Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of soft tissue tumors 2020 - Secondary publication.

BACKGROUND: These clinical practice guidelines are intended to provide recommendations based on the best evidence obtained to date on key issues in clinical practice to improve the prognosis, diagnostic and therapeutic processes for patients with soft tissue tumors. METHODS: The Guidelines Development Committee and Systematic Review Committee were composed of a multidisciplinary team of specialists who play an important role in soft tissue tumor care. Clinical questions (CQs) were determined by choosing key decision-making points based on Algorithms for the diagnosis and treatment of soft tissue tumors. The guidelines were developed according to the "Medical Information Network Distribution Service (Minds) Handbook for Clinical Practice Guideline Development 2014" and "Minds Manual for Clinical Practice Guideline Development 2017." Recommendation strength was rated on two levels and the strength of evidence was rated on four levels. The recommendations were decided based on agreement by 70% or more voters. RESULTS: Twenty-two CQs were chosen by the Guidelines Development Committee. The Systematic Review Committee reviewed the evidence concerning each CQ, a clinical value judgment was added by experts, and the text of each recommendation was determined. CONCLUSION: We established 22 CQs and recommendations for key decision-making points in the diagnosis and treatment of soft tissue tumors according to the Minds Clinical Practice Guideline development methods. We hope that these guidelines will assist the decision-making of all medical staff engaged in the treatment and diagnosis of soft tissue tumors, and eventually lead to improved soft tissue tumor care in the country.

Prognostic and therapeutic factors influencing the clinical outcome of metastatic Ewing sarcoma family of tumors: A retrospective report from the Japan Ewing Sarcoma Study Group.

BACKGROUND: The prognosis of patients with metastatic Ewing sarcoma family of tumors (ESFT) remains poor. PROCEDURE: We retrospectively analyzed 57 patients diagnosed with metastatic ESFT between 2000 and 2018 to identify prognostic and therapeutic factors affecting the clinical outcome. RESULTS: The 3-year overall survival (OS) rate of the entire cohort was 46.8% (95% confidence interval [CI], 33.0-59.4%). Treatment-related death was not observed. Multivariate analysis identified stem cell transplantation (SCT), response to first-line chemotherapy, and bone metastasis as independent risk factors for OS. Objective response rate to first-line chemotherapy was 65.1% in the 43 evaluable patients. There was no significant difference in the response to different types of first-line chemotherapy. Among patients with lung metastasis alone, the 3-year OS rate was higher in 13 patients who received local treatment than in four who did not, although the difference was not significant. CONCLUSIONS: One possible reason for the high OS rates was the absence of treatment-related mortality even in patients receiving SCT, which could be attributed to advances in the management of post-SCT complications. Novel first-line chemotherapy strategies need to be established to improve the disease status prior to SCT in a higher proportion of patients.

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

Multimodal treatment including standard chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for the Ewing sarcoma family of tumors in Japan: Results of the Japan Ewing Sarcoma Study 04.

BACKGROUND: The survival rate in patients with Ewing sarcoma family of tumors (ESFT) in Japan was reported to be < 50% in the 1990s. The Japan Ewing Sarcoma Study Group was established to improve the prognosis of ESFT in Japan. The aim of this phase II trial was to determine the efficacy and safety of multimodal treatment for nonmetastatic ESFT. PROCEDURE: Patients with ESFT aged < 30 years were eligible for participation. The chemotherapy regimen consisted of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) repeating every 21 days for 52 weeks. Local treatment included surgery and/or radiation therapy (0-55.8 Gy) based on the margin of resection and histologic response. The primary endpoint was progression-free survival (PFS) at three years. The study was designed to test whether the lower limit of the 90% confidence interval for PFS would exceed the threshold of 60%. The planned sample size was 53 patients, allowing for 10% of patients being ineligible. RESULTS: Of the 53 patients screened for entry, seven were deemed ineligible. Forty-six patients were considered as the per-protocol set and were used for the efficacy analysis. Three-year PFS was 71.7% (0.59-0.81). Estimated five-year PFS and overall survival were both 69.6%. Although no previously unknown adverse event was reported, three patients developed secondary malignancies (acute lymphoblastic leukemia, myelodysplastic syndrome, and osteosarcoma, one patient each). CONCLUSIONS: Multimodal treatment with standard VDC-IE chemotherapy improved the prognosis for patients with ESFT in Japan, although statistical confirmation of efficacy compared to historical control was not achieved.

Outcomes analysis of pre-brachytherapy MRI in patients with locally advanced cervical cancer.

