Kilian E. Salerno

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Treatment Guidelines for Preoperative Radiation Therapy for Retroperitoneal Sarcoma: Preliminary Consensus of an International Expert Panel.

PURPOSE Evidence for external beam radiation therapy (RT) as part of treatment for retroperitoneal sarcoma (RPS) is limited. Preoperative RT is the subject of a current randomized trial, but the results will not be available for many years. In the meantime, many practitioners use preoperative RT for RPS, and although this approach is used in practice, there are no radiation treatment guidelines. An international expert panel was convened to develop consensus treatment guidelines for preoperative RT for RPS. METHODS AND MATERIALS An expert panel of 15 academic radiation oncologists who specialize in the treatment of sarcoma was assembled. A systematic review of reports related to RT for RPS, RT for extremity sarcoma, and RT-related toxicities for organs at risk was performed. Due to the paucity of high-quality published data on the subject of RT for RPS, consensus recommendations were based largely on expert opinion derived from clinical experience and extrapolation of relevant published reports. It is intended that these clinical practice guidelines be updated as pertinent data become available. RESULTS Treatment guidelines for preoperative RT for RPS are presented. CONCLUSIONS An international panel of radiation oncologists who specialize in sarcoma reached consensus guidelines for preoperative RT for RPS. Many of the recommendations are based on expert opinion because of the absence of higher level evidence and, thus, are best regarded as preliminary. We emphasize that the role of preoperative RT for RPS has not been proven, and we await data from the European Organization for Research and Treatment of Cancer (EORTC) study of preoperative radiotherapy plus surgery versus surgery alone for patients with RPS. Further data are also anticipated pertaining to normal tissue dose constraints, particularly for bowel tolerance. Nonetheless, as we await these data, the guidelines herein can be used to establish treatment uniformity to aid future assessments of efficacy and toxicity.

NCCN Guidelines Update: Breast Cancer

The emergence of CDK4/6 inhibitors has changed the treatment algorithm for advanced/metastatic estrogen receptor-positive breast cancer. In pivotal trials of palbociclib, ribociclib, and abemaciclib, doubling in progression-free survival has been seen. All 3 agents in this class are now included in the NCCN Guidelines for Breast Cancer, and clinicians should be incorporating these agents into their treatment algorithms. The other important issue in this breast cancer setting is extended duration of endocrine therapy. Most of the benefit is modest and toxicity is an issue; therefore, extended-duration endocrine therapy should be highly individualized. For triple-negative disease, platinum agents and PARP inhibitors are helping some patients, but immunotherapies and other novel classes of drugs now in development hold the promise of even better outcomes. In HER2-positive early-stage disease, dual HER2 blockade is of modest benefit, and extended treatment with neratinib may be a good option for some high-risk patients.

Role of Repeat 18F-Fluorodeoxyglucose Positron Emission Tomography Examination in Predicting Pathologic Response Following Neoadjuvant Chemoradiotherapy for Esophageal Adenocarcinoma

IMPORTANCE Predicting complete pathologic response (CPR) preoperatively can significantly affect surgical decision making. There are conflicting data regarding positron emission tomography computed tomography (PET CT) characteristics and the ability of PET CT to predict pathologic response following neoadjuvant chemoradiotherapy in esophageal adenocarcinoma because most existing studies that include squamous histology have limited numbers and use nonstandardized PET CT imaging. OBJECTIVE To determine if PET CT characteristics are associated with CPR in patients undergoing trimodality treatment for esophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS A retrospective medical record review was conducted at a large tertiary cancer center from a prospectively maintained database from January 1, 2005, to December 31, 2012. Inclusion criteria were patients undergoing esophagectomy for locally advanced esophageal adenocarcinoma post-neoadjuvant chemoradiotherapy with 2 standardized PET CT studies done at our institution (pre-neoadjuvant chemoradiotherapy and post-neoadjuvant chemoradiotherapy) for review. Data collected included clinical, pathologic, imaging, and treatment characteristics. MAIN OUTCOME AND MEASURE The primary study outcome was the association of PET CT characteristics with histologic confirmed pathologic response. RESULTS Of the total participants, 77 patients met the inclusion criteria. Twenty-two patients (28.6%) had CPR vs 55 patients (71.4%) who had incomplete pathologic response. The 2 groups were similar in age, sex, race/ethnicity, comorbid conditions, Eastern Cooperative Oncology Group status, tumor grade, chemotherapy, and radiation regimen and days between the 2 PET CTs. The mean prestandardized uptake variable (SUV; 14.5 vs 11.2; P = .05), δ SUV (10.3 vs 5.4; P = .02), and relative δ SUV (0.6 vs 0.4; P = .02) were significantly higher in those with CPR vs incomplete pathologic response. Using the Youden Index, a δ SUV value less than 45% was predictive of residual disease with a positive predictive value of 91.7% (95% CI, 73-99; P < .05). CONCLUSIONS AND RELEVANCE To our knowledge, this is the largest study examining the role of PET CT characteristics in esophageal adenocarcinoma for patients undergoing neoadjuvant chemoradiotherapy that demonstrates that δ SUV of less than 45% is associated with patients with residual disease but not CPR. Based on the findings from our study, the current recommendation is still surgical resection regardless of the posttherapy PET SUV in the primary tumor. However, our study highlights the ability to detect patients with residual disease and the need to critically evaluate these patients for consideration of additional therapies.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update

PurposeA joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT).MethodsA recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data.RecommendationsThe panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Retroperitoneal Sarcoma (RPS) High Risk Gross Tumor Volume Boost (HR GTV Boost) Contour Delineation Agreement Among NRG Sarcoma Radiation and Surgical Oncologists

PurposeCurative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering “boost doses” of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams.MethodsRadiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics.ResultsHRGTV boost volume contour agreement between the seven teams was “substantial” or “moderate” for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection.ConclusionsAgreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for “individualized” target delineation on the basis of areas deemed at risk and planned resection.

