Jens Jakob

Variability in Patterns of Recurrence After Resection of Primary Retroperitoneal Sarcoma (RPS): A Report on 1007 Patients From the Multi-institutional Collaborative RPS Working Group

Background:Retroperitoneal sarcomas (RPS) are rare tumors composed of several well defined histologic subtypes. The aim of this study was to analyze patterns of recurrence and treatment variations in a large population of patients, treated at reference centers. Methods:All consecutive patients with primary RPS treated at 6 European and 2 North American institutions between January 2002 and December 2011 were included. Five, 8, and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were calculated. Multivariate analyses for OS, CCI of LR, and DM were performed. Results:In all, 1007 patients were included. Median follow-up was 58 months (first and third quartile range 36–90). The 5, 8, and 10-year OS were 67% [95% confidence interval (CI), 63, 70), 56% (95% CI, 52, 61), and 46% (95% CI, 40, 53). The 5, 8, and 10-year CCI of LR and DM were 25.9 (95% CI, 23.1, 29.1), 31.3 (95% CI, 27.8, 35.1), 35% (95% CI, 30.5, 40.1), and 21% (95% CI, 18.4, 23.8%), 21.6 (95% CI, 19.0, 24.6), and 21.6 (95% CI, 19.0, 24.6), respectively. Tumour size, histologic subtype, malignancy grade, multifocality, and completeness of resection were significant predictors of outcome. Patterns of recurrence varied depending on histologic subtype. Different treatment policies at participating institutions influenced LR of well differentiated liposarcoma without impacting OS, whereas discrepancies in adjuvant systemic therapies did not impact LR, DM, or OS of leiomyosarcoma. Conclusions:Reference centers are critical to outcomes of RPS patients, as the management strategy requires specific expertise. Histologic subtype predicts patterns of recurrence and should inform management decision. A prospective international registry is under preparation, to further define our understanding of this disease.

Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients?

BACKGROUND Surgical indication for metastatic gastrointestinal stromal tumor (GIST) treated with imatinib is not yet established. MATERIALS AND METHODS We analyzed 80 patients who underwent surgery for metastatic GIST after imatinib therapy from July 2002 to October 2007. Patients were divided into those with surgery at best clinical response (group A, n = 49) and those with surgery at focal progression (group B, n = 31). Primary end points were progression-free survival (PFS) and disease-specific survival (DSS). RESULTS Two-year postoperative PFS was 64.4% in group A and 9.7% in group B (P < 0.01). In group A, median PFS was not reached; in group B, it was 8 months. Median DSS from the time of imatinib onset was not reached in either group. Five-year DSS was 82.9% in group A and 67.6% in group B (P < 0.01). Multivariate analysis confirmed a significantly shorter PFS and DSS in group B. Surgical morbidity occurred in 13 patients (16.3%). CONCLUSIONS Surgery for focal progressive lesions could be considered as part of the second-line/third-line armamentarium in selected cases. Surgery of residual disease upon best clinical response seems associated with survival benefit compared with historical controls in similar patient collectives treated with imatinib alone. However, evidence from prospective randomized trials is needed to make definite recommendations.

Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group

IntroductionRetroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence.MethodsAn RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma.ResultsRecurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein.ConclusionsInternational collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established.

Clinical Pathways in surgery—should we introduce them into clinical routine? A review article

Background and aimsIn modern health care systems, care providers face ever new challenges with regard to quality and cost of care, as well as to satisfaction and training of staff. Due to the intensiveness of the subject, these challenges are particularly pronounced in surgery. Clinical Pathways, i.e. detailed care plans defining the desired measures to be performed for each treatment period, are thought to be a tool to improve care in surgery with regard to these issues.MethodsWe performed a literature review to identify studies reporting effects of the implementation of Clinical Pathways into clinical care for the most common surgical interventions. We subdivided findings into Clinical Pathways’ effects on economic aspects, quality of care, treatment transparency, staff satisfaction and staff training.ResultsOur search identified 30 studies. Twenty four studies were trials with a before–after design. Four trials had only an intervention group, one trial was a non-randomised controlled trial and one was a randomised controlled trial. Study sizes ranged from six to 1,200 patients. The mean number of patients was 119 in the treatment group and 120 in the comparison group (where existent). Clinical Pathway implementation in surgery has manifold advantages. They improve objective and subjective quality of care, decrease hospitals’ costs, increase staff satisfaction and are valuable tools for training. Their effect seems to be most pronounced for high-volume or particularly complex treatments.ConclusionThere is substantial evidence that Clinical Pathways lead to various improvements in clinical care in surgery. Their widespread use should therefore be encouraged. However, more research encompassing all facets of Clinical Pathway usage and implying sound methods is strongly required.

Post‐relapse outcomes after primary extended resection of retroperitoneal sarcoma: A report from the Trans‐Atlantic RPS Working Group

Despite a radical surgical approach to primary retroperitoneal sarcoma (RPS), many patients experience locoregional and/or distant recurrence. The objective of this study was to analyze post‐relapse outcomes for patients with RPS who had initially undergone surgical resection of their primary tumor at a specialist center.

