Alexandra J. Stewart

Prostate-Specific Antigen Nadir and Cancer-Specific Mortality Following Hormonal Therapy for Prostate-Specific Antigen Failure

PURPOSE For men receiving androgen-suppression therapy (AST) for a rising postoperative or postradiation prostate-specific antigen (PSA), we evaluated whether a PSA nadir of more than 0.2 ng/mL was significantly associated with prostate cancer-specific mortality (PCSM). PATIENTS AND METHODS The study cohort comprised 747 men with rising PSA and negative bone scan after surgery (n = 486) or radiation therapy (n = 261) who were treated with AST. Cox regression was used to evaluate whether a significant association existed between the PSA nadir level after 8 months of AST and the time to PCSM, controlling for treatment and known prognostic factors. RESULTS The post-AST PSA nadir (pCox < .0001), the pre-AST PSA doubling time (DT) (pCox = .002), PSA level (P = .0001), and Gleason eight to 10 cancers (pCox = .01) were significantly associated with time to PCSM. The adjusted hazard ratio for PCSM was 20 (95% CI, 7 to 61; pCox < .0001), for men with a PSA nadir of more than 0.2 ng/mL as compared with all others. A PSA DT of less than 3 months was observed in 30% (224 of 747) of the study cohort. Of the 28 observed prostate cancer deaths, 21 (75%) occurred in men whose PSA nadir was more than 0.2 ng/mL and who had a PSA DT of less than 3 months. CONCLUSION A PSA nadir of more than 0.2 ng/mL after 8 months of AST given for postoperative or postradiation PSA failure is significantly associated with PCSM and is clinically significant because it accounted for 75% of the cancer deaths observed in this study.

Current controversies in high‐dose‐rate versus low‐dose‐rate brachytherapy for cervical cancer

The use of brachytherapy in the treatment of cervical cancer has increased worldwide since its initial introduction over 100 years ago. However, certain aspects of the use of high‐dose‐rate (HDR) versus low‐dose‐rate (LDR) brachytherapy continue to be controversial, particularly the role of HDR in FIGO Stage III cervical cancer and the use of HDR with concurrent chemotherapy. This study represents a systematic literature review of prospective and retrospective series of patients with cervical carcinoma treated with external‐beam radiation (EBRT) followed by either HDR or LDR radiation. The local control rates, survival rates, and treatment‐related complications in patients with Stage III cervical cancer treated with HDR or LDR and those treated with concomitant chemotherapy are examined. Patients with Stage III cervical cancer treated with EBRT and brachytherapy have a local control rate of >50% in most series. Randomized prospective and retrospective studies show overall statistically equivalent local control, overall survival, and complication rates between HDR and LDR. However, LDR may be preferable for large, bulky tumors at the time of brachytherapy. Retrospective studies of HDR and concurrent chemotherapy are limited but have demonstrated toxicity rates similar to those with LDR. Selected patients with Stage III cervical carcinoma who have an adequate response to EBRT and concomitant chemotherapy may be treated with HDR brachytherapy. The existing literature shows no significant increase in complications in patients treated with HDR and concurrent chemotherapy; however, sufficient tumor shrinkage prior to HDR and careful monitoring of the dose to the normal tissues are imperative. Cancer 2006.

Dose volume histogram analysis of normal structures associated with accelerated partial breast irradiation delivered by high dose rate brachytherapy and comparison with whole breast external beam radiotherapy fields

