Eric D. Donnelly

Receipt of vaginal brachytherapy is associated with improved survival in women with stage I endometrioid adenocarcinoma of the uterus: A National Cancer Data Base study.

Randomized controlled trials have consistently shown that the use of postoperative radiotherapy (RT) for stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in overall mortality. It was hypothesized that a reduction in mortality associated with the receipt of RT could be identified in a large data set with greater statistical power.

c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target.

Purpose: This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), distant metastases (DM) control, and local-regional control (LC). Patients and Methods: This Institutional Review Board–approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H score). Treatment outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses. Results: The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%) and 18 patients (64.3%) had c-Met H index >30 and<30, respectively. c-Met overexpression was significantly associated with worse 3- and 5-year OS (P=0.003), PFS (P=0.002), LC (P=0.01), and DC (P=0.0003). Patients with c-Met overexpression had a hazard ratio of 6.297, 5.782, 6.28, and 18.173 for the risks of death, disease progression, local recurrence, and DM, respectively. Conclusion: c-Met overexpression could be a potential predictive marker and therapeutic target for local-regional advanced cervical cancer patients treated definitively with CRT.

Evaluation of Outcomes in Patients With Carcinoma of the Cervix Treated With Concurrent Radiation and Cisplatin Versus Cisplatin/5-FU Compared With Radiation Alone.

Objectives:The objective of this study was to compare outcomes for patients with cervical cancer treated with radiation concurrently with cisplatin, cisplatin/5-fluorouracil (5-FU), or without chemotherapy. Materials and Methods:We reviewed the records of eligible patients with locoregionally confined, stage IB1 through IVA, intact cervical cancer who were treated at Northwestern Memorial Hospital. All patients underwent definitive radiotherapy with combined external beam radiation—the majority with extended-field (62%)—and received low-dose rate brachytherapy. Results:A total of 236 patients were included: 99 had no concurrent chemotherapy, 95 were treated with concurrent cisplatin, and 42 were treated with cisplatin/5-FU. For all patients treated with or without chemotherapy, overall survival at 5 and 10 years was 64% and 59%, respectively. Patients treated with chemotherapy had a superior recurrence-free survival rate of 69% at 5 years versus 49% in patients who did not receive chemotherapy (P=0.09). Twenty-six percent of patients treated with cisplatin alone, 31% of patients treated with cisplatin/5-FU, and 45% of patients who did not receive chemotherapy experienced a disease recurrence. Adenosquamous histology conferred a higher rate of recurrence as compared with adenocarcinoma and squamous cell histologies (54% vs. 34%, respectively; P=0.05). Conclusions:Cisplatin-based concurrent chemoradiotherapy showed a trend toward improved recurrence-free survival survival in the definitive treatment of nonmetastatic cervical cancer. The addition of 5-FU to cisplatin did not appear to significantly impact survival or recurrence-free survival. Adenosquamous histology was associated with a higher risk of recurrence as compared with other histologic subtypes.

Dosimetry and toxicity outcomes in postoperative high-dose-rate intracavitary brachytherapy for endometrial carcinoma.

Purpose The optimal dosimetric parameters and planning techniques for high-dose-rate vaginal brachytherapy (HDR-VB) are unclear. Our aim was to evaluate the utility of bladder and rectal dosimetry for patients receiving HDR-VB for postoperative treatment of endometrial carcinoma. Material and methods Patients with endometrial cancer who underwent postoperative HDR-VB from January 1, 2004 through December 31, 2010 were included. All patients underwent primary surgery consisting of total hysterectomy and bilateral salpingo-oophrectomy (TH-BSO) with or without lymph node dissection and were treated with HDR-VB without pelvic external beam radiotherapy (EBRT) or chemotherapy. Demographic, pathologic, dosimetric and clinical data were collected. Results One hundred patients were identified with the majority of patients receiving HDR-VB in 700 cGy × 3 fractions (45%) or 550 cGy x 4 fractions (53%). No plan was altered based on bladder dosimetry at the time of planning. The rate of acute urinary reactions (< 90 days from beginning of RT) grades 1 and 2 were 14% and 2%, respectively. The rate of late urinary reactions (> 90 days after RT) grades 1 and 2 were 7% and 3%, respectively. Dose to the bladder point did not correlate with urinary toxicity. No rectal toxicity was reported by patients receiving HDR-VB. Conclusions In the setting of HDR-VB without EBRT, the measured dose to the bladder point does not predict urinary toxicity and is very unlikely to indicate the need to change the treatment plan. The treatment of endometrial carcinoma utilizing HDR-VB alone is associated with very low rates of high-grade acute or late bladder toxicity.

