Efficacy of carbon-ion radiotherapy and high-dose chemotherapy for patients with unresectable Ewing's sarcoma family of tumors.

BACKGROUND: Treatment for unresectable Ewing's sarcoma family of tumors (ESFT) is a formidable challenge because of its high tendency for local and distant failure. Recently, carbon-ion radiotherapy (CIRT) has been applied to unresectable bone and soft tissue sarcoma. Additionally, high-dose chemotherapy (HDC) with stem cell rescue has been used to improve the survival of patients with relapsed ESFT. Here we report our experience with CIRT and HDC in the treatment of unresectable ESFT. METHODS: Five unresectable ESFT patients including 4 who underwent CIRT and HDC and one who underwent CIRT from 1999-2009 were retrospectively studied. After neoadjuvant chemotherapy, CIRT was conducted at the National Institute of Radiological Sciences in Chiba as local therapy. Consecutively, we employed HDC including busulfan, melphalan, and thiotepa with stem cell rescue. RESULTS: Two patients showed tumor shrinkage after CIRT, including 1 patient who achieved partial response. No severe acute toxicity related to CIRT was observed. Local failure was observed in only 1 patient at 22 months after CIRT. Four patients conducted HDC with stem cell rescue after CIRT and 1 patient suffered from veno-occlusive disease just after HDC. Distant failure was observed in 3 patients after completion of the treatment. CONCLUSIONS: CIRT and HDC for unresectable ESFT patients show favorable local control, with unsatisfactory results for distant control.

SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group.

In the present study, we evaluated the safety and effectiveness of SYT-SSX-derived peptide vaccines in patients with advanced synovial sarcoma. A 9-mer peptide spanning the SYT-SSX fusion region (B peptide) and its HLA-A*2402 anchor substitute (K9I) were synthesized. In Protocols A1 and A2, vaccines with peptide alone were administered subcutaneously six times at 14-day intervals. The B peptide was used in Protocol A1, whereas the K9I peptide was used in Protocol A2. In Protocols B1 and B2, the peptide was mixed with incomplete Freund's adjuvant and then administered subcutaneously six times at 14-day intervals. In addition, interferon-α was injected subcutaneously on the same day and again 3 days after the vaccination. The B peptide and K9I peptide were used in Protocols B1 and B2, respectively. In total, 21 patients (12 men, nine women; mean age 43.6 years) were enrolled in the present study. Each patient had multiple metastatic lesions of the lung. Thirteen patients completed the six-injection vaccination schedule. One patient developed intracerebral hemorrhage after the second vaccination. Delayed-type hypersensitivity skin tests were negative in all patients. Nine patients showed a greater than twofold increase in the frequency of CTLs in tetramer analysis. Recognized disease progression occurred in all but one of the nine patients in Protocols A1 and A2. In contrast, half the 12 patients had stable disease during the vaccination period in Protocols B1 and B2. Of note, one patient showed transient shrinkage of a metastatic lesion. The response of the patients to the B protocols is encouraging and warrants further investigation.

Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk.

BACKGROUND: The authors summarized the outcomes of patients with unresectable osteosarcoma of the trunk who received carbon ion radiotherapy (CIRT). METHODS: The authors performed a retrospective analysis of 78 patients who had medically inoperable osteosarcoma of the trunk and received treatment with CIRT between 1996 and 2009. Tumor sites included the pelvis in 61 patients, the spine and paraspinal region in 15 patients, and other sites in 2 patients. The median applied CIRT dose was 70.4 Gray equivalent (GyE) in a total of 16 fixed fractions over 4 weeks. RESULTS: The minimum duration of follow-up for survivors was 14 months. Forty-eight patients remained alive. The 5-year overall survival rate was 33%, and the local control rate was 62%. Thirty-eight patients who had a clinical target volume <500 cm(3) had a 5-year overall survival rate of 46% and a 5-year local control rate of 88%. Except for 3 patients who experienced severe skin/soft tissue complications requiring skin grafts, no other severe toxicities were observed. Of 9 patients who were continuously disease free for >5 years, 8 were able to walk with or without the help of a cane, and 6 were free from pain killers. CONCLUSIONS: CIRT appeared to be a safe and effective modality for the management of unresectable osteosarcoma of the trunk, providing good local control and offering a survival advantage and good long-term functional results without unacceptable morbidity.

