Neoadjuvant Chemoradiation Compared With Neoadjuvant Radiation Alone in the Management of High-Grade Soft Tissue Extremity Sarcomas.

PURPOSE: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone. METHODS: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported. RESULTS: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years (P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively (P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively. CONCLUSIONS: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS.

Characterization and predictive value of volume changes of extremity and pelvis soft tissue sarcomas during radiation therapy prior to definitive wide excision.

PURPOSE: The purpose of this study was to characterize and evaluate the clinical significance of volume changes of soft tissue sarcomas during radiation therapy (RT), prior to definitive surgical resection. MATERIALS AND METHODS: Patients with extremity or pelvis soft tissue sarcomas treated at our institution from 2013 to 2016 with RT prior to resection were identified retrospectively. Tumor volumes were measured using cone-beam computed tomography obtained daily during RT. Linear regression evaluated the linearity of volume changes. Kruskal-Wallis tests, Mann-Whitney U tests, and linear regression evaluated predictors of volume change. Logistic and Cox regression evaluated volume change as a predictor of resection margin status, histologic treatment response, and tumor recurrence. RESULTS: Thirty-three patients were evaluated. Twenty-nine tumors were high grade. Prior to RT, median tumor volume was 189 mL (range, 7.2 to 4,885 mL). Sixteen tumors demonstrated significant linear volume changes during RT. Of these, 5 tumors increased and 11 decreased in volume. Myxoid liposarcoma (n = 5, 15%) predicted decreasing tumor volume (p = 0.0002). Sequential chemoradiation (n = 4, 12%) predicted increasing tumor volume (p = 0.008) and corresponded to longer times from diagnosis to RT (p = 0.01). Resection margins were positive in three cases. Five patients experienced local recurrence, and 7 experienced distant recurrence, at median 8.9 and 6.9 months post-resection, respectively. Volume changes did not predict resection margin status, local recurrence, or distant recurrence. CONCLUSION: Volume changes of pelvis and extremity soft tissue sarcomas followed linear trends during RT. Volume changes reflected histologic subtype and treatment characteristics but did not predict margin status or recurrence after resection.

Evaluating the Role of Interdigitated Neoadjuvant Chemotherapy and Radiation in the Management of High-Grade Soft-Tissue Sarcoma: The Johns Hopkins Experience.

OBJECTIVES: High-grade soft-tissue sarcoma (STS) has a poor prognosis. The goal of this study was to review treatment outcomes of patients with high-grade STS treated with interdigitated neoadjuvant chemotherapy (CT) and radiation at our institution. MATERIALS AND METHODS: Patients with high-grade STS (1997 to 2010) were planned for treatment with 3 cycles of neoadjuvant CT, interdigitated preoperative radiation therapy (44 Gy administered in split courses with a potential 16 Gy postoperative boost), and 3 cycles of postoperative CT. Cancer control outcomes at 3 years were analyzed. RESULTS: Sixteen patients with high-grade STS were evaluated. Median age was 53 years, the median longest tumor diameter was 14.6 cm, and median follow-up was 33 months. All 16 patients received 2 or 3 cycles of neoadjuvant CT and all patients completed neoadjuvant RT. The estimated 3-year rate for local control was 100%, disease-free survival 62.5%, and overall survival 73.4%. CONCLUSIONS: Patients with high-grade STS treated with interdigitated neoadjuvant CT and radiation before surgical resection had excellent rates of local control, along with disease-free survival and overall survival similar to previously published reports. This combined-modality approach continues to have a role in the treatment of patients with high-grade STS.

Long-term outcomes in treatment of retroperitoneal sarcomas: A 15 year single-institution evaluation of prognostic features.

BACKGROUND: Retroperitoneal sarcomas are connective tissue tumors arising in the retroperitoneum. Surgical resection is the mainstay of treatment. Debate has arisen over extent of resection, changes in histological classification/grading, and interest in incorporating radiotherapy. Therefore, we reviewed our institution's experience to evaluate prognostic factors. METHODS: Retrospective chart review of all primary RPS patients at Johns Hopkins Hospital from 1994 to 2010. Histologic diagnosis and grading were re-evaluated with current criteria. Prognostic factors for survival, and recurrence were assessed. RESULTS: One hundred thirty-one primary RPS patients met inclusion criteria. Median survival for patients who undergo en-bloc resection to negative margins (R0/R1) is 81.7 months. Surgical margins and grade were the most important factors for survival along with age, gender, presence of metastases and resection of ≥5 organs. Five-year survival for R0/R1 resection was 60%, similar to compartmental resection. Radiotherapy significantly decreased local recurrence (P = 0.026) on multivariate analysis. Grade in leiomyosarcomas and dedifferentiation in liposarcomas dictated patterns of local versus distal recurrence. CONCLUSIONS: En bloc surgical resection to R0/R1 margins remains the cornerstone of therapy and provides comparable outcomes to compartmental resections. Grade remains important for prognosis, and histology dictates recurrence patterns. Radiotherapy appears promising for local control and warrants further investigation. J. Surg. Oncol. 2016;114:56-64. © 2016 Wiley Periodicals, Inc.