Neoadjuvant chemotherapy for primary cutaneous/soft tissue angiosarcoma: Determining tumor behavior prior to surgical resection

Given the propensity for hematogenous metastases, neoadjuvant chemotherapy (NAC) could treat occult metastatic disease early, potentially improving survival and better defining which primary angiosarcomas (AS) benefit from surgical resection.

Margin reduction from image guided radiation therapy for soft tissue sarcoma: Secondary analysis of Radiation Therapy Oncology Group 0630 results.

PURPOSE Six imaging modalities were used in Radiation Therapy Oncology Group (RTOG) 0630, a study of image guided radiation therapy (IGRT) for primary soft tissue sarcomas of the extremity. We analyzed all daily patient-repositioning data collected in this trial to determine the impact of daily IGRT on clinical target volume-to-planning target volume (CTV-to-PTV) margin. METHODS AND MATERIALS Daily repositioning data, including shifts in right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions and rotations for 98 patients enrolled in RTOG 0630 from 18 institutions were analyzed. Patients were repositioned daily on the basis of bone anatomy by using pretreatment images, including kilovoltage orthogonal images (KVorth), megavoltage orthogonal images (MVorth), KV fan-beam computed tomography (KVCT), KV cone beam CT (KVCB), MV fan-beam CT (MVCT), and MV cone beam CT (MVCB). Means and standard deviations (SDs) for each shift and rotation were calculated for each patient and for each IGRT modality. The Students t tests and F-tests were performed to analyze the differences in the means and SDs. Necessary CTV-to-PTV margins were estimated. RESULTS The repositioning shifts and day-to-day variations were large and generally similar for the 6 imaging modalities. Of the 2 most commonly used modalities, MVCT and KVorth, there were no statistically significant differences in the shifts and rotations (P = .15 and .59 for the RL and SI shifts, respectively; and P = .22 for rotation), except for shifts in AP direction (P = .002). The estimated CTV-to-PTV margins in the RL, SI, and AP directions would be 13.0, 10.4, and 11.7 mm from MVCT data, respectively, and 13.1, 8.6, and 10.8 mm from KVorth data, respectively, indicating that margins substantially larger than 5 mm used with daily IGRT would be required in the absence of IGRT. CONCLUSIONS The observed large daily repositioning errors and the large variations among institutions imply that daily IGRT is necessary for this tumor site, particularly in multi-institutional trials. Otherwise, a CTV-to-PTV margin of 1.5 cm is required to account for daily setup variations.

A Case of Metaplastic Breast Cancer with Prolonged Response to Single Agent Liposomal Doxorubicin

Female breast cancer accounts for 14% of all new cancer cases in the United States. Metaplastic breast carcinomas (MpBC) are less than 1% of all mammary tumors. Limited clinical information exists on the prognosis and treatments for MpBC due to its rarity and the histological diversity of the tumor cells. We report a case of metastatic MpBC with osseous differentiation who had a marked response to liposomal doxorubicin. This 54-year-old female presented with a 2.5 x 2.6 cm oval-shaped irregularly marginated density in the outer lower quadrant of the left breast, cT2N0M0. Biopsy revealed an invasive metaplastic carcinoma, triple negative, with osseous and focal chondroid differentiation. Genetic testing showed a mutation in the BRCA1 gene. Approximately seven months after a left mastectomy, the patient presented with biopsy-proven metastatic disease and was initiated on therapy with a single agent, liposomal doxorubicin, 50 mg/m2 every 28 days. The patient achieved maximum response after cycle three and continued to have stable disease for 18 months (20 cycles). Based on the pathologic phenotype, we would have predicted that she would have had a poor and short response to anthracycline. This case illustrates an increased sensitivity of BRCA1-mutated cancers to anthracycline therapies, irrespective of pathologic classification.

Exceptional Clinical Response to BRAF-Targeted Therapy in a Patient with Metastatic Sarcoma

Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors arising from mesenchymal tissue comprising 1% of all adult cancers. The prognosis of metastatic STS is dismal. As there are few active drugs, there is a critical need to find new therapeutic alternatives in order to improve outcomes. Most sarcoma subtypes are fairly resistant to standard chemotherapy regimens and/or have a short duration of response. The era of molecular targeted therapy may present new treatment options for metastatic STS and an opportunity to drive biomarker discovery and personalized medicine. This case report describes a patient with a synchronous metastatic high-grade sarcoma who was treated with BRAF-targeted therapy with resolution of his metastatic lesions. To our knowledge, this exceptional response has not been described in sarcoma literature. The patient presented with a large anterior abdominopelvic wall mass. Biopsy showed a high-grade spindle cell sarcoma. Staging scans confirmed two pulmonary metastases. He was initiated on combination chemotherapy with mixed results. He received 50 Gy of radiation to the primary tumor followed by two additional cycles of combination chemotherapy, with an interval increase in the size of the pulmonary metastases. Molecular testing revealed a BRAF V600E mutation in the primary tumor. The patient was initiated on dabrafenib/trametinib with a dramatic response and resolution of his pulmonary metastases. The patient underwent surgical resection of his primary mass, and pathology confirmed no evidence of residual disease. Detailed genetic characterization of STS coupled with novel therapeutic strategies, including molecular targeted therapy, may have the potential to transform the care of patients diagnosed with sarcoma.