Early Toxicity of a Phase 2 Trial of Combined Salvage Radiation Therapy and Hormone Therapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS GETUG P07).

PURPOSE: Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique. METHODS AND MATERIALS: BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography-positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1 year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25). RESULTS: Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1 year did not worsen significantly. CONCLUSIONS: The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.

Respiratory motion variability of primary tumors and lymph nodes during radiotherapy of locally advanced non-small-cell lung cancers.

BACKGROUND AND PURPOSE: The need for target adjustment due to respiratory motion variation and the value of carina as a motion surrogate is evaluated for locally advanced non-small-cell lung cancer. MATERIAL AND METHODS: Using weekly 4D CTs (with audio-visual biofeedback) of 12 patients, respiratory motion variation of primary tumors (PT), lymph nodes (LN) and carina (C) were determined. RESULTS: Mean (SD) 3D respiratory motion ranges of PT, LN and C were 4 (3), 5 (3) and 5 (3) mm. PT and LN (p = 0.003), and LN and C motion range were correlated (p = 0.03). Only 20 %/5 % of all scans had variations >3 mm/5 mm. Large respiratory motion range on the initial scan was associated with larger during-treatment variations for PT (p = 0.03) and LN (p = 0.001). Mean (SD) 3D relative displacements of PT-C, LN-C and PT-LN were each 6 (2) mm. Variations of displacements >3 mm/5 mm were observed in 28 %/6 % of scans for PT-LN, 20 %/9 % for PT-C, and 20 %/8 % for LN-C. CONCLUSIONS: Motion reassessment is recommended in patients with large initial motion range. Relative motion-related displacements between PT and LN were larger than PT and LN motion alone. Both PT and C appear to be comparable surrogates for LN respiratory motion.

Involved node radiation therapy: an effective alternative in early-stage hodgkin lymphoma.

PURPOSE: The involved node radiation therapy (INRT) strategy was introduced for patients with Hodgkin lymphoma (HL) to reduce the risk of late effects. With INRT, only the originally involved lymph nodes are irradiated. We present treatment outcome in a retrospective analysis using this strategy in a cohort of 97 clinical stage I-II HL patients. METHODS AND MATERIALS: Patients were staged with positron emission tomography/computed tomography scans, treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy, and given INRT (prechemotherapy involved nodes to 30 Gy, residual masses to 36 Gy). Patients attended regular follow-up visits until 5 years after therapy. RESULTS: The 4-year freedom from disease progression was 96.4% (95% confidence interval: 92.4%-100.4%), median follow-up of 50 months (range: 4-71 months). Three relapses occurred: 2 within the previous radiation field, and 1 in a previously uninvolved region. The 4-year overall survival was 94% (95% confidence interval: 88.8%-99.1%), median follow-up of 58 months (range: 4-91 months). Early radiation therapy toxicity was limited to grade 1 (23.4%) and grade 2 (13.8%). During follow-up, 8 patients died, none from HL, 7 malignancies were diagnosed, and 5 patients developed heart disease. CONCLUSIONS: INRT offers excellent tumor control and represents an effective alternative to more extended radiation therapy in the combined modality treatment for early-stage HL.

Curative chemoradiotherapy in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph node metastases.

PURPOSE: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with curative intent in patients with stage IVB cervical cancer initially presenting with paraortic and left supraclavicular lymph node metastases. METHODS AND MATERIALS: The medical records of 25 patients with both paraortic and left supraclavicular lymph nodal metastases (group I) were reviewed and compared with those of 101 women with paraortic lymph node metastases alone (group II). Group I received a mean 59.4 Gy to the paraortic and left supraclavicular areas and 50.4 Gy to the pelvis, followed by 30 Gy of high-dose-rate brachytherapy in 6 fractions. Group II received the same dose to the paraortic area and pelvis followed by intracavitary brachytherapy. All patients received platinum-based chemotherapy simultaneously. RESULTS: Of the 25 patients in group I, 16 (64%) experienced acute grade 3-4 hematologic toxicities, and 1 had a late grade 3 genitourinary toxicity. Complete responses, including the primary mass and pelvic, paraortic, and left supraclavicular lymph nodes, were observed in 13 patients (52%). At a median follow-up of 32 months for surviving patients, 3 experienced in-field failure, 6 showed distant failure, and 9 showed both. The 3-year overall and disease-free survival rates were 49% and 33%, respectively. In comparison, of the 101 patients in group II, 16 showed in-field failure, 14 experienced distant failure, and 11 showed both. The 3-year overall and disease-free survival rates were 69% and 57%, respectively. CONCLUSIONS: Curative CCRT is feasible in patients with stage IVB cervical cancer presenting with paraortic and left supraclavicular lymph nodal metastases, with acceptable late toxicity and high response rates, despite high rates of acute hematologic toxicity.

