MIBC patients who received radiotherapy from March 1999 to October 2016 in our hospital were analyzed.41 of the patients were transitional cell carcinomas. The radiation volume included the bladder±pelvic lymph node with or without local tumor boost, with a median bladder dose of 45 Gy and median tumor dose of 56 Gy.24 patients received concurrent chemoradiotherapy.14 patients received neoadjuvant chemotherapy, and 29 underwent transurethral resection of bladder tumors before radiotherapy. Results The median follow-up duration was 28 months (range, 4–101 months). The 3-year overall survival were 51%.Concurrent chemoradiotherapy had a better survival than that of radiation alone, with 3-year overall survival of 64% and 30%(P=0.001). The effect of neoadjuvant chemotherapy on 3-year overall survival was not obvious, 59% and 47%(P=0.540) with or without neoadjuvant chemotherapy. The 3-year overall survival were 58% and 43%(P=0.160), respectively for patients with or without the transurethral resection of bladder tumors. The 3-year overall survival were 20% and 79%(P=0.001) for patients with or without relapse. Nine patients recurred locally and fourteen patients developed metastases. The highest bowel toxicity of more than 3 months after radiotherapy was grade 2 in 2 patients. Late grade 2 urinary toxicity occurred in 4 patients, grade 3 in 2 patients. All other patients preserved their functional bladders except 7 patients who had an uncontrolled bladder tumors or radiation induced severe injury of bladder function. Conclusions A better survival could be obtained for localized muscle invasive bladder cancer treated with concurrent chemoradiotherapy. Most of the patients can preserve their functional bladders after radiotherapy, and the late toxicity is acceptable. Key words: Bladder neoplasms/chemoradiotherapy; Treatment outcome

Radiation Therapy against Pediatric Malignant Central Nervous System Tumors : Embryonal Tumors and Proton Beam Therapy.

Radiation therapy is highly effective for the management of pediatric malignant central nervous system (CNS) tumors including embryonal tumors. With the increment of long-term survivors from malignant CNS tumors, the radiation-related toxicities have become a major concern and we need to improve the treatment strategies to reduce the late complications without compromising the treatment outcomes. One of such strategies is to reduce the radiation dose to craniospinal axis or radiation volume and to avoid or defer radiation therapy until after the age of three. Another strategy is using particle beam therapy such as proton beams instead of photon beams. Proton beams have distinct physiologic advantages over photon beams and greater precision in radiation delivery to the tumor while preserving the surrounding healthy tissues. In this review, I provide the treatment principles of pediatric CNS embryonal tumors and the strategic improvements of radiation therapy to reduce treatment-related late toxicities, and finally introduce the increasing availability of proton beam therapy for pediatric CNS embryonal tumors compared with photon beam therapy.

Concurrent versus sequential administration of CMF chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer.

To compare the outcome of concurrent versus sequential administration of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. From February 1992 to January 2002, 156 patients underwent CMF chemotherapy and radiotherapy, either concurrently (CCRT group, 88 patients) or sequentially (SCRT group, 68 patients). There was a predilection of patients with a larger tumor (P = 0.0035), with more frequent nodal involvement (P = 0.0686), and younger age (P = 0.0776) in the CCRT group. The planned radiotherapy was completed in every patient. No grade 3 or 4 late treatment-related toxicity was observed in the CCRT or SCRT group. Compliance to the treatment as well as cosmetic outcome of the two groups were comparable. Despite more adverse factors for local-regional recurrence in the CCRT group, the 5-year local-regional control rate of the CCRT group was similar to that of the SCRT group (97.7% vs 93.8%, respectively, P = 0.1688). On multivariate analysis, concomitant administration of chemotherapy and radiotherapy was associated with improved local-regional control (P = 0.0463). Concurrent administration of CMF chemotherapy and radiotherapy resulted in improved local-regional control over sequential administration without an increase in significant toxicity. Concurrent CMF chemoradiotherapy may serve as a viable option for patients at high-risk of local-regional relapse not suitable for anthracycline or taxane-based chemotherapy.