Commentary on "Accelerated partial breast irradiation consensus statement: Update of an ASTRO Evidence-Based Consensus Statement"

5 Although the new American Society for Radiation Oncology (ASTRO) consensus statement on accelerated partial breast irradiation (APBI) reflects many important changes relative to case selection and inclusion criteria for APBI, we would like to address our concerns specifically regarding the recommendations on the use of low-energy x-ray intraoperative radiation therapy (IORT). The consensus should include a statement that targeted intraoperative radiation therapy (TARGIT) IORT achieves local control similar to external beam radiation therapy (EBRT) with a potential for a survival benefit.1-4 Although the panel correctly recognized that the local recurrence rate in prepathology (TARGIT given simultaneously during lumpectomy) stratum was NOT significantly different from the whole-breast external beam irradiation (WBI) arm (2.1% vs 1.1%, P = .31), the panel gave “greater weight” to the local recurrence rate of the entire IORT cohort (prepathology and postpathology [TARGIT given after lumpectomy as a second procedure by reopening the wound at a median of 37 days after the initial excision] strata combined). Sometimes the devil is in the details. The TARGIT-A trial specified stratification between preand postpathology before randomization to

Assessing long-term complications in patients undergoing immediate postmastectomy breast reconstruction and adjuvant radiation

PURPOSE The purpose of this article is to report the long-term rate and timing of complications associated with postmastectomy radiation therapy (PMRT) following immediate breast reconstruction in a large patient population. METHODS AND MATERIALS We identified and reviewed the charts of all patients with stages I through IIIC breast cancer who underwent mastectomy with immediate reconstruction followed by subsequent radiation therapy between November 1997 and May 2010. We aimed to assess the rate of major complications, defined as events requiring a separate and distinct procedure. Statistical analysis between variables was evaluated using Fisher exact test and Pearson χ2 Elder et al. (2005) test. RESULTS In total, 134 patients met inclusion criteria for having adequate long-term follow-up and documentation. The median follow-up for all patients was 77.4 months (range, 6-185 months). The overall major complication rate was found to be 44%. Nine patients (6.7%) experienced complications for which a secondary procedure could not be performed to retain a reconstructed breast. The average time between initiation of PMRT and the first major complication was 13.5 months, with 68.3% of first major complications occurring within 1 year of PMRT initiation and 81.7% within 2 years. The difference in incidence of major complications for patients undergoing immediate tissue expander/implant reconstruction followed by PMRT was not statistically different when compared with that for patients with immediate autologous tissue reconstruction followed by PMRT (47.3% vs 30.4%, P = .168). CONCLUSIONS The risk of first major complications and reconstruction loss in patients undergoing PMRT on immediately reconstructed breasts is greatest within 1 year of beginning radiation therapy and decreases significantly with time. Immediate autologous tissue reconstruction followed by PMRT can be performed with reasonable complication rates.

Therapeutic analysis of high-dose-rate 192Ir vaginal cuff brachytherapy for endometrial cancer using a cylindrical target volume model and varied cancer cell distributions

