Is it important to maintain high-dose intensity chemotherapy in the treatment of adults with osteosarcoma?

Neoadjuvant chemotherapy for osteosarcoma is the standard of care, but there is still confusion regarding the best chemotherapy regimen and the optimal intensity. This retrospective study intends to evaluate whether there is a clear correlation between the chemotherapy dose intensity (DI) and the percentage of tumor necrosis, the risk of tumor recurrence after surgery and patient survival. The medical records of all adult patients with localized osteosarcoma that received treatment between the years of 1998 and 2009 at the Tel Aviv Sourasky Medical Center were analyzed. We used multiple logistic/linear regression models to test the effect of the neoadjuvant chemotherapy relative DI (RDI) on histological response, recurrence and time to recurrence. A Cox regression analysis was conducted for the effects of neoadjuvant chemotherapy RDI, histological response, tumor location, gender and age on patient survival. Thirty medical records were analyzed. Survival, histological response, recurrence and time to recurrence were not affected by the chemotherapy RDI. The 5-year overall survival of the patient's population was found to be 63% with a median survival of 9.4 years. Patients with a good histological response had a longer survival than those with a bad response (mean survival times 11.0 vs. 6.6 years, log-rank test, P = 0.046). High DI is not a prognostic factor in osteosarcoma and maintaining it should not be a prime priority. Histological response is a prognostic but possibly not a reliable predictive factor, and further research is needed in order to find other reliable factors.

Hypofractionated adjuvant radiation therapy of soft-tissue sarcoma achieves excellent results in elderly patients.

OBJECTIVE: Adjuvant radiation therapy (RT) is an essential part of combined limb-sparing treatment of soft-tissue sarcoma (STS). Elderly or medically unfit patients often have difficulty in completing 6-7 weeks of standard fractionated daily treatment. Our aim was to evaluate the efficacy of a hypofractionated adjuvant approach with RT for STS in elderly and debilitated patients. METHODS: 21 elderly patients were treated with a short course of adjuvant RT (39-48 Gy, 3 Gy per fraction) for STS. The medical records of the patients were retrospectively reviewed for local or distant recurrence and side effects of RT. RESULTS: At a mean 26 months of follow-up, three local recurrences (14%) were detected. Eight patients (38%) had lung metastases during the observed period. Three of them died from metastatic disease. The hypofractionated radiation was well tolerated with minimum long-term side effects. CONCLUSION: Hypofractionated adjuvant radiation appears to be an effective treatment in terms of local control in elderly and debilitated patients. ADVANCES IN KNOWLEDGE: The results of this study might provide an alternative to commonly used standard fractionation of radiotherapy in sarcoma patients.

Fifteen years of bone tumor cryosurgery: a single-center experience of 440 procedures and long-term follow-up.

BACKGROUND: This summary of a single center's extensive cumulative experience in bone tumor cryosurgery assesses the long-term outcome of bone conservation surgery in which adjuvant cryosurgery plays a pivotal role. MATERIALS AND METHODS: We performed 440 cryosurgical procedures between January 1988 and December 2002. Two-thirds of the series comprised a variety of primary benign-aggressive and low-grade malignant lesions, and one-third were primary high-grade and metastatic bone tumors. The anatomical locations included almost every bone of the skeleton. Two methods of bone cryosurgery were used: Marcove's "open" direct-pour system using liquid nitrogen (1988-1997) and Meller's "closed" argon-based system (1998 to the present). RESULTS: The study cohort consisted of 214 males and 191 females (age range 5-82 years). The median follow-up was 7 years (range 3-18). The overall local recurrence rate was 8%: fractures=1%, infections=2% and skin burns=1.3%. There were three cases of transient nerve palsies in areas other than the sacrum, and four cases of late osteoarthritis of an adjacent joint. The functional outcome for the 372 patients with no evidence of disease was almost 100% "good" and "excellent" (American Musculo-skeletal Tumor Society System). Only two patients needed secondary amputations. CONCLUSIONS: Bone cryosurgery is a safe and effective limb-, joint- and even epiphysis-sparing surgical technique in suitable types of bone tumors, temporarily or permanently obviating the need for resection surgery.

Synovial sarcoma of the extremities and trunk: a long-lasting disease.