PurposeTo assess the radiation dose delivered to the heart and ipsilateral lung during accelerated partial breast brachytherapy using a MammoSite™ applicator and compare to those produced by whole breast external beam radiotherapy (WBRT).Materials and methodsDosimetric analysis was conducted on patients receiving MammoSite breast brachytherapy following conservative surgery for invasive ductal carcinoma. Cardiac dose was evaluated for patients with left breast tumors with a CT scan encompassing the entire heart. Lung dose was evaluated for patients in whom the entire lung was scanned. The prescription dose of 3400 cGy was 1 cm from the balloon surface. MammoSite dosimetry was compared to simulated WBRT fields with and without radiobiological correction for the effects of dose and fractionation. Dose parameters such as the volume of the structure receiving 10 Gy or more (V10) and the dose received by 20 cc of the structure (D20), were calculated as well as the maximum and mean doses received.ResultsFifteen patients were studied, five had complete lung data and six had left-sided tumors with complete cardiac data. Ipsilateral lung volumes ranged from 925–1380 cc. Cardiac volumes ranged from 337–551 cc. MammoSite resulted in a significantly lower percentage lung V30 and lung and cardiac V20 than the WBRT fields, with and without radiobiological correction.ConclusionThis study gives low values for incidental radiation received by the heart and ipsilateral lung using the MammoSite applicator. The volume of heart and lung irradiated to clinically significant levels was significantly lower with the MammoSite applicator than using simulated WBRT fields of the same CT data sets.Trial registrationDana Farber Trial Registry number 03-179

Clinical validation and benchmarking of knowledge-based IMRT and VMAT treatment planning in pelvic anatomy

PURPOSE The aim of this work was to determine whether a commercial knowledge-based treatment planning (KBP) module can efficiently produce IMRT and VMAT plans in the pelvic region (prostate & cervical cancer), and to assess sensitivity of plan quality to training data and model parameters. METHODS Initial benchmarking of KBP was performed using prostate cancer cases. Structures and dose distributions from 40 patients previously treated using a 5-field IMRT technique were used for model training. Two types of model were created: one excluded statistical outliers (as identified by RapidPlan guidelines) and the other had no exclusions. A separate model for cervix uteri cancer cases was subsequently developed using 37 clinical patients treated for cervical cancer using RapidArc™ VMAT, with no exclusions. The resulting models were then used to generate plans for ten patients from each patient group who had not been included in the modelling process. Comparisons of generated RapidPlans with the corresponding clinical plans were carried out to indicate the required modifications to the models. Model parameters were then iteratively adjusted until plan quality converged with that obtained by experienced planners without KBP. RESULTS Initial automated model generation settings led to poor conformity, coverage and efficiency compared to clinical plans. Therefore a number of changes to the initial KBP models were required. Before model optimisation, it was found that the PTV coverage was slightly reduced in the superior and inferior directions for RapidPlan compared with clinical plans and therefore PTV parameters were adjusted to improve coverage. OAR doses were similar for both RapidPlan and clinical plans (p>0.05). Excluding outliers had little effect on plan quality (p≫0.05). Manually fixing key optimisation objectives enabled production of clinically acceptable treatment plans without further planner intervention for 9 of 10 prostate test patients and all 10 cervix test patients. CONCLUSIONS The Varian RapidPlan™ system was able to produce IMRT & VMAT treatment plans in the pelvis, in a single optimisation, that had comparable sparing and comparable or better conformity than the original clinically acceptable plans. The system allows for better consistency and efficiency in the treatment planning process and has therefore been adopted clinically within our institute with over 100 patients treated.

Comparison of conventional radiotherapy and intensity-modulated radiotherapy for post-operative radiotherapy for primary extremity soft tissue sarcoma

