Severe Late Toxicity Research Articles

Integration of MRI Target Delineation Into Rapid Workflow Cervical Cancer Brachytherapy: Impact on Clinical Outcomes

INTRODUCTION We evaluated the impact of MRI-based target delineation on toxicity and tumour control after implementation of a protocol to incorporate MRI while minimizing impact on overall procedural time. METHODS We retrospectively reviewed outcomes for a cohort of 96 consecutive patients who received intracavitary brachytherapy for cervical cancer at our institution during 2012-2016. Starting in October 2014, an outpatient MRI was obtained for patients after Smit sleeve placement and first insertion to assess concurrent chemoradiotherapy tumour response. Then, for subsequent fractions, the MRI was co-registered by the Smit sleeve to the planning CT for target volume delineation. The primary and secondary outcomes were toxicity and local control, respectively. RESULTS Median follow-up for the pre- (n = 50) and post-MRI-based (n = 46) planning groups was 24.6 and 14.7 months, respectively. Median treatment duration for patients before and after MRI implementation was 56 and 58 days (P = 0.052), respectively. Cumulative rectal D2 cc was less for those with MRI-based target delineation (P = 0.005). On multivariable analysis, patients with MRI-based target delineation experienced fewer severe late (CTCAE grade ≥ 3) toxicities (P = 0.025, hazard ratio = 0.25). Local control was 86% and 91% of the pre- and post-MRI groups, respectively (P = 0.959). CONCLUSIONS Preliminary findings using this technique, which is applicable to other institutions without in-room MRI availability, are associated with lower radiation prescription doses, lower rectal doses and favourable toxicity rates while maintaining a rapid workflow. Longer follow-up is required to confirm equivalent local control.

Cisplatin radiosensitizes radioresistant human mesenchymal stem cells.

Cisplatin-based chemo-radiotherapy is widely used to treat cancers with often severe therapy-associated late toxicities. While mesenchymal stem cells (MSCs) were shown to aid regeneration of cisplatin- or radiation-induced tissue lesions, the effect of the combined treatment on the stem cells remains unknown. Here we demonstrate that cisplatin treatment radiosensitized human bone marrow-derived MSCs in a dose-dependent manner and increased levels of radiation-induced apoptosis. However, the defining stem cell properties of MSCs remained largely intact after cisplatin-based chemo-radiation, and stem cell motility, adhesion, surface marker expression and the characteristic differentiation potential were not significantly influenced. The increased cisplatin-mediated radiosensitivity was associated with a cell cycle shift of MSCs towards the radiosensitive G2/M phase and increased residual DNA double-strand breaks. These data demonstrate for the first time a dose-dependent radiosensitization effect of MSCs by cisplatin. Clinically, the observed increase in radiation sensitivity and subsequent loss of regenerative MSCs may contribute to the often severe late toxicities observed after cisplatin-based chemo-radiotherapy in cancer patients.

A Nomogram to Predict Severe Late Toxicity after Definitive Reirradiation for Squamous Carcinoma of the Head and Neck

A Nomogram to Predict Severe Late Toxicity after Definitive Reirradiation for Squamous Carcinoma of the Head and Neck

Re-irradiation of cervical and endometrial cancer.

Re-irradiation historically has been associated with unacceptable toxicity and limited benefit. Recent advances in radiotherapy can change the treatment paradigm to provide new salvage treatments for recurrences of cervical and endometrial cancer. Image-guided brachytherapy is an effective method for salvaging central pelvic recurrence, although it has resulted in 20-25% severe late toxicity. Pelvic sidewall disease is not accessible to brachytherapy, so a combined modality approach with radical surgery and intraoperative radiotherapy is an alternative approach. Stereotactic body radiotherapy (SBRT) now provides the option of radical re-irradiation with local control rates of 50-80% and a low incidence of severe late complications. Initial outcomes using SBRT and image-guided brachytherapy for re-irradiation of gynaecological cancer are encouraging. There has been good local control and acceptable toxicity. Further, large-scale studies are required to define optimal target doses and OAR limits.

Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma

To evaluate long-term results of a phase II study of induction and adjuvant gemcitabine and cisplatin (GP) chemotherapy with intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). One hundred and twelve patients (Stage III: 65, IVA-B: 47) with locoregionally advanced NPC were enrolled in this study. All patients received induction chemotherapy consisting of 1000 mg/m2 gemcitabine on day 1 and 8, and cisplatin 25 mg/m2 on day 1–3, every 3 weeks for 2 cycles. Adjuvant chemotherapy for 2 cycles of the same regime was given 28 days after the end of IMRT. The IMRT technique was utilized for all patients. In total, 97.3% patients completed 2 cycles of induction chemotherapy. The overall response rate (RR) of cervical lymph nodes was 89.0%. Acute toxicities were mainly grade 1–2 myleosuppression and vomiting. And 83.9% patients completed 2 cycles of adjuvant chemotherapy. All patients finished IMRT with RR at the end of IMRT for nasopharynx, lymph nodes of neck and retropharyngeal area being 99.1%, 97.9% and 97.7%, respectively. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 93.2%, 92.3%, 89.0% and 82.1%, respectively. The 5-year overall survival of stage III and IVA-B were 87.0%, and 75.5%, respectively. The incidence of grade 3–4 acute radiotherapy-related mucositis was 28.6%. Severe late toxicities were uncommon. IMRT combined with GP for locoregionally advanced NPC is well tolerated, effective, and convenient, and warrants further studies.

Présentation de l’étude Gortec 2017-03 : radiothérapie en conditions stéréotaxiques postopératoire des cancers localisés de l’oropharynx et de la cavité buccale avec marges à risque (PHRC-K-16-164)

The GORTEC 2017-03-Stereo-postop study is a phase 2, multicentric, nationwide study, funded by the hospital clinical research program (PHRC). The sponsor is Centre Jean-Perrin in Clermont-Ferrand, in partnership with the GORTEC. The principal investigators are Dr J Biau and Dr M Lapeyre. The main objective is to study severe late toxicity of postoperative stereotactic radiotherapy (6×6Gy) for early stage oropharyngeal and oral cavity cancer with high risk margins. The secondary objectives include acute toxicity, efficacy, nutritional impact and quality of life. The population is adult patients, with pT1 or pT2 squamous cell carcinoma of the oropharynx or oral cavity (except lips), without indication of neck irradiation or concomitant chemotherapy, with at risk margin (R1, less than 5mm or uncertain). Ninety patients will be included over a 2-year period; this was calculated to limit the rate of 2-year severe toxicity at 5 to 15%, with a 2-year local control of at least 80 to 90%. If this study is considered as positive, stereotactic radiotherapy (6×6Gy) could become the third therapeutic option, with brachytherapy and normofractionated intensity-modulated radiotherapy (IMRT), for postoperative irradiation of oropharyngeal and oral cavity cancer with high risk margins.

Research progress of proton therapy in rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Radiation therapy has been integrated into the primary treatment of most patients with rhabdomyosarcoma, but which in turn potentially induces severe acute and late toxicities. Proton therapy in recent years has been more and more used in the treatment of rhabdomyosarcoma, which is safe and effective, with no serious adverse events. Compared with conventional photon therapy, proton therapy has distinct physical advantages and enables greater precision in the delivery of tumoricidal radiation doses with reduced irradiation of normal tissues, and improves quality of life for patients. Additional follow-up and prospectively studies are needed to determine whether proton therapy truly reduces the incidence and severity of late effects in comparison to patients treated with modern photon techniques. Key words: Rhabdomyosarcoma; Child; Proton therapy