PURPOSE To evaluate high-dose-rate (HDR) vaginal cuff brachytherapy (VCBT) in the treatment of endometrial cancer in a cylindrical target volume with either a varied or a constant cancer cell distributions using the linear quadratic (LQ) model. METHODS A Monte Carlo (MC) technique was used to calculate the 3D dose distribution of HDR VCBT over a variety of cylinder diameters and treatment lengths. A treatment planning system (TPS) was used to make plans for the various cylinder diameters, treatment lengths, and prescriptions using the clinical protocol. The dwell times obtained from the TPS were fed into MC. The LQ model was used to evaluate the therapeutic outcome of two brachytherapy regimens prescribed either at 0.5 cm depth (5.5 Gy × 4 fractions) or at the vaginal mucosal surface (8.8 Gy × 4 fractions) for the treatment of endometrial cancer. An experimentally determined endometrial cancer cell distribution, which showed a varied and resembled a half-Gaussian distribution, was used in radiobiology modeling. The equivalent uniform dose (EUD) to cancer cells was calculated for each treatment scenario. The therapeutic ratio (TR) was defined by comparing VCBT with a uniform dose radiotherapy plan in term of normal cell survival at the same level of cancer cell killing. Calculations of clinical impact were run twice assuming two different types of cancer cell density distributions in the cylindrical target volume: (1) a half-Gaussian or (2) a uniform distribution. RESULTS EUDs were weakly dependent on cylinder size, treatment length, and the prescription depth, but strongly dependent on the cancer cell distribution. TRs were strongly dependent on the cylinder size, treatment length, types of the cancer cell distributions, and the sensitivity of normal tissue. With a half-Gaussian distribution of cancer cells which populated at the vaginal mucosa the most, the EUDs were between 6.9 Gy × 4 and 7.8 Gy × 4, the TRs were in the range from (5.0)(4) to (13.4)(4) for the radiosensitive normal tissue depending on the cylinder size, treatment lengths, prescription depth, and dose as well. However, for a uniform cancer cell distribution, the EUDs were between 6.3 Gy × 4 and 7.1 Gy × 4, and the TRs were found to be between (1.4)(4) and (1.7)(4). For the uniformly interspersed cancer and radio-resistant normal cells, the TRs were less than 1. The two VCBT prescription regimens were found to be equivalent in terms of EUDs and TRs. CONCLUSIONS HDR VCBT strongly favors cylindrical target volume with the cancer cell distribution following its dosimetric trend. Assuming a half-Gaussian distribution of cancer cells, the HDR VCBT provides a considerable radiobiological advantage over the external beam radiotherapy (EBRT) in terms of sparing more normal tissues while maintaining the same level of cancer cell killing. But for the uniform cancer cell distribution and radio-resistant normal tissue, the radiobiology outcome of the HDR VCBT does not show an advantage over the EBRT. This study strongly suggests that radiation therapy design should consider the cancer cell distribution inside the target volume in addition to the shape of target.

Radical hysterectomy compared with primary radiation for treatment of stage IB1 cervix cancer

Objective:We reviewed data on treatment of stage IB1 cervical cancer at our institution to compare recurrence, complications, and survival of women treated primarily by radical hysterectomy versus radiation. Methods:Records for women treated for stage IB1 cervical cancer between January 1, 1990 and June 1, 2010 were retrospectively reviewed. Recurrence, survival outcomes, and complications were examined and compared. Demographic, clinical, and histopathologic factors were also analyzed. Results:Of 198 patients with stage IB1 cervix cancer, 169 (85%) underwent radical hysterectomy, including 37 (20%) who received postoperative radiation, and 29 (15%) were treated primarily with radiotherapy±chemotherapy. Progression-free survival, overall survival, and disease-specific survival were all longer in the surgery group (89%, 95%, and 96%) versus the radiation group (70%, 70%, and 78%), respectively (P<0.001). Patients in the radiation group were older, had larger tumors, and were more likely to have medical comorbidities than patients in the surgery group. Within the surgical cohort, lymphvascular space invasion, outer third cervical stromal invasion, positive surgical margins, and lymph node metastasis were all predictive of recurrence (P<0.002), whereas histopathology, smoking, diabetes, and immunosuppression were not. Grade 3 or 4 complication rates were higher among the 29 patients who had primary radiotherapy (20.7%) and the 37 patients who had surgery followed by radiotherapy (21.6%) compared with the 132 patients who had surgery only (9.1%) (P=0.047). Conclusions:Primary treatment of stage IB1 cervix cancer with radical hysterectomy±adjuvant radiation resulted in a significantly lower rate of recurrence and an improved survival with fewer complications compared with radiotherapy with or without chemotherapy.