INTRODUCTION Doses in conventional radiotherapy for extremity soft tissue sarcoma (STS) potentially exceed normal tissue tolerances. This study compares 3D-conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) in optimising target volume coverage and minimising integral dose to organs-at-risk (OAR). METHODS AND MATERIALS Ten patients undergoing post-operative radiotherapy for extremity STS were assessed. PTV(1) was defined as tumour bed plus 5cm superiorly/inferiorly and 3cm circumferentially, PTV(2) was defined as 2cm isotropically. OAR were defined as whole femur, neurovascular bundle, tissue corridor and normal tissue outside PTV(1). For each patient 2-phase 3D-CRT was compared to 2/3 field (2/3f) and 4/5 field (4/5f) IMRT with simultaneous integrated boost (SIB). The primary planning objective was to minimise femur and skin corridor dose. Volumetric analysis and conformity and heterogeneity indices were used for plan comparison. RESULTS A planning protocol containing dose/volume constraints for target and OAR was defined. 4/5f IMRT showed greatest conformity and homogeneity. IMRT resulted in significantly lower femur V45 using 2/3f (p=0.01) and 4/5f (p=0.0009) than 3D-CRT. 4/5f IMRT resulted in significantly lower normal tissue V55 (p=0.004) and maximum dose (p=0.04) than 3D-CRT. CONCLUSIONS A reproducible set of planning guidelines and dose-volume constraints for 3D-CRT and IMRT planning for extremity sarcomas was devised. 4/5f IMRT with SIB resulted in better target coverage and significantly decreased OAR dose. Further evaluation of this technique within a clinical trial is recommended to demonstrate that the technical benefit of the more complex technique translates into patient-derived benefit by reducing late toxicity.

Prospective Clinical Trial of Bladder Filling and Three-Dimensional Dosimetry in High-Dose-Rate Vaginal Cuff Brachytherapy

PURPOSE To investigate the effect of bladder filling on dosimetry and to determine the best bladder dosimetric parameter for vaginal cuff brachytherapy. METHODS AND MATERIALS In this prospective clinical trial, a total of 20 women underwent vaginal cylinder high-dose-rate brachytherapy. The bladder was full for Fraction 2 and empty for Fraction 3. Dose-volume histogram and dose-surface histogram values were generated for the bladder, rectum, and urethra. The midline maximal bladder point (MBP) and the midline maximal rectal point were recorded. Paired t tests, Pearson correlations, and regression analyses were performed. RESULTS The volume and surface area of the irradiated bladder were significantly smaller when the bladder was empty than when full. Of the several dose-volume histogram and dose-surface histogram parameters evaluated, the bladder maximal dose received by 2 cm(3) of tissue, volume of bladder receiving >/=50% of the dose, volume of bladder receiving >/=70% of the dose, and surface area of bladder receiving >/=50% of the dose significantly predicted for the difference between the empty vs. full filling state. The volume of bladder receiving >/=70% of the dose and the maximal dose received by 2 cm(3) of tissue correlated significantly with the MBP. Bladder filling did not alter the volume or surface area of the rectum irradiated. However, an empty bladder did result in the nearest point of bowel being significantly closer to the vaginal cylinder than when the bladder was full. CONCLUSIONS Patients undergoing vaginal cuff brachytherapy treated with an empty bladder have a lower bladder dose than those treated with a full bladder. The MBP correlated well with the volumetric assessments of bladder dose and provided a noninvasive method for reporting the MBP dose using three-dimensional imaging. The MBP can therefore be used as a surrogate for complex dosimetry in the clinic.

PERMANENT IODINE-125 INTERSTITIAL PLANAR SEED BRACHYTHERAPY FOR CLOSE OR POSITIVE MARGINS FOR THORACIC MALIGNANCIES

PURPOSE To assess toxicity and outcome following permanent iodine-125 seed implant as an adjunct to surgical resection in cases of advanced thoracic malignancy. METHODS AND MATERIALS An institutional review board-approved retrospective review was performed. Fifty-nine patients were identified as having undergone thoracic brachytherapy seed implantation between September 1999 and December 2006. Data for patient demographics, tumor details, and morbidity and mortality were recorded. RESULTS Fifty-nine patients received 64 implants. At a median follow-up of 17 months, 1-year and 2-year Kaplan-Meier rates of estimated overall survival were 94.1% and 82.0%, respectively. The 1-year and 2-year local control rates were 80.1% and 67.4%, respectively. The median time to develop local recurrence was 11 months. Grades 3 and 4 toxicity rates were 12% at 1 year. CONCLUSIONS This review shows relatively low toxicity for interstitial planar seed implantation after thoracic surgical resection. The high local control results suggest that an incomplete oncologic surgery plus a brachytherapy implant for treating advanced thoracic malignancy merit further investigation.

