Victor J. Gonzalez

Primary vaginal cancer and chemoradiotherapy: A patterns-of-care analysis

Introduction: No prospective randomized trials exist to delineate the role of combined chemoradiotherapy (CRT) in the treatment of vaginal cancer (VC). We sought to describe the utilization rate of CRT and evaluate the potential survival benefit of CRT over radiotherapy alone in VC. Methods: A retrospective analysis of the SEER-Medicare-linked database was performed analyzing women with VC treated with external beam radiation and/or brachytherapy and diagnosed between 1991 and 2005. Results: Of the 1709 primary VC patients in the SEER-Medicare database, 326 met inclusion criteria. Most were white (80.1%) and in the 70- to 74-year age group (42.1%). Squamous cell carcinoma was the most predominant histologic diagnosis (80.4%). Brachytherapy was used in 34% of patients, whereas cisplatin was the chemotherapy of choice in 59% of CRT patients. Median follow-up was 21.5 months. Kaplan-Meier estimated that 5-year cause-specific survival (CSS) and overall survival (OS) was 67.6% and 27.1%, respectively. Before 1999, CRT was used in 7.5% of patients compared with 36.1% of patients thereafter (P < 0.001). Chemoradiotherapy was less likely to be used in patients older than 80 years (P < 0.001) but was otherwise balanced in race, stage, grade, histologic diagnosis, comorbidities, and brachytherapy use. Chemoradiotherapy did not correlate with CSS (hazard ratio [HR], 0.91; P = 0.84) or OS (HR, 1.34; P = 0.21) by multivariate analysis. Factors associated with worse CSS include stage IVA disease (HR, 4.2; P = 0.003) and 2 or more comorbidities (HR, 2.89; P = 0.03). Factors associated with worse OS include age older than 80 years (HR, 1.78; P = 0.04), stage IVA disease (HR, 3.35; P < 0.0001), and 2 or more comorbidities (HR, 2.58; P = 0.001). Conclusions: Chemoradiotherapy utilization for VC has increased since 1999. We failed to delineate a CSS or OS benefit for CRT in this cohort.

The role of radiation therapy in the control of locoregional and metastatic cancer.

High energy X‐rays have been used for cancer therapy since their discovery in 1895. Major radiobiological discoveries and technological advances in radiation physics have greatly increased the accuracy of radiation. The recent integration of radiation therapy and imaging systems provides radiation oncologists with sophisticated dose delivery capability allowing continued improvements in the control of loco‐regional and metastatic disease while decreasing toxicity. Key technical aspects of current radiation therapy are described with examples extending to several clinical areas. J. Surg. Oncol. 2011;103:627–638.

Role of Radiation Therapy in the Treatment of Hodgkin Lymphoma

Radiation therapy has historically been the pillar of curative treatment for Hodgkin lymphoma (HL). With improved efficacy of systemic therapy and the ever-increasing recognition of treatment-related morbidity in long-term survivors, the role of radiotherapy has evolved significantly. Modern combined modality therapy (CMT) with multi-agent chemotherapy followed by involved site radiation therapy (ISRT) to initially involved sites of disease remains the gold standard for the majority of patients with HL. Reduction of long-term treatment-related toxicity has become the major driver in clinical trial design for early-stage HL while improved disease-specific survival remains the goal in patients with more advanced and unfavorable disease. This review will address the data supporting the use of radiotherapy in HL as well as specific methods for reducing late toxicity from radiotherapy.

