A qualitative study to evaluate physician attitudes regarding omission of surgery among exceptional responders to neoadjuvant systemic therapy for breast cancer (NRG-CC006).

PURPOSE: Accrual to clinical trials that challenge well-established treatment paradigms represents a unique challenge. Physician opinions on investigation of a novel approach to breast cancer treatment, in which patients with complete response to neoadjuvant chemotherapy are offered omission of lumpectomy, are unknown. NRG-CC006 sought to describe physician attitudes toward a novel approach to breast cancer treatment. METHODS: We recruited 18 participants in the fields of surgery, medical oncology, and radiation oncology to participate in the semi-structured telephone interviews. Main outcomes are qualitative themes associated with omission of surgery. RESULTS: Of 18 interview participants, specialty and gender were evenly represented across surgery, medical oncology, and radiation oncology. Qualitative themes included general attitudes toward treatment de-escalation, stakeholder considerations, and trial/protocol considerations. The vast majority of participants expressed interest in investigation of omission of surgery, with all participants endorsing need for further investigation into treatment de-escalation. Stakeholder considerations in opening such a trial emphasized need for multidisciplinary involvement and, particularly, the unique role of surgeons as gatekeepers in breast cancer treatment. Finally, participants endorsed a need for further foundational studies to develop ways to predict complete pathologic response to chemotherapy without surgical intervention. CONCLUSIONS: Physicians expressed interest in investigating a novel approach to breast cancer treatment that would omit surgery in complete responders to neoadjuvant chemotherapy. Multidisciplinary input, and specifically surgeon engagement, will be key to the success of future investigations. Ongoing work to develop approaches to predict pathologic complete response accurately is needed to achieve the promise of this idea. ClinTrials #: BR005: NCT03188393 June 13, 2017.

Less Toxic Chemotherapy in Locally Advanced Breast Cancer.

OBJECTIVES: Preoperative chemotherapy produces tumor shrinkage in most patients with locally advanced breast cancer, including some pathological complete responses (pCRs). We attempted this using a much less toxic sequential regimen, given with concurrent bevacizumab. METHODS: Patients with locally advanced breast cancer received 3 intravenous doses each of preoperative sequential liposome encapsulated doxorubicin 25 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2, with concurrent bevacizumab every 2 weeks without growth factor support. RESULTS: Between March 2008 and December 2009, 32 patients received treatment. There was no cardiotoxicity, and other toxicity was mild (no grade 4 or 5 toxicity). No long-term toxicity, including cardiotoxicity, has been observed. Every patient had ≥30% reduction in tumor size; 9 of 31 patients who completed chemotherapy had pCR at operation. Seven years later, 22 of 32 patients remain free of recurrence and 27 of 32 are alive. CONCLUSIONS: The preoperative chemotherapy used appears to be comparably effective, but much less toxic than that used in most conventional regimens and should be studied further. Concurrent treatment with bevacizumab (reported separately) did not provide any additional benefit.

A home-based mentored vegetable gardening intervention demonstrates feasibility and improvements in physical activity and performance among breast cancer survivors.

BACKGROUND: The current study assessed the feasibility of a mentored home-based vegetable gardening intervention and examined changes in health-related outcomes among breast cancer survivors (BCS). METHODS: BCS were randomized to either a year-long vegetable gardening intervention to begin immediately or a wait-list control. Master Gardeners mentored participants in planning, planting, and maintaining 3 seasonal gardens over the course of 1 year. Participant accrual, retention, and satisfaction rates of ≥80% served as feasibility (primary outcome) benchmarks. Secondary outcomes (ie, vegetable consumption, physical activity, performance and function, anthropometrics, biomarkers, and health-related quality of life) were collected at baseline and post-intervention (1-year follow-up) using subjective and objective measures. RESULTS: The trial surpassed all feasibility benchmarks at 82% of targeted accrual, 95% retention, and 100% satisfaction (ie, experience ratings of "good to excellent" and willingness to "do it again"). Compared with the controls, intervention participants reported significantly greater improvements in moderate physical activity (+14 vs -17 minutes/week) and demonstrated improvements in the 2-Minute Step Test (+22 vs + 10 steps), and Arm Curl (+2.7 vs + 0.1 repetitions) (P values < .05). A trend toward improved vegetable consumption was observed (+0.9 vs + 0.2 servings/day; P = .06). Approximately 86% of participants were continuing to garden at the 2-year follow-up. CONCLUSIONS: The results of the current study suggest that a mentored, home-based vegetable gardening intervention is feasible and offers an integrative and durable approach with which to improve health behaviors and outcomes among BCS. Harvest for Health led to the establishment of a group of trained Master Gardeners and gave rise to local and global community-based programs. Larger studies are needed to confirm the results presented herein and to define applicability across broader populations of survivors.

