Salvage Stereotactic Body Radiation Therapy for Local Prostate Cancer Recurrence After Radiation Therapy: A Retrospective Multicenter Study of the GETUG.

PURPOSE: To assess the efficacy and safety of salvage stereotactic body radiation therapy (SBRT) in patients with biopsy-proven local prostate cancer recurrence after radiation therapy. METHODS AND MATERIALS: Between April 2010 and January 2017, 100 patients were included in 7 centers. Disease extension was assessed by pelvic multiparametric magnetic resonance imaging and choline positron emission tomography in 87% and 94% of patients, respectively. The median time interval between the 2 treatments was 7.5 years (range, 2-18). Median prostate-specific antigen at recurrence was 4.3 ng/mL (range, 2-38). Median SBRT dose was 36 Gy (range, 25-36.25) in 6 fractions (range, 5-6), every other day. Thirty-four percent of patients were treated by androgen deprivation therapy for a median duration of 12 months. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03. RESULTS: Median follow-up was 29.3 months (range, 4-91). Second biochemical recurrence-free survival rate at 3 years was 55% (95% confidence interval [CI], 42%-66%). The initial D'Amico group, time interval after first radiation therapy, and SBRT dose were prognostic factors of biochemical recurrence-free survival in multivariate analysis (P = .09, P = .025, P = .018, respectively). No patient developed acute gastrointestinal toxicity of grade >1; rates of acute genitourinary toxicity of grade 2 and 3 were 8% and 1%, respectively. The actuarial 3-year grade ≥2 genitourinary and gastrointestinal toxicity was 20.8% (95% CI, 13%-29%) and 1% (95% CI, 0.1%-5.1%), respectively. One patient presented with neuritis of grade 3. CONCLUSIONS: With a short follow-up, this study shows that salvage SBRT allows for encouraging control and acceptable toxicity. Further prospective studies are necessary to confirm these preliminary results and to determine late toxicity.

Salvage prostate re-irradiation using high-dose-rate brachytherapy or focal stereotactic body radiotherapy for local recurrence after definitive radiation therapy.

BACKGROUND: Optimal management of locally recurrent prostate cancer after definitive radiation therapy is still challenging. With the development of highly accurate radiotherapy devices, prostate salvage re-irradiation might generate lower toxicity rates than classical salvage therapies. We retrospectively evaluated the toxicity and the feasibility of a prostate re-irradiation after definitive radiation therapy failure. Two modalities were investigated: high-dose-rate brachytherapy (HDRB) on whole prostate gland and focal stereotactic radiotherapy (SBRT) using CyberKnife® linac. METHODS: Between 2011 and 2015, 28 patients with imaged and/or biopsy-proven intra-prostatic recurrence of cancer after definitive radiation therapy underwent a salvage re-irradiation using HDRB (n = 10) or focal SBRT (n = 18). The schedule of re-irradiation was 35 Gy in 5 fractions. Biological response (defined as post-salvage radiation PSA variation) and biochemical no-evidence of disease (bNED) were evaluated in the whole cohort. For patients who had a positive biological response after salvage radiation, biochemical recurrence (BCR) and survival after salvage radiotherapy were evaluated. Post-salvage toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and were compared to baseline status. RESULTS: Within a median follow-up of 22.5 months (IQR = 8-42), 9 (90%) patients experienced a positive biological response after salvage HDRB and 5 (50%) remained bNED at the end of the follow-up. Among patients who initially responded to salvage HDRB, the BCR rate was 44.4% after a median interval of 19.5 months (IQR = 11.5-26). Only one patient experienced a transient grade 3 urinary complication. In the SBRT group, the median follow-up was 14.5 months (IQR = 7-23) and 10 (55.6%) out of the 18 patients remained bNED. Among the 15 patients who initially responded to salvage SBRT, 5 (33.3%) experienced a BCR. One patient experienced a transient grade 4 urinary complication. At the end of the follow-up, all evaluated patients had a urinary status grade variation ≤ +1 grade. No grade 3-4 digestive toxicity was observed. CONCLUSIONS: Salvage prostate re-irradiation for locally recurrent cancer is feasible and generate low toxicities rates when using with HDRB or focal SBRT. However, further investigations are necessary to confirm these findings and to determine predictive features for patients who might benefit from such an approach.

Selecting patients for exclusive permanent implant prostate brachytherapy: the experience of the Paris Institut Curie/Cochin Hospital/Necker Hospital group on 809 patients.