Posttraumatic stress symptom (PTSS) and posttraumatic growth (PTG) in parents of childhood, adolescent and young adult patients with high-grade osteosarcoma.

BACKGROUND: Posttraumatic stress symptom (PTSS) and posttraumatic growth (PTG) were surveyed in parents of childhood, adolescent and young adult patients with high-grade osteosarcoma. METHODS: A questionnaire survey was performed in parents of patients with osteosarcoma (51 families). The Impact of Event Scale-Revised (IES-R) and posttraumatic growth inventory (PTGI) were employed for the evaluation of PTSS and PTG, respectively. The mean scores were compared with those in preceding studies employing the same scales. In addition, the correlation between the IES-R and PTGI scores was investigated in the parents. RESULTS: Fifty-eight subjects of 34 families (30 fathers and 28 mothers) replied to the questionnaire. The mean IES-R score in the parents was 18.5, which was higher than that in patients with osteosarcoma (9.7) in our previous study. The mean PTGI score in the parents was 44.9, which was higher than that in university students (33.9) reported by Taku et al. A positive correlation was noted between the IES-R and PTGI scores in the parents. CONCLUSIONS: The PTSS level tended to be higher in the parents rather than in patients with osteosarcoma. The PTG level increased as the PTSS level rose in the parents.

Polycomb group molecule PHC3 regulates polycomb complex composition and prognosis of osteosarcoma.

Polyhomeotic homolog 3 (PHC 3) is a member of the human polycomb complex and has been regarded as a candidate tumor suppressor of osteosarcoma. In the present paper, we performed a mutation survey and PHC3 expression analysis by quantitative real-time PCR using 10 osteosarcoma cell lines and 42 primary osteosarcoma samples. Relative PHC3 expression values of clinical samples were analyzed with clinical outcomes, and it was suggested that lower PHC3-expressing patients had significantly worse overall survival. Relative PHC3 values of clinical samples were less than those of normal bone tissues, whereas they were greater than those of cell lines. By denaturing high performance liquid chromatography analysis and direct sequencing, we found a PHC3 missense mutation in U2OS cells, which resulted in arginine56 to proline substitution. The same point mutation existed in four of 42 primary osteosarcoma samples. Regarding functional analysis, PHC3 expression significantly suppressed the colony formation of tumor cells. Intriguingly, polycomb repressive complex 1 members, Bmi1 and Ring1b proteins, were reduced in PHC3-expressing osteosarcoma cells. Deletion mutant PHC3 expression suggested that the carboxyl terminus of PHC3 has a role in suppression; the above-mentioned point mutation of PHC3 also lost inhibitory activities. Conversely, Bmi1 expression reduced PHC3 at the mRNA level and induced the proliferation of osteosarcoma cells. Taken together, we confirmed the role of PHC3 as a tumor suppressor in osteosarcoma cells and found that PHC3-dependent tumor suppression may be caused by modification of the composition of polycomb repressive complex 1 in cancer cells.

Effect of carbon ion radiotherapy for sacral chordoma: results of Phase I-II and Phase II clinical trials.

PURPOSE: To summarize the results of treatment for sacral chordoma in Phase I-II and Phase II carbon ion radiotherapy trials for bone and soft-tissue sarcomas. PATIENTS AND METHODS: We performed a retrospective analysis of 38 patients with medically unresectable sacral chordomas treated with the Heavy Ion Medical Accelerator in Chiba, Japan between 1996 and 2003. Of the 38 patients, 30 had not received previous treatment and 8 had locally recurrent tumor after previous resection. The applied carbon ion dose was 52.8-73.6 Gray equivalents (median, 70.4) in a total of 16 fixed fractions within 4 weeks. RESULTS: The median patient age was 66 years. The cranial tumor extension was S2 or greater in 31 patients. The median clinical target volume was 523 cm(3). The median follow-up period was 80 months. The 5-year overall survival rate was 86%, and the 5-year local control rate was 89%. After treatment, 27 of 30 patients with primary tumor remained ambulatory with or without supportive devices. Two patients experienced severe skin or soft-tissue complications requiring skin grafts. CONCLUSION: Carbon ion radiotherapy appears effective and safe in the treatment of patients with sacral chordoma and offers a promising alternative to surgery.