Comparison Long-term Outcome of Definitive Radiotherapy plus Different Chemotherapy Schedules in Patients with Advanced Nasopharyngeal Carcinoma

Concurrent chemoradiotherapy (CCRT) is the current standard of care for advanced nasopharyngeal carcinoma (NPC). We hypothesize that shifting CCRT to neoadjuvant chemotherapy followed by radiotherapy (NeoCT-RT) is an alternative option. From December 2004 to January 2009, 256 NPC patients with stage II-IVB were treated by either CCRT or NeoCT-RT. All patients received the same dosage and fractionation schedule of RT. After long-term follow-up, 26.8% (34/127) and 23.3% (30/129) of patients who received CCRT and NeoCT-RT respectively, developed a tumor relapse (P = 0.6134). Overall survival (HR = 1.52, 95%CI = 0.91–2.55, P = 0.1532) and progression-free survival (HR = 1.22, 95%CI = 0.75–1.99, P = 0.4215) were similar in both groups. However, acute toxicities during RT period revealed a significant reduction of grade 3/4 vomiting (23% vs. 0%, P < 0.0001), mucositis (55% vs. 16%, P < 0.0001), and neck dermatitis (31% vs. 16%, P = 0.0041) in the NeoCT-RT group, resulting in fewer emergency room visits (10.2% vs. 1.6%, P = 0.0071). Severe treatment-related late toxicity (15% vs. 14%, P = 0.9590) and the occurrence of second malignancy (3.9% vs. 5.4%, P = 0.7887) also showed no differences. We concluded that NeoCT-RT could be an attractive alternative option of CCRT for advanced NPC.

Stereotactic Body Radiotherapy Treatment for Recurrent, Previously Irradiated Head and Neck Cancer

Purpose:Locally recurrent, previously irradiated primary head and neck tumors have historically been associated with poor outcomes. Stereotactic body radiation therapy has emerged as a feasible and promising treatment option for tumor recurrence, particularly in nonsurgical candidates. This study aimed to assess the associated outcomes of stereotactic body radiation therapy used in this setting.Methods:Retrospective analysis of a prospectively collected database of 25 patients treated with CyberKnife for unresectable, recurrent head and neck cancer in a previously irradiated field. The primary end points evaluated were rates of survival, tumor control, and treatment-related toxicities.Results:Median survival of the study population was 7.5 months (range, 1.5-47.0 months). Median survival of the 20 (80%) patients who were treated with curative purpose was 8.3 months. One-year overall survival rate for the entire population was 32%. The respective 1-year and 2-year survival rates for the curative subcohort were 40% and 20%, respectively. Local and locoregional failure occurred in 8 (32%) and 7 (28%) patients, respectively. Low severe acute (4%) and late (6%) treatment-related toxicity rates were observed. No grade 4 or 5 toxicities were observed.Conclusion:Stereotactic body radiation therapy is a viable treatment option for patients with unresectable, recurrent head and neck cancer. Significant tumor control rates are achievable with minimal severe toxicity. Although perhaps associated with patient selection and a heterogeneous sample, overall survival of stereotactic body radiation therapy outcomes appears unfavorable.

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study.

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30g/m2 , administered over 3 consecutive days in infants <1year old (n=12) and 42g/m2 in children ≥1year old (n=65). Mean day 1 treosulfan exposure was 1744±795mg*h/l (10g/m2 ) and 1561±511mg*h/l (14g/m2 ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P=0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P=0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.

Treatment results of adjuvant pelvic radiotherapy after radical hysterectomy for low-risk Stage IB1-IIA cervical cancer.

The aim of the present retrospective analysis was to determine the effectiveness of pelvic radiotherapy (RT) as postoperative adjuvant therapy for low-risk cervical cancer. Between June 2003 and April 2011, the clinical data of 225 International Federation of Gynecology and Obstetrics (FIGO) Stage IB1-IIA cervical cancer patients with low-risk factors were retrospectively reviewed, to analyze the relationship between adjuvant pelvic RT after radical hysterectomy and tumor recurrence or the patients' survival. The 5-year overall survival (OS) of 225 patients was 91.2% and 5-year disease-free survival (DFS) was 84.5%. The 5-year DFS and local regional disease-free survival was significantly better for patients in the RT group compared with that in the non-RT group (5-year DFS, 91.2% vs. 77.1%, P = 0.006; 5-year local regional disease-free survival 94.6% vs. 79.0%, P = 0.001). There were no statistically significant differences in the 5-year OS (92.9% vs. 89.4%, P = 0.371) and distant metastasis-free survival (96.4% vs. 96.5%, P = 0.887) between the two groups. Grade 3-4 treatment-related acute and late toxicities were not significantly different between the two groups. Subgroup analysis shows the 5-year DFS of RT alone, chemotherapy (CT) alone, non-RT/CT, RT and CT was, respectively, 90.5%, 62.9%, 81.4%, 92.5% separately (P = 0.002). The 5-year OS was not significantly different (91.6% vs. 78.2% vs. 92.9% vs. 96.9%, P = 0.887) between the four groups. Performing univariate analysis, postoperative CT was the only significant risk factor for DFS. Our results indicate that postoperative adjuvant pelvic RT has a tendency to improve DFS especially local regional disease-free survival for FIGO Stage IB1-IIA cervical cancer patients with low-risk factors, without increased Grade 3-4 treatment-related acute and late toxicities, but non-standard CT is harmful to the prognosis (DFS) of these patients.