Abstract 1794: Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer

Abstract Aims: Emerging evidence in viral-associated oro- and naso-pharynx cancers supports the concept of radiotherapy (RT) dose de-intensification in these radiosensitive tumours. This notion is particularly relevant in the background that a majority of head and neck cancer patients develop severe late toxicities despite modern precision RT. A reasonable strategy could thus entail stratifying patients at risk of late toxicities to dose de-intensification. Here, we investigated the utility of a lymphocyte apoptosis (RILA) assay to predict for late toxicities in EBV-positive nasopharynx cancer patients. We also test if a multi-modal approach incorporating DNA damage induction and repair improves the prediction of clinical radiosensitivity. Methods: Assays were assessed retrospectively among survivors of a randomised controlled trial (NCC-0902), where patients were assigned to weekly cisplatin-RT with or without neoadjuvant gemcitabine, carboplatin, and paclitaxel. Late toxicities were assessed by CTCAE v.2 at the following intervals - 2-mo year 1, 4-mo year 2, 6-mo years 3-5, and annually thereafter; and considered severe if CTCAE v.2 ≥Grade 2. RILA was based on a fluorogenic inhibitor of caspases assay (48 h post-8 Gy). DNA damage induction and repair were assessed by semi-automated scoring of ϒH2AX foci at 30 min post-1 Gy and 24 h post-4 Gy, respectively. Results: Median follow-up of patients was 5.7 (range 4.6-7.4) years. Clinical and treatment indices, including assigned study arm and RT dosimetry to normal tissue structures, were balanced between patients with and without late toxicities (p >0.05). We observed a trend between decreasing RILA scores and increased risks of late toxicities; odds ratio (OR) 1.27 (95% CI = 0.92-1.72) for lowest quartile cut-off, corresponding to an AUC of 0.608 for prediction accuracy (p = 0.049). A multi-modal approach incorporating DNA damage induction and repair did not improve upon the predictive accuracy of RILA for clinical radiosensitivity. Independently, DNA damage induction and repair were not associated with risks of late toxicities; OR 1.03 (95% CI = 0.69-1.53, p = 0.901) and 1.04 (95% CI = 0.73-1.49, p = 0.829), respectively. Interestingly, onset of late toxicities was correlated to an improved disease-free survival in our cohort (5-y DFS = 94.1% vs 73.3%, no late toxicity, p = 0.003), which suggests a common mechanism underlying tumour and normal tissue radiosensitivity in EBV-positive nasopharynx cancer. Conclusions: Herein, we report on the potential utility of a RILA assay in stratifying for patients at risk of late RT-induced toxicities. The clinical implication of this assay is further exemplified by the observation of a superior survival in these sensitive individuals, which supports the approach of selecting this subgroup for treatment de-intensification. Citation Format: Kevin L.M. Chua, Shihabuddeen Waseem Ahamed, Ma Than Than Shwe, Li-lian Kwok, Joseph T.S. Wee, Terence W.K. Tan, Prakash M. Hande, Kai Rothkamm, Melvin L.K. Chua. Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1794. doi:10.1158/1538-7445.AM2017-1794

Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer.

e17545 Background: Emerging evidence in viral-associated head and neck cancers supports the concept of dose de-intensification in these radiosensitive tumors, but different strategies exist in selecting patients for treatment de-intensification. We hypothesize that patients who develop severe late toxicities (LT) to radiation (RT) have better tumor control, due to a common radiosensitivity index. Here, we investigate the utility of a normal tissue radiosensitivity assay (RT-induced lymphocyte apoptosis, RILA) in predicting clinical outcomes (tumor control and normal tissue toxicity) of patients with EBV-associated nasopharynx cancer (NPC). Methods: RILA assay was assessed in a cohort of locally advanced NPC patients from a randomized controlled phase III trial (N = 172, NCC0901) of cisplatin-RT with or without induction gemcitabine, carboplatin and paclitaxel. LT was assessed by CTCAE v.2 at the following intervals (2 mo yr 1, 4 mo yr 2, 6 mo yr 3-5, annually thereafter). We performed the RILA assay (48 h post 8 Gy) in a subset of cases (N = 87). Results: At a median follow-up of 5.7y, DFS (3y 74.9% GCP vs 67.4% Control, p = 0.362) and incidence of severe Grade ≥3 LT did not differ between the treatment arms. In keeping with our hypothesis, onset of severe LT was associated with reduced risk of disease relapse; OR 0.19 (95% CI = 0.02 – 1.59, p = 0.168). High %RILA, stratified by top quartile, was associated with severe LT (OR 1.92 [95% CI = 0.67-5.5], p = 0.26); and lower rate of recurrence (4.5% (1/22), high %RILA vs19.7% (12/61), low %RILA, p = 0.086). Interestingly, subset analyses revealed that CD8+, but not CD4+ subpopulation of immune cells, was strongly associated with recurrence; OR 8.58 for low %CD8-RILA (p = 0.001). Conclusions: Herein, we showed that %RILA may be a useful biomarker for tumor and normal tissue radiosensitivity of EBV-associated NPC. If validated, this predictive assay will enable precision matching of RT-sensitive patients for de-intensification in EBV- and other viral-associated head and neck cancers. The association between tumor control and CD8-subset of immune cells suggests an immune dependency for RT.

