Marie Duclos

Ductal carcinoma in situ--the influence of the radiotherapy boost on local control.

PURPOSE Local recurrence (LR) of ductal carcinoma in situ (DCIS) is reduced by whole-breast irradiation after breast-conserving surgery (BCS). However, the benefit of adding a radiotherapy boost to the surgical cavity for DCIS is unclear. We sought to determine the impact of the boost on LR in patients with DCIS treated at the McGill University Health Centre. METHODS AND MATERIALS A total of 220 consecutive cases of DCIS treated with BCS and radiotherapy between January 2000 and December 2006 were reviewed. Of the patients, 36% received a radiotherapy boost to the surgical cavity. Median follow-up was 46 months for the boost and no-boost groups. Kaplan-Meier survival analyses and Cox regression analyses were performed. RESULTS Compared with the no-boost group, patients in the boost group more frequently had positive and <0.1-cm margins (48% vs. 8%) (p < 0.0001) and more frequently were in higher-risk categories as defined by the Van Nuys Prognostic (VNP) index (p = 0.006). Despite being at higher risk for LR, none (0/79) of the patients who received a boost experienced LR, whereas 8 of 141 patients who did not receive a boost experienced an in-breast LR (log-rank p = 0.03). Univariate analysis of prognostic factors (age, tumor size, margin status, histological grade, necrosis, and VNP risk category) revealed only the presence of necrosis to significantly correlate with LR (log-rank p = 0.003). The whole-breast irradiation dose and fractionation schedule did not affect LR rate. CONCLUSIONS Our results suggest that the use of a radiotherapy boost improves local control in DCIS and may outweigh the poor prognostic effect of necrosis.

Hypofractionated Radiotherapy for Favorable Risk Prostate Cancer

PURPOSE Since the recognition that prostate cancer probably has a low alpha/beta ratio, hypofractionated radiotherapy has become an attractive treatment option for localized prostate cancer. However, there is little experience with the use of hypofractionation delivering a high biologically equivalent dose. We report our experience with high-dose hypofractionated radiotherapy. MATERIAL AND METHODS A total of 129 patients with favorable risk prostate cancer were treated with three-dimensional conformal radiotherapy treatment plans to the dose of 66 Gy in 22 fractions, prescribed at the isocenter. Planning target volume consisted of the prostate plus a uniform 7-mm margin, including the rectal margin. No patient received hormonal therapy. Toxicity was prospectively graded by the Common Toxicity Criteria version 3. Biochemical relapse was defined as postradiotherapy nadir prostate-specific antigen + 2 ng/mL. RESULTS With a median follow-up of 51 months, the 5-year actuarial biochemical control rate is 98%. The only 3 cases with biochemical failure did not have a clinical local relapse. More than 50% of patients did not develop acute toxicity. For late toxicity, the worst crude rate of Grade >or=2 genitourinary (GU) and gastrointestinal (GI) toxicity seen at any time during follow-up were 32% and 25%, respectively. There was no Grade 4 or 5 toxicity. At the last follow-up, persistent Grade >or=2 late GU and GI toxicity were 2% and 1.5%, respectively. CONCLUSIONS This hypofractionated regimen provides excellent biochemical control in favorable risk prostate cancer with an acceptable rate of late toxicity. Further studies exploring this hypofractionation regimen are warranted.

Absence of toxicity with hypofractionated 3-dimensional radiation therapy for inoperable, early stage non-small cell lung cancer.

PurposeHypofractionated radiotherapy may overcome repopulation in rapidly proliferating tumors such as lung cancer. It is more convenient for the patients and reduces health care costs. This study reports our results on patients with medically inoperable, early stage, non-small cell lung cancer (NSCLC) treated with hypofractionation.Materials and methodsStage T1-2N0 NSCLC patients were treated with hypofractionation alone, 52.5 Gy/15 fractions, in 3 weeks, with 3-dimensional conformal planning. T1-2N1 patients with the hilar lymphnode close to the primary tumor were also eligible for this treatment. We did not use any approach to reduce respiratory motion, but it was monitored in all patients. Elective nodal radiotherapy was not performed. Routine follow up included assessment for acute and late toxicity and radiological tumor response. Median follow up time was 29 months for the surviving patients.ResultsThirty-two patients with a median age of 76 years, T1 = 15 and T2 = 17, were treated. Median planning target volume (PTV) volume was 150cc and median V16 of both lungs was 13%. The most important finding of this study is that toxicity was minimal. Two patients had grade ≤ 2 acute pneumonitis and 3 had mild (grade 1) acute esophagitis. There was no late toxicity. Actuarial 1 and 2-year overall survival rates are 78% and 56%, cancer specific survival rates (CSS) are 90% and 74%, and local relapse free survival rates are 93% and 76% respectively.Conclusion3-D planning, involved field hypofractionation at a dose of 52.5 Gy in 15 daily fractions is safe, well tolerated and easy radiation treatment for medically inoperable lung cancer patients. It shortens by half the traditional treatment. Results compare favorably with previously published studies. Further studies are needed to compare similar technique with other treatments such as surgery and stereotactic radiotherapy.

