Rick L. Haas

Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal; University Hospital Essen, Essen, Germany; Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy; Klinikum Stuttgart-Olgahospital, Stuttgart, Germany; Institut Curie, Paris, France; NORDIX, Athens, Greece; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria; Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain; Centro di Riferimento Oncologico di Aviano, Aviano; Ospedale Regionale di Treviso “S.Maria di Cà Foncello”, Treviso, Italy; Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain; Sarcoma Unit, University College London Hospitals, London, UK; Skane University Hospital-Lund, Lund, Sweden; N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; Institute of Scientific Hospital Care (IRCCS), Regina Elena National Cancer Institute, Rome; Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; Istituto Ortopedico Rizzoli, Bologna; Azienda Ospedaliera Universitaria Careggi Firenze, Florence, Italy; Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands; Institut Jules Bordet, Brussels, Belgium; Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy; Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam and Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands; Turku University Hospital (Turun Yliopistollinen Keskussairaala), Turlu, Finland; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Mannheim University Medical Center, Mannheim; Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Helsinki University Central Hospital (HUCH), Helsinki, Finland; Royal Marsden Hospital, London; The Institute of Cancer Research, London, UK; University Medical Center Groningen, Groningen; Radboud University Medical Center, Nijmegen, The Netherlands; University Hospital Motol, Prague; Masaryk Memorial Cancer Institute, Brno, Czech Republic; Gustave Roussy Cancer Campus, Villejuif, France; Maria Skłodowska Curie Institute, Oncology Centre, Warsaw, Poland; Tel Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel; Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland; Azienda Ospedaliera, Universitaria, Policlinico S Orsola-Malpighi Università di Bologna, Bologna; Azienda Ospedaliero, Universitaria Cita della Salute e della Scienza di Torino, Turin, Italy; Fundacio de Gestio Sanitaria de L’hospital de la SANTA CREU I Sant Pau, Barcelona, Spain; Helios Klinikum Berlin Buch, Berlin, Germany; YCRC Department of Clinical Oncology, Weston Park Hospital NHS Trust, Sheffield, UK; Aarhus University Hospital, Aarhus, Finland; Leuven Cancer Institute, Leuven, Belgium; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Institute of Oncology of Ljubljana, Ljubljana, Slovenia; Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, The Netherlands; University College Hospital, London, UK; Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany; Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Centre Leon Bernard and UCBL1, Lyon, France

High Response Rates and Lasting Remissions After Low-Dose Involved Field Radiotherapy in Indolent Lymphomas

PURPOSE To study the response rates and duration of response after low-dose (4 Gy) involved field radiotherapy (LD-IF-RT) in patients with recurrent indolent lymphoma. PATIENTS AND METHODS A total of 109 assessable patients (304 symptomatic sites) were irradiated (53 males and 56 females; median age, 62 years; range, 35 to 93), including 98 patients with follicular lymphoma (43 grade 1 and 55 grade 2), nine extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue-type and two patients with lymphoplasmacytoid lymphoma. Bulky disease (> or =5 cm) was present in 52% of all patients. A median of two prior regimens (range, 0 to 11) preceded LD-IF-RT. The median time since diagnosis was 41 months (range, 2 to 358 months). Time to (local) progression was calculated according to the Kaplan-Meier method. Differences in response rates between treatments within the same patient were compared using the McNemar test. RESULTS The overall response rate was 92%; complete response was reached in 67 patients (61%), partial response in 34 patients (31%), stable disease in six patients (6%), and progressive disease in two patients (2%). The median time to progression was 14 months. The median time to local progression was 25 months. The 67 patients with complete response showed a median time to progression of 25 months and a median time to local progression of 42 months. None of the factors studied (age, sex, follicular lymphoma grade, radiotherapy regimen, number of previous regimens and previous history, number of positive sites or largest lymphoma diameter) were found to be related to response rate. CONCLUSION LD-IF-RT is a valuable asset in the management of patients with follicular lymphoma and should be considered in patients with recurrent disease.

Does the combination of radiotherapy and debulking surgery favor survival in paranasal sinus carcinoma

PURPOSE To determine the contribution of debulking surgery on local control and survival in paranasal sinus tumors. As most patients present with locally advanced disease, the possibility of radical surgery is limited. Consequently, radiotherapy is often needed as monotherapy or as an adjunct to surgery. METHODS AND MATERIALS Between 1977 and 1996, 73 patients (50 male: 23 female) with a paranasal sinus carcinoma were treated. The histology distribution was as follows: squamous cell carcinoma, 55%; adenocarcinoma, 19%; adenoid cystic carcinoma, 11%; and undifferentiated carcinoma, 15%. The clinical T classification was (UICC/TNM 1997): T2 14%, T3 27%, and T4 59%. Pathological neck nodes were found in 11% of patients. Treatment consisted of surgery only in 3, chemotherapy only in 1, radiotherapy only in 18, both surgery and radiotherapy in 50 patients. One patient did not receive any treatment at all. Three patients had concurrent chemotherapy. Median follow-up was 66 months (range, 1-213 months). RESULTS Five-year local control (LC) was 65% with combination of radiotherapy and debulking surgery in comparison with 47% with radiotherapy alone, but this difference was not statistically significant (p = 0.58). However, combination treatment gave significantly better 5-year overall survival (OS) (60% vs. 9%; p = 0.001) and 5-year disease-free survival (DFS) (53% vs. 6%; p < 0. 0001). Cox-regression analysis showed that pathologic N status (p = 0.04), palliative intention of treatment (p = 0.018), clinical orbital invasion (p = 0.003), and orbital wall invasion (p = 0.003) were parameters significantly associated with poor local control. Total radiation dose of greater than 65 Gy (p = 0.05) and treatment consisting of radiotherapy alone (p = 0.002) were associated with worse overall survival; for disease-free survival clinical orbital invasion (p = 0.0005), age of greater than 65 years (p = 0.013) and pathologic T4 classification (p = 0.002) were significant factors for an unfavorable outcome. In 19 of 73 patients, 26 serious (mainly ophthalmological) complications were reported; in the majority of these, the visual tract was (partly) included in the treatment fields because of tumor extension. To analyze on which basis patients were selected for the combination therapy, a logistic regression was performed, concluding that clinical T4 classification (p = 0.05), radiological evidence of skull base invasion (p = 0.005), age of greater than 65 years (p = 0.026), radiological evidence of nasopharynx invasion (p = 0.02), clinical suspicion of palate invasion (p = 0.02), and radiological evidence of skin invasion (p = 0.009) were associated with choosing radiotherapy alone. CONCLUSION Debulking surgery of paranasal sinus malignancies followed by high-dose radiotherapy to the involved sites was associated with better survival and (although not statistically significant) local control. Patient selection, based on clinical and radiological impression of tumor extension, was the main factor explaining these favorable results. We favor this combination regimen because the surgery gives quick relief of complaints and, at the same time, offers an excellent histologically proven staging method, enabling radiotherapy to be adjusted to the involved sites, thereby decreasing the risk of complications. This can all be achieved with a very low orbital exenteration rate.