External validation of a multi-institutional retroperitoneal sarcoma nomogram

A multi‐institutional nomogram for predicting disease‐free survival (DFS) and overall survival (OS) in patients with primary retroperitoneal sarcoma (RPS) incorporating relevant prognostic factors not included in the American Joint Committee on Cancer staging system for soft tissue sarcoma has been reported. The authors validated this nomogram with an independent, transatlantic cohort.

Oncological outcome of primary non-metastatic soft tissue sarcoma treated by neoadjuvant isolated limb perfusion and tumor resection

Isolated limb perfusion (ILP) is an effective limb salvage strategy in patients with advanced soft tissue sarcoma (STS) where surgery alone would result in significant functional morbidity or mandate an amputation. Most previous reports of patients undergoing ILP focus on limb salvage rates rather than local and distant relapse rates. Here, we report the oncological outcome of sarcoma patients treated by ILP and surgery.

Role of isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan in locally advanced extremity soft tissue sarcoma.

The management of locally advanced extremity soft tissue sarcoma of the limbs is challenging, particularly for recurrent tumors and those adjacent to neurovascular bundles and joints. Typically, the tumors are large, below the fascia, and high‐grade (T2b or stage III according to the American Joint Committee on Cancer) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics. Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF‐ILP) adds a therapeutic option to radiation therapy (RT) and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method and has been used now for almost 2 decades at more than 50 centers worldwide. TNF‐ILP yields a high rate of complete or nearly complete pathologic tumor remission. In combination with surgical resection of the tumor remnant after isolated limb perfusion, the limb salvage rate is close to 90%. Often, patients can be spared adjuvant RT without long‐term local tumor control rates being compromised. Nevertheless, TNF‐ILP has never been compared with another treatment regimen in a randomized trial. This review summarizes the mode of action and standard application of TNF‐ILP and focuses on a critical discussion of the role of TNF‐ILP in the multimodal treatment of locally advanced primary and recurrent extremity sarcoma. Cancer 2016.

Preoperative Intensity-Modulated Radiotherapy Combined with Temozolomide for Locally Advanced Soft-Tissue Sarcoma

PURPOSE To evaluate the toxicity and efficacy of preoperative intensity-modulated radiotherapy (IMRT) combined with temozolomide to improve local tumor control in soft-tissue sarcoma (STS). PATIENTS AND METHODS A cohort of 15 consecutive patients with nonmetastasized, primary high-grade or locally recurrent Stage III (n = 14) or IIb (n = 1) STS not amenable to surgical resection without significant organ or extremity function loss was prospectively investigated. Median tumor size was 9.8 cm, and most tumors were non-extremity sarcomas. Patients preoperatively received 50 mg/m(2) of temozolomide during IMRT (50.4 Gy). Resection was intended 6 weeks thereafter. Toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS Of 15 patients, 14 completed preoperative treatment. No Grade 4 toxicities occurred. Nausea and vomiting were the most frequent Grade 3 toxicities. The most frequent toxicities of any grade were dermatologic, gastrointestinal, and hematologic. Response was partial response in 5, stable disease in 7, and progressive disease in 2 patients. Ten patients underwent surgery: 7 were resected with clear margins (R0), and 2 patients had an R1 resection; in 1 patient the tumor was not resectable. Postoperative complications occurred in 4 patients. Five patients did not undergo surgery because of intercurrent metastatic disease, unresectable disease, or refusal. CONCLUSIONS Preoperative chemoradiation with temozolomide and IMRT can be administered safely and with promising efficacy in patients with locally advanced STS.

Phase I trial of concurrent sunitinib and radiation therapy as preoperative treatment for soft tissue sarcoma

Introduction Although the introduction of multimodal treatment of soft tissue sarcoma improved local tumour control, local failure still occurs in a good number of patients. Therefore, further improvement of current treatment strategies is necessary. The proposed study treatment will combine standard external beam radiation and the orally administered receptor tyrosine kinase inhibitor sunitinib. Methods and analysis Patients with soft tissue sarcoma will receive sunitinib and irradiation as neoadjuvant treatment. Radiotherapy will be administered as intensity modulated radiation therapy with a total dose of 50.4 Gy in 28 fractions (5 1/2 weeks). Patients will receive sunitinib daily for 2 weeks prior to and then concurrently with irradiation. Sunitinib will be given in two dose levels. The first dose level will be 25 mg sunitinib per os daily. The second dose level will be 37.5 mg. A dose modification schedule according to a 3+3 design will be applied. Restaging and tumour resection will be performed 6 weeks after completion of sunitinib and irradiation. Primary outcome measures will be the dose-limiting toxicity and maximal tolerated dose of sunitinib administered concurrently with irradiation. Toxicity of the study treatment will be documented according to Common Terminology Criteria of Adverse Events (CTCAE) 4.0. Secondary outcome measures will be the response to the study treatment and morbidity of the tumour resection. Imaging response will be determined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria comparing MRI performed prior to and 6 weeks after completion of study treatment. Pathological response will be determined evaluating the fraction of non-viable tumour in the resection specimen. Resection morbidity will be evaluated according to CTCAE 4.0. Ethics and dissemination Approval was obtained from the ethics committee II of the University of Heidelberg, Germany (Reference number 2011-064F-MA). Furthermore, the study was approved by the German Federal Institute for Drugs and Medical Devices (Reference number 4037708). Trial Registration EudraCT 2007-002864-87 Clinicaltrials.gov: NCT01498835