Brachytherapy for Conservative Treatment of Invasive Penile Carcinoma: Prognostic Factors and Long-Term Analysis of Outcome.

PURPOSE: To report the largest experience with brachytherapy as a conservative approach for the treatment of penile carcinoma. METHODS AND MATERIALS: We examined the outcomes of 201 patients treated at our institution over 45 years for invasive squamous cell carcinoma of the glans penis by brachytherapy. RESULTS: With a median follow-up of 10.7 years, local relapse as first failure was reported in 37 patients (18.9%), and 24 of 31 patients (77.4%) with local failure only were in complete remission after new treatment. At last follow-up 25 patients (12.4%) underwent partial surgery and 7 (3.5%) total penectomies for relapse. Fifty patients (24.8%) presented urethral stenosis requiring at least 1 dilatation, and 14 (7%) required limited surgeries for toxicities. At 5 years the estimated overall survival rate was 79% (95% confidence interval 73%-85%). The estimated original local control rate was 82% (95% confidence interval 76%-88%). Presence of inguinal lymph node metastasis and tumor size correlated with a poorer overall and disease-free survival in univariate and multivariate analyses. In univariate analysis, neutrophilia at diagnosis correlated with a higher probability of distant relapse (P=.025), and a dose ≥62 Gy correlated with better local control in N0 patients (P=.038). The risk of complication correlated with the dose, treated volume, and dose rate. CONCLUSION: This large institutional experience confirms the high local control achieved with brachytherapy for penile carcinoma, with the advantage of organ preservation. Most local relapses are efficiently salvaged by second-intent surgery.

Stereotactic ablative radiotherapy for early stage non-small cell lung cancer: A critical literature review of predictive factors of relapse.

Stereotactic ablative radiation therapy (SABR) has become the standard treatment for peripheral medically non-operable patients with early stage non-small cell lung cancer (NSCLC). Previous attempts of trials to compare SABR and surgery have failed and new randomized studies (SABRtooth, STABLEMATES, and VALOR) are ongoing. While predictive factors of relapse have been extensively studied in patients receiving surgery, there is scarce data on such putative factors in SABR patients. The purpose of this review is to analyze such predictive factors through a critical review of the literature.

Image-guided adaptive brachytherapy in cervical cancer: Patterns of relapse by brachytherapy planning parameters.

PURPOSE: Cervical cancer patients with a bulky high-risk clinical target volume (HR-CTV) get the largest benefit of dose escalation in terms of local control. However, the expected survival benefit could be lessened by a higher metastatic risk. We examined the patterns of relapse according to major prognostic factors: the HR-CTV volume and to the D90 HR-CTV. METHODS AND MATERIALS: The clinical records of patients treated with pulsed-dose-rate image-guided adaptive brachytherapy after concurrent pelvic chemoradiation were reviewed. All patients had an optimal workup before treatment comprising a 18-fluorodeoxyglucose positron emission tomography/computed tomography and a para-aortic lymph node dissection. Patients with initial extrapelvic disease were excluded. RESULTS: A total of 109 patients fulfilled inclusion criteria. Median followup was 39 months. An HR-CTV volume ≥40 cm(3) was associated with a poorer local failure-free survival. There was a strong inverse correlation between the HR-CTV volume and the D90 of the HR-CTV (correlation coefficient r = -0.696; p < 0.001) with increasing HR-CTV volume being associated with a decreasing D90 HR-CTV. A D90 HR-CTV <85 Gy and an HR-CTV volume ≥40 cm(3) were significant univariate factors for experiencing nonlocal failure (p = 0.002 and 0.035, respectively), even after exclusion of local relapses. CONCLUSION: A lower ability to reach the target D90 HR-CTV planning and an HR-CTV volume ≥ 40 cm(3) correlated with a high propensity of relapsing at distance, these factors being interrelated. Next step of treatment personalization should design strategies integrating this risk, which is now the main cause of failure.

MRI-guided brachytherapy in locally advanced cervical cancer: Small bowel [Formula: see text] and [Formula: see text] are not predictive of late morbidity.

