Eleonor Rivin del Campo

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/β=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.

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.

Leukocytosis and neutrophilia predicts outcome in anal cancer

OBJECTIVE Leukocytosis and neutrophilia could be the tip of the iceberg in the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a cohort of patients treated with definitive chemoradiation for anal squamous cell carcinoma (SCC). MATERIALS & METHODS Clinical records from all consecutive patients treated in a single institution between 2006 and 2016 with curative-intent radiotherapy were retrospectively analyzed. Leukocytosis and neutrophilia, defined as leukocyte or neutrophil count over 10,000 and 7500/mm3, respectively, were studied in terms of overall survival (OS), progression (PFS), locoregional (LFS) and distant (DFS)-free survival. RESULTS We identified 103 non-metastatic HIV-negative patients, with concurrent chemotherapy use in 78%. Twelve and 8% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year OS and PFS were 88% and 67%, respectively. In univariate analysis, both leukocytosis and neutrophilia were strongly associated with inferior OS, PFS, LFS and DFS (p<0.01). In multivariate analysis, leukocytosis and neutrophilia remained strongly associated with patient outcome (p<0.01), independently from tumor T and N-stage. Anemia was an independent predictor of worse OS and PFS, while chemoradiation overall treatment time below 50days improved PFS. CONCLUSION Leukocytosis and neutrophilia are strong prognostic factors for OS, PFS, LFS and DFS in anal cancer treated with chemoradiation. These biomarkers could help identify patients with higher risk of tumor relapse that require treatment intensification.

Intrafractional organs movement in three-dimensional image-guided adaptive pulsed-dose-rate cervical cancer brachytherapy: Assessment and dosimetric impact

PURPOSE To prospectively evaluate the intrafractional movements of organs at risk (OARs) and their dosimetric impact during the delivery of pulsed-dose-rate brachytherapy in cervical cancer. PATIENTS AND METHODS An MRI on Day 1 was used for treatment planning in 19 patients. CT scans were acquired at Days 1, 2, and 3 with delineation of the OARs. The MRI plan was transferred to each CT. The intersection volume between the 10 Gy isodose and the OARs were monitored, reflecting movement. Lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ and lower dose evaluated in the maximally exposed 2 cm(3) of an organ (D(2cm3)) were evaluated on each CT and compared. Results were averaged considering that each CT reflected one-third of the treatment course to evaluate the delivered dose. RESULTS No major movements of the sigmoid and bladder were observed, whereas the rectum got significantly closer to the implant at Day 2. The consequence was an increase of 6% ± 5.3 (3.7 Gy, α/β = 3 Gy) of the delivered D(2cm3) from the planned dose, in contrast to 0.2% ± 6.1 for the bladder and 1.1% ± 6.4 for the sigmoid. The increase of the D(2cm3) of the rectum was reported in 17 patients, ranging from 0.4 to 9.4 Gy, leading to a 10.5% overcoming of the dose constraint (75 Gy). Similar tendencies were reported for lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ. CONCLUSIONS A significant systematic variation was observed for the rectum (+3.7 Gy). As significant random variations were observed, caution should be exercised when the planned D(2cm3) is close to the dose constraints.

Leukocytosis and neutrophilia predict outcome in locally advanced esophageal cancer treated with definitive chemoradiation

Purpose To investigate the prognostic value of leukocyte and neutrophil count as biomarkers in patients with locally advanced esophageal squamous cell carcinoma (SCC) undergoing exclusive chemoradiation. Results A total of 126 patients were identified. Respectively, 33% and 35% displayed baseline leukocytosis and neutrophilia. Estimated 3-year OS and PFS from chemoradiation completion were 31% and 25%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS, and LRC (p < 0.01). In multivariate analysis, leukocytosis remained an independent risk factor associated with poorer OS, PFS and LRC (p < 0.05), independently from tumor stage and length, with higher prognostic value for OS compared with patients’ performance status (PS). Materials and Methods Bi-institutional clinical records from consecutive non-operable patients treated between 2003 and 2015 with definitive chemoradiation for locally advanced esophageal carcinoma were reviewed. Leukocytosis and neutrophilia were defined as a leukocyte or neutrophil count over 10 G/L and 7 G/L, respectively. These parameters were studied for their potential correlation with overall survival (OS), progression free survival (PFS), locoregional control (LRC) and distant metastases control (DMC). Conclusions Leukocytosis and neutrophilia were independent prognostic factors of poor OS, PFS, and LRC in this bi-institutional series of locally advanced esophageal SCC treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters might be clinically relevant biomarkers to be considered for further clinical investigations.

Post radiation hysterectomy in locally advanced cervical cancer: Outcomes and dosimetric impact.