Chronic granulomatous dermatitis induced by talimogene laherparepvec therapy of melanoma metastases.

Talimogene laherparepvec (TVEC) is the first oncolytic viral immunotherapy approved by the FDA, for advanced melanoma consisting of genetically modified herpes simplex type 1 virus which selectively replicates causing tumor lysis, expressing granulocyte macrophage-colony stimulating factor (GM-CSF) and activating dendritic cells. Intratumoral injection of TVEC produces objective response in 41% of stage IIB-IV M1a melanoma. However, clinical response assessment can be problematic due to immune-related inflammation at established tumor sites. Herein, we report 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient was rendered melanoma-free by resection of the 1 nodule out of 4 with persistent tumor. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Tumor biopsies are encouraged after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation. Patients with confirmed granulomatous dermatitis replace continued with remained in remission after treatment discontinuation. Inflammatory nodules typically regress spontaneously.

Surgical patterns of care in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast magnetic resonance imaging: results of a secondary analysis of TBCRC 017.

BACKGROUND: Neoadjuvant chemotherapy (NCT) downstages advanced primary tumors, with magnetic resonance imaging (MRI) being the most sensitive imaging predictor of response. However, the impact of MRI evaluation on surgical treatment decisions in the neoadjuvant setting has not been well described. We report surgical patterns of care across 8 National Cancer Institute comprehensive cancer centers in women receiving both NCT and MRI to evaluate the impact of MRI findings on surgical planning. METHODS: Seven hundred seventy women from 8 institutions received NCT with MRI obtained both before and after systemic treatment. Univariate and multivariate analyses of imaging, patient-, and tumor-related covariates associated with choice of breast surgery were conducted. RESULTS: MRI and surgical data were available on 759 of 770 patients. A total of 345 of 759 (45 %) patients received breast-conserving surgery and 414 of 759 (55 %) received mastectomy. Mastectomy occurred more commonly in patients with incomplete MRI response versus complete (58 vs. 43 %) (p = 0.0003). On multivariate analysis, positive estrogen receptor status (p = 0.02), incomplete MRI response (p = 0.0003), higher baseline T classification (p < 0.0001), younger age (p < 0.0006), and institution (p = 0.003) were independent predictors of mastectomy. A statistically significant trend toward increasing use of mastectomy with increasing T stage at presentation (p < 0.0001) was observed in patients with incomplete response by MRI only. Among women with complete response on MRI, 43 % underwent mastectomy. CONCLUSIONS: Within a multi-institutional cohort of women undergoing neoadjuvant treatment for breast cancer, MRI findings were not clearly associated with extent of surgery. This study shows that receptor status, T stage at diagnosis, young age, and treating institution are more significant determinants of surgical treatment choice than MRI response data.

Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial.

PURPOSE: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. METHODS AND MATERIALS: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. RESULTS: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. CONCLUSIONS: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.

Magnetic resonance imaging as a predictor of pathologic response in patients treated with neoadjuvant systemic treatment for operable breast cancer. Translational Breast Cancer Research Consortium trial 017.

BACKGROUND: Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast. METHODS: MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 327), HR-positive/HER2-positive, (n = 148), HR-negative/HER2-positive, (n = 101), and triple-negative (HR-negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2-positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed. RESULT: For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple-negative subtype (57 of 155 patients; 37%) and the HER2-positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple-negative (60%) and HER2-positive (62%) subtypes. CONCLUSIONS: The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response.

Accelerated partial breast irradiation for early-stage breast cancer: controversies and current indications for use.