Bone cancer.

Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma.

Epithelioid sarcoma: one institution's experience with a rare sarcoma.

BACKGROUND: Epithelioid sarcomas (ES) are extremely rare soft tissue sarcomas. As such, their clinical behavior and response to treatment are poorly described in the literature. METHODS: We queried the centralized cancer registry and pathology archives at the Johns Hopkins Medical Institution and identified 22 patients with a diagnosis of ES. We excluded two patients because of inadequate data. A pathologist reviewed patient charts and reexamined available histological slides. This study was performed with institutional review board approval. RESULTS: The median age at diagnosis was 27.8 y; most patients (75%) were male. Regional lymph node metastases were present in 10% of patients at presentation. The majority of tumors (57.9%) recurred and 35% recurred more than once, although the number of recurrences did not affect survival (P = 0.48). Patients did not experience a decrease in time to recurrence with increasing number of resections. The median time between resection and recurrence was 1.23 y and the maximum was 18.8 y. Median overall survival was 56.2 mo and 5-y survival was 92%. CONCLUSIONS: Our study reveals that ES is an extremely rare tumor with a protracted and recurrent course, but overall survival may be more favorable than in the past. Patients benefit from aggressive and repeated resection. Epithelioid sarcoma is unique because it metastasizes to regional nodal basins. Extended surveillance is indicated, because recurrences can appear after decades of quiescence.

Initial validation and clinical experience with 3D optical-surface-guided whole breast irradiation of breast cancer.

We had introduced 3D optical surface-guided radiotherapy (SGRT) of the breast cancer (BC). We then initiated the feasibility, accuracy, and precision studies of stereovision in detection of any breast displacement through the course of treatment for total thirty breasts undertaken whole breast irradiation (WBI). In the SGRT, CT-based plan data were parsed into an in-house computer program through which the reference surfaces were generated in 3D video format. When patients were positioned on treatment Tables, real-time stereovisions were rapidly acquired while the live surface tracking shown steady thorax motion. The real-time surface images were automatically aligned with the reference surface and detected shape and location changes of the breast were online corrected through the Table and beam adjustments. Accumulated dose to each patient was computed according to the frequency distribution of the measured breast locations during beam on time. Application of SGRT had diminished large skin-marking errors of > 5-mm and daily breast-setup errors of >10-mm that occurred on half of cases. Accuracy (mean) and precision (two standard deviations) of the breast displacements across the tangential field edges in the (U, V) directions were improved from (-0.5 ± 8.8, 2.2 ± 10.8) mm in conventional setup to (0.4 ± 4.6, 0.7 ± 4.4) mm in the final position while intra-fractional motion contributed only (0.1 ± 2.8, 0.0 ± 2.2) mm in free breathing. Dose uniformity and coverage to targets had both been increased by up to 10% and the lung or heart intersections have been decreased by half of those volumes if they were irradiated at the initial positions. SGRT of BC appears to be feasible regardless of skin tones, as fast as a snapshot for 3D imaging, and very accurate and precise for daily setup of flexible breast targets. Importantly, the technique allows us to verify the breast shape and position during beam-on time.

Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells.