Intraoperative seed placement for thoracic malignancy—A review of technique, indications, and published literature

PURPOSE This review examines the role of permanent radioactive seed implantation in thoracic malignancy. This technique can be used intraoperatively to provide additional highly localized radiation therapy in cases where optimal oncologic margins are unattainable or to palliate unresectable disease. METHODS AND MATERIALS Relevant trials were identified through a systematic literature search using Pubmed. RESULTS The intraoperative placement of brachytherapy seeds has been described after sublobar resection for non-small-cell lung cancer (NSCLC), where surgical margins are close or microscopically positive and in the presence of macroscopic residual disease. This brachytherapy technique is currently the focus of a randomized prospective trial in the USA in patients unfit for lobectomy for early-stage NSCLC. CONCLUSIONS This review summarizes the methods of brachytherapy seed placement and the published experience of brachytherapy implants within the thorax, also examining radiation safety and postoperative dosimetry. This technique has the potential to improve local control with optimal sparing of normal tissue owing to its highly conformal radiotherapy delivery.

Consensus recommendations for radiation therapy contouring and treatment of vulvar carcinoma

PURPOSE The purpose of this study was to develop a radiation therapy (RT) contouring atlas and recommendations for women with postoperative and locally advanced vulvar carcinoma. METHODS AND MATERIALS An international committee of 35 expert gynecologic radiation oncologists completed a survey of the treatment of vulvar carcinoma. An initial set of recommendations for contouring was discussed and generated by consensus. Two cases, 1 locally advanced and 1 postoperative, were contoured by 14 physicians. Contours were compared and analyzed using an expectation-maximization algorithm for simultaneous truth and performance level estimation (STAPLE), and a 95% confidence interval contour was developed. The level of agreement among contours was assessed using a kappa statistic. STAPLE contours underwent full committee editing to generate the final atlas consensus contours. RESULTS Analysis of the 14 contours showed substantial agreement, with kappa statistics of 0.69 and 0.64 for cases 1 and 2, respectively. There was high specificity for both cases (≥99%) and only moderate sensitivity of 71.3% and 64.9% for cases 1 and 2, respectively. Expert review and discussion generated consensus recommendations for contouring target volumes and treatment for postoperative and locally advanced vulvar cancer. CONCLUSIONS These consensus recommendations for contouring and treatment of vulvar cancer identified areas of complexity and controversy. Given the lack of clinical research evidence in vulvar cancer radiation therapy, the committee advocates a conservative and consistent approach using standardized recommendations.

Equivalent uniform dose for accelerated partial breast irradiation using the MammoSite applicator

INTRODUCTION This study aims to quantify the radiobiology of the MammoSite applicator and examine whether there is a relationship between equivalent uniform dose (EUD) and radiotherapy-associated toxicity. METHODS AND MATERIALS A previously-published version of the linear quadratic (LQ) model, designed to address the impact of dose-gradients in brachytherapy applications, was used to determine the biological effective dose (BED), equivalent dose in 2 Gray per fraction (EQD2) and EUD for the most common fractionation scheme for the MammoSite catheter (34 Gy in 10 fractions prescribed to 1cm from the balloon surface), using a range of balloon sizes in a series of patients treated with single or multiple dwell positions. Toxicity from the MammoSite catheter was assessed and statistical associations with the calculated EUDs were investigated. RESULTS The acute- and late-toxicity EUDs respectively range from 34.8-39.4 Gy and 33.4-37.6 Gy, with EUD decreasing as balloon diameter increases and/or the number of dwell positions increases. There was a positive association between EUD and hyperpigmentation and telangiectasia. CONCLUSIONS For APBI using the Mammosite applicator, EUD is higher than the marginal prescription dose and, for the dose-fractionation patterns considered here, was associated with acute and late skin toxicity. EUD is a potentially useful parameter to characterize non-uniform dose distributions related to brachytherapy treatments. Further evaluation in future studies is warranted.