Radiation therapy options for early-stage breast cancer have evolved during the past 40 years. Several choices are currently available to certain patient subsets that allow radiation oncologists to individualize care. Multiple phase II and several phase III trials have been published that support the safety and efficacy of accelerated partial breast irradiation (APBI) as part of breast conservation in selected patients. In contrast, a recent large retrospective analysis of patients aged 67 or older who received brachytherapy for APBI has raised concerns about its effectiveness. As the radiation community awaits results from NSABP B-39/RTOG 0413, the largest randomized trial of whole breast radiation therapy (WBRT) versus APBI, to provide more conclusive data, many academic and private radiation oncology practices are utilizing APBI off-protocol to treat early-stage breast cancer patients. Because of this, the American Society for Radiation Oncology (ASTRO) published a consensus statement in 2009 to aid in proper patient selection (Table 1). Until more definitive data is garnered, we advocate strict adherence to these selection criteria to ensure optimal outcomes. Specifically, we caution against the use of APBI in lymph node-positive disease outside of a clinical trial. There is a paucity of comparative data to guide oncologists in selection of the best APBI delivery method. The current NSABP B-39/RTOG 0413 trial allows any of the three most common forms of delivery to be utilized (multicatheter interstitial brachytherapy, balloon intracavitary brachytherapy, and external beam 3D conformal therapy) and will be instrumental to compare outcome differences between these methods.

Intraoperative ultrasound guidance during intracavitary brachytherapy applicator placement in cervical cancer: the University of Alabama at Birmingham experience.

OBJECTIVE: The objective of this study was to evaluate the University of Alabama at Birmingham experience with routine intraoperative ultrasound (IUS)-guided tandem placement for cervical cancer. METHODS: Between 1999 and 2008, 243 cervical cancer patients underwent IUS-guided tandem placement. One hundred thirty-nine patients received low-dose-rate brachytherapy, and 104 received high-dose-rate brachytherapy. Three hundred fifty-six IUS-guided procedures were performed. Clinical and imaging data were retrospectively analyzed to evaluate complications requiring reinsertion of tandem placement in the context of IUS. RESULTS: All 243 cervical cancer patients completed intracavitary brachytherapy. Five (1.4%) of 356 IUS-guided applicator placements resulted in uterine perforation. All of these patients underwent successful tandem insertion on the second attempt, and no significant clinical sequelae occurred. Intraoperative ultrasound enabled direct uterine visualization and facilitated real-time feedback for selection of a suitable tandem length and curvature; no suboptimal placements requiring return to the operating room occurred (excluding perforation). CONCLUSIONS: In this large series, IUS guidance substantially increased the rate of successful applicator placement and diminished the rate of uterine perforation relative to historical controls. We strongly recommend the use of IUS guidance during operative intrauterine tandem placement for cervical cancer.

The Evolving Role of Postmastectomy Radiation Therapy.

Throughout various eras of breast cancer therapy, postmastectomy radiation therapy (PMRT) has played an important role in the treatment of locally advanced breast cancer. PMRT decreases locoregional recurrence and may improve overall survival in patients with tumors over 5 cm or positive lymph nodes. As novel cancer therapies improve survival in breast cancer, the role of radiation therapy is evolving. Individualized recommendations for PMRT dependent on pathologic response after neoadjuvant systemic therapy are under investigation. This review summarizes the role of PMRT during breast cancer therapy and discusses open questions that may change the landscape of future breast cancer treatment.

Postmastectomy Radiation Therapy: Are We Ready to Individualize Radiation?

Contemporary recommendations for postmastectomy radiation have undergone a shift in thinking away from simple stage based recommendations (one size fits all) to a system that considers both tumor biology and host factors. While surgical staging has traditionally dictated indications for postmastectomy radiation therapy (PMRT), our current understanding of tumor biology, host, immunoprofiles, and tumor microenvironment may direct a more personalized approach to radiation. Understanding the interaction of these variables may permit individualization of adjuvant therapy aimed at appropriate escalation and deescalation, including recommendations for PMRT. This article summarizes the current data regarding tumor and host molecular biomarkers in vitro and in vivo that support the individualization of PMRT and discusses open questions that may alter the future of breast cancer treatment.

Pilot Randomized Controlled Trial of a Home Vegetable Gardening Intervention among Older Cancer Survivors Shows Feasibility, Satisfaction, and Promise in Improving Vegetable and Fruit Consumption, Reassurance of Worth, and the Trajectory of Central Adiposity.