Synovial sarcoma (SS) of an extremity or trunk is relatively rare and is approached by limb sparing surgery (LSS), radiation therapy (RT) and chemotherapy. We conducted a retrospective analysis of the clinical and histopathological data of 73 patients with proven SS. At a median follow-up time of 6 years, local recurrence was seen in 17.8 and systemic recurrence 35.6% of patients (local-only, 6.8; systemic-only, 24.6; combined, 11%). The 10-year local recurrence-free survival (LRFS), systemic recurrence-free survival (SRFS) and overall survival (OS) rates were 78, 68 and 61%, respectively. LRFS was significantly better in patients treated with isolated limb perfusion (ILP); SRFS was influenced by the delay until diagnosis. The practical aspects of our observations are the need for long-term follow-up in order to diagnose recurrences, the fact that not all local or distant recurrences are necessarily associated with a shortening of OS time and the important role of induction ILP with TNF in cases of extremity SS.

Ewing Sarcoma tumor cells express CD34: implications for autologous stem cell transplantation.

The significance of tumor cell contamination in marrow and peripheral blood stem cell (PBSC) collections of patients with solid tumors remains controversial. Various methods have been developed to purge tumor cells from autologous stem cell products, including CD34+ selection. PBSC harvests from patients with Ewing family of tumors (EFT) were analyzed for contaminating tumor cells prior and after CD34+ selection using reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC) analyzes. The expression of CD34 was studied by RT-PCR and FC in 14 primary tumors and 13 PBSC harvests, respectively. Tumor cells were identified in the harvests by both methods. In two patients, contaminating tumor cells were evident by RT-PCR only after positive selection. FC analysis confirmed a higher level of tumor cells in the CD34+ fraction. In an attempt to explore this finding, expression of CD34 was detected in 93% of primary tumors and 67% of contaminated harvests. As CD34 is expressed on EFT cells, these cells may be enriched following CD34+ selection of harvests, although the total number of tumor cells is reduced. Other methods of purging, rather than CD34+ selection, should be explored in patients with EFT undergoing autologous stem cell transplantation.

Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy.

Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumour, the type of liposarcoma and the quality of resection. Our results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma.

Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors.

PURPOSE: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT). PATIENTS AND METHODS: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated. RESULTS: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P <.0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P =.0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery. CONCLUSION: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.

ErbB-4 expression in limb soft-tissue sarcoma: correlation with the results of neoadjuvant chemotherapy.

ErbB-4 is a recently described growth factor receptor. Relatively little is known about its expression in human tumours. In this study, we assessed the possible role of erbB-4 as a tissue marker for soft-tissue sarcomas (STS) and its correlation with the response to chemotherapy. The histological specimen of 29 patients with STS of a limb who had received preoperative doxorubicin (ADR)-based chemotherapy were studied for the degree of necrosis and the expression of erbB-4 (by an avidin-biotin-peroxidase technique). ErbB-4 expression in the preoperative tissue samples was compared with the expression in the postchemotherapy resected tumour. The true objective response rate to preoperative chemotherapy was 34%. Wide resection of the tumour was done in 12 patients, marginal in 14, amputation in 2 and no surgery in 1. The tumour necrosis was above 90% in 9 patients, 60-90% in 12, and less than 60% in 7 patients. An increase in erbB-4 expression was more common in cases with no response to chemotherapy, while no change or a decrease in erbB-4 was more common in responsive tumours (P=0.004). No correlation could be found between the degree of necrosis or the chemotherapeutic regimen and the change in expression of erbB-4. The median disease-free survival (DFS) was longer for patients with a decrease or no change in expression of erbB-4 than for patients with increased expression. It is believed that postchemotherapy new expression or no downregulation of the erbB-4 molecule represents tumour aggressiveness and increased capability of growth and spread.

Primary chronic sclerosing (Garré's) osteomyelitis in children.

Three children with unifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were located at the metaphyseal region of long bones. Three was progressive sclerosis and hyperostosis in the tibia or femur, such as the changes described in Garré's osteomyelitis. No pus was released by exploration of the lesions. Tissue and blood cultures were negative. The histology was typical of chronic osteomyelitis: the symptoms returned intermittently over several years, together with the development of sclerosis but without disturbance of bone growth. It is not clear whether Garré's chronic sclerosing osteomyelitis is a different entity from chronic recurrent multifocal osteomyelitis.

Cellular and molecular properties associated with osteosarcoma cells.