Hypofractionated radiation therapy (66 Gy in 22 fractions at 3 Gy per fraction) for favorable-risk prostate cancer: long-term outcomes.

PURPOSE To report long-term outcomes of low- and intermediate-risk prostate cancer patients treated with high-dose hypofractionated radiation therapy (HypoRT). METHODS AND MATERIALS Patients with low- and intermediate-risk prostate cancer were treated using 3-dimensional conformal radiation therapy to a dose of 66 Gy in 22 daily fractions of 3 Gy without hormonal therapy. A uniform 7-mm margin was created around the prostate for the planning target volume, and treatment was prescribed to the isocenter. Treatment was delivered using daily ultrasound image-guided radiation therapy. Common Terminology Criteria for Adverse Events, version 3.0, was used to prospectively score toxicity. Biochemical failure was defined as the nadir prostate-specific antigen level plus 2 ng/mL. RESULTS A total of 129 patients were treated between November 2002 and December 2005. With a median follow-up of 90 months, the 5- and 8-year actuarial biochemical control rates were 97% and 92%, respectively. The 5- and 8-year actuarial overall survival rates were 92% and 88%, respectively. Only 1 patient died from prostate cancer at 92 months after treatment, giving an 8-year actuarial cancer-specific survival of 98%. Radiation therapy was well tolerated, with 57% of patients not experiencing any acute gastrointestinal (GI) or genitourinary (GU) toxicity. For late toxicity, the worst grade ≥2 rate for GI and GU toxicity was 27% and 33%, respectively. There was no grade >3 toxicity. At last follow-up, the rate of grade ≥2 for both GI and GU toxicity was only 1.5%. CONCLUSIONS Hypofractionation with 66 Gy in 22 fractions prescribed to the isocenter using 3-dimensional conformal radiation therapy produces excellent biochemical control rates, with moderate toxicity. However, this regimen cannot be extrapolated to the intensity modulated radiation therapy technique.

Contrasting analytical and data-driven frameworks for radiogenomic modeling of normal tissue toxicities in prostate cancer

BACKGROUND AND PURPOSE We explore analytical and data-driven approaches to investigate the integration of genetic variations (single nucleotide polymorphisms [SNPs] and copy number variations [CNVs]) with dosimetric and clinical variables in modeling radiation-induced rectal bleeding (RB) and erectile dysfunction (ED) in prostate cancer patients. MATERIALS AND METHODS Sixty-two patients who underwent curative hypofractionated radiotherapy (66 Gy in 22 fractions) between 2002 and 2010 were retrospectively genotyped for CNV and SNP rs5489 in the xrcc1 DNA repair gene. Fifty-four patients had full dosimetric profiles. Two parallel modeling approaches were compared to assess the risk of severe RB (Grade⩾3) and ED (Grade⩾1); Maximum likelihood estimated generalized Lyman-Kutcher-Burman (LKB) and logistic regression. Statistical resampling based on cross-validation was used to evaluate model predictive power and generalizability to unseen data. RESULTS Integration of biological variables xrcc1 CNV and SNP improved the fit of the RB and ED analytical and data-driven models. Cross-validation of the generalized LKB models yielded increases in classification performance of 27.4% for RB and 14.6% for ED when xrcc1 CNV and SNP were included, respectively. Biological variables added to logistic regression modeling improved classification performance over standard dosimetric models by 33.5% for RB and 21.2% for ED models. CONCLUSION As a proof-of-concept, we demonstrated that the combination of genetic and dosimetric variables can provide significant improvement in NTCP prediction using analytical and data-driven approaches. The improvement in prediction performance was more pronounced in the data driven approaches. Moreover, we have shown that CNVs, in addition to SNPs, may be useful structural genetic variants in predicting radiation toxicities.

Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiation Therapy in the Treatment of Intermediate-Risk Prostate Cancer – Long Term Results

PURPOSE We present the long-term results of a cohort of patients with intermediate-risk prostate cancer (PC) treated with single-fraction high-dose-rate brachytherapy (HDRB) combined with hypofractionated external beam radiation therapy (HypoRT). METHODS AND MATERIALS Patients were treated exclusively with HDRB and HypoRT. HDRB delivered a dose of 10 Gy to the prostate surface and HypoRT consisted of 50 Gy delivered in 20 daily fractions. The first 121 consecutive patients with a minimum of 2 years posttreatment follow-up were assessed for toxicity and disease control. RESULTS The median follow-up was 65.2 months. No acute Grade III or higher toxicity was seen. Late Grade II gastrointestinal toxicity was seen in 9 patients (7.4%) and Grade III in 2 (1.6%). Late Grade III genitourinary toxicity was seen in 2 patients (1.6%). After a 24-month follow-up, a rebiopsy was offered to the first 58 consecutively treated patients, and 44 patients agreed with the procedure. Negative biopsies were found in 40 patients (91%). The 5-year biochemical relapse-free survival rate was 90.7% (95% CI, 84.5-96.9%), with 13 patients presenting biochemical failure. Among them, 9 were diagnosed with distant metastasis. Prostate cancer-specific and overall survival rates at 5 years were 100% and 98.8% (95% CI, 96.4-100%), respectively. CONCLUSION The combination of HDRB and HypoRT is well tolerated, with acceptable toxicity rates. Furthermore, results from rebiopsies revealed an encouraging rate of local control. These results confirm that the use of conformal RT techniques, adapted to specific biological tumor characteristics, have the potential to improve the therapeutic ratio in intermediate-risk PC patients.

Prostate gland edema after single-fraction high-dose rate brachytherapy before external beam radiation therapy

PURPOSE High-dose rate brachytherapy (HDRB) is frequently used as a boost to external beam radiation therapy (EBRT) in prostate cancer patients. With the increasing use of small planning target volume margins in EBRT, prostatic edema induced by HDRB can be a contributing factor to geometric miss when HDRB is performed before or during EBRT. We assessed prostate gland volumetric change after single-fraction HDRB and its impact on definition of treatment volume for EBRT. METHODS AND MATERIALS Thirty-one consecutive patients with intermediate-risk prostate cancer treated with single-fraction HDRB (10 Gy) combined with hypofractionated EBRT were analyzed. A second CT scan was performed 7 days after HDRB, and images were coregistered with the planning CT scan that contained the original clinical target volume (CTV). The post-HDRB prostate CTV volume was compared with the original CTV by a single observer. RESULTS All patients presented volumetric variation. In most cases (68%), the prostate increased in volume, whereas it decreased in 32%. The mean prostatic volume was 42.2 cc before HDRB and 43.6 cc after HDRB, representing a mean volume difference of 3.4%, ranging from -14.2% to 23.8% (p=0.756). This difference is the result of mean changes of 0.6mm (-6.1 to 6.6) in the anterior-posterior, 0.5mm (-5.5 to 3.0) in the lateral, and 0.2mm (-5.0 to 5.0) in the superior-inferior axes. CONCLUSIONS Although a nonsignificant volumetric change occurs after single-fraction HDRB, individual variations on specific axis could lead to important uncertainties during EBRT.

Is there a detrimental effect of waiting for radiotherapy for patients with localized prostate cancer