Radiation therapy can result in bone injury with the development of fractures and often can lead to delayed and nonunion of bone. There is no prevention or treatment for irradiation-induced bone injury. We irradiated the distal half of the mouse left femur to study the mechanism of irradiation-induced bone injury and found that no mesenchymal stem cells (MSCs) were detected in irradiated distal femora or nonirradiated proximal femora. The MSCs in the circulation doubled at 1 week and increased fourfold after 4 wk of irradiation. The number of MSCs in the proximal femur quickly recovered, but no recovery was observed in the distal femur. The levels of free radicals were increased threefold at 1 wk and remained at this high level for 4 wk in distal femora, whereas the levels were increased at 1 wk and returned to the basal level at 4 wk in nonirradiated proximal femur. Free radicals diffuse ipsilaterally to the proximal femur through bone medullary canal. The blood vessels in the distal femora were destroyed in angiographic images, but not in the proximal femora. The osteoclasts and osteoblasts were decreased in the distal femora after irradiation, but no changes were observed in the proximal femora. The total bone volumes were not affected in proximal and distal femora. Our data indicate that irradiation produces free radicals that adversely affect the survival of MSCs in both distal and proximal femora. Irradiation injury to the vasculatures and the microenvironment affect the niches for stem cells during the recovery period.

Chordoma of the sacrum and vertebral bodies.

Chordomas are relatively rare tumors of bone. These primary malignant lesions occur throughout the spinal column and often show advanced growth at the time of diagnosis. Because such tumors are minimally responsive to radiation and chemotherapy, surgical resection is the mainstay of treatment. Patient survival and local control are associated with the ability to achieve wide surgical margins during excision. However, surgical morbidity may be substantial given the propensity for chordomas to abut or surround neural, vascular, and visceral structures. Thus, early recognition is essential, and treatment by a multidisciplinary team is ideal.

Prognostic indicators following ipsilateral tumor recurrence in patients treated with breast-conserving therapy.

BACKGROUND: We attempt to determine significant predictors of systemic recurrence following ipsilateral breast tumor recurrence (IBTR). METHODS: A retrospective single-institution chart review of all newly diagnosed breast cancer patients was conducted to identify women treated with breast-conserving therapy (BCT) who developed IBTR. Charts were reviewed for demographics, clinical presentation, method of detection, stage, type of therapy, histopathology, and margin status for both the primary and recurrent tumors. RESULTS: Of 1,733 patients who were treated with BCT, 157 experienced IBTR. Multivariate Cox regression showed that time to recurrence and method of detection of local recurrence remained significant predictors of distant metastases-free survival (DMFS). Median DMFS times for clinically and radiographically detected IBTRs were 54 months and 231 months, respectively. Adjusted relative risk for clinically detected IBTRs was 2.2. CONCLUSIONS: Given the prognostic significance of post-treatment mammography in our study, combined with median time to recurrence of 44 months, we believe that routine long-term mammographic surveillance is indicated following BCT.

Pigmented villonodular synovitis of the knee: diagnosis and treatment.

Pigmented villonodular synovitis (PVNS) of the knee is a benign but locally aggressive disease of synovial proliferation that occurs in localized nodular and diffuse villous growth patterns. Although inflammatory and neoplastic causes have been hypothesized, etiology remains unknown. Presenting as unilateral knee pain and swelling, PVNS mimics other knee ailments. Radiographs are often unremarkable, whereas magnetic resonance imaging may show characteristic intra-articular masses with signal dropout on T2-weighted sequences. Pigmented villonodular synovitis is surgically treated with open or arthroscopic total or partial synovectomy. High recurrence rates are associated with all treatments of diffuse PVNS. Complications of open synovectomy include arthrofibrosis and wound breakdown. Total arthroscopic synovectomy is technically demanding but can be advantageous. Transcondylar notch views, accessory posterior portals, and the posterior transseptal portal maximize arthroscopic access to the posterior knee. Intra-articular radioisotope injection and external beam radiation may be beneficial adjuvant therapy for extensive diffuse and recurrent PVNS of the knee.

Feasibility trial of partial breast irradiation with concurrent dose-dense doxorubicin and cyclophosphamide in early-stage breast cancer.