Evaluation of Partial Breast Reirradiation with Intraoperative Radiotherapy after Prior Thoracic Radiation: A Single-Institution Report of Outcomes and Toxicity.

Mastectomy is the current standard of care for ipsilateral breast tumor recurrences after prior whole breast irradiation (WBI). We report our single-institution experience with breast-conserving surgery (BCS) followed by intraoperative radiotherapy (IORT) as an alternative to salvage mastectomy for new or recurrent breast cancers that develop in the setting of prior thoracic radiation. We performed an IRB-approved retrospective review of patients treated with breast IORT between September 2013 and November 2016. We identified 12 patients who declined salvage mastectomy for their breast cancer after prior thoracic radiation. IORT was delivered using the Intrabeam™ device (Carl Zeiss, Germany). A dose of 20 Gy was prescribed to the lumpectomy cavity surface using 50 kV X-rays. We graded both acute and late treatment-related breast toxicities using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Local control, mastectomy-free survival, distant metastasis, and overall survival were determined. Our study included nine patients who developed a new or recurrent ipsilateral breast cancer after prior WBI for early-stage breast cancer, two patients with primary breast cancer after mantle-field radiation for Hodgkin's lymphoma, and one patient with a synchronous stage III non-small cell lung cancer treated with definitive radiation to the ipsilateral lung and mediastinum. The median time from prior radiation to presentation was 18 years (range: 2 months to 46 years). All patients successfully underwent partial breast reirradiation with IORT and were able to preserve their breast. At a median follow-up of 14 months (4-25 months), there were no local or distant recurrences. There was a single non-cancer-related death. In the acute setting, we observed grade 1 toxicity in 58% (n = 7), grade 2 toxicity in 17% (n = 2), and no grade 3 or higher toxicity. In the late setting, at least 3 months after IORT, we observed grade 1 hyperpigmentation and/or fibrosis in 50% (n = 6), symptomatic seroma requiring drainage in 33% (n = 4). A single patient developed an abscess requiring hospitalization and intravenous antibiotic therapy. BCS with IORT is a feasible salvage option for patients who present with localized breast cancer after prior thoracic radiation treatment. Continued follow-up of these patients is warranted given the incidence of delayed toxicity.

Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. We used standard methodological procedures expected by Cochrane. The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow-up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision. We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Clinical results of proton beam therapy for hepatocellular carcinoma over 5cm.

This study aimed to evaluate the safety and efficacy of proton beam therapy for large hepatocellular carcinoma (HCC). Twenty-four patients with a HCC larger than 5.0cm were treated with proton beam therapy at our institution between 2008 and 2015. The clinical stage was I in 2 patients, II in 9 patients, and IIIB in 13 patients. Ten of the 24 patients were not surgical candidates because of advanced HCC or old age. Median tumor size was 90mm (range, 50-180mm). Median total dose delivered was 72.6 Gray-equivalents (GyE) in 22 fractions (range, 60.8-85.8 GyE). Median follow-up period was 17.5months (range, 3-70months). Local control rate at 2years was 87.0%. The 2-year overall survival rate was 52.4%. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No acute or late treatment-related toxicity of grade 3 or higher, other than dermatitis, was observed. These results show that proton beam therapy offers an effective and safe method for treating patients with large HCC. Proton beam therapy represents a promising method for treatment of large-volume HCC.