8 Gy single-fraction radiation for bone metastases: Do the data support a 1-size-fits-all approach?

The newly released evidence-based guidelines from the American Society of Radiation Oncology (ASTRO) on palliative radiation therapy (RT) for bone metastases provide a much-needed update on this clinically relevant topic.1 As previous guidelines have highlighted, an overwhelming body of data supports the equivalence of a single 8 Gy fraction (single-fraction radiation therapy [SFRT]) to commonly used multiple-fraction radiation therapy (MFRT) regimens for the palliation of symptomatic osseous metastases. Still, we question whether truly high-level evidence demonstrates the equivalence of SFRT to MRFT “for the prevention of morbidity from uncomplicated bone metastases involving spine or other critical structures ... and from peripheral metastases,” as stated in Key Question 2 of the ASTRO Guidelines. In contrast to data supporting equivalence between regimens for pain relief, comparatively few data are available on the use of 8 Gy per 1 fraction (8 Gy/1 fx) for prevention of long-term morbidity, and data on current treatment of patients with a good prognosis are even fewer. Thus, we caution against blanket rejection of fractionated palliative RT, a treatment regimen that provides equivalent pain relief, lower rates of retreatment, and potentially improved disease control compared with SFRT.2–4 Randomized trials and meta-analyses evaluating SFRT have conclusively demonstrated that 8Gy/1 fx provides pain relief equivalent to that provided by commonly used hypofractionated palliative regimens.1 Despite this finding, routine adoption of 8 Gy/1 fx has been low. Explanations for this lack of adoption have included concerns about increased retreatment rates after SFRT, lack of formal training in SFRT, unfamiliarity with supporting single-fraction to multiple-fraction treatment, and a financial disincentive against use of SFRT. Two recently published Canadian studies found that the utilization rate of SFRT was less than 60%, even after publication of guidelines endorsing the use of SFRT and after direct provider education regarding

Impact of prone versus supine positioning on small bowel dose with pelvic intensity modulated radiation therapy

Purpose To report the results of a prospective study that compares small bowel doses during prone and supine pelvic intensity modulated radiation therapy. Methods and materials Ten patients receiving pelvic radiation therapy each had 2 intensity modulated radiation therapy plans generated: supine and prone on a belly board (PBB). Computed tomography on rails was performed weekly throughout treatment in both positions (10 scans per patient). After image fusion, doses to small bowel (SB) loops and clinical target volume were calculated for each scan. Changes between the planned and received doses were analyzed and compared between positions. The impact of bladder filling on SB dose was also assessed. Results Prone treatment was associated with significantly lower volumes of SB receiving ≥20 Gy. On average, prone on a belly board positioning reduced the volume of SB receiving a given dose of radiation by 28% compared with supine positioning. Target coverage throughout the treatment course was similar in both positions with an average minimum clinical target volume dose of 88% of the prescribed prone dose and 89% of the supine (P = .54). For supine treatment, SB dose was inversely correlated with bladder filling (P = .001-.013; P > .15 for prone). For 96% of treatments, the volume of SB that received a given dose deviated >10% from the plan. The deviation between the planned and delivered doses to SB did not differ significantly between the positions. Conclusions Prone positioning on a belly board during pelvic IMRT consistently reduces the volume of SB that receives a broad range of radiation doses. Prone IMRT is associated with interfraction dose variation to SB that is similar to that of supine positioning. These findings suggest that prone positioning with daily image guided radiation therapy is an effective method for maximizing SB sparing during pelvic IMRT.

Pentoxifylline and vitamin E drug compliance after adjuvant breast radiation therapy

Purpose Breast fibrosis is a common late effect after therapeutic irradiation that can result in pain, poor cosmesis, and functional impairment. Randomized trials have demonstrated that radiation fibrosis may be preventable with a medication regimen of pentoxifylline and vitamin E. This study investigates patient compliance with pentoxifylline therapy while examining possible correlations to compliance. Methods and materials We identified 90 patients who were prescribed pentoxifylline (400 mg 3 times daily) and vitamin E (400 IU once daily) after adjuvant breast radiation. A retrospective cohort study was conducted using medical record analysis. Data were collected, including patient age, comorbid conditions, concurrent medications, duration of pentoxifylline and vitamin E therapy, dose adjustments, patient-reported side effects, and cause for discontinuation. A multivariate analysis of the correlation between medication compliance and these categorical variables was assessed with a χ2 analysis of independence. Results Patient compliance with pentoxifylline and vitamin E therapy was found to be poor in 33 of 87 patients (38%) in the cohort, necessitating either dose reductions or discontinuation of therapy. There was a statistically significant correlation between concurrent antiemetic therapy and successful completion of pentoxifylline regimen. Of those on antiemetic therapy, 89% completed pentoxifylline as prescribed versus 48% of those without antiemetics (P < .001). There was a statistically significant correlation between concurrent proton pump inhibitor (PPI) therapy and discontinuation of pentoxifylline. Of those on PPI therapy, 33% completed pentoxifylline versus 81% of those not on PPIs (P < .001). All other variables examined were not significantly correlated with compliance. Conclusions Patient compliance with pentoxifylline appears to be worse in clinical practice compared with previously published studies. Nausea was the most frequently reported indication for treatment modification or discontinuation. Concurrent antiemetic therapy was correlated with strong regimen compliance, but concurrent PPI therapy was correlated with poor compliance, independent of comorbid conditions.