PURPOSE: The aim of this study was to analyze overall and relapse-free survival in a cohort of 809 patients, 34% of whom corresponded to a higher-risk group than American Brachytherapy Society (ABS) criteria. METHODS AND MATERIALS: Between January 1999 and September 2004, 809 patients were treated with permanent loose 125 iodine seed implantation (IsoSeed Bebig, Eckert and Ziegler) by the Paris Institut Curie, Cochin Hospital, and Necker Hospital group. Of these 809 patients, 533 (65.9%) corresponded exactly to ABS criteria. Two hundred and seventy-six patients (34.1%) had a prostate-specific antigen (PSA) level between 10 and 15, or a Gleason score of 7, or both (non-ABS group). RESULTS: Overall 5-year survival was 98%, with no difference between the ABS group and the non-ABS patient subgroups (p = 0.62).Five-year relapse-free survival was 97% in the ABS group; it was significantly lower (p = 0.001) in the non-ABS group but remained satisfactory at 94%. On subgroup analysis, the results appeared to be better for the subgroup of patients with PSA 10-15 than for the subgroup with a Gleason score of 7. CONCLUSIONS: Our results suggest that selected patients in the intermediate-risk group of localized prostate cancers can be safely proposed as recipients of permanent implant brachytherapy as monotherapy.

[Nonsurgical treatment of chronic radiation-induced hemorrhagic proctitis]. / Traitement non chirurgical des rectites radiques chroniques hémorragiques.

The incidence of radiation-induced chronic hemorrhagic proctitis is less than 10 to 20%. The onset of this proctitis is delayed relative to the radiation therapy and generally develops from 6 to 24 months later. There are numerous predisposing factors, the most important of which is the radiation therapy dose: risk increases exponentially above 40-45 Gy. Its pathophysiology involves progressive obliterating endarteritis and transmural interstitial fibrosis, which induce chronic ischemia that is irreversible and progressive during the years after radiation therapy. Its diagnosis depends most often on the combination of clinical history and typical endoscopic appearance (congestive mucosa and/or telangiectases). Topical administrative of sucralfate or corticosteroids as well as argon plasma coagulation, with formalin treatment if necessary, provides relief for most patients.

Brachytherapy versus prostatectomy in localized prostate cancer: results of a French multicenter prospective medico-economic study.

PURPOSE: To prospectively compare health-related quality of life (HRQOL), patient-reported treatment-related symptoms, and costs of iodine-125 permanent implant interstitial brachytherapy (IB) with those of radical prostatectomy (RP) during the first 2 years after these treatments for localized prostate cancer. METHODS AND MATERIALS: A total of 435 men with localized low-risk prostate cancer, from 11 French hospitals, treated with IB (308) or RP (127), were offered to complete the European Organization for Research and Treatment of Cancer core Quality of Life Questionnaire QLQ-C30 version 3 (EORTC QLQ-C30) and the prostate cancer specific EORTC QLQ-PR25 module before and at the end of treatment, 2, 6, 12, 18, and 24 months after treatment. Repeated measures analysis of variance and analysis of covariance were conducted on HRQOL changes. Comparative cost analysis covered initial treatment, hospital follow-up, outpatient and production loss costs. RESULTS: Just after treatment, the decrease of global HRQOL was less pronounced in the IB than in the RP group, with a 13.5 points difference (p < 0.0001). A difference slightly in favor of RP was observed 6 months after treatment (-7.5 points, p = 0.0164) and was maintained at 24 months (-8.2 points, p = 0.0379). Impotence and urinary incontinence were more pronounced after RP, whereas urinary frequency, urgency, and urination pain were more frequent after IB. Mean societal costs did not differ between IB (8,019 euros at T24) and RP (8,715 euros at T24, p = 0.0843) regardless of the period. CONCLUSIONS: This study suggests a similar cost profile in France for IB and RP but with different HRQOL and side effect profiles. Those findings may be used to tailor localized prostate cancer treatments to suit individual patients' needs.

Prognosis and histopathologic features in papillary tumors of the pineal region: a retrospective multicenter study of 31 cases.