Changes in tumor volume of sacral chordoma after carbon ion radiotherapy.

OBJECTIVE: We evaluated changes in tumor volume in cases of sacral chordoma after carbon ion radiotherapy. METHODS: Thirty-four patients with sacral chordoma underwent carbon ion radiotherapy between June 1996 and June 2003. We assessed 23 patients without previous surgery using T2-weighted magnetic resonance imaging. The tumor volume was calculated semiautomatically. RESULTS: Two cases showed local recurrence. The median interval of this examination was 46 months. At the end of the treatment, the tumor showed an enlargement larger than 10% of its volume in 13 of the 23 cases, no change in 4 cases, and regression in 6 cases. At the last examination, 20 cases showed a reduction in tumor volume, and the median ratio, determined as the tumor volume at the last examination divided by that before the treatment, was 0.36. CONCLUSIONS: An increase in tumor volume at the end of the treatment does not indicate the ineffectiveness of carbon ion radiotherapy.

Psychosocial outcomes in long-term survivors of high-grade osteosarcoma: a Japanese single-center experience.

AIM: The psychosocial outcomes in long-term survivors of osteosarcoma were investigated. PATIENTS AND METHODS: A questionnaire concerning the psychosocial status was completed by 30 long-term survivors of osteosarcoma. The family APGAR was employed for the evaluation of family function, social support questionnaire (SSQ) for social support, impact of event scale-revised (IES-R) for posttraumatic stress symptoms (PTSS), and posttraumatic growth inventory (PTGI) for posttraumatic growth (PTG). RESULTS: The family APGAR and SSQ scores were comparable to those of controls. The IES-R score was low, showing a low incidence of PTSS. The PTGI score was high, revealing marked PTG. On multiple regression analysis regarding the IES-R as a dependent variable, the family APGAR was associated with the IES-R. On multiple regression analysis regarding the PTGI as a dependent variable, the age at diagnosis, state of the affected limb and SSQ were associated with the PTGI. CONCLUSION: The incidence of PTSS was low, and PTG was marked in the long-term survivors of osteosarcoma. A high age at onset and amputation of the affected limb were associated with PTG. Support of the family function reduces PTSS, and the strengthening of social support facilitates PTG.

Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J.

BACKGROUND: Osteosarcoma is the most frequent primary malignant bone tumor. In Europe and the United States, its prognosis has been greatly improved by the use of multimodal treatment, including preoperative and postoperative chemotherapy as well as surgery. In Japan, however, only a few clinical studies on osteosarcoma have been carried out. METHODS: To evaluate the efficacy of neoadjuvant chemotherapy on nonmetastatic, operable osteosarcoma arising in the extremities, a prospective multi-institutional phase II trial, the Neoadjuvant Chemotherapy for Osteosarcoma (NECO) study, was conducted. Preoperative chemotherapy included high-dose methotrexate (HD-MTX), cisplatin (CDDP), and adriamycin (ADR). If the induction therapy was assessed as not effective, high-dose ifosfamide (IFO) was added to the chemotherapy regimen. A total of 124 patients were enrolled in this trial, and ultimately 113 patients were eligible. RESULTS: The 5-year overall survival (OAS) and event-free survival (EFS) rates in the NECO study were 77.9% and 65.5%, respectively. A good histological response to the induction chemotherapy resulted in favorable OAS (78.7%). The patients assessed as poor histological responders with progressive disease after the induction chemotherapy exhibited comparable outcomes (OAS 89.5%, EFS 68.2%). There were no significant differences between the OAS and EFS rates of the patients in terms of response to preoperative chemotherapy. CONCLUSIONS: We analyzed the results of the intensive neoadjuvant chemotherapy and the effects of adding IFO on patients with osteosarcoma in Japan. The results suggest efficacy of the high-dose IFO addition to the standard three-drug chemotherapy regimen. However, a randomized clinical study is needed to establish the true impact of IFO on patients with osteosarcoma.

