Ofer Merimsky

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

METASTATIC RENAL CELL CARCINOMA OF BONE: INDICATIONS AND TECHNIQUE OF SURGICAL INTERVENTION

PURPOSE We describe the efficacy of surgical excision of metastatic renal cell carcinoma of bone for achieving local tumor control, pain control and functional outcome with emphasis on the indications and techniques of surgical intervention as well as oncological outcome. MATERIALS AND METHODS Between 1980 and 1997 we performed surgery on 45 patients (56 lesions) with metastatic renal cell carcinoma of bone. Indications for surgery were solitary bone metastasis, intractable pain, or impending or present pathological fracture. Surgery involved wide excision in 29 cases, marginal excision with adjunctive liquid nitrogen in 25 and amputation in 2. RESULTS None of the patients had significant bleeding intraoperatively. Mean hospital stay was 9.8 days, during which there was no flap necrosis, deep wound infection, nerve palsy or thromboembolic complication. Postoperatively pain was significantly relieved in 91% of patients, while 89% achieved a good to excellent functional outcome, and 94% with metastatic lesions of the pelvic girdle and lower extremities were ambulatory. Local recurrence developed in only 4 of the 56 lesions (7.1%), including 3 after marginal resection. Survival was more than 2 years in 22 patients (49%) and more than 3 in 17 (38%). CONCLUSIONS Surgical excision is safe and reliable for restoring mechanical bone stability, relieving pain and providing good function in most patients with metastatic renal cell carcinoma who meet the criteria for surgical intervention. Relatively prolonged survival in these cases justifies considering surgical intervention when feasible.

Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study

Purpose: To assess the efficacy of gemcitabine in patients with a variety of sarcomas that have failed to respond or escaped Adriamycin- and ifosfamide-based chemotherapy. Patients and methods: A group of 18 symptomatic heavily pretreated patients with sarcomas of bone or soft tissue received one induction course of gemcitabine at a dose of 1000 mg/m2 per week for 7 consecutive weeks, followed by 1 week rest. Response to the induction course was assessed by interview and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000 mg/m2 per week for 3 weeks every 28 days was given until failure was clinically or radiologically evident. Results: A total of 51 cycles of gemcitabine were given including 18 cycles of induction. A mean of 3.6 postinduction cycles were given to nine patients. The treatment was well tolerated by the patients. One partial response (leiomyosarcoma) and one minimal response (angiosarcoma) were observed, yielding a true objective response rate of 5.5%. An additional six patients achieved stabilization of disease (chondrosarcoma and osteosarcoma), yielding an overall progression-free rate of 44%. The median time to progression was more than 27 weeks. Clinical benefit response was observed only in those who also achieved a progression-free state. Conclusion: Gemcitabine was found to be effective in achieving stabilization and even a minimal response of soft tissue or bone sarcoma refractory to standard chemotherapy.

Neurotoxicity of interferon-alpha.

Interferon (IFN) related neurotoxicity includes somnolence and confusion, fatigue, lethargy, psychiatric symptoms, conceptual disorganization, neurological deficits, cortical blindness, coma and, rarely, death. The neurologic syndromes seem to be more common in elderly patients, following intramuscular or intravenous administration, at higher doses of frequent injections of IFN-alpha and in primary renal cell carcinoma. The duration of the treatment was not strongly related to neurotoxicity. Computed tomography findings were non-specific and included atrophy or periventricular lucencies. Electroencephalograph studies demonstrated a generalized increase in slow wave activity which returned to normal after cessation of treatment. Behavioral and mental changes in patients treated with IFN are warning signs, and indicate the need to withdraw treatment.

Comparison between two iodine-125 brachytherapy implant techniques: pre-planning and intra-operative by various dosimetry quality indicators

PURPOSE To prospectively compare two widely used seed implant techniques: pre-planning and intra-operative planning, based on 1 month post-implant CT-based evaluation. METHODS We report results of a detailed 1 month post-operative dosimetric evaluation and comparison between 142 consecutive men with prostate adenocarcinoma treated by the pre-planning methodology and 214 men treated with the real-time, intra-operative seed implant method. RESULTS Baseline parameters patients age, Gleason score, clinical stage, and gland volume were similar in both groups (p>0.05). Length of physicist time and operating room team time were more than double in the pre-planned group compared to the intra-operative one (205 vs 100 min). Based on day 30 post-implant CT, for patients treated with the pre-planning method, mean V90, V100 and V150 (percent prostate volume receiving 90, 100 and 150% of the prescribed dose) were 67.5, 58.35 and 21.5%, respectively, while for the intra-operative group they were 97.9, 95.2 and 45%, respectively (p<0.01). Mean D90, expressed as percent of target matched peripheral dose (minimal dose covering 90% of the gland volume) was 53% for the pre-planned group and 114% for the intra-operative group of men (p<0.01). Short-term morbidity was minimal in both groups and did not correlate with the technique employed. CONCLUSIONS This large-scale comparison of implant adequacy favours real-time intra-operative method. While all dosimetric parameters are significantly better with this method, no increased early morbidity was noted. Longer-term PSA-based clinical outcome should substantiate our contention of the superiority of the intra-operative method when compared to the pre-planning one.