Association of circulating tumor cell status with benefit of radiotherapy and survival in early-stage breast cancer

Importance Circulating tumor cells (CTCs) represent the liquid component of solid tumors and are a surrogate marker for residual cancer burden. Although CTC status is prognostic of recurrence and death in breast cancer, its role in guiding clinical management remains unknown. Objective To determine whether CTC status is predictive of radiotherapeutic benefit in early-stage breast cancer. Design, Setting, and Participants The cohort studies in the present analysis included patients with stages pT1 to pT2 and pN0 to pN1 breast cancer and known CTC status from the National Cancer Database (NCDB) and the multicenter phase 3 SUCCESS clinical trial. Multivariable parametric accelerated failure time models were used to evaluate the association of CTC status and radiotherapy (RT) with survival outcomes. Data were collected from January 1, 2004, through December 31, 2014, from the NCDB cohort. The SUCCESS trial collected data from September 1, 2005, through September 30, 2013. The analyses were completed from November 1, 2016, through December 17, 2017. Exposure Adjuvant RT. Main Outcomes and Measures Overall survival (OS), local recurrence-free survival (LRFS), and disease-free survival (DFS). Results A total of 1697 patients from the NCDB (16 men [0.9%] and 1681 women [99.1%]; median age, 63 years; interquartile range, 53-71 years) and 1516 patients from the SUCCESS clinical trial (median age, 52 years; interquartile range, 45-60 years) were identified. Circulating tumor cells were detected in 399 patients (23.5%) in the NCDB cohort and 294 (19.4%) in the SUCCESS cohort. The association of RT with survival was dependent on CTC status within the NCDB cohort (4-year OS, 94.9% for CTC-positive RT vs 88.0% for CTC-positive non-RT vs 93.9% for CTC-negative RT vs 93.4% for CTC-negative non-RT groups; P < .001) and 5-year DFS within the SUCCESS cohort (88.0% for CTC-positive RT vs 75.2% for CTC-positive non-RT vs 92.3% for CTC-negative RT vs 88.3% for CTC-negative non-RT; P = .04). In the NCDB cohort, RT was associated with longer OS in patients with CTCs (time ratio [TR], 2.04; 95% CI, 1.55-2.67; P < .001), but not in patients without CTCs (TR, 0.80; 95% CI, 0.52-1.25; P = .33). In the SUCCESS cohort, CTC-positive patients treated with RT exhibited longer LRFS (TR, 2.73; 95% CI, 1.62-4.80; P < .001), DFS (TR, 3.03; 95% CI, 2.22-4.13; P < .001), and OS (TR, 1.83; 95% CI, 1.23-2.72; P = .003). Among patients from both cohorts who underwent breast-conserving surgery, RT was associated with longer OS in patients with CTCs (TR, 4.37; 95% CI, 2.71-7.05; P < .001) but not in patients without CTCs (TR, 0.87; 95% CI, 0.47-1.62; P = .77). Radiotherapy was not associated with OS after mastectomy in CTC-positive or CTC-negative patients. Conclusions and Relevance Treatment with RT was associated with longer LRFS, DFS, and OS in patients with early-stage breast cancer and detectable CTCs. These results are hypothesis generating; a prospective trial evaluating CTC-based management for RT after breast-conserving surgery in women with early-stage breast cancer is warranted.

Role of adjuvant external beam radiotherapy and chemotherapy in one versus two or more node-positive vulvar cancer: A National Cancer Database study

BACKGROUND AND PURPOSE Inguinal lymph node involvement is considered the most important prognostic risk factor for survival in vulvar cancer. However, controversy exists concerning the optimal adjuvant therapy for node-positive disease. This study sought to identify the optimal adjuvant therapy for each subset of women with node-positive disease. MATERIAL AND METHODS The National Cancer Database (NCDB) was queried to identify women with inguinal node positive vulvar cancer. Survival analysis was performed using log-rank test, the Kaplan-Meier estimates, and Cox proportional hazards to both clarify prognosis and identify the benefit of each treatment modality in individual subsets of women. RESULTS A total of 2779 women with inguinal node positive vulvar cancer were identified. On multivariate Cox model hazard ratio, radiotherapy yielded a survival advantage for women with one positive node (HR 0.81, p = 0.027) and two or more positive nodes (HR = 0.59, p < 0.001). The addition of chemotherapy to radiotherapy yielded an incremental improvement in survival for women with 2 or more positive nodes (HR = 0.79, p = 0.022) but not women with 1 positive node (HR = 0.93, p = 0.605). CONCLUSIONS All patients with node positive disease benefited from radiotherapy. By contrast, only those with 2 or more positive nodes benefited from the addition of chemotherapy to radiotherapy.