Recently intensified chemotherapy for high-grade osteosarcoma may affect fertility in long-term male survivors.

AIM: To investigate the marital status and fertility in long-term survivors of high-grade osteosarcoma. PATIENTS AND METHODS: We surveyed the marital rate (number of married persons/total number of persons) in 46 long-term survivors of osteosarcoma who were treated in our hospital between 1976 and 2002. In addition, we examined the fertility rate (number of persons having offspring/number of married persons) in 29 married patients. The participants were divided into 2 groups: one group (MC) in which moderate-dose chemotherapy was performed between 1976 and 1986; and another group (IC) in which intensive-dose chemotherapy was performed between 1987 and 2002. In each group, the fertility rate was investigated. As controls, we surveyed the marital and fertility rates in 52 siblings of the patients. RESULTS: In the patients, the marital rate was 63.0% (29/46). There was no significant difference in the marital rate between the patients and their siblings. In the patients, the overall fertility rate was 58.6% (17/29). The fertility rate of male patients in the IC group (16.7%, 1/6) was significantly lower than that of their male siblings (76.5%, 13/17) (p = 0.018). CONCLUSION: These results suggest that recently intensified chemotherapy for osteosarcoma affects fertility in long-term male survivors.

Prognostic impact and immunogenicity of a novel osteosarcoma antigen, papillomavirus binding factor, in patients with osteosarcoma.

To develop peptide-based immunotherapy for osteosarcoma, we previously identified papillomavirus binding factor (PBF) as a cytotoxic T lymphocytes (CTL)-defined osteosarcoma antigen in the context of human leukocyte antigen (HLA)-B55. In the present study, we analyzed the distribution profile of PBF in 83 biopsy specimens of osteosarcomas and also the prognostic impact of PBF expression in 78 patients with osteosarcoma who had completed the standard treatment protocols. Next, we determined the antigenic peptides from PBF that react with peripheral T lymphocytes of HLA-A24(+) patients with osteosarcoma. Immunohistochemical analysis revealed that 92% of biopsy specimens of osteosarcoma expressed PBF. PBF-positive osteosarcoma conferred significantly poorer prognosis than those with negative expression of PBF (P = 0.025). In accordance with the Bioinformatics and Molecular Analysis Section score, we synthesized 10 peptides from the PBF sequence. Subsequent screening with an HLA class I stabilization assay revealed that peptide PBF A24.2 had the highest affinity to HLA-A24. CD8(+) T cells reacting with a PBF A24.2 peptide were detected in eight of nine HLA-A24-positive patients with osteosarcoma at the frequency from 5 x 10(-7) to 7 x 10(-6) using limiting dilution/mixed lymphocyte peptide culture followed by tetramer-based frequency analysis. PBF A24.2 peptide induced CTL lines from an HLA-A24-positive patient, which specifically killed an osteosarcoma cell line that expresses both PBF and HLA-A24. These findings suggested prognostic significance and immunodominancy of PBF in patients with osteosarcoma. PBF is the candidate target for immunotherapy in patients with osteosarcoma.

Evaluation of quality of life (QOL) in long-term survivors of high-grade osteosarcoma: a Japanese single center experience.