Comparison of surface matching and target matching for image-guided pelvic radiation therapy for both supine and prone patient positions

We investigate the difference between surface matching and target matching for pelvic radiation image guidance. The uniqueness of our study is that all patients have multiple CT‐on‐rails (CTOR) scans to compare to corresponding AlignRT images. Ten patients receiving pelvic radiation were enrolled in this study. Two simulation CT scans were performed in supine and prone positions for each patient. Body surface contours were generated in treatment planning system and exported to AlignRT to serve as reference images. During treatment day, the patient was aligned to treatment isocenter with room lasers, and then scanned with both CTOR and AlignRT. Image‐guidance shifts were calculated for both modalities by comparison to the simulation CT and the differences between them were analyzed for both supine and prone positions, respectively. These procedures were performed for each patient once per week for five weeks. The difference of patient displacement between AlignRT and CTOR was analyzed. For supine position, five patients had an average difference of displacement between AlignRT and CTOR along any direction (vertical, longitudinal, and lateral) greater than 0.5 cm, and one patient greater than 1 cm. Four patients had a maximum difference greater than 1 cm. For prone position, seven patients had an average difference greater than 0.5 cm, and three patients greater than 1 cm. Nine patients had a maximum difference greater than 1 cm. The difference of displacement between AlignRT and CTOR was greater for the prone position than for the supine position. For the patients studied here, surface matching does not appear to be an advisable image‐guidance approach for pelvic radiation therapy for patients with either supine or prone position. There appears to be a potential for large alignment discrepancies (up to 2.25 cm) between surface matching and target matching. PACS number(s): 87.55.‐xWe investigate the difference between surface matching and target matching for pelvic radiation image guidance. The uniqueness of our study is that all patients have multiple CT-on-rails (CTOR) scans to compare to corresponding AlignRT images. Ten patients receiving pelvic radiation were enrolled in this study. Two simulation CT scans were performed in supine and prone positions for each patient. Body surface contours were generated in treatment planning system and exported to AlignRT to serve as reference images. During treatment day, the patient was aligned to treatment isocenter with room lasers, and then scanned with both CTOR and AlignRT. Image-guidance shifts were calculated for both modalities by comparison to the simulation CT and the differences between them were analyzed for both supine and prone positions, respectively. These procedures were performed for each patient once per week for five weeks. The difference of patient displacement between AlignRT and CTOR was analyzed. For supine position, five patients had an average difference of displacement between AlignRT and CTOR along any direction (vertical, longitudinal, and lateral) greater than 0.5 cm, and one patient greater than 1 cm. Four patients had a maximum difference greater than 1 cm. For prone position, seven patients had an average difference greater than 0.5 cm, and three patients greater than 1 cm. Nine patients had a maximum difference greater than 1 cm. The difference of displacement between AlignRT and CTOR was greater for the prone position than for the supine position. For the patients studied here, surface matching does not appear to be an advisable image-guidance approach for pelvic radiation therapy for patients with either supine or prone position. There appears to be a potential for large alignment discrepancies (up to 2.25 cm) between surface matching and target matching. PACS number(s): 87.55.-x.