Osteosarcoma cells are recognized by abnormal function that causes a primary bone tumor. Osteosarcoma cells U(2)OS and SAOS-2 were analyzed for the expression of cell surface markers. High expression was quantified for hyaloronidase receptor (CD-44) > moderate for integrins (CD-51 and -61), > and lower for selectins (CD-62). High mitotic capacity were demonstrated by gene expression (measured by RT-PCR) and the protein level (measured by FACS) for cFOS, cMYC, and cJUN. The basic definition of osteosarcoma is excessive production of pathological osteoid. Expression of mRNA for matrix genes osteocalcin, osteonectin, and biglycan was studied. Osteocalcin and osteonectin were detected in RNA from primary cultured marrow stromal, trabecular bone cells, and osteosarcoma cell lines (U(2)OS, SAOS-2). mRNA for biglycan was detected only in primary cells and MG-63 cell line and was undetectable in RNA from U(2)OS, SAOS-2 osteosarcoma cell lines and by RNA extracted from bone biopsies of osteosarcoma patients. The absence of biglycan message observed in osteosarcoma samples provides evidence for the alterations in the extra cellular matrix which result with non-mineralized osteoid produced by the osteosarcoma cells.

Carcinoid tumor of the coccyx: case report and review of the literature.

STUDY DESIGN: Report of a patient with a carcinoid tumor of the coccyx. OBJECTIVES: To describe the clinical presentation, diagnosis, and treatment of a patient with a carcinoid tumor of the coccyx and to review the relevant medical literature in English. SUMMARY OF BACKGROUND DATA: No reports of a carcinoid tumor of the coccyx were found in the literature. Seven reports of carcinoid of the sacrum are described. METHODS: Clinical history, magnetic resonance imaging studies, and light and electronic microscope micrographs are reviewed. RESULTS: A coccygeal mass was detected during evaluation of coccygodynia in a 40-year-old woman. Four years after extended coccygectomy, there are no signs of local tumor recurrence. CONCLUSIONS: Carcinoid tumor of the coccyx is extremely rare. An extended coccygectomy may lead to a cure or at least to a prolonged disease-free interval.

Chondrosarcoma of the larynx: a therapeutic challenge.

The diagnosis of laryngeal chondrosarcoma is likely to be missed because of its infrequent occurrence and its indolent pattern of growth. A 53-year-old woman came to our service with an 18-year history of hoarseness and increasing dyspnea. She had been previously documented as having left vocal fold paralysis and a bulging laryngeal mass. Computed tomography revealed the presence of a large calcified tumor that had caused a deformity of the larynx and an erosion of the arytenoid and cricoid cartilages. Direct laryngoscopy detected a large supraglottic mass with a normal-appearing mucosa. Total excision of the tumor was achieved through a lateral neck incision that spared the larynx. This case emphasizes the importance of a high index of suspicion for laryngeal chondrosarcoma in a patient who has unexplained vocal fold paralysis and a submucosal subglottic mass. Every effort should be made to take a conservative surgical approach that preserves laryngeal function when possible.

Effect of P-glycoprotein expression on outcome in the Ewing family of tumors.

This study was designed to determine the prognostic significance of multidrug resistance, mediated by P-glycoprotein (Pgp) expression, in Ewing sarcoma. The clinical and laboratory features, treatment protocol, and outcome of 75 patients with Ewing sarcoma or peripheral neuroectodermal tumor treated between 1972 and 1997 were reviewed. Pgp expression was tested with the monoclonal antibody JSB-1. Thirty-four (64%) of the 53 tissue samples from untreated patients stained positive for Pgp. Progression-free and overall survival were 44 and 59%, respectively, in patients with negative findings, and 28 and 41% in those with positive findings; neither difference was significant. Of the 12 relapsed patients, 6 (50%) expressed more Pgp after chemotherapy than at diagnosis and 4 (33%) expressed less. Within these subgroups, 5 out of 6 and 3 out of 4 died from the disease. No correlation was found between Pgp and known prognostic factors of Ewing tumors. Pgp expression is probably an intrinsic factor of Ewing tumors but has no correlation to prognosis.

Multiple primary malignancies in association with soft tissue sarcomas.