PURPOSE: To establish dose-volume effect correlations for late small bowel (SB) toxicities in patients treated for locally advanced cervical cancer with concomitant chemoradiation followed by pulsed-dose rate MRI-guided adaptive brachytherapy. METHODS AND MATERIALS: Patients treated with curative intent and followed prospectively were included. The SB loops closed to CTV were delineated, but no specific dose constraint was applied. The dosimetric data, converted in 2-Gy equivalent, were confronted with the occurrence of late morbidity assessed using the CTC-AE 3.0. Dose-effect relationships were assessed using mean-dose comparisons, log-rank tests on event-free periods, and probit analyses. RESULTS: A total of 115 patients with a median followup of 35.5 months were included. Highest grade per patient was: Grades 0 for 17, 1 for 75, 2 for 20, and 3 for 3. The mean [Formula: see text] and [Formula: see text] were, respectively, 68.7 ± 13.6 Gy and 85.8 ± 33.1 Gy and did not differ according to event severity (p = 0.47 and p = 0.52), even when comparing Grades 0-1 vs. 2-4 events (68.0 ± 12.4 vs. 71.4 ± 17.7 Gy; p = 0.38 and 83.7 ± 26.4 vs. 94.5 ± 51.9 Gy; p = 0.33). Log-rank tests were performed after splitting the cohort according to four [Formula: see text] levels: >80 Gy, 70-79 Gy, 60-70 Gy, and <60 Gy. No difference was observed for Grades 1-4, Grades 2-4, or Grades 3-4 (p = 0.21-0.52). Probit analyses showed no correlation between the dosimetric parameters and probability of Grades 1-4, 2-4, or 3-4 events (p = 0.19-0.48). CONCLUSION: No significant dose-volume effect relationships were demonstrated between the [Formula: see text] and [Formula: see text] and the probability of late SB morbidity. These parameters should not limit the pulsed-dose rate brachytherapy optimization process.

Vaginal dose assessment in image-guided brachytherapy for cervical cancer: Can we really rely on dose-point evaluation?

PURPOSE: Although dose-volume parameters in image-guided brachytherapy have become a standard, the use of posterior-inferior border of the pubic symphysis (PIBS) points has been recently proposed in the reporting of vaginal doses. The aim was to evaluate their pertinence. METHODS AND MATERIALS: Nineteen patients who received image-guided brachytherapy after concurrent radiochemotherapy were included. Per treatment, CT scans were performed at Days 2 and 3, with reporting of the initial dwell positions and times. Doses delivered to the PIBS points were evaluated on each plan, considering that they were representative of one-third of the treatment. The movements of the applicator according to the PIBS point were analysed. RESULTS: Mean prescribed doses at PIBS -2, PIBS, PIBS +2 were, respectively, 2.23 ± 1.4, 6.39 ± 6.6, and 31.85 ± 36.06 Gy. Significant differences were observed between the 5 patients with vaginal involvement and the remaining 14 at the level of PIBS +2 and PIBS: +47.60 Gy and +7.46 Gy, respectively (p = 0.023 and 0.03). The variations between delivered and prescribed doses at PIBS points were not significant. However, at International commission on radiation units and measurements rectovaginal point, the delivered dose was decreased by 1.43 ± 2.49 Gy from the planned dose (p = 0.019). The delivered doses at the four points were strongly correlated with the prescribed doses with R(2) ranging from 0.93 to 0.95. The movements of the applicator in regard of the PIBS point assessed with the Digital Imaging and Communications in Medicine coordinates were insignificant. CONCLUSION: The doses evaluated at PIBS points are not impacted by intrafractional movements. PIBS and PIBS +2 dose points allow distinguishing the plans of patients with vaginal infiltration. Further studies are needed to correlate these parameters with vaginal morbidity.

Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer.