Abstract P3-12-12: Incidence of internal mammary node, sternum, and manubrium failure as detected by FDG-18 PET/CT

Introduction: Elective radiotherapy to the internal mammary (IM) lymph nodes remains an ongoing subject of debate. While the incidence of occult IM involvement on extended mastectomy ranges from 15-65%, reported rates of IM failure are substantially lower (approximately 1%). Interest in this subject has resurfaced recently as randomized trials have shown a survival benefit to adjuvant regional node irradiation including the IM chain. The mechanism by which extended field radiotherapy leads to improved systemic outcomes has not been clearly demonstrated and the degree of benefit directly attributable to IM irradiation remains to be seen. We hypothesized that the IM lymphatic chain may provide a direct route for tumor cell dissemination into the the sternum or manubrium. As such, sternal metastases may be a manifestation of IM involvement rather than true hematogenous metastases. We sought to better elucidate patterns of failure by evaluating the incidence and timing of IM, sternal, or manubrial involvement identified by PET/CT imaging following diagnosis of metastatic breast cancer. Patients and Methods: Between 2007 and 2014, 96 patients with invasive breast cancer were found to have metastatic disease as diagnosed on FDG-18 PET/CT. Site of recurrence was scored as breast/chest wall, axilla/supraclav, IM chain, sternum/manubrium, or distant. IM or sternum/manubrium failure was scored as isolated (occurring without distant metastatic disease), synchronous (involved at initial diagnosis of distant metastatic disease), or metachronous (involved at any time after diagnosis of metastatic disease). Results: Isolated IM failures were observed in 3.1% of patients while isolated sternum/manubrium failures were recorded in 7.3% of patients. Isolated involvement of the sternum/manubrium or IM nodes occurred in 11.4%. The rate of synchronous IM failure was 11.4% with the rate of metachronous failure being 13.5%. The rate of synchronous sternum/manubrium failure was 17.7% with the rate of metachronous failure being 23.9%. The incidence of sternum/manubrium or IM involvement at the initial diagnosis of distant metastatic disease was 29.2% with the rate of involvement at any point increasing to 36.5%. Conclusion: The rate of internal mammary node failure by PET/CT at the time of metastatic diagnosis is higher than the incidence reported in previous trials. This discrepancy is likely due increased sensitivity of PET/CT and the difficulty of accurately assessing this region once patients have been found to have metastatic disease. Interestingly, sternum and manubrium were more often the first site of recurrence than the IM nodes. This could be due to a tropism of hematogenous metastases for these bones or could represent direct tumor cell dissemination from the internal mammary chain. This is of special interest as this region is incidentally included in the radiotherapy fields when targeting the IM nodes. Overall, our findings suggest that historic patterns of failure studies may underestimate the local benefit of internal mammary node radiotherapy. Citation Format: Grow JL, Choudhary G, Kuo P, Livingston RB, Gonzalez VJ. Incidence of internal mammary node, sternum, and manubrium failure as detected by FDG-18 PET/CT. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-12.

Abstract P6-04-10: Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma of breast