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.

Radiotherapy for management of extremity soft tissue sarcomas: why, when, and where?

This critical review will focus on published data on the indications for radiotherapy in patients with extremity soft tissue sarcomas and its role in local control, survival, and treatment complications. The differences between pre- and postoperative radiotherapy will be discussed and consensus recommendations on target volume delineation proposed.

Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma.

AbstractBackground:Malignant pleural mesothelioma (MPM) is a disease mostly confined to the thoracic cavity. Untreated, the median survival is <1 year. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy is used to kill residual tumor cells on the surface of the thoracic cavity while having limited systemic side effects. Methods:From August 1998 to August 2001, 22 patients with stage I MPM were included in this study. Two patients were irresectable at operation because of extrathoracic tumor growth. Twenty procedures were performed. After cytoreduction, a perfusion was performed with cisplatin and doxorubicin at 40°C to 41°C for 90 minutes. Adjuvant radiotherapy was given to surgical scars and drainage tracts. Results:There was no perioperative mortality, but significant morbidity was seen in 13 patients (65%), including bronchopleural fistula, diaphragm rupture, wound dehiscence, persistent air leakage, and chylous effusion. No hair loss or leucopenia was noticed. The median follow-up was 14 months. The median survival (Kaplan-Meier) was 11 months, with a 1-year survival of 42%. A favorable pharmacokinetic ratio was observed for both cisplatin and doxorubicin. Conclusions:Cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy for stage I MPM is feasible. However, this treatment is accompanied by considerable morbidity. Survival data were less encouraging.

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.

The role of radiotherapy in the local management of dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP), a fibrohistiocytic tumour of intermediate malignancy, has a strong tendency to recur locally. Wide local excision is the recommended treatment modality. A retrospective analysis was performed on 38 consecutive DFSP patients presenting to The Netherlands Cancer Institute, to define the role of radiotherapy. Of the 21 patients treated surgically (all with negative resection margins) seven recurred, a local control probability of 67%. Combined modality treatment was given to 17 patients. Prior to radiotherapy, these patients experienced 33 occurrences of DFSP, but after irradiation only three recurrences were seen, a local control probability of 82%. These results are in keeping with the recent literature where increasing value is being given to both adjuvant and curative radiotherapy in the local management of DFSP. We recommend radiotherapy in DFSP patients where repeated surgery may cause mutilation or functional impairment.

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis

Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crows feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio- and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n=16) were compared to primary extremity myxoid/round cell liposarcoma (n=20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum.

99mTc-HYNIC-rh-annexin-V scintigraphy: visual and quantitative evaluation of early treatment-induced apoptosis to predict treatment outcome.

AimTo determine the reliability of visual analysis of 99mTc-HYNIC-rh-annexin-V tumour uptake (ATU) compared to quantitative tracer uptake evaluation. MethodsThirty-eight patients (22 male, 16 female, mean age 57) with histologically proved lymphoma (n=31), non-small cell lung cancer (NSCLC) (n=4) and head and neck squamous cell carcinoma (H&NSCC) (n=3) were examined. 99mTc-HYNIC-rh-annexin-V scintigraphy (TAS) was acquired before and within 2 days after the start of anti-cancer treatment. Maximal counts per pixel in the tumour volume (Cmax) were calculated for every target lesion. To match the quantitative and visual ATU, both were expressed as a four-grade score. Cmax as percentages of baseline values: grade 1, decrease >25%; grade 0, 1–25% decrease; grade 1, 1–25% increase; grade 2, >25% increase. Visual analysis: 0=absent, 1=weak, 2=moderate, 3=intense. Intra-observer and inter-observer variability and methodological agreement between visual and quantitative evaluation of ATU was expressed by computing Cohens κ statistics. ResultsA statistically highly significant correlation was found between the changes in ATU and therapy outcome: r=0.97 (P<0.0001) and r=0.99 (P<0.0001) for visual and quantitative analysis, respectively. Good intra-observer reproducibility, with a high κ of 0.82 for observer 1 and a κ of 0.90 for observer 2, was determined. Inter-observer variability was 0.82. ConclusionVisual evaluation of ATU after image co-registration appears to be a reliable and reproducible method for preliminary assessment of early treatment-induced apoptosis.