BACKGROUND: Modern cancer treatment has increased the survival of patients with various malignancies substantially. One of the late sequelae of successful treatment is the development of a second malignant tumor. However, in many cases of second primary tumors, exposure to chemotherapy or radiation therapy is not evident, and it should be postulated that the putative mechanism for the development of the second tumor is different. In the current series, the association between soft tissue sarcoma (STS) in adults and the development of other primary malignancies was studied. METHODS: A retrospective search of the data files of 610 patients with STS or bone sarcomas who were treated at the study institution between January 1995 and December 1999 was performed. All files regarding patients with STS who developed a second malignant tumor were retrieved for analysis. RESULTS: Of 375 patients with STS, 28 (7.5%) developed other malignant neoplasms either before or after the diagnosis of STS. STS as the first tumor occurred in 14 patients (ages 16-72 years). Only three patients were treated with chemotherapy for their sarcoma. Radiation therapy was administered to five patients as an adjuvant to surgery for the first tumor. The second tumor types mainly included STS and renal cell carcinoma. The time interval between the diagnosis of the STS and the second malignancy was 0 (for synchronous tumors) to 21 years. Three patients developed a third primary tumor within 3 years after the diagnosis of the second tumor. The median overall survival was > 78 months. Fourteen patients (ages 35-87 years) had a first primary tumor other than STS (mainly breast carcinoma and genitourinary malignancies). The second tumors (mainly STS) appeared within 0 (for synchronous tumors) to 27 years. The median overall survival for the 14 patients in this group from the time of diagnosis of the first tumor was > 102 months. CONCLUSIONS: The phenomenon of two or three primary neoplasms developing in patients in whom one of the tumors was STS occurs at a rate of 7.5%, a significantly higher rate than that reported for the occurrence of STS among the general cancer population (1%). The majority of cases occur incidentally. The clinical implication includes the need to search for an occult second primary tumor in patients with STS as an integral part of their follow-up. This is especially true in patients with primary malignant fibrous histiocytoma who demonstrate a risk for developing a renal cell carcinoma.

Is forequarter amputation justified for palliation of intractable cancer symptoms?

BACKGROUND: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. METHODS: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. RESULTS: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90-100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3-24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. CONCLUSIONS: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.

The effect of pneumoperitoneum on dissemination and scar implantation of intra-abdominal tumor cells.

PURPOSE: The role of laparoscopy for the treatment of cancer remains controversial, and a particular concern is port site metastases after laparoscopic surgery. Since laparoscopy is being performed with increasing frequency, the question arises as to whether it is a safe oncological procedure. After intraperitoneal inoculation of renal cell carcinoma cells in a mouse model, we compare abdominal wall scar implantation following laparoscopic trocar insertion and pneumoperitoneum with standard laparotomy, and examine the effects on tumor dissemination in the peritoneal cavity. MATERIALS AND METHODS: Following intra-abdominal RENCA cell inoculation, Balb/c mice were randomized into group 1-20 mice that underwent carbon dioxide pneumoperitoneum and telescope trocar insertion, group 2-20 subjected to laparotomy and group 3-10 anesthetized only. All animals were sacrificed 2 weeks after inoculation, and abdominal wall metastases and intraperitoneal tumor distribution were evaluated. RESULTS: Overall, intra-abdominal implantation of inoculated RENCA tumor cells was detected in 15 of 20 animals (75%) in group 1, 14 of 20 (70%) in group 2 and 10 of 10 (100%) in group 3. Wound metastases developed in 46.7% of the mice in group 1 and 50% in group 2. CONCLUSIONS: There was no difference among the groups in the pattern of intraperitoneal tumor implants and scar seeding incidence. Pneumoperitoneum does not facilitate port site metastases.

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in advanced soft-tissue sarcomas: histopathological considerations.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients. METHODS: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels. RESULTS: The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (>90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size. CONCLUSIONS: This is the first serial histological description of the effects of tumor necrosis factor-alpha and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies.

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/m(2) 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/m(2) 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.

Gemcitabine in bone sarcoma resistant to Doxorubicin-based chemotherapy.

SUBJECTS AND METHODS: Seven patients with progressive localized or metastatic chemo-resistant osteosarcoma were treated by gemcitabine.The protocol included gemcitabine 1000 mg/m2/w for 7 consecutive weeks, followed by 1 week rest. If no progression was observed,maintenance by gemcitabine 1000 mg/m2/w for 3 weeks every 28 days was given until failure was clinically or radiologically evident.Results. The true objective response rate was 0%. However, disease stabilization and clinical benefit response were observed in five patients (70%) for 13-96 weeks.Discussion. Postponing the inevitable death with a relatively non-toxic treatment, is, in our opinion, an important issue especially in young patients.Thus it may be justified and warranted to investigate the activity of gemcitabine in a larger group of patients with bone sarcomas.