BACKGROUND: This study aimed to evaluate the quality of life (QOL) in long-term survivors of high-grade osteosarcoma. PATIENTS AND METHODS: The QOL of 33 long-term survivors of osteosarcoma was evaluated using the Short Form 36 (SF-36) Health Survey Questionnaire. The patients were divided into a limb-sparing group (14 patients) and an amputation group (19 patients), and the QOL was compared between them. In addition, limb function was assessed using the system for functional evaluation of the limb of the American Musculoskeletal Tumor Society (MSTS score), and the relationship between the MSTS score and SF-36 scores was studied. RESULTS: The QOL of all patients was lower than the national standard concerning physical functioning but was higher than the national standards in the other parameters. The QOL of the limb-sparing group was significantly better than that of the amputation group with regard to social functioning. No significant correlation was noted between the MSTS score and the mental component summary. CONCLUSION: The QOL of the long-term survivors of osteosarcoma was satisfactory except for physical functioning. Limb-sparing surgery improved the QOL of long-term survivors of osteosarcoma with regard to social functioning, but no correlation was noted between limb function and mental QOL.

Histological vascular invasion by tumors is a risk factor for distant metastasis in malignant fibrous histiocytoma.

BACKGROUND: The appearance of distant metastasis is a fatal sign in patients with soft tissue sarcoma. Therefore, we studied the risk factors associated with distant metastasis that appear in malignant fibrous histiocytoma. MATERIALS AND METHODS: The study group comprised sixty patients treated for malignant fibrous histiocytoma at our hospital between 1991 and 2002. We retrospectively studied whether age, tumor size, tumor site, developmental form, surgical margin, local recurrence, histological subtype, vascular invasion and histological grade are risk factors associated with the appearance of distant metastasis. RESULTS: A univariate analysis showed that, for those patients older than 70 years of age, insufficient surgical margin, the presence of local recurrence and vascular invasion are significant risk factors associated with the appearance of distant metastasis. A multivariate analysis showed only the presence of vascular invasion to be a significant risk factor as well. CONCLUSION: Histological vascular invasion by tumors is a risk factor associated with distant metastasis that appears in malignant fibrous histiocytoma. Taking early measures for patients with vascular invasion is necessary to improve the prognosis.

Phase I vaccination trial of SYT-SSX junction peptide in patients with disseminated synovial sarcoma.

BACKGROUND: Synovial sarcoma is a high-grade malignant tumor of soft tissue, characterized by the specific chromosomal translocation t(X;18), and its resultant SYT-SSX fusion gene. Despite intensive multimodality therapy, the majority of metastatic or relapsed diseases still remain incurable, thus suggesting a need for new therapeutic options. We previously demonstrated the antigenicity of SYT-SSX gene-derived peptides by in vitro analyses. The present study was designed to evaluate in vivo immunological property of a SYT-SSX junction peptide in selected patients with synovial sarcoma. METHODS: A 9-mer peptide (SYT-SSX B: GYDQIMPKK) spanning the SYT-SSX fusion region was synthesized. Eligible patients were those (i) who have histologically and genetically confirmed, unresectable synovial sarcoma (SYT-SSX1 or SYT-SSX2 positive), (ii) HLA-A*2402 positive, (iii) between 20 and 70 years old, (iv) ECOG performance status between 0 and 3, and (v) who gave informed consent. Vaccinations with SYT-SSX B peptide (0.1 mg or 1.0 mg) were given subcutaneously six times at 14-day intervals. These patients were evaluated for DTH skin test, adverse events, tumor size, tetramer staining, and peptide-specific CTL induction. RESULTS: A total of 16 vaccinations were carried out in six patients. The results were (i) no serious adverse effects or DTH reactions, (ii) suppression of tumor progression in one patient, (iii) increases in the frequency of peptide-specific CTLs in three patients and a decrease in one patient, and (iv) successful induction of peptide-specific CTLs from four patients. CONCLUSIONS: Our findings indicate the safety of the SYT-SSX junction peptide in the use of vaccination and also give support to the property of the peptide to evoke in vivo immunological responses. Modification of both the peptide itself and the related protocol is required to further improve the therapeutic efficacy.

Carbon ion radiotherapy for unresectable sacral chordomas.