Magnetic resonance lymphography-guided selective high-dose lymph node irradiation in prostate cancer.

PURPOSE: To demonstrate the feasibility of magnetic resonance lymphography (MRL) -guided delineation of a boost volume and an elective target volume for pelvic lymph node irradiation in patients with prostate cancer. The feasibility of irradiating these volumes with a high-dose boost to the MRL-positive lymph nodes in conjunction with irradiation of the prostate using intensity-modulated radiotherapy (IMRT) was also investigated. METHODS AND MATERIALS: In 4 prostate cancer patients with a high risk of lymph node involvement but no enlarged lymph nodes on CT and/or MRI, MRL detected pathological lymph nodes in the pelvis. These lymph nodes were identified and delineated on a radiotherapy planning CT to create a boost volume. Based on the location of the MRL-positive lymph nodes, the standard elective pelvic target volume was individualized. An IMRT plan with a simultaneous integrated boost (SIB) was created with dose prescriptions of 42 Gy to the pelvic target volume, a boost to 60 Gy to the MRL-positive lymph nodes, and 72 Gy to the prostate. RESULTS: All MRL-positive lymph nodes could be identified on the planning CT. This information could be used to delineate a boost volume and to individualize the pelvic target volume for elective irradiation. IMRT planning delivered highly acceptable radiotherapy plans with regard to the prescribed dose levels and the dose to the organs at risk (OARs). CONCLUSION: MRL can be used to select patients with limited lymph node involvement for pelvic radiotherapy. MRL-guided delineation of a boost volume and an elective pelvic target volume for selective high-dose lymph node irradiation with IMRT is feasible. Whether this approach will result in improved outcome for these patients needs to be investigated in further clinical studies.

Phase I trial of pelvic nodal dose escalation with hypofractionated IMRT for high-risk prostate cancer.

PURPOSE: Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks. METHODS AND MATERIALS: Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months. RESULTS: The median follow-up time was 25.4 months (range, 4.2-57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only. CONCLUSIONS: Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.

Ferumoxtran-10 MR lymphography for target definition and follow-up in a patient undergoing image-guided, dose-escalated radiotherapy of lymph nodes upon PSA relapse.

PURPOSE: Evaluation of the lymph node situation in patients with prostate cancer is essential for effective radiotherapy. Using magnet resonance imaging (MRI) of the lymph nodes with ferumoxtran-10 (MR lymphography), it is possible to detect lymph node metastasis. We present our initial experience with ferumoxtran-10 MR lymphography as the basis for image-guided, dose-escalated lymph node radiotherapy and for early follow-up after radiotherapy. PATIENTS AND METHODS: A patient with suspicion for lymph node metastasis after radical prostatectomy was examined with MR lymphography with the lymph node-specific contrast media ferumoxtran-10. Radiotherapy was performed as intensity-modulated radiotherapy with a total dose of 44 Gy to the whole lymphatic drainage, 60 Gy to the area of affected lymph nodes, 71 Gy to the prostate bed, and 75 Gy to the anastomosis region. 8 weeks after completion of radiotherapy, a follow-up MR lymphography with ferumoxtran-10 was performed. RESULTS: In the first MRI with ferumoxtran-10, 5 metastatic lymph nodes were found in the iliac region. The scan 8 weeks postradiotherapy no longer showed lymph nodes suspicious for metastases. PSA (prostate-specific antigen) decreased from 2.06 ng/ml pretherapeutically to 0.02 ng/ml at 2 weeks after treatment and was no longer detectable at 8 months after treatment. CONCLUSIONS: Lymph node staging with ferumoxtran-10 and subsequent dose escalation with intensity-modulated radiotherapy led to the elimination of positive lymph nodes and a decrease in the PSA value.