Papillary tumor of the pineal region (PTPR) is a recently described tumor entity thought to arise from the specialized ependyma of the subcommissural organ. Whereas histologic features of PTPR are well defined, data on the prognostic value of PTPR remain scarce. We therefore investigated clinicopathologic features, including data on progression-free survival and overall survival, in a retrospective series of 31 PTPR. The age of the 14 males and 17 females ranged from 5 to 66 years (median age, 29 years). Histologically, all tumors were characterized by an epithelial-like growth pattern in which the vessels were covered by layers of columnar or cuboidal tumor cells forming perivascular pseudorosettes. Most of the tumor cells showed strong expression of neuron-specific enolase, cytokeratins (particularly CK18), S-100 protein, and vimentin. Most PTPRs examined also expressed microtubule-associated protein-2. Expression of synaptophysin, epithelial membrane antigen, transthyretin, neural cell adhesion molecule, and nestin was encountered in some tumors. Gross total resection could be achieved in 21 of 31 cases; 15 patients received radiotherapy on resection of the primary tumor. Nevertheless, the majority of patients experienced recurrences; 5-year estimates for overall survival and progression-free survival were 73% and 27%, respectively. To conclude, the clinical course of PTPR is characterized by frequent local recurrence, and the value of radiotherapy on disease progression will need to be investigated in future prospective trials.

PSA bounce after permanent implant prostate brachytherapy may mimic a biochemical failure: a study of 295 patients with a minimum 3-year followup.

PURPOSE: To assess the frequency and features of the PSA bounce phenomenon in a series of patients treated with permanent implant brachytherapy for prostate cancer, and to evaluate the percentage of cases in which this bounce could have mimicked a biochemical relapse according to the American Society for Therapeutic Radiology and Oncology consensus criteria. METHODS AND MATERIALS: From January 1999 to December 2001, 295 patients were treated with a permanent prostate implantation (real-time technique, with free (125)I seeds) by the Paris Institut Curie/Hospital Cochin/Hospital Necker Paris group. Duration of followup is 40.3 months (9-66 months). PSA level was reported at intervals not exceeding 6 months. Bounce was defined by temporary elevation in PSA level, followed by a spontaneous decrease. RESULTS: In our series, 161 patients (55%) showed a transitory PSA increase (bounce) of at least 0.1 ng/mL; 145 patients (49%) a bounce of 0.2 ng/mL; 93 patients (32%) a bounce of 0.4 ng/mL; and 43 patients (15%) a bounce of at least 1 ng/mL. Mean PSA bounce was 0.8 ng/mL (0.1-4.1), and mean time to bounce was 19 months. Thirty-two patients (11% of total) presented three successive PSA increases, and therefore were to be considered as experiencing a biochemical relapse according to the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria. Among those 32 patients, 18 (56%) subsequently showed, without any treatment, a complete normalization of their PSA. In multivariate analysis, age <70 (p<0.0001) and D90>200Gy (p<0.003) were identified as independent factors for a PSA bounce of at least 0.4 ng/mL. CONCLUSIONS: The observed rate of 32% of patients showing a PSA bounce of at least 0.4 ng/mL in our series is in good agreement with what has been previously reported in the literature. Among 32 patients fulfilling the classical ASTRO criteria for a biochemical relapse, 18 (56%) subsequently showed a spontaneous PSA decrease, questioning the ASTRO consensus for the biochemical followup of patients undergoing permanent implant prostate brachytherapy.

Specific TP53 mutation pattern in radiation-induced sarcomas.

The mutagenic properties of ionizing radiation are well known, but the presence of specific mutations in human radiation-induced tumours is not established. We have studied a series of 36 secondary sarcomas arising in the irradiation field of a primary tumour following radiotherapy. The allelic status and the presence of mutations of the TP53 gene were investigated. The mutation pattern was compared with data from sporadic sarcomas recorded in the IARC TP53 somatic mutations database. A high proportion (58%) of the radiation-induced sarcomas exhibited a somatic inactivating mutation for one allele of TP53, systematically associated with a loss of the other allele. The high frequency (52%) of short deletions observed in the mutation pattern of radiation-induced sarcomas may be related to the induction of DNA breaks by ionizing radiation. The lack of hyper-reactivity of CpG dinucleotides and the presence of recurrent sites of mutation at codons 135 and 237 seem also to be specific for radiation tumorigenesis.

Non-homologous end-joining genes are not inactivated in human radiation-induced sarcomas with genomic instability.

DNA double-strand break (DSB) repair pathways are implicated in the maintenance of genomic stability. However the alterations of these pathways, as may occur in human tumor cells with strong genomic instability, remain poorly characterized. We analyzed the loss of heterozygosity (LOH) and the presence of mutations for a series of genes implicated in DSB repair by non-homologous end-joining in five radiation-induced sarcomas devoid of both active Tp53 and Rb1. LOH was recurrently observed for 8 of the 9 studied genes (KU70, KU80, XRCC4, LIG4, Artemis, MRE11, RAD50, NBS1) but not for DNA-PKcs. No mutation was found in the remaining allele of the genes with LOH and the mRNA expression did not correlate with the allelic status. Our findings suggest that non-homologous end-joining repair pathway alteration is unlikely to be involved in the high genomic instability observed in these tumors.