Prostate cancer treated with brachytherapy; an exploratory study of dose-dependent biomarkers and quality of life

BackgroundLow-dose-rate permanent prostate brachytherapy (PPB) is an attractive treatment option for patients with localised prostate cancer with excellent outcomes. As standard CT-based post-implant dosimetry often correlates poorly with late treatment-related toxicity, this exploratory (proof of concept) study was conducted to investigate correlations between radiation − induced DNA damage biomarker levels, and acute and late bowel, urinary, and sexual toxicity.MethodsTwelve patients treated with 125I PPB monotherapy (145Gy) for prostate cancer were included in this prospective study. Post-implant CT based dosimetry assessed the minimum dose encompassing 90% (D90%) of the whole prostate volume (global), sub-regions of the prostate (12 sectors) and the near maximum doses (D0.1cc, D2cc) for the rectum and bladder. Six blood samples were collected from each patient; pre-treatment, 1 h (h), 4 h, 24 h post-implant, at 4 weeks (w) and at 3 months (m). DNA double strand breaks were investigated by staining the blood samples with immunofluorescence antibodies to γH2AX and 53BP1 proteins (γH2AX/53BP1). Patient self-scored quality of life from the Expanded Prostate Cancer Index Composite (EPIC) were obtained at baseline, 1 m, 3 m, 6 m, 9 m, 1 year (y), 2y and 3y post-treatment. Spearman’s correlation coefficients were used to evaluate correlations between temporal changes in γH2AX/53BP1, dose and toxicity.ResultsThe minimum follow up was 2 years. Population mean prostate D90% was 144.6 ± 12.1 Gy and rectal near maximum dose D0.1cc = 153.0 ± 30.8 Gy and D2cc = 62.7 ± 12.1 Gy and for the bladder D0.1cc = 123.1 ± 27.0 Gy and D2cc = 70.9 ± 11.9 Gy. Changes in EPIC scores from baseline showed high positive correlation between acute toxicity and late toxicity for both urinary and bowel symptoms. Increased production of γH2AX/53BP1 at 24 h relative to baseline positively correlated with late bowel symptoms. Overall, no correlations were observed between dose metrics (prostate global or sector doses) and γH2AX/53BP1 foci counts.ConclusionsOur results show that a prompt increase in γH2AX/53BP1foci at 24 h post-implant relative to baseline may be a useful measure to assess elevated risk of late RT − related toxicities for PPB patients. A subsequent investigation recruiting a larger cohort of patients is warranted to verify our findings.

Hypofractionated Radiotherapy for Prostate Cancer

Hypofractionated Radiotherapy for Prostate Cancer

Accelerated hypofractionated radiation therapy (AHRT) for non-small-cell lung cancer: can we leave standard fractionation?

To report interim results from a single-institution study conducted to assess accelerated hypofractionated radiotherapy (AHRT) delivered with 3D conformal radiotherapy in two groups of patients with non-small cell lung cancer: (1) patients with early stage disease unable to tolerate surgery and ineligible for stereotactic body radiation therapy, and (2) patients with locally advanced disease unsuitable for concurrent chemoradiotherapy. A total of 83 patients (51 stage I-II, 32 stage III) were included. Radiotherapy targets included the primary tumor and positive mediastinal areas identified on the pre-treatment PET-CT. Mean age was 77.8±7.8years. ECOG performance status (PS) was ≥2 in 50.6% of cases. Radiotherapy was delivered in daily fractions of 2.75Gy to a total dose of 66Gy (BED10 84Gy). Acute and late toxicities were evaluated according to NCI CTC criteria. At a median follow-up of 42months, median overall survival (OS) and cause-specific survival (CSS) were 23 and 36months, respectively. On the multivariate analysis, PS [HR 4.14, p=0.0001)], stage [HR 2.51, p=0.005)], and maximum standardized uptake values (SUVmax) [HR 1.04, p=0.04)] were independent risk factors for OS. PS [HR 5.2, p=0.0001)] and stage [HR 6.3, p=0.0001)] were also associated with CSS. No cases of severe acute or late treatment-related toxicities were observed. OS and CSS rates in patients treated with AHRT for stage I-II and stage III NSCLC were good. Treatment was well tolerated with no grade three or higher treatment-related toxicity. PS, stage, and SUV max were predictive for OS and CSS.

Long-Term Outcomes in Hodgkin Lymphoma: The Impact of Initial Therapy

Maintaining high cure rates while lowering early and late treatment-related toxicity remains a challenge for patients with advanced-stage Hodgkin

Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Atypical Teratoid/Rhabdoid Tumor.