BACKGROUND: Holistic approaches are sought to improve lifestyle behaviors and health of cancer survivors long term. OBJECTIVE: Our aim was to explore whether a home-based vegetable gardening intervention is feasible and whether it improves diet and other health-related outcomes among older cancer survivors. DESIGN: We conducted a feasibility trial in which cancer survivors were randomized to receive a year-long gardening intervention immediately or to a wait-list control arm. Home visits at baseline and 1 year assessed physical performance, anthropometric indices, behavioral and psychosocial outcomes, and biomarkers. PARTICIPANTS/SETTING: Participants included 46 older (aged 60+ years) survivors of locoregionally staged cancers across Alabama from 2014 to 2016. Forty-two completed 1-year follow-up. INTERVENTION: Cooperative extension master gardeners delivered guidance to establish three seasonal vegetable gardens at survivors' homes. Plants, seeds, and gardening supplies were provided. OUTCOMES: Primary outcomes were feasibility targets of 80% accrual and retention, and an absence of serious adverse events; other outcomes were secondary and explored potential benefits. STATISTICAL ANALYSES: Baseline to follow-up changes were assessed within and between arms using paired t, McNemar's, and χ2 tests. RESULTS: This trial proved to be safe and demonstrated 91.3% retention; 70% of intervention participants rated their experience as "excellent," and 85% would "do it again." Data suggest significantly increased reassurance of worth (+0.49 vs -0.45) and attenuated increases in waist circumference (+2.30 cm vs +7.96 cm) in the gardening vs control arms (P=0.02). Vegetable and fruit consumption increased by approximately 1 serving/day within the gardening arm from baseline to follow-up (mean [standard error]=1.34 [1.2] to 2.25 [1.9] servings/day; P=0.02)] compared to controls (1.22 [1.1] to 1.12 [0.7]; P=0.77; between-arm P=0.06). CONCLUSIONS: The home vegetable gardening intervention among older cancer survivors was feasible and suggested improvements in vegetable and fruit consumption and reassurance of worth; data also suggest attenuated increases in waist circumference. Continued study of vegetable gardening interventions is warranted to improve health, health behaviors, and well-being of older cancer survivors.

A dosimetric comparison of electronic compensation, conventional intensity modulated radiotherapy, and tomotherapy in patients with early-stage carcinoma of the left breast.

PURPOSE: Intensity modulated radiation therapy (IMRT) has been shown to significantly reduce dose to normal tissue while maintaining coverage of the clinical target volume (CTV) in patients with intact breast cancer. We compared delivery of whole breast irradiation utilizing three techniques: electronic tissue compensation (ECOMP), inverse-planned dynamic multileaf collimation IMRT (DMLC), and tomotherapy (TOMO). PATIENTS AND METHODS: Ten patients with early stage, left-sided breast cancer were selected for planning. CTV was defined as breast encompassed in a standard tangent field minus the superficial 5 mm from the skin edge. Normal tissue contours included the heart, lungs, and contralateral breast. Plans included delivery of 45 Gy in 25 fractions and were normalized to ensure > or =95% coverage of the CTV. Isodose distributions and dose-volume histograms for CTV and normal tissue were compared between plans. The time it took to plan each patient excluding contouring, as well as number of monitor units (MUs) required to execute each plan were additionally tabulated. RESULTS: The TOMO plans resulted in significantly greater heterogeneity (CTV V(115)) versus ECOMP (p = 0.0029). The ECOMP plans resulted in significantly lower doses to heart, lung, and contralateral breast when compared with TOMO plans. The ECOMP plans were generated in the shortest time (12 min) and resulted in the lowest number of MUs when compared with DMLC (p = 0.002, p < 0.0001) and TOMO (p = 0.0015, p < 0.0001). CONCLUSIONS: The ECOMP plans produced superior dose distributions in both the CTV and normal tissue when compared with TOMO or DMLC plans. In addition, ECOMP plans resulted in the lowest number of MUs and labor cost.

Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy.

BACKGROUND: Clear cell sarcoma (CCS) is a rare, aggressive soft tissue sarcoma thought to derive from neural crest and characterized by a 12;22 translocation. The resulting fusion protein directly activates expression of the melanocyte master transcription factor and drives the same down-stream pathways in CCS and melanoma leading to significant clinical parallels between these malignancies. Striking success of immune checkpoint blockade in melanoma has promoted interest in immunotherapy of CCS. CASE PRESENTATION: We report the first complete clinical response of a bulky chest wall recurrence of mediastinal CCS in a young woman to anti-PD1 checkpoint blockade with pembrolizumab combined with standard fractionation radiotherapy to enhance regional control and potentially boost the systemic immune response. The treatment was well tolerated with grade 2 skin toxicity within the range expected with radiation alone. Significant reduction in tumor bulk occurred after only 2 radiation fractions and complete response was achieved at 50 Gray. CONCLUSION: The complete clinical response observed in our patient suggests synergy between concurrent radiotherapy and PD1 blockade in CCS. This case and the striking parallels between CCS and melanoma indicate the need for prospective trials of immune checkpoint blockade combined with radiotherapy in this rare malignancy.