Antigens and antibodies in malignant melanoma

Antigens, antibodies and immune complexes seem to play a major role in the course of malignant melanoma, in detection of the disease progression, in treatment planning and monitoring. Of particular interest are cell and matrix adhesion molecules, growth factors and cytokines, proteases, gangliosides and major histocompatibility complex class I and II molecules. Antigens expressed on melanoma cells, but not on mature melanocytes, may be used as markers for the degree of the differentiation of the melanoma cells. The more the melanoma cells are dedifferentiated, the smaller is the antigenic similarity to normal melanocytes. Also, different antigens may be identified in various stages of the disease and may be used as tumor markers for disease recurrence or progression. Certain melanoma-associated antigens (MAA) such as epidermal growth factor receptor and adhesium molecules can be modulated by cytokines. Early melanoma evokes an antigen-derived T cell response, which becomes attenuated with the progression of the disease. A variety of cell adhesion molecules present on melanoma cell surfaces may play a role in regulation of cellular cytotoxicity. Free antimelanoma antibodies are usually not detectable in the sera of patients with melanoma, possibly due to their binding to shed antigens and formation of immune complexes or to tissue antigens. When bound to normal melanocytes, they cause the appearance of associated hypopigmentation. The identification of melanoma surface antigens led to generation of monoclonal antimelanoma antibodies (MAb) by laboratories. Strategies utilizing MAb based on immunologic approaches have been developed. MAb to tumor-associated antigens of melanoma cells may be used for therapeutic purposes in man. Sera of patients with vitiligo were capable of causing regression of melanoma metastases in mice due to the presence of a high titer of naturally occurring antimelanoma antibodies. Immunization of melanoma patients with vaccines containing treated melanoma cells or specific melanoma antigens or anti-idiotypic antibodies resulted in an increasing titer of antimelanoma antibodies and regression of the tumor to some extent. The appearance of hypopigmentation in patients with melanoma serves as proof for the activity of antimelanoma antibodies, although its association with the prognosis is still not clear. The thorough investigation in the field of MAA and related antibodies is aimed at improving specific antimelanoma immunotherapy, such as antigenic targeting or enhancement of production of autoantibodies, as well as better understanding of the process of metastasis and the melanoma-immune system interaction.

Oral Vinorelbine and Cisplatin as Induction Chemotherapy and Concomitant Chemo-Radiotherapy in Stage III Non-small Cell Lung Cancer: Final Results of an International Phase II Trial

Introduction: Cisplatin in combination with vinorelbine has reported an optimal activity/tolerance ratio when used in combination with radiotherapy in locally advanced unresectable non-small cell lung cancer. The currently available oral formulation of vinorelbine should be easier to use assuming a similar activity profile. An international phase II trial with vinorelbine oral and cisplatin as induction followed by oral vinorelbine and cisplatin with concomitant radiotherapy was implemented to evaluate the efficacy in terms of objective response (OR) following this combination as primary end point and duration or response, progression-free survival, overall survival, and safety as secondary endpoints. Material and Methods: The study included patients between 18 and 75 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular lymph nodes and pleural effusion excluded) non-small cell lung cancer, adequate bone marrow, hepatic and renal function, Karnofsky performance status ≥80%. Patients were treated with oral vinorelbine 60 mg/m2 day 1,8 cycle 1 and 80 mg/m2 day 1,8 cycle 2 (if no grade 3-4 toxicity) and cisplatin 80 mg/m2 day 1 every 3 weeks for 2 cycles as induction. Patients without progression received oral vinorelbine 40 mg/m2 day 1, 8 and cisplatin 80 mg/m2 day 1 every 3 weeks for 2 more cycles with radiotherapy 66 Gy in 6.5 weeks. Results: Patient and disease characteristics (n = 54) included: median age 57 years; female sex 24%; stage IIIA 48% and IIIB 52%; Squamous carcinoma 59%, Karnofsky performance status 100% (range, 80-100%) 50%, patients ≥5% weight loss at baseline 7%. Relative dose intensities of oral vinorelbine/cisplatin were 86%/93% and 97%/98% at induction and in combination with radiotherapy, respectively. Forty-one patients (76%) increased oral vinorelbine from 60 to 80 mg/m2 day during induction (reasons for nonescalation: hematological 7 patients, nonhematological 2 patients, error 4 patients). After two cycles of chemotherapy induction, the OR intent-to-treat in the 54 patients was 37%. Toxicities during induction were as follows: Neutropenia G3-4 (28%), Febrile Neutropenia (7%), nausea G3 (11%), vomiting G3-4 (9%), anorexia G3 (4%), diarrhea G4 (2%), constipation G3 (2%). Forty-seven out of 54 (87%) patients received concomitant chemo-radiotherapy. Median radiotherapy delivered dose was 66 Gy. Tolerance: 9% G3 Neutropenia; 4% G3 dysphagia/radiation; 2% G3 radiation dermatitis. Late pulmonary fibrosis was reported in one patient (1.8%). One month after completion of chemo-radiotherapy, the overall OR intent-to-treat in the 54 patients was 54% (95% CI: 40-67%). With a median follow-up of 37 months (95% CI: 34-41) the median progression-free survival and overall survival were: 12.5 (95% CI: 9.6-16.4) and 23.4 (95% CI: 17.6-29.8) months, respectively. Conclusion: Oral vinorelbine in combination with cisplatin is an effective combination in stage IIIA/IIIB patients. The excellent tolerance profile allowed to complete concomitant chemo-radiotherapy in 87% of patients. Oral vinorelbine in combination with cisplatin is a new and promising option that facilitates the administration of concomitant chemo-radiotherapy with high rates of treatment completion.