PurposeWe prospectively evaluated the effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in improving the survival of patients with atypical teratoid/rhabdoid tumors while reducing the risks of late adverse effects from radiotherapy (RT).Materials and MethodsFor young children (< 3 years old), tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. RT was deferred until after 3 years of age unless the tumor showed relapse or progression. For older patients (> 3 years old), RT including reduced-dose craniospinal RT (23.4 or 30.6 Gy) was administered either after two cycles of induction chemotherapy or after surgery, and tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy.ResultsA total of 13 patients (five young and eight older) were enrolled from November 2004 to June 2012. Eight patients, including all five young patients, had metastatic disease at diagnosis. Six patients (four young and two older) experienced progression before initiation of RT, and seven were able to proceed to HDCT/auto-SCT without progression during induction treatment. Three of six patients who experienced progression during induction treatment underwent HDCT/auto-SCT as salvage treatment. All five young patients died from disease progression. However, four of the eight older patients remain progression-freewith a median follow-up period of 64 months (range, 39 to 108 months). Treatment-related late toxicities were acceptable.ConclusionThe required dose of craniospinal RT might be reduced in older patients if the intensity of chemotherapy is increased. However, early administration of RT should be considered to prevent early progression in young patients.

What is the price of functional surgical organ preservation in local-regionally advanced supraglottic cancer? Long-term outcome for partial laryngectomy followed by radiotherapy in 32 patients.

To achieve the goal of organ preservation, both a chemoradiotherapy and a conservative surgical approach can be proposed. The aim of the study was to review all patients treated in our Institute with conservative surgery and postoperative radiotherapy for locally advanced supraglottic tumor. A retrospective analysis of 32 patients treated between 2000 and 2010 was performed. Overall survival, disease-free survival and late laryngeal toxicity were evaluated. The impact of surgical procedures, radiotherapy characteristics and addition of chemotherapy on late laryngeal toxicity was studied. The median follow-up was 38 months. Overall survival and disease-free survival at 5 years were 73% and 66%, respectively. Three (9%) patients experienced local recurrence (after 22, 25 and 40 months, respectively) and were treated with total laryngectomy. The larynx preservation rate was 93%. Severe treatment-related late laryngeal toxicity (grade 3 and 4 laryngeal edema, laryngeal stenosis, presence of tracheotomy at last follow-up because of treatment-related toxicity, and the need for enteral nutrition) was experienced by 34% of patients. The functional larynx preservation rate was 81%. The statistically significant risk factors for severe late toxicity were: female gender, extension of the surgical procedure, removal of one arytenoid and association with concomitant chemotherapy. We confirmed literature data on the feasibility and efficacy of a surgical organ preservation strategy. However, the high incidence of severe late toxicity requires further studies to improve patient selection and to reduce side effects.

Phase I dose-escalation study of stereotactic body radiotherapy (SBRT) for poor surgical candidates with localized renal cell carcinoma

PurposeTo evaluate the tolerability of escalating doses of stereotactic body radiotherapy (SBRT) for primary treatment of localized renal cell carcinoma (RCC) in poor surgical candidates. Patients and methodsEligible patients included those with clinically staged radiographic and or pathologically confirmed RCC who had not undergone previous abdominal or pelvic radiotherapy. All patients had comorbid medical conditions which precluded surgery. Median (range) patient age was 77.6years (range 59–89) years and all patients had Karnofsky Performance Status of ⩾60. Median tumor volume was 57.9cm3 (range 13.8–174.7cm3). Dose-limiting toxicity (DLT) was defined as grade 3 or worse gastrointestinal/genitourinary toxicity by Common Terminology Criteria of Adverse Events (version 4). Tumor response was assessed by imaging results using Response Evaluation Criteria In Solid Tumors (RECIST) measurement and percutaneous biopsy. ResultsA total of 19 patients (13 men and 6 women) were treated on protocol from June 2006 through August 2011. Groups of 3–6 patients received 24, 32, 40, and 48Gy in 4 fractions. Median (range) follow-up was 13. 7months (5.9–34.7months). For possibly treatment-related acute toxicities, one patient developed grade 2 fatigue and one developed grade 4 duodenal ulcer. For possibly treatment-related late toxicities, 2 patients experienced grade 3 renal toxicity (worsening chronic kidney disease), one reported grade 2 urinary incontinence and one developed grade 4 duodenal ulcer. Among the 15 patients with evaluable response, 3 and 12 had partial response and stable disease, respectively, utilizing RECIST criteria. Among the 11 patients who had post-SBRT biopsy, only one (9%) was negative on first biopsy and an additional one (9%) turned negative without further therapy on second biopsy. ConclusionsDose escalation to 48Gy in 4 fractions has been achieved successfully without dose-limiting toxicities. A planned extension of this phase I trial is currently underway treating patients to 60Gy in 3 fractions to further evaluate this experimental therapy.