A prospective study on neoadjuvant chemoradiotherapy plus nimotuzumab followed by surgery for patients with advanced cervical cancer.

e17000 Background: This study was to investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus nimotuzumab followed by surgery for advanced cervical cancer. Methods: The inclusion criteria of this study were as follows: age: 18-75 years old; ECOG 0-1; FIGO stages IB2-IIIB; not eligible for surgery. IMRT with a total dose of 50-54 Gy was delivered to the tumor and the whole uterus, and 45-48.6 Gy to the high-risk regions. Weekly cisplatin or nedaplatin was administered concurrently with IMRT. Weekly nimotuzumab was given for 6 cycles. Patients were then assessed for clinical tumor response and operability. For those who were candidates for surgery, radical hysterectomy and pelvic lymph node dissection were performed 5-6 weeks after the completion of neoadjuvant therapy. Results: Twenty-eight patients were enrolled. Stage distributions were as follows: IB2, 3 pts; IIA, 5 pts; IIB, 16 pts; IIIA, 2 pts; IIIB, 2 pts. Twenty six (92.8%) patients completed ≥ 5 cycles of chemotherapy, and all completed ≥5 cycles of nimotuzumab. Complete clinical response and partial response were found in 8 patients (28.5%) and 20 patients (71.5%), respectively. Four patients were not eligible for surgery and 2 candidates refused surgery. They were not included in this analysis. Radical surgery was performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease. Median follow-up was 22 months (range, 5-39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicity profiles were mainly manifested as marrow suppression, nausea, diarrhea, and loss of appetite. They were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed Conclusions: This treatment approach is highly effective and safe in advanced cervical cancer. Further studies are warranted to confirm the findings. Clinical trial information: NCT01938105.

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

ObjectiveTo evaluate the effects of prophylactic sub-renal vein radiotherapy (SRVRT) using intensity-modulated radiotherapy (IMRT) for cervical cancer. MethodsA 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. ResultsOverall, 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. ConclusionProphylactic SRVRT using IMRT reduced PALN recurrence with tolerable toxicities, supporting the application of risk-based radiation fields for cervical cancer.

79P - Long term survival of stage IIIB non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiation

Background: The optimal treatment strategy for Stage IIIB NSCLC patients with a T4N0-1 tumor is a matter of debate. In prospective combined modality series including surgery, the median overall survival (OS) is approximately 24 months. We hypothesized that results comparable to regimens including surgery can be achieved with concurrent chemoradiation in this patient group. Methods: In our retrospectively collected database of NSCLC patients, all patients with T4 (mediastinal invasion) N0-1 NSCLC receiving concurrent chemoradiation were included. One patient had a recurrence after previous pneumonectomy. All patients were given 3 cycles of chemotherapy (cisplatin and etoposide). Radiotherapy (RT) was started at the 2nd course of chemotherapy. OS was calculated from date of diagnosis (Kaplan-Meier method). Toxicity was scored according to CTCAEv3.0. Results: 42 patients (8 females, 34 males) with a median age of 62.5 ± 9 years (44-80 years) were included from January 2005 until December 2009. Stage distribution: 86% T4N0 (n = 36), 14% T4N1 (n = 6). The maximal tumor dose was 66 Gy using conventional fractionation. The median prescribed mean lung dose was 15 ± 4.4 Gy (5.03 -19.9 Gy). Acute toxicity: 1 patient experienced grade 3 dyspnea during RT. Grade 3 dysphagia occurred in 5 patients (12%) during RT requiring tube feeding in 3 of these patients (7%). Dysphagia persisted later than 1 month after RT in 1 patient (2%). Grade 3 dysphagia only occurred in patients treated concurrently. Grade 3 cough occurred in 1 patient during RT, no patient experienced grade 3 cough 1 month after RT. 2 patients died within 3 months after start of RT, one due to myocardial infarction, one of unknown causes. Severe late toxicity was not present: no grade 3 complications more than 3 months after the end of radiotherapy. With a median follow-up of 42 months, the median OS for the whole group is 34 months (95% CI 24-43 months). 2-year OS survival is 55%. Conclusions: Concurrent accelerated chemoradiation using an individualized dose prescription is a valid treatment strategy for stage IIIb, T4N0-1 NSCLC patients yielding very promising OS results with low toxicity. Legal entity responsible for the study: SKMH, Lahore Funding: SKMH, Lahore Disclosure: The author has declared no conflicts of interest.

Salvage radiotherapy with or without concurrent chemotherapy for pelvic recurrence after hysterectomy alone for early-stage uterine cervical cancer.

Treatment outcomes of patients with pelvic recurrence after hysterectomy alone for uterine cervical cancer who received salvage radiotherapy (RT) with or without concurrent chemotherapy were investigated. Salvage RT for recurrent cervical cancer confined to the pelvic cavity after hysterectomy alone was received by 33patients. The median interval between initial hysterectomy and recurrence was 26months. Whole-pelvic irradiation was delivered to median dose of 45 Gy, followed by aboost with amedian dose of 16 Gy to the gross tumor volume. Cisplatin-based concurrent chemotherapy was administered to 29patients. The median follow-up period was 53months for surviving patients. Most patients (97.0%) completed salvage RT of ≥45 Gy. Complete response (CR) was achieved in 23patients (69.7%). Pelvic sidewall involvement and evaluation with positron-emission tomography-computed tomography were significantly associated with CR. The 5‑year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 62.7, 79.5, 72.5, and 60.1%, respectively. Initial International Federation of Gynecology and Obstetrics stage, pelvic sidewall involvement, and CR status were significant factors for PFS and OS rates in multivariate analysis. The incidence of severe acute and late toxicities (≥grade3) was 12.1 and 3.0%, respectively. Aggressive salvage RT with or without concurrent chemotherapy for recurrent cervical cancer confined to the pelvic cavity was feasible, with promising treatment outcomes and acceptable toxicities. However, even more intensive novel treatment strategies should be investigated for patients with unfavorable prognostic factors.

Pelvic radiotherapy in the setting of rheumatoid arthritis: Refining the paradigm

PurposeConflicting results concerning the toxicity of radiotherapy in the setting of rheumatoid arthritis were reported in literature. This work describes the toxicity profiles of patients with rheumatoid arthritis undergoing pelvic radiotherapy for gynecologic malignancies at our institution. Patients and methodsCharts of patients with rheumatoid arthritis who underwent pelvic radiotherapy for cervical or endometrial cancer in a curative intent at the Gustave-Roussy Cancer Campus between 1990 and 2015 were reviewed for treatment-related toxicities. Acute and late effects were graded as per the Common Terminology Criteria for Adverse Events version 4.0 scoring system. ResultsEight patients with cervical cancer and three with endometrial cancer were identified. Median follow-up was 56 months. Median external beam radiotherapy dose was 45Gy. All patients received a brachytherapy boost using either pulse- or low-dose rate technique. Concomitant chemotherapy was used in seven cases. Median time from rheumatoid arthritis diagnosis to external beam radiation therapy was 5 years. No severe acute gastrointestinal or genitourinary toxicity was reported. One patient had grade 3 dermatitis. Any late toxicity occurred in 7 /11 patients, and one patient experienced severe late toxicities. One patient with overt systemic rheumatoid arthritis symptoms at the time of external beam radiation therapy experienced late grade 3 ureteral stenosis, enterocolitis and lumbar myelitis. ConclusionPelvic radiotherapy, in the setting of rheumatoid arthritis, appears to be feasible, with potentially slight increase in low grade late events compared to other anatomic sites. Patients with overt systemic rheumatoid arthritis manifestation at the time of radiotherapy might be at risk of potential severe toxicities.