OBJECTIVE: To report the outcomes and late toxicities of patients with locally advanced cervical cancer treated with concomitant chemoradiation (CRT) followed by intracavitary image-guided adaptive brachytherapy (IGABT). METHODS: Data from consecutive patients with histologically proven stage IB-IVA cervical cancer treated with curative intent in a single institution were analyzed. After pelvic +/- para-aortic external-beam radiation therapy, they received pulsed-dose rate IGABT following GEC-ESTRO recommendations. RESULTS: Two hundred and twenty-five patients were enrolled. Sixty-five percent were stage≥IIB according to FIGO classification. Ninety-five percent received CRT. Mean D90 to HR and IR-CTV were 80.4+/-10.3Gy and 67.7+/-6.1Gy. After a median follow-up of 38.8months, 3-year local control and overall survival rates were 86.4% and 76.1%, respectively. A trend for a detrimental effect of tumor stage on local control rates was observed with 3-year local control rates of 100% for stages IB1 and IIA, 90.5 for IB2, 85.8% for IIB, 50% for IIIA, 77.1 for IIIB, and 66.7% for IVA tumors (p=0.06). Local control rates at 3years were 95.6% in the group of patients with D90 of HR-CTV≥85Gy, 88.8% in those with D90 between 80 and 85Gy, and 80% when D90<80Gy (p=0.018). Eighteen severe late gastrointestinal and urinary effects affecting 14 patients were reported corresponding with a crude incidence of 6.6%. CONCLUSIONS: CRT followed by IGABT provides high local control rates with limited toxicity. Reaching high doses is mandatory to achieve local control and interstitial brachytherapy is necessary in advanced diseases.

Pulsed-dose rate image-guided adaptive brachytherapy in cervical cancer: Dose-volume effect relationships for the rectum and bladder.

PURPOSE: To establish dose-volume effect correlations for late bladder and rectum side effects in patients treated for locally advanced cervical cancer with concomitant chemoradiation followed by pulsed-dose rate image-guided adaptive brachytherapy. MATERIAL AND METHODS: The dosimetric data, converted in 2 Gy equivalent, from 217 patients were confronted to late morbidity defined as any event lasting or occurring 90 days after treatment initiation. Toxicity was assessed using the CTC-AE 3.0. Probit analyses and Log rank tests were performed to assess relationships. RESULTS: One hundred and sixty-one urinary and 58 rectal events were reported, affecting 98 (45.1%) and 51 (23.5%) patients, respectively. Cumulative incidences for grade 2-4 bladder and rectal morbidity were 24.3% and 9.6% at 3 years, respectively. Significant relationships were observed between grade 2-4 and 3-4 events and D0.1cm(3) and D2 cm(3) for the bladder and between grade 1-4 and 2-4 event probability and rectal D2 cm(3). The effective doses for 10% grade 2-4 morbidity were 65.3 Gy (59.8-81.3), and 55.4 Gy (15.7-63.6), respectively, for the rectum and bladder. Without considering urinary and rectal incontinence, for which the pertinence of correlating them with D2 cm(3) is questionable, ED10 were 68.5 Gy (62.9-110.6) and 65.5 Gy (51.4-71.6 Gy). When sorting patients according to D2 cm(3) levels, patients with high D2 cm(3) had significantly lower morbidity free survival rates for grade 1-4 and 2-4 urinary and rectal morbidity. CONCLUSION: Significant dose-volume effect relationships were demonstrated between the modern dosimetric parameters and the occurrence of late rectal and urinary morbidity in patients treated with pulsed-dose-rate brachytherapy. Further studies are required to refine these relationships according to clinical cofactors, such as comorbidities.

D2cm³/DICRU ratio as a surrogate of bladder hotspots localizations during image-guided adaptive brachytherapy for cervical cancer: assessment and implications in late urinary morbidity analysis.