Radiotherapy to Control Limited Melanoma Progression Following Ipilimumab.

Durable local control of irradiated cancer and distant abscopal effects are presumably immune mediated. To evaluate the role of radiotherapy (RT) for limited progression after anti-CTLA4 checkpoint inhibition, medical records of all patients with surgically incurable stage III or IV melanoma from a single institution who received ipilimumab as first-line immunotherapy and subsequent RT were reviewed. Sixteen patients who received RT to all sites of limited melanoma progression were analyzed. Eight patients with an incomplete initial response to ipilimumab received RT to new or progressive disease, whereas the remaining 8 patients with a complete initial response to ipilimumab received RT to sites of subsequent recurrence. The median interval from ipilimumab initiation to start of RT was 30 weeks (range, 15-130 wk), a timeframe where delayed response to ipilimumab is rare. The RT dose was predominantly 30 Gy in 5 fractions (41%) or 36 Gy in 6 fractions (26%). Brain radiation was limited to stereotactic radiosurgery in a single patient. The median local control with RT was 31.4 months. The median disease control was 18.7 months, defined as the interval from completion of RT to the start of additional systemic therapy known to impact survival (anti-programmed death-1 or targeted BRAF therapy), hospice enrollment, or death. The overall survival at 1 and 2 years was 87% and 61%, respectively. Seven patients (44%) had no evidence of melanoma at median follow-up of 29.5 months since completion of RT with no additional therapy. This series supports use of RT to limited sites of progression following ipilimumab as an alternative to other systemic treatments such as anti-programmed death-1 antibodies.

Detailed methods of two home-based vegetable gardening intervention trials to improve diet, physical activity, and quality of life in two different populations of cancer survivors.

BACKGROUND: Cancer survivors suffer from long-term adverse effects that reduce health-related quality of life (QOL) and physical functioning, creating an urgent need to develop effective, durable, and disseminable interventions. Harvest for Health, a home-based vegetable gardening intervention, holds promise for these domains. METHODS: This report describes the methods and recruitment experiences from two randomized controlled feasibility trials that employ a waitlist-controlled design. Delivered in partnership with Cooperative Extension Master Gardeners, this intervention provides one-on-one mentorship of cancer survivors in planning and maintaining three seasonal vegetable gardens over 12months. The primary aim is to determine intervention feasibility and acceptability; secondary aims are to explore effects on objective and subjective measures of diet, physical activity and function, and QOL and examine participant factors associated with potential effects. One trial is conducted exclusively among 82 female breast cancer survivors residing in the Birmingham, AL metropolitan area (BBCS); another broadly throughout Alabama among 46 older cancer survivors aged >60 (ASCS). RESULTS: Response rates were 32.6% (BBCS) and 52.3% (ASCS). Both trials exceeded 80% of their accrual target. Leading reasons for ineligibility were removal of >10 lymph nodes (lymphedema risk factor), lack of physician approval, and unwillingness to be randomized to the waitlist. CONCLUSION: To date, recruitment and implementation of Harvest for Health appears feasible. DISCUSSION: Although both studies encountered recruitment challenges, lessons learned can inform future larger-scale studies. Vegetable gardening interventions are of interest to cancer survivors and may provide opportunities to gain life skills leading to improvements in overall health and QOL.

Simultaneous optimization of sequential IMRT plans.