Prostate Cancer Patients with Late Radiation Toxicity Exhibit Reduced Expression of Genes Involved in DNA Double-Strand Break Repair and Homologous Recombination.

Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of γ-H2AX foci and reduced induction of DNA double-strand break repair genes. Here, we report evidence of prognostic utility in prostate cancer for γ-H2AX foci decay ratios and gene expression profiles derived from ex vivo-irradiated patient lymphocytes. Patients were followed ≥2 years after radiotherapy. Clinical characteristics were assembled, and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The γ-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grade ≥3 and grade 0 patients (P = 0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade ≥3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade ≥3 toxicity (P = 0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double-strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade ≥3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy. Cancer Res; 77(6); 1485-91. ©2017 AACR.

The challenge in treating locally recurrent T3-4 nasopharyngeal carcinoma: the survival benefit and severe late toxicities of re-irradiation with intensity-modulated radiotherapy

BackgroundEffective treatments for patients with advanced locally recurrent nasopharyngeal carcinoma (NPC) are limited. This investigation was to determine the potential benefits from re-irradiation by intensity-modulated radiotherapy (IMRT) on survival and the effects of severe late toxicities.MethodsA retrospective study was conducted in 245 patients diagnosed with locally recurrent T3–T4 NPC who had undergone re-irradiation with IMRT. Follow-up data was colleted and factors associated with survival and severe late toxicities were analyzed.ResultsThe 5-year local-regional failure-free survival, distant failure-free survival and overall survival rates were 60.9%, 78.3% and 27.5%, respectively. The presence of severe late complications, recurrent T4 disease and gross tumor volume >30 cm3 were associated with poor survival. The incidences of mucosal necrosis, temporal lobe necrosis, cranial neuropathy and trismus were 22.0%, 14.6%, 27.0% and 14.6% respectively. Conclusions: Re-irradiation with IMRT is an effective choice in patients with locally recurrent T3–T4 NPC. However, the survival benefits can be partly offset by severe late complications and optimum treatments in these patients remain a challenge.

Outcomes of uterine cervical cancer patients with pelvic lymph node metastases after radiotherapy without boost irradiation of metastases

The aim of this study was to evaluate the outcomes of uterine cervical cancer patients with pelvic lymph node (PLN) metastases after radiotherapy without boost irradiation of the metastases and to clarify the necessity of the boost irradiation of metastatic lesions. Thirty-two patients with uterine cervical cancer metastasizing only to the PLN were treated with definitive radiotherapy without boost irradiation of the metastases between 2008 and 2012 at our institution and were selected for this study. The pattern of progression, overall survival, and progression-free survival were analyzed. Ninety percent of the PLN metastases were controlled by radiotherapy. Twenty-two of 32 patients (69%) experienced progression. Distant metastases as initial progression were observed in 21 of these 22 patients (95%). Only two patients experienced failures in pre-treatment metastatic PLN as initial progression, along with other failures. Severe late lower gastrointestinal toxicities were not observed in any patients. Two-year cumulative overall survival and progression-free survival were 74% and 31%, respectively. Boost irradiation of PLN metastases is not necessarily indispensable. Further studies to examine the necessity of boost irradiation of PLN metastases in radiotherapy for uterine cervical cancer patients with metastases are required.