PURPOSE: To evaluate the efficiency and potential implications of the lowest dose evaluated in the maximally exposed 2cm(3) of the bladder/dose evaluated at the International Commission for Radiation Units and Measurements (ICRU) bladder point (D2cm(3)/DICRU) ratio as surrogate to locate the D2cm(3) in patients treated with MRI-guided adaptive brachytherapy for cervical cancer. METHODS AND MATERIALS: The D2cm(3) area of the bladder was located in 69 patients, using the Digital Imaging and Communications in Medicine coordinates of its barycenter, with respect to the ICRU bladder point. The D2cm(3)/DICRU ratio was correlated with the longitudinal coordinate of the D2cm(3). Afterward, the ratio was used in a retrospective cohort of 216 patients to evaluate its impact in dose-effect analyses for late urinary incontinence. RESULTS: The mean position of the D2cm(3) was 1.73±0.98 cm cranially, 0.59±0.65 cm backwardly, and 0.02±0.89 cm to the right of the ICRU point. It was located above the ICRU point in 95.7% of the patients. Its position was lower in patients with vaginal involvement at diagnosis (p=0.03). The D2cm(3)/DICRU ratio was correlated with the position of the D2cm(3) (R²=0.716, p<10(-6)). In speculating that a ratio greater than one would predict a D2cm(3) located above the ICRU point, the sensibility, specificity, positive, and negative predictive values were 95.2%, 100%, 100%, and 66.8%, respectively. Among the retrospective cohort, 85 patients had a ratio lower than 1.1, reflecting a D2cm(3) located in the lower bladder. In these patients, analyses showed significant dose relationship with Grade 2-4 incontinence (p=0.017), whereas no correlation was demonstrated in the remaining patients. CONCLUSIONS: The D2cm(3)/DICRU ratio is a relevant surrogate to estimate the localization of the D2cm(3). Significant dose-effect correlations for incontinence were established in patients with low values for this ratio.

Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.

PURPOSE: To report the prognostic factors for local control in patients treated for locally advanced cervical cancer with image guided pulsed-dose rate brachytherapy. MATERIALS/METHODS: Patients treated with curative intent by a combination of external beam radiotherapy and pulsed-dose rate brachytherapy were selected. Local failure was defined as any relapse in the cervix, vagina, parametria, or uterus during follow-up. Prognostic factors were selected based on log rank tests and then analyzed with a Cox model. Dose/effect correlations were performed using the probit model. RESULTS: Two hundred and twenty-five patients treated from 2006 to 2011 were included. According to the FIGO classification, 29% were stage IB, 58% stage II, 10% stage III, and 3% stage IVA; 95% received concomitant chemotherapy. Thirty patients were considered having incomplete response or local failure. Among the selected parameters, D90 for HR-CTV, D90 for IR-CTV, the overall treatment time, the TRAK, and the HR-CTV volume appeared significantly correlated with local control in univariate analysis. In multivariate analysis, overall treatment time >55days and HR-CTV volume >30cm(3) appeared as independent. The probit analysis showed significant correlations between the D90 for both CTVs, and the probability of achieving local control (p=0.008 and 0.024). The thresholds to reach to warrant a probability of 90% of local control were 85Gy to the D90 of the HR-CTV and 75Gy to 90% of the IR-CTV (in 2Gy equivalent, α/ß=10). To warrant the same local control rate, the D90 HR-CTV should be significantly increased in stage III-IV tumors, in case of HR-CTV >30cm(3), excessive treatment time, or tumor width at diagnosis >5cm (97, 92, 105, and 92Gy respectively). CONCLUSIONS: Overall treatment time and HR-CTV volume were independent prognostic factors for local control. The D90 for HR and IR CTV were significantly correlated with local control, and D90 HR-CTV should be adapted to clinical criteria.

Challenges in the treatment of early non-small cell lung cancer: what is the standard, what are the challenges and what is the future for radiotherapy?

In the last 15 years, the use of Stereotactic Ablative Radiation Therapy (SABRT) in the management of small peripheral lung tumours has developed considerably, so that it currently represents a standard of care for inoperable stage I non-small cell lung cancer (NSCLC), offering a survival advantage over traditional radiotherapy, local control rates at 3 years around 90%, with a low risk of toxicity. Indications have extended to larger tumours up to 5 cm and centrally located tumours. In this review we will explore the role of SABRT in early stage NSCLC, the state of the art, the challenges and the future for this technique. There are ongoing studies to optimize such approaches within a multicentric setting. Trials comparing surgery to SABRT in operable or marginally operable have failed because of poor accrual. Several questions remain that need to be addressed in prospective studies.