PURPOSE: Anthracyclines and concurrent whole-breast irradiation result in prohibitive cutaneous toxicity. We hypothesized that anthracycline-based chemotherapy and concurrent partial breast irradiation (PBI) is safe and conducted a single-arm feasibility trial testing this hypothesis with dose-dense doxorubicin and cyclophosphamide (ddAC). PATIENTS AND METHODS: Women with T1-2, N0-1 breast cancer with > or = 3 mm lumpectomy margins received PBI (40.5 Gy, 15 daily 2.7-Gy fractions) concurrently with the first two of four cycles of ddAC (60 and 600 mg/m2 of doxorubicin and cyclophosphamide, respectively, every 14 days with colony-stimulating support). Primary end points were local and systemic toxicity. Additional systemic therapy was given at the physician's discretion. RESULTS: Twenty-seven patients enrolled between November 2004 and January 2007, but two patients did not receive protocol therapy (one found with additional local disease and one withdrew consent). Twenty-five women completed all planned PBI. Four (16%) of 25 did not complete all ddAC (febrile neutropenia [FN], n = 2; diverticulitis and neutropenia, n = 1; and social/economic reasons, n = 1). Four among the remaining 21 who completed all ddAC had a cycle delayed (FN, n = 1; acute respiratory illness, n = 1; foot blisters, n = 1; perianal dermatitis, n = 1). There was no grade 3 to 4 anemia or thrombocytopenia. Grade 3 nonhematologic toxicities (none grade 4) occurred in 28% (seven of 25) of patients (nausea/vomiting, n = 3; stomatitis, n = 2; contralateral breast abscess, n = 1; fatigue, n = 1; and cough/bronchospasms, n = 1). The observed rate of > or = grade 2 skin toxicity was 0% (0 of 25; one-sided 95% CI, 0% to 11%). CONCLUSION: PBI with concurrent ddAC is feasible, and local/systemic toxicity is acceptable. Larger studies are warranted to assess long-term locoregional control and late toxicities.

Comparison of FDG-PET/CT and CT for delineation of lumpectomy cavity for partial breast irradiation.

PURPOSE: The success of partial breast irradiation critically depends on proper target localization. We examined the use of fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) for improved lumpectomy cavity (LC) delineation and treatment planning. METHODS AND MATERIALS: Twelve breast cancer patients underwent FDG-PET/CT on a GE Discovery scanner with a median time from surgery to PET/CT of 49 days. The LC was contoured on the CT scan by a radiation oncologist and, together with a nuclear medicine physician, on the PET/CT scan. The volumes were calculated and compared in each patient. Treatment planning target volumes (PTVs) were calculated by expanding the margin 2 cm beyond the LC, maintaining a 5-mm margin from the skin and chest wall, and the treatment plans were evaluated. In addition, a study with a patient-like phantom was conducted to evaluate the effect that the window/level settings might have on contouring. RESULTS: The margin of the LC was well visualized on all FDG-PET images. The phantom results indicated that the difference between the known volume and the FDG-PET-delineated volume was <10%, regardless of the window/level settings. The PET/CT volumes were larger than the CT volumes in all cases (median volume ratio, 1.68; range, 1.24-2.45; p = 0.004). The PET/CT-based PTVs were also larger than the CT-based PTV (median volume ratio, 1.16; range, 1.08-1.64; p = 0.006). In 9 of 12 patients, a CT-based treatment plan did not provide adequate coverage of the PET/CT-based PTV (99% of the PTV received <95% of the prescribed dose), resulting in substantial cold spots in some plans. In these cases, treatment plans were generated which were specifically designed to cover the larger PET/CT-based PTV. Although these plans showed an increased dose to the normal tissues, the increases were modest: the non-target breast volume receiving > or =50 Gy, lung volume receiving > or =30 Gy, and heart volume receiving > or =5 Gy increased by 5.7%, 0.8%, and 0.2%, respectively. The normal tissue dose-volume objectives were still met with these plans. CONCLUSION: The results of our study have shown that FDG-PET/CT can be used to define the LC volume. The increased FDG uptake was likely a result of postoperative inflammation in the LC. The targets defined using PET/CT were significantly larger than those defined with CT alone. Our results have shown that treatment plans can be generated to cover these larger PET/CT target volumes with only a modest increase in irradiated tissue volume compared with CT-determined PTVs.

Perineural invasion affects biochemical recurrence-free survival in patients with prostate cancer treated with definitive external beam radiotherapy.