Anal canal carcinoma: early-stage tumors < or =10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy.

PURPOSE: To investigate the clinical history, management, and pattern of recurrence of very early-stage anal canal cancer in a French retrospective survey. METHODS: The study group consisted of 69 patients with Stage Tis and T1 anal canal carcinoma < or =1 cm treated between 1990 and 2000 (12 were in situ, 57 invasive, 66 Stage N0, and 3 Stage N1). The median patient age was 67 years (range, 27-83 years). Of the 69 patients, 66 received radiotherapy (RT) and 3 with in situ disease were treated by local excision alone without RT. Twenty-six patients underwent local excision before RT (12 with negative and 14 with positive surgical margins). Of the 66 patients who underwent RT, 8 underwent brachytherapy alone (median dose, 55 Gy), 38 underwent external beam RT (median dose, 45 Gy) plus a brachytherapy boost (median boost dose, 20 Gy), and 20 underwent external beam RT alone (median dose, 55 Gy). RESULTS: Of the 69 patients, 68 had initial local control. Of the 66 patients treated by RT, 6 developed local recurrence at a median interval of 50 months (range, 13-78 months). Four patients developed local failure outside the initial tumor bed. Of the 3 patients with Tis treated by excision alone, 1 developed local recurrence. No relation was found among prior excision, dose, and local failure. The 5-year overall survival, colostomy-free survival, and disease-free survival rate was 94%, 85%, and 89%, respectively. The rate of late complications (Grade 1-3) was 28% and was 14% for those who received doses <60 Gy and 37% for those who received doses of > or =60 Gy (p = 0.04). CONCLUSION: Most recurrences occurred after a long disease-free interval after treatment and often outside the initial tumor site. These small anal cancers could be treated by RT using a small volume and moderate dose (40-50 Gy for subclinical lesions and 50-60 Gy for T1).

Prostate cancer brachytherapy: is real-time ultrasound-based dosimetry predictive of subsequent CT-based dose distribution calculation? A study of 450 patients by the Institut Curie/Hospital Cochin (Paris) Group.

PURPOSE: Real-time ultrasound (US)-based dosimetry performed during (125)I loose seed implantation provides the radiation oncologist with an estimation of the dose distribution at seed insertion. However, for a number of reasons, this distribution may not reflect the real (reference) dosimetry as determined by subsequent CT, usually performed 1-2 months after implantation. The present study compared the two dosimetry data sets (US and CT) to evaluate how predictive extemporaneous US-based dosimetry can be of the real dose distribution. METHODS AND MATERIALS: A total of 450 patients with prostate cancer were treated with loose (125)I seed implantation between June 1999 and October 2002 by the Institut Curie/Hospital Cochin (Paris) Group. The mean patient age was 65 years. Most patients (74%) had Stage T1c; the stage did not exceed T2b for the others. All patients had a prostate-specific antigen level of <15 ng/mL and was <10 ng/mL for 72%; 84% had a Gleason score of < or =6 and did not exceed 7 for the others; and 56% were treated with neoadjuvant hormonal therapy for a mean of 4.3 months. All patients were treated with loose seed implantation. Real-time US-based dosimetry was performed intraoperatively for all patients. CT-based dosimetry was performed 2 months after implantation, using the VariSeed software. The minimal dose to 90% of the outlined volume (D(90)) and percentage of volume receiving at least 100% of the prescribed dose (V(100)) were calculated with the two methods and compared for all patients. RESULTS: On CT-based dosimetry, the D(90) was found to be > or =145 Gy (range, 115-240 Gy) in all patients except one. A large majority (86%) of patients showed a CT-based V(100) of >95%, and 48% had a V(100) of >98%. The mean CT-based D(90)/US-based D(90) ratio was 1.0 (range, 0.66-1.33). For 89% of the patients, the difference between the two values was <20% and for 62% was <10%. The mean CT-based V(100)/US-based V(100) ratio was 0.98 (range, 0-1.02), with 89% of patients showing a difference of <5%. CONCLUSION: Our results indicate that the D(90) and V(100) values obtained intraoperatively with our real-time US-based dosimetry are in reasonable agreement with the subsequent values obtained with CT-based dosimetry performed 2 months after implantation. Recent innovations in our dose planning software allowed better control of the longitudinal seed position and could still improve the correlation between real-time US-based dosimetry and the subsequent CT-based dose distribution.

Post-brachytherapy transurethral resection of the prostate in patients with localized prostate cancer.