Background: Pleomorphic invasive lobular carcinoma (PILC) is described as a distinct morphological variant of invasive lobular carcinoma (ILC) but its clinical behavior is not well characterized. PILCs have loss of E-cadherin similar to ILCs but have distinct morphological features like nuclear contour irregularity, a single prominent nucleolus, increased hyperchromasia and more frequent mitoses. In addition, some studies have reported that PILCs have acquired further molecular alterations such as gain of HER2/neu, amplification of c-myc and loss of p53. To the best of our knowledge there have been no studies evaluating Phosphoinositide 3 kinase/Akt/mammalian (or mechanistic) target of rapamycin (PI3K/Akt/mTOR) pathway in PILC. We hypothesize that there is increased activation of PI3K/Akt/mTOR pathway in PILC compared to ILC. Activation of the PI3k/Akt/mTOR pathway was evaluated by quantifying protein expression of phosphatase and tensin homolog (PTEN) and phosphorylated-S6 kinase1 (p-S6K1). PTEN is a negative regulator of the PI3K pathway and its loss/decreased expression (by mutation or allelic imbalance) activates downstream signaling. Loss (or decrease) of PTEN expression has been reported to be associated with PI3K pathway activation in more than 50% of ER+ breast tumors. Since PI3K pathway can be activated by other mechanisms in addition to PTEN loss, we hypothesized that evaluation of pS6K1 may predict activation of this pathway more than PTEN protein expression alone. Methods: We conducted a retrospective translational study at the University of Arizona Cancer Center. Our Pathology database was searched to identify PILCs from 2012-2014. Two investigators reviewed the pathology reports independently and abstracted clinocopathological data. Formalin-fixed paraffin embedded (FFPE) primary PILCs were stained for PTEN and pS6K1 expression. Expression of PTEN and pS6K1 was quantified by long score methodology as low (≤ 10), moderate (11-50) or high (≥ 50) expression. Results: We identified 19 patients with PILC. All tumors were either moderately (n=10) or poorly differentiated (n=9). Estrogen receptor (ER) was positive in all, progesterone receptor (PR) was positive in 11(52%) and HER2 was negative in all tumors. Proliferation index (Ki67) was elevated in all tumors (median 32%, range 20-70%). Lymph nodes were involved with metastatic carcinoma in 7 patients (negative in 9 and unknown in 3). The 21-gene recurrence score assay (Oncotype Dx) was performed in 10 patients and demonstrated higher scores (median 23, range 6-36) with the majority being in the intermediate or high range (8/10). Expression of PTEN and p-S6K1 was quantified on 10 FFPE tumor tissues. PTEN expression was high in all while pS6K1 was high in 8 and low in 2 tumors. Conclusion: PILCs are a biologically distinct group of ILC. Clinicopathological characteristics suggest they would have a more clinically aggressive behavior (higher grade, high proliferative index and 21 gene recurrence score). In addition, our results indicate that PI3k/Akt/mTOR pathway in activated in majority of these tumors and that PTEN is not the key regulator of this pathway. Genomic profiling is currently underway to further analyze other causes of pathway activation. Citation Format: Segar J, Baker AF, MacKerricher W, Nagle R, Livingston R, Clarke K, Ley M, Viscusi R, Gonzalez V, LeBeau L, Chalasani P. Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma of breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-10.

SU-E-T-325: Dosimetric Impact Due to FlexiShield in Electronic Brachytherapy (eBx) of Breast IORT: A Phantom Study

Purpose: To evaluate dosimetric change of eBx plan due to Flexishield. Methods: To simulate a clinically difficult case (skin spacing < 1 cm and touching chest wall), prostheses breast tissue phantom overlaid Xoft spherical balloon applicator. To minimize significant metal streak artifact, megavoltage CT (MVCT) scan was acquired using helical TomoTherapy HiART. Two sets of MVCT images were taken with/without FlexiShield for 15 cases: 4 for small (3–4 cm), 4 for medium (4–5 cm) and 7 for large (5–6 cm) balloon. Total 30 MVCT scans were obtained with 50 % contrast to improve image contrast of balloon relative to breast tissue phantom. Balloon deformation was measured in anterior-posterior (AP) and lateral (LAT) dimensions in the middle of balloon. Skin spacing was also evaluated. Treatment plan was made based on each MVCT scan and two balloon surface doses (AP and LAT directions) and skin dose were compared between plans with/without FlexiShield. Results: The balloon was deformed due to pressure from both FlexiShield (skin side) and FlexiShield mini (chest wall side). Mean ± standard deviation (maximum) value was 1.5 ± 1.0 mm (3.3 mm) for AP compression and 0.4 ± 0.3 mm (1.1 mm) for LAT expansion. Balloon surface dose was increased by 1.8 ± 1.2 Gy (4.9 Gy) at AP point and decreased by 0.4 ± 0.4 Gy (1.3 Gy) at LAT point. Skin spacing was constantly reduced by 1.1 ± 0.8 mm (3 mm). Skin surface dose was increased by 1.5 ± 0.8 Gy (3.3 Gy) and its relative increase was 17.9 ± 9.3% (39.6%). Conclusion: FlexiShield deforms the balloon and reduces skin spacing, thereby resulting in higher dose in AP direction, lower dose in LAT direction, and elevated skin dose compared to the plan without FlexiShield. In the clinic, this balloon deformation and corresponding dose variation should be considered.