Palliative Major Amputation and Quality of Life in Cancer Patients

Limb sparing surgery has replaced the amputation surgery in the treatment of limb sarcomas. Recurrent or persistent disease constitutes a major problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patients quality of life. In this clinical set-up palliative amputation should be considered. Eighteen patients with soft-tissue or bone sarcomas and 3 patients with metastatic carcinoma underwent palliative major amputation. Hemipelvectomy was performed in 3 patients, hip disarticulation in 10, knee disarticulation or below-knee amputation in 3 patients, shoulder disarticulation in one patient and forequarter amputation in 4 patients. Local control of the disease and pain and improvement of the performance status were observed in 19 evaluable patients. The mobility was restored in 15 patients with lower limb surgery. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. To conclude, we have, found palliative major amputation surgery worth performing in low-performance status cancer patients with locally advanced disease.

Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: A beneficial strategy to combat non-small cell lung cancer

The potential therapeutic value of combinatorial regimens based on an EGF receptor tyrosine kinase inhibitor (TKI) and autophagy inducing drugs was evaluated by comparing their molecular impacts on H1299 and A549 non-small cell lung cancer (NSCLC) cells, which overexpress wild type EGF receptor, but are either deficient or have wild type p53 alleles, respectively. We show that H1299 cells display a considerably lower sensitivity to erlotinib treatment, which can be restored by combining erlotinib with rapamycin or with imatinib, though to a lesser extent. Cytotoxicity was associated with increased autophagy and hyperpolarization of the mitochondrial membrane potential. Therefore, combining an EGF receptor directed TKI with an autophagy-inducing drug, preferably, rapamycin, might be beneficial in treating poor responding NSCLC patients.

Cutaneous and subcutaneous metastases of rectal cancer

The occurrence of cutaneous metastatic disease from colorectal cancer is uncommon and typically signifies widespread disease with poor prognosis. Colorectal metastases usually occur within the first 3 years of follow up, and the median survival of patients after the appearance of cutaneous metastatic lesions is 18 to 20 months. We describe an unusual case of a 60-year-old woman with a metachronous skin lesion as the sole site of metastatic disease, and a relatively long interval between the appearance of skin metastases and death. The woman was found to have an adenocarcinoma of the rectum, a Dukes’ C lesion, extending over the entire rectal wall into the perirectal fat; five of eight regional lymph nodes showed metastases. Adjuvant radiotherapy followed by chemotherapy was administered for about 1 year. A subcutaneous lump on the left abdominal wall found 16 months postoperatively was metastatic of rectal origin. A metastatic adenocarcinoma of rectal origin was found in a single left lower axillary node 26 months later. Despite metastatic work-up for the next 2 years, an enlarged and palpated metastatic left inguinal lymph node appeared and was subjected to radiation. Computerized tomography (CT) examination 5 years after the first presentation of the rectal tumor and almost 4 years after the diagnosis of abdominal skin metastases disclosed recurrent pelvic disease with severe left hydronephrosis. Treatment by systemic chemotherapy was partially successful, but she died 8 months after this chemotherapy was initiated.