PURPOSE: We assessed the rate and results of transurethral resection of the prostate (TURP) in patients previously treated with brachytherapy as monotherapy for localized prostate cancer. MATERIALS AND METHODS: From May 1998 to May 2003, 600 patients with localized prostate cancer were treated with brachytherapy at our institution. Brachytherapy was performed as monotherapy with curative intent for clinically localized prostate cancer without adjuvant treatment in patients with clinical stages T1c (68.4%) or T2a (31.6%) disease. -Iodine and palladium implants were used in 583 and 7 patients, respectively. A real-time interactive implantation technique was used in all but the first 17 patients, who were treated using a preplanned technique. RESULTS: Of the 600 patients 19 (3.1%) underwent TURP after brachytherapy. Among the patients with acute urinary retention the median interval between prostate brachytherapy and urinary retention was 2 months (range 0.5 to 32). No TURP was done within 6 months after implant. The median interval between prostate brachytherapy and TURP was 7 months (range 6 to 41) and median prostate specific antigen (PSA) before TURP was 0.5 ng/ml (range 0.04 to 3.4). In the 19 patients the median weight of resected prostatic tissue was 8 gm (range 2 to 19) and 1 to 11 seeds were removed (median 5). The perioperative and postoperative courses were uneventful. There was no TURP related incontinence. With a median followup of 28 months after brachytherapy (range 7 to 48) no patient had clinical or biochemical evidence of disease progression, and for the group of 19 patients who underwent TURP median serum PSA at the end of followup was 0.38 ng/ml (range 0.03 to 3.4). CONCLUSIONS: After brachytherapy as monotherapy, TURP can be done safely if indicated. In our experience the resection of prostatic tissue along with a limited number of seeds at least 6 months after implantation did not impair PSA based biological and clinical results of brachy-therapy.

Extraprostatic spread of clinically localized prostate cancer: factors predictive of pT3 tumor and of positive endorectal MR imaging examination results.

PURPOSE: To identify the factor(s) most predictive of pT3 tumor and those most predictive of a positive endorectal magnetic resonance (MR) imaging result in patients with clinically localized prostate cancer. MATERIALS AND METHODS: At multivariate analysis, five preoperative clinical parameters-prostate-specific antigen (PSA) level, digital rectal examination (DRE) result, Gleason score and number of involved sextants at transrectal US-guided biopsy, and endorectal MR imaging result-were used to predict pT3 tumor in 336 patients who underwent radical prostatectomy. On the basis of results of the first four examinations, multivariate analysis was performed also to determine predictors of a positive MR imaging study. RESULTS: Significant predictors of pT3 tumor were positive MR imaging result (P < 2 x 10(-8)), more than one sextant involved at biopsy (P < 5 x 10(-5)), and PSA level greater than 10 ng/mL (P < 7 x 10(-3)). Significant predictors of a positive MR imaging result were three or more sextants involved at biopsy (P < 10(-5)), positive DRE result (P < 5 x 10(-3)), and PSA level greater than 10 ng/mL (P < 16 x 10(-3)). In the subgroup of 175 patients who had at least three positive biopsy specimens, the sensitivity of MR imaging was 50% for detection of occult pT3 tumor and 69% for detection of extensive pT3 tumor. The overall specificity of MR imaging was 95%. CONCLUSION: Endorectal MR imaging seems to be indicated in carefully selected patients-specifically, those with three or more positive biopsy specimens, a palpable tumor, and/or a PSA level greater than 10 ng/mL.

[Update in radiation-induced neoplasms: genetic studies]. / Actualités sur les tumeurs radio-induites: les études génétiques.

Radiation induced tumors are a possible (very) late complications of radiotherapy. The evaluation of the risks of radiation-induced tumors has been presented in different epidemiological studies, with the evaluation of the relative risk for different tissues. But, the genetic studies are rare, and no global theory exists. Two cytogenetic profiles are described, one with translocations and one with genetic material losses, evoking two different genetic evolutions. Two questions are stated. What are the radiation-induced genetic mechanisms? Is it possible to differentiate the radiation-induced and spontaneous tumors with genetic approaches? With 37 cytogenetic cases, 12 analyzed in our laboratory, the radiation-induced tumors were characterized by genetic material losses. An anti-oncogenic evolution is probable. A new molecularly study confirm these results. Only thyroid tumors do not have this evolution. For tumors with simple karyotype, like meningioma, radiation-induced tumors seem to be more complex than spontaneous tumors. But for the others, the differentiation is impossible to be done with cytogenetic. The mechanism of the chromosomic material losses in unknown, but some hypothesis are discussed.