Radiotherapy often comprises two phases, in which irradiation of a volume at risk for microscopic disease is followed by a sequential dose escalation to a smaller volume either at a higher risk for microscopic disease or containing only gross disease. This technique is difficult to implement with intensity modulated radiotherapy, as the tolerance doses of critical structures must be respected over the sum of the two plans. Techniques that include an integrated boost have been proposed to address this problem. However, clinical experience with such techniques is limited, and many clinicians are uncomfortable prescribing nonconventional fractionation schemes. To solve this problem, we developed an optimization technique that simultaneously generates sequential initial and boost IMRT plans. We have developed an optimization tool that uses a commercial treatment planning system (TPS) and a high level programming language for technical computing. The tool uses the TPS to calculate the dose deposition coefficients (DDCs) for optimization. The DDCs were imported into external software and the treatment ports duplicated to create the boost plan. The initial, boost, and tolerance doses were specified and used to construct cost functions. The initial and boost plans were optimized simultaneously using a gradient search technique. Following optimization, the fluence maps were exported to the TPS for dose calculation. Seven patients treated using sequential techniques were selected from our clinical database. The initial and boost plans used to treat these patients were developed independently of each other by dividing the tolerance doses proportionally between the initial and boost plans and then iteratively optimizing the plans until a summation that met the treatment goals was obtained. We used the simultaneous optimization technique to generate plans that met the original planning goals. The coverage of the initial and boost target volumes in the simultaneously optimized plans was equivalent to the independently optimized plans actually used for treatment. Tolerance doses of the critical structures were respected for the plan sum; however, the dose to critical structures for the individual initial and boost plans was different between the simultaneously optimized and the independently optimized plans. In conclusion, we have demonstrated a method for optimization of initial and boost plans that treat volume reductions using the same dose per fraction. The method is efficient, as it avoids the iterative approach necessitated by currently available TPSs, and is generalizable to more than two treatment phases. Comparison with clinical plans developed independently suggests that current manual techniques for planning sequential treatments may be suboptimal.

Induction vemurafenib followed by consolidative radiation therapy for surgically incurable melanoma.

Approximately half of melanomas are driven by a point mutation in the BRAF kinase gene, targetable with vemurafenib. However, the chief limitation of continuous BRAF inhibition is that the majority of patients develop resistance within 8 months, including those with surgically unresectable stage III melanoma. Researchers retrospectively reviewed medical records of all patients at our institution with surgically incurable BRAF V600E mutated stage III or limited stage IV melanoma treated with induction vemurafenib, stopped electively during ongoing response, followed by consolidative radiation therapy with or without intervening surgery to debulk nodal metastases. In our six-patient cohort, the median duration of vemurafenib was 5.8 months and the median radiation dose was 57 Gy using conventional fractionation. This algorithm produced 100% locoregional control at 29+ months following radiation and a median progression-free survival of 32.5+ months. Three of six patients remained progression free, and three relapsed in a single organ and achieved ongoing complete response to subsequent therapy. Outcomes greatly exceeding those reported with either BRAF inhibition or radiation alone suggest unanticipated synergies with this therapeutic sequence for both in-field and distant melanoma control, which may be mediated by radiosensitization and immune activation, respectively. In patients with surgically incurable melanoma encompassed within a radiation field, induction vemurafenib and consolidative radiation therapy, rather than continuing vemurafenib until progression, also limit the duration of vemurafenib toxicity and preserve sensitivity to future BRAF inhibition.

TBCRC 019: A Phase II Trial of Nanoparticle Albumin-Bound Paclitaxel with or without the Anti-Death Receptor 5 Monoclonal Antibody Tigatuzumab in Patients with Triple-Negative Breast Cancer.

PURPOSE: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5(+) human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. RESULTS: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4-5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. CONCLUSIONS: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation.

The role of amifostine in the treatment of carcinoma of the uterine cervix: an update of RTOG-0116 and review of future directions.

Approximately 10,520 women will be diagnosed with carcinoma of the uterine cervix in 2004, resulting in significant mortality. While definitive or adjuvant radiation therapy remains a critical component of treatment, both local and distant recurrences may occur. The recent addition of chemotherapy has helped reduce these recurrences and improve survival, albeit at a cost of increased toxicity, especially in patients requiring extended-field treatment. New agents, such as amifostine (Ethyol, MedImmune Inc, Gaithersburg, MD), that possess cytoprotective and radioprotective properties may help ameliorate toxicity. This report reviews and updates the rationale and current experience with amifostine in the treatment of carcinoma of the uterine cervix. Data suggest a benefit in patients with pelvic malignancies receiving amifostine before either chemotherapy or radiation, and that subcutaneous administration may be as efficacious and less toxic than the intravenous route. Ongoing trials will likely provide more data to the role of amifostine in the treatment of carcinoma of the uterine cervix, and especially whether the administration of subcutaneous amifostine before both chemotherapy/radiation therapy will translate into a reduction in acute and late toxicity.