Endorectal Brachytherapy Boost After External Beam Radiation Therapy in Elderly or Medically Inoperable Patients With Rectal Cancer: Primary Outcomes of the Phase 1 HERBERT Study

To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer. A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13×3Gy) followed by 3 weekly brachytherapy applications 6weeks later. The HDREBT dose started at 5Gy per fraction, increasing with 1Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis <6weeks after HDREBT) occurred in ≤2 patients per dose level. The primary endpoint was the maximum tolerated dose, defined as 1 dose level below the dose at which 3 patients experienced DLT. Secondary endpoints were toxicity, clinical tumor response, freedom from local progression, and local progression-free and overall survival (L-PFS and OS). Thirty-eight patients with a median age of 83years were included in the study. Thirty-two were evaluable for DLT and late toxicity and 33 for response evaluation. Maximum delivered dose was 8Gy per fraction, resulting in a recommended dose of 7Gy per fraction. Response occurred in 29 of 33 patients (87.9%), with 60.6% complete response (CR). The L-PFS and OS rates were 42% and 63%, respectively, at 2years. Patients with CR showed a significantly improved L-PFS (60% at 2years, P=.006) and a trend in improved OS (80% at 2years, P=.11). Severe late toxicity occurred in 10 of 32 patients. We found that HDREBT after EBRT results in a high overall response rate, with improved L-PFS for patients with a CR. The high observed rate of severe late toxicity requires further evaluation of the risks and benefits of an HDREBT boost.

PUB084 Long Term Survival of Stage IIIb Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Concurrent Chemoradiation

The optimal treatment strategy for Stage IIIB NSCLC patients with a T4N0-1 tumor is a matter of debate. In prospective combined modality series including surgery, the median overall survival (OS) is approximately 24 months. We hypothesized that results comparable to regimens including surgery can be achieved with concurrent chemoradiation in this patient group. In our retrospectively collected database of NSCLC patients, all patients with T4 (mediastinal invasion) N0-1 NSCLC receiving concurrent chemoradiation were included. One patient had a recurrence after previous pneumonectomy. All patients were given 3 cycles of chemotherapy (cisplatin and etoposide). Radiotherapy (RT) was started at the 2nd course of chemotherapy. OS was calculated from date of diagnosis (Kaplan-Meier method). Toxicity was scored according to CTCAEv3.0. 42 patients (8 female, 34 male) with a median age of 62.5 ± 9 years (44-80 years) were included from January 2005 until December 2009. Stage distribution: 86% T4N0 (n=36), 14% T4N1 (n=6). The maximal tumor dose was 66 Gy using conventional fractionation. The median prescribed mean lung dose was 15 ± 4.4 Gy (5.03 -19.9 Gy). Acute toxicity: 1 patient experienced grade 3 dyspnea during RT. Grade 3 dysphagia occurred in 5 patients (12%) during RT requiring tube feeding in 3 of these patients (7%). Dysphagia persisted later than 1 month after RT in 1 patient (2%). Grade 3 dysphagia only occurred in patients treated concurrently. Grade 3 cough occurred in 1 patient during RT, no patient experienced grade 3 cough 1 month after RT. 2 patients died within 3 months after start of RT, one due to myocardial infarction, one of unknown causes. Severe late toxicity was not present: no grade 3 complications more than 3 months after the end of radiotherapy. With a median follow-up of 42 months, the median OS for the whole group is 34 months (95% CI 24-43 months). 2-year OS survival is 55%. Concurrent accelerated chemoradiation using an individualized dose prescription is a valid treatment strategy for stage IIIb, T4N0-1 NSCLC patients yielding very promising OS results with low toxicity.

Comparison of toxicity and outcome in advanced stage non-small cell lung cancer patients treated with intensity-modulated (chemo-)radiotherapy using IMRT or VMAT

Retrospective evaluation of 188 advanced stage non-small cell lung cancer patients treated with IMRT or VMAT revealed a limited increase of moderate to severe acute esophageal toxicity after VMAT. Acute pulmonary toxicity and severe late toxicity were low. Overall survival did not differ between the IMRT and VMAT groups.