Is duodenal invasion a relevant prognosticator in patients undergoing adjuvant chemoradiotherapy for distal common bile duct cancer?

PURPOSE: To analyze the outcome of adjuvant chemoradiotherapy for patients with distal common bile duct (CBD) cancer who underwent curative surgery, and to identify the prognostic factors for these patients. METHODS AND MATERIALS: Between January 1991 and December 2002, 38 patients with adenocarcinoma of the distal CBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 27 men and 11 women, and the median age was 60 years (range, 34-73). Adjuvant radiotherapy was delivered to the tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/day) was given on day 1 to day 3 of each split course. The median follow-up period was 39 months. RESULTS: The 5-year overall survival rate of all patients was 49.1%. On univariate analysis, only histologic differentiation (p = 0.0005) was associated with overall survival. Tumor size (< or =2 cm vs. >2 cm) had a marginally significant impact on the treatment outcome (p = 0.0624). However, there was no difference in overall survival rates between T3 and T4 tumors (p = 0.6189), for which the main determinants were pancreatic and duodenal invasion, respectively. On multivariate analysis, histologic differentiation (p = 0.0092) and tumor size (p = 0.0046) were independent risk factors for overall survival. CONCLUSIONS: Long-term survival can be expected in patients with distal CBD cancer undergoing curative surgery and adjuvant chemoradiotherapy. Histologic differentiation and tumor size were significant prognostic factors predicting overall survival, whereas duodenal invasion was not. This finding suggests the need for further refinement in tumor staging.

Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer.

PURPOSE: To report the 8-year outcome of local dose escalation using high-dose-rate conformal brachytherapy combined with elective irradiation of the pelvic lymphatics for localized prostate cancer. METHODS AND MATERIALS: One hundred forty-four consecutively treated men (1986-1992) were recorded prospectively. Twenty-nine (20.14%) patients had T1b-2a tumors, and 115 (79.86%) patients had T2b-3 tumors according to, respectively, American Joint Committee on Cancer/Union Internationale Contre le Cancer 1992. All patients had a negative nodal status, proven by CT or MRI. The mean initial PSA value was 25.61 ng/mL (Initial value for 41.66% of patients was <10 ng/mL, for 21.52% was 10-20 ng/mL, and for 32.63% was >20 ng/mL). The total dose applied by external beam radiotherapy was 50 Gy in the pelvis and 40 Gy in the prostate. The high-dose-rate brachytherapy was delivered in two fractions, which were incorporated into the external beam treatment (after 20-Gy and 40-Gy external beam radiotherapy dose). The dose per fraction was 15 Gy for the PTV1 (peripheral prostate zone) and 9 Gy for the PTV2 (entire prostatic gland). Any patient free of clinical or biochemical evidence of disease was termed bNED. Actuarial rates of outcome were calculated by Kaplan-Meier and compared using the log-rank. Cox regression models were used to establish prognostic factors of the various measures of outcome. RESULTS: The median follow-up was 8 years (range 60-171 months). The overall survival rate was 71.5%, and the disease-free survival rate was 82.6%. The bNED survival rate was 72.9%. Freedom from local recurrence for T3 stage was 91.3%, whereas for G3 lesions it was 88.23%. Freedom from distant recurrence for T3 stage was 82.6% and for G3 lesions 70.59%. Univariate survival analyses revealed that low stage (T1-2), low grade (G1-2), no hormonal therapy, initial PSA value less than 40 ng/mL, and PSA normalization <1.0 ng/mL after irradiation were associated with long survival. In multivariate analyses, initial PSA value, PSA kinetics after radiation therapy, and no adjuvant hormonal treatment were independent prognostic factors. Grade 3 late radiation toxicity (according to RTOG/EORTC scoring scheme) was 2.3% for the genitourinary system in terms of cystitis and 4.10% for the gastrointestinal system in terms of proctitis. Grades 4 and 5 genitourinary/gastrointestinal morbidity was not observed. A history of transurethral resection of the prostate with a median interval of less than 6 months from radiotherapy was associated with a high risk of genitourinary toxicity. CONCLUSION: The 8-year results confirm the feasibility and effectiveness of combined elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for cure of localized and especially high-risk prostate cancer.