OBJECTIVES: To assess the prognostic effect of perineural invasion (PNI) for patients undergoing external beam radiotherapy for prostate cancer. METHODS: We evaluated 657 consecutive patients who had undergone external beam radiotherapy for clinically localized prostate cancer. The clinical/treatment parameters used for analysis included PNI, clinical stage, biopsy Gleason score, pretreatment prostate-specific antigen, radiation dose, and androgen deprivation. The primary endpoint was biochemical recurrence defined by the Radiation Therapy Oncology Group-American Society for Therapeutic Radiology Oncology Phoenix consensus; the secondary endpoint was prostate cancer death. RESULTS: Of 586 men with a minimum of 24 months of follow-up, 112 (19.1%) had PNI present in the biopsy specimen. When patients were stratified into risk groups using the National Comprehensive Cancer Network criteria, PNI was more prevalent in patients within higher risk groups (6.8% in low-risk versus 18.3% in intermediate-risk versus 30.1% in high-risk groups; P <0.001). The presence of PNI was associated with lower biochemical recurrence-free (P = 0.003) and cancer-specific (P = 0.040) survival rates by Kaplan-Meier analysis. Cox regression analysis showed that PNI was a statistically significant prognostic factor of biochemical recurrence on both univariate (hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.19 to 2.46, P = 0.004) and multivariate (HR 1.57, 95% CI 1.06 to 2.32, P = 0.025) analyses. Regression analysis after stratification by risk group and adjustment for treatment covariates demonstrated a significant association between PNI and the risk of biochemical recurrence for low-risk (HR 4.14, 95% CI 1.55 to 11.02, P = 0.005) and intermediate/high-risk patients (HR 1.53, 95% CI 1.02 to 2.29, P = 0.040). CONCLUSIONS: The results of our study have shown that the presence of PNI is an independent risk factor associated with an increased risk of biochemical recurrence in patients with prostate cancer undergoing external beam radiotherapy.

Proximal femoral replacement for metastatic bone disease.

Between 1994 and 2000, 13 patients (8 women and 5 men; 14 hips) underwent proximal femoral replacement secondary to metastatic disease. Average patient age was 62 years (range: 46-77 years). The most common diagnosis was renal cell carcinoma. Seven pathologic fractures were noted. Patients ambulated with full weight bearing postoperatively and wore an abduction brace for 3-4 months. Ten patients died of their diseases at 0.5-3.5 years postoperatively. No dislocations, infections, or reoperations occurred. Proximal femoral replacement provides excellent pain relief and good restoration of function when more simple reconstructive options are not feasible.

The role of radiation treatment in the contemporary management of bone tumors.

Radiotherapy is integral in the multidisciplinary approach to patients with musculoskeletal neoplasms. Multiple studies have established a role for radiotherapy as a definitive local treatment of unresectable lesions or when surgery might yield unacceptable functional outcomes, such as in Ewing's tumor or base of skull chondrosarcoma. Radiotherapy is also used as an adjuvant treatment after surgery with close or positive margins. In the metastatic setting, external beam radiotherapy and bone-seeking intravenous radioisotopes are used on a case-by-case basis for palliation. As radiotherapy and its delivery techniques have evolved, so has its role in treating tumors such as Ewing's sarcoma, chordoma and chondrosarcoma, osteosarcoma, primary lymphoma of bone, malignant fibrous histiocytoma of bone, and vascular tumors. Radiation can also be successfully used to treat unresectable or recurrent benign tumors, such as giant cell tumor and aneurysmal bone cyst. This article reviews the indications for radiotherapy for various bone tumors and summarizes some of the important data supporting its use.

Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum.

HYPOTHESIS: Adjuvant chemoradiation improves local control and survival in patients with node-positive duodenal adenocarcinoma treated with pancreaticoduodenectomy. DESIGN: A retrospective review of outcomes, with a planned comparison with historical controls. SETTING: A single, high-volume academic referral center. PATIENTS: All patients with periampullary carcinoma treated with pancreaticoduodenectomy and adjuvant chemoradiotherapy at The Johns Hopkins Hospital between 1994 and 2003. Fourteen cases of node-positive duodenal adenocarcinoma were identified. Median radiation dose was 5000 cGy (range, 4000-5760 cGy). Concurrent fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. RESULTS: The median follow-up was 12 months for patients who died and 42 months for those who lived. Death occurred in 7 of 14 patients (50%) during the follow-up period. Median survival for all patients was 41 months, and the 5-year survival rate was 44%. Of the 7 patients who experienced disease recurrence, 6 experienced distant metastasis as first recurrence. One of these 7 patients experienced both local recurrence and distant metastasis. Local control for all patients in the study was 93%, which compares favorably with local control reported in a series of patients treated with surgery alone (67%). Compared with historical controls treated with surgery alone, patients who received adjuvant chemoradiation therapy had an improved median survival (21 months vs 41 months, respectively). Overall 5-year survival, however, was not improved (44% vs 43%, respectively). CONCLUSION: Adjuvant chemoradiation therapy after pancreaticoduodenectomy for node-positive duodenal adenocarcinoma may improve local control and median survival but does not impact 5-year overall survival.