Objective:To evaluate a possible deleterious effect of waiting time to radiotherapy on the biochemical relapse (BR) of patients with localized prostate cancer. Patients and Methods:Patients included in this retrospective study had localized prostate adenocarcinoma treated with external-beam irradiation alone. Waiting time was defined as the interval between the first consultation and the first radiation treatment. BR was defined as 3 consecutive rises of prostatic specific antigen (PSA). Patients were split into 3 groups of waiting time: group A were treated within 40 days; group B waited 41 to 80 days; group C waited >80 days to receive radiotherapy. The effect of waiting on BR was estimated by the Kaplan-Meier method. Multivariate Cox proportional hazards modeling was adjusted for known prognostic factors. Results:There were 289 patients who participated in the analysis. Median follow-up time was 6.1 year. Overall BR rate was 44% at 5 years. The median waiting time increased over the study period from 26 days in 1992 to 123 days in 2000. In adjusted multivariate analysis there was a nonsignificant higher risk of BR with waiting for 41 to 80 days (hazard ratio [HR] = 0.8; 95% confidence interval [CI] = 0.3–1.6) and for >80 days (HR = 0.6; 95% CI = 0.2–1.5) when compared with patients treated within 40 days after consultation. Conclusion:Delaying the start of radiotherapy showed little effect on the rate of BR in the group of 288 prostate cancer patients analyzed in this study.

CONE BEAM CT-BASED THREE-DIMENSIONAL PLANNING IN HIGH-DOSE-RATE BRACHYTHERAPY FOR CERVICAL CANCER

PURPOSE To evaluate dose-volume histograms (DVHs) of bladder and rectum from the use of cone beam CT (CBCT)-based three-dimensional (3D) treatment planning in intracavitary high-dose-rate brachytherapy (HDRB) for cervical cancer patients and to compare these parameters with International Commission on Radiation Units and Measurements (ICRU) of rectal and bladder reference point dose measurements. METHODS AND MATERIALS Thirteen patients with cervical cancer underwent HDRB insertions. CT-compatible tandem and ovoid applicators were used to obtain intraoperative CBCT images. The use of a rectal tube and injection of bladder contrast before scanning facilitated contouring the rectum and bladder. All patients underwent intraoperative orthogonal x-ray filming, and treatments were prescribed using standard two-dimensional planning and dosimetry. DVHs for the bladder and rectum were constructed for each treatment. The minimum dose in the most irradiated 2.0-cm(3) volume of bladder (B(D2V)) and rectum (R(D2V)) were determined from DVHs and compared to ICRU reference point estimates of bladder (B(ICRU)) and rectum (R(ICRU)) doses. RESULTS Twenty-six CBCT-based plans were evaluated. The median B(ICRU) dose (347 cGy; range, 164-601 cGy) was significantly lower (p < 0.001) than the median B(D2V) (594 cGy; range, 260-969 cGy). The median R(ICRU) dose (405 cGy; range, 189-700 cGy) was also significantly lower (p = 0.037) than the median R(D2V) (488 cGy; range, 227-786 cGy). CONCLUSIONS CBCT-based 3D planning can be used in HDRB for cervical cancer and is a convenient alternative to CT-based planning, with the advantage of minimizing applicator motion. Correlation with late effects will further define the role of CBCT-based 3D dosimetry in HDRB planning.

Prostate-specific antigen bounce after high-dose-rate prostate brachytherapy and hypofractionated external beam radiotherapy

PURPOSE To report the frequency, timing, and magnitude of prostate-specific antigen (PSA) bounce (PB) in patients who received high-dose-rate (HDR) brachytherapy (HDRB) plus hypofractionated external beam radiation therapy (HypoRT) and to assess a possible correlation between PB and biochemical failure (BF). METHODS AND MATERIALS Patients with intermediate-risk prostate cancer received 10Gy single-fraction (192)Ir HDRB followed by 50Gy in 20 daily fractions of HypoRT without androgen deprivation therapy. All patients had a minimum 2-year followup. The PB was defined as PSA elevation higher than 0.2ng/mL from previous measurement with subsequent drop to pre-bounce level. The BF was defined as PSA nadir+2ng/mL. RESULTS A total of 114 patients treated between 2001 and 2009 were eligible for analysis. At a median followup of 66 months, the PB was found in 45 (39%) patients with a median time to bounce of 16 months (range, 3-76 months). The median time to PSA normalization after a PB was 9 months (range, 2-40 months). The median magnitude of PB was 0.45ng/mL (range, 0.2-6.62). The BF occurred in 12 (10.5%) patients of whom three had a PB. Median time to BF was 52.5 months. Four patients (3.5%) in the PB group fit the criteria for BF. CONCLUSIONS The PB is common after HDRB and HypoRT and can occur up to 76 months after treatment. It can rarely fit the criteria for BF. The time to PB is shorter than the time to BF. There is a lower incidence of BF in patients with a PB. An acknowledgment of this phenomenon should be made when interpreting PSA results during followup to prevent unnecessary interventions.