PURPOSE: The purpose is to evaluate the efficacy and toxicity of carbon ion radiotherapy for unresectable sacral chordomas. EXPERIMENTAL DESIGN: We performed a retrospective analysis of 30 patients with unresectable sacral chordomas treated with carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba, Japan. Twenty-three patients presented with no prior treatment, and the remaining 7 patients had locally recurrent disease following previous surgical resection. The median clinical target volume was 546 cm(3). The applied carbon ion dose ranged from 52.8 to 73.6 GyE (gray equivalent, median 70.4) in 16 fixed fractions over 4 weeks. RESULTS: At median follow-up of 30 months (range, 9 to 87 months), 26 patients were still alive and 24 patients remained continuously disease-free. Overall and cause-specific survival rates at 5 years were 52 and 94%, respectively. The overall local control rate at 5 years was 96%. Two patients experienced severe skin/soft tissue complications requiring skin grafts. No other treatment-related surgical interventions, including colostomy or urinary diversion, were carried out. All patients have remained ambulatory and able to stay at home after carbon ion radiotherapy. CONCLUSIONS: Carbon ion radiotherapy is effective and safe in the management of patients with unresectable sacral chordomas and offers a promising alternative to surgery.

Multiple primary cancers in patients with osteosarcoma: influence of anticancer drugs and genetic factors.

One hundred thirty-five patients younger than 30 years with osteosarcoma were treated at the Chiba Cancer Center between 1976 and 1999. They included six patients with second cancer after cure of osteosarcoma (group A) and three patients with osteosarcoma as second cancer after cure of childhood cancers (group B). Third cancer occurred in one patient of group A. The clinical features of these nine patients were studied. The diagnoses of second cancer in group A consisted of two acute myelogenous leukemias, two breast carcinomas, one malignant phyllodes tumor of breast, and one ovarian carcinoma. The third cancer was uterine leiomyosarcoma. Second cancer occurred an average of 7.2 years after occurrence of osteosarcoma. The diagnoses of first cancer in group B consisted of one adrenocortical carcinoma, one malignant teratoma of sacrum, and one ovarian carcinoma (yolk sac tumor). Osteosarcoma occurred on average 12.7 years after occurrence of first cancer. Two patients had germ-line p53 gene mutation. Anticancer drugs and genetic factors are presumed to be concerned with occurrence of second cancer. The frequency of multiple primary cancers in patients with osteosarcoma is by no means low. Strict follow-up is thus needed over a long period.

Marriage and fertility in long-term survivors of high grade osteosarcoma.

One hundred fifteen patients with high grade osteosarcoma were treated at our hospital between 1976 and 1995. Of these, 45 patients still surviving and disease free for more than 5 years since the conclusion of treatment were enrolled as the subjects. The marriage proportion (number of married persons/number of all persons) and fertility proportion (number of persons having an offspring/number of married persons) of these 45 patients were investigated. The marriage proportion of male patients was 20.8% (5/24), whereas that of female patients was 76.2% (16/21). The marriage proportion in male patients was dramatically lower than that in female patients (p = 0.0003). The marriage proportion in male patients was significantly lower than that in brothers of the patients (p = 0.0223). In female patients, the treatment of osteosarcoma had no influence on marriage, whereas in male patients it had a great influence on marriage. The fertility proportion in married patients was 76.2% (16/21) and that in siblings of the patients was 81.0% (17/21). A total of 18 offspring were born to married patients. These offspring had no birth defects or congenital anomalies. The chemotherapy used in the treatment of osteosarcoma had little influence on the fertility of patients or the health of their offspring.

Longterm survival after surgical removal of solitary brain metastasis from osteosarcoma.

The prognosis of osteosarcoma with brain metastasis is very poor. We report a 14-year-old girl with osteosarcoma of the right distal femur who is alive and free of disease 6 years after the craniotomy and irradiation for brain metastasis. This longterm survival is attributed to the absence of active pulmonary metastasis at the onset of brain metastasis and the complete removal of the brain metastasis by craniotomy. Patients without active pulmonary metastasis at the onset of brain metastasis may achieve longterm survival. In such patients, it would be worthwhile to perform craniotomy aggressively.