PURPOSES Firstly, to evaluate the impact of completion hysterectomy after chemoradiation and image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Secondly, to assess a potential differential dose-effect relationship for the rectum and bladder according to the realization of hysterectomy. MATERIAL AND METHODS Two cohorts of patients were identified, differing by the realization of completion hysterectomy. Inclusions were limited to FIGO stage I-II, with no para-aortic involvement. All patients received a combination of pelvic chemoradiation followed by IGABT. Their outcomes and morbidity were reviewed. Log-rank tests were used to compare survivals. Probit analyses were performed to study dose-volume effect relationships. RESULTS The two cohorts comprised 54 patients in the completion surgery group and 157 patients in the definitive radiotherapy group. They were well balanced, except for the mean follow-up, significantly longer in the post hysterectomy cohort and the use of PET-CT in the work-up, more frequent in the definitive radiotherapy cohort. Although less local relapses were reported in the hysterectomy group, the 5-year disease-free and overall survival did not differ between groups. The cumulative incidence of severe late morbidity was significantly increased in the hysterectomy cohort: 22.5% versus 6.5% at 5years (p=0.016). Dose-volume effects were observed for the bladder, with the D2cm3 corresponding with a 10% probability of late severe morbidity urinary events (ED10) of 67.8Gy and 91.9Gy in the hysterectomy and definitive radiotherapy cohorts, respectively. A D90 CTVHR of 85Gy (planning aim) corresponded with a 93.3% rate of local control in the definitive radiotherapy cohort whereas it corresponded with a 77.3% chance to have a good histologic response (complete response or microscopic residual disease) in the hysterectomy group. CONCLUSION No benefit from completion hysterectomy in terms of overall or disease-free survival rates was observed, which was moreover responsible for an increase of the severe late morbidity. The realization of post-radiation hysterectomy resulted in a shift of the ED10 of 24.1Gy.

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.

External validation of leukocytosis and neutrophilia as a prognostic marker in anal carcinoma treated with definitive chemoradiation

PURPOSE To validate the prognostic value of leukocyte disorders in anal squamous cell carcinoma (SCC) patients receiving definitive concurrent chemoradiation. MATERIALS AND METHODS Bi-institutional clinical records from consecutive patients treated between 2001 and 2015 with definitive chemoradiation for anal SCC were retrospectively reviewed. Prognostic value of pretreatment leukocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as leukocyte or neutrophil count exceeding 10G/L and 7G/L, respectively. RESULTS We identified 133 patients, treated in two institutions. Eight% and 7% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year overall survival (OS) and progression-free survival (PFS) were 88% and 77%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS (p<0.01), locoregional control (LRC) and Distant Metastasis Control (DMC) (p<0.05), also after stratification by each institution. In multivariate analysis, leukocytosis and neutrophilia remained as independent risk factors associated with poorer OS, PFS, LRC and DMC (p<0.05). CONCLUSION This study validates leukocytosis and neutrophilia as independent prognostic factors in anal SCC patients treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters are clinically relevant biomarkers to be considered for further clinical investigations.

Assessment of the novel online delineation workshop dummy run approach using FALCON within a European multicentre trial in cervical cancer (RAIDs)

BACKGROUND AND PURPOSE Online delineation workshops (ODW) permit training of geographically dispersed participants. The purpose is to evaluate the methodology of an ODW using FALCON to harmonize delineation within a European multicentre trial on locally advanced cervical cancer (LACC). MATERIAL AND METHODS Two ODW included 46 clinicians (14 centres). Clinicians completed baseline (C1), guideline (C2) and final contours (C3) for external beam radiotherapy (EBRT) and brachytherapy (BT) for LACC. Interobserver and intraobserver variability was evaluated quantitatively (using the DICE index) and qualitatively compared to expert contours. RESULTS Nine clinicians submitted for EBRT and BT for C1-C3. Thirty-two sent any contour. Interobserver quantitative comparisons for EBRT showed significant improvement for C2 vs. C1 for bowel, CTV node, CTV-p and GTV node with significant detriment for GTV node (C3 vs. C1; C2), CTV-p (C3 vs. C2) and bowel (C3 vs. C2), showing in general an improvement in C2 vs. C1, with a detriment in C3 vs. C2 for two target volumes and an organ at risk. For BT there was significant improvement for C2 vs. C1 for bladder, GTV, HR-CTV and IR-CTV, with significant detriment for bladder (C3 vs. C2), thus overall improvement in C2 vs. C1, with only a detriment in C3 vs. C2 for bladder. Centres using MRI imaging for BT contouring did significantly better in the BT case for HR-CTV than those which used other techniques (C2 vs. C1: p<0.005; C3 vs. C1: p=0.02). Intraobserver quantitative comparisons showed significant improvement contouring a region of interest between C2 vs. C1, C3 vs. C1 and C3 vs. C2 for EBRT and between C2 and C1 for BT. CONCLUSIONS ODW offer training, initial contouring harmonization and allow assessment of centres.