INTRODUCTION: Various brachytherapy options are available for treating cervical cancer. This study investigated whether pre-brachytherapy magnetic resonance imaging (MRI) findings could help identify the appropriate brachytherapy technique for cervical cancer. METHODS: We retrospectively evaluated patients with cervical cancer who underwent pre-brachytherapy MRI within 7 days before their first high-dose rate brachytherapy treatment between December 2009 and September 2015. Patients who could not undergo MRI at pre-treatment and/or pre-brachytherapy and complete radical radiotherapy were excluded. Conventional intracavitary brachytherapy was the preferred treatment for ≤4 cm and symmetrical tumors. Non-conventional intracavitary brachytherapy, including interstitial brachytherapy, was the preferred treatment for bulky tumors, asymmetrical tumors, tumors with severe vaginal invasion, or bulky barrel-shaped tumors. The 3-year rates of overall survival, disease-free survival, and local control were compared using the Kaplan-Meier method and the log-rank test. Overall survival and local control rates were assessed using Cox regression analysis to identify risk factors for poor overall survival and local control outcomes. RESULTS: A total of 146 patients were included in the study. The median tumor sizes were 52 mm (range 17-85) at the pre-treatment MRI and 30 mm (range 0-78) at the pre-brachytherapy MRI. Six patients had International Federation of Gynecology and Obstetrics (FIGO) stage IB2, 67 patients had stage II, 64 patients had stage III, and nine patients had stage IVA disease. A total of 124 (85%) patients had squamous cell carcinoma and 22 (15%) patients had adenosquamous cell carcinoma or adenocarcinoma. The MRI findings showed severe vaginal invasion (pre-treatment: 19 patients, pre-brachytherapy: 10 patients), asymmetrical bulky tumors (pre-treatment: 28 patients, pre-brachytherapy: 16 patients), and severe corpus invasion (pre-treatment: 39 patients, pre-brachytherapy: 18 patients). Based on the pre-brachytherapy MRI findings, non-conventional intracavitary brachytherapy was administered to 34 (23.3%) patients. Brachytherapy seemed to be appropriate for 133 (91.1%) patients and inappropriate for 13 (8.9%) patients. The 3-year rates were 84.2% for overall survival and 90.1% for local control. Grade 3 late rectal complications occurred in two (1%) patients. Multivariate analysis showed that tumor characteristics (size, shape, and extent of invasion) were not risk factors, although inappropriate brachytherapy was significantly related to poor local control (p<0.001). CONCLUSION: Pre-brachytherapy MRI may help to select appropriate brachytherapy for cervical cancer and reduce the likelihood of inappropriate brachytherapy leading to poor local control.

A multicenter randomized phase III study for newly diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by chemoradiotherapy with temozolomide with chemoradiotherapy alone; Japan Clinical Oncology Group Study JCOG1703 (MACS study).

A randomized phase III trial in Japan commenced in June 2019. The present standard treatment for newly diagnosed glioblastoma is maximal resection followed by chemoradiotherapy with temozolomide. The purpose of this study is to confirm the superiority of maximal resection with carmustine wafer implantation followed by chemoradiotherapy with temozolomide over the standard maximal resection followed by chemoradiotherapy with temozolomide in terms of overall survival for newly diagnosed glioblastoma. A total of 250 patients will be accrued from 35 Japanese institutions in 5.5 years. Patients with >90% surgical resection will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, loco-regional progression-free survival and incidence of adverse events. This trial has been registered in the Japan Registry of Clinical Trial, as jRCT1031190035 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031190035].

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonß plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma.

PURPOSE: This study explored the superiority of temozolomide (TMZ) + interferonß (IFNß) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design. EXPERIMENTAL DESIGN: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m2, daily) followed by TMZ maintenance (100-200 mg/m2/day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNß + RT arm intravenously received IFNß (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8). RESULTS: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNß + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNß + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%. CONCLUSIONS: TMZ + IFNß + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

A Clinical Evaluation of American Brachytherapy Society Consensus Guideline for Bulky Vaginal Mass in Gynecological Cancer.

OBJECTIVES: American Brachytherapy Society (ABS)-recommended interstitial brachytherapy (IBT) should be considered for bulky vaginal tumor thicker than 5 mm. The aim of this study was to evaluate the ABS consensus guideline for patients with severe vaginal invasion based on our long-term follow-up results. METHODS/MATERIALS: The study included 7 patients with vaginal cancer and 14 patients with cervical cancer invading to the lower vagina. Based on prebrachytherapy magnetic resonance imaging findings, patients received intracavitary brachytherapy (ICT) for vaginal tumors 5 mm or less or IBT for vaginal tumors less than 5 mm. Nine patients received ICT and the remaining 12 patients received IBT. For dosimetric comparison, an experimental recalculation as the virtual IBT for patients actually treated by ICT, and vice versa, was performed. RESULTS: The 5-year local control rate for all tumors was 89.4%. No differences in local control between ICT- and IBT-treated groups were observed (P = 0.21). One patient experienced a grade 3 rectal complication. There were no significant differences in the CTV D90 and rectum D2cc between the 2 groups (P = 0.13 and 0.39, respectively). In the dosimetric study of ICT-treated patients, neither the actual ICT plans nor the experimental IBT plans exceeded the limited dose for organs at risk, which were recommended in the guideline published from the ABS. In the IBT-treated patients, D2cc for bladder and rectum of the experimental ICT plans was significantly higher than for the actual IBT plans (P < 0.001 and <0.001, respectively), and 11 experimental ICT plans (92%) exceeded the limited dose for bladder and/or rectum D2cc. CONCLUSIONS: Tumor control and toxicity after selected brachytherapy according to vaginal tumor thickness were satisfactory; IBT instead of ICT is recommended for patients with vaginal tumor thickness greater than 5 mm to maintain bladder and/or rectum D2cc.

Present clinical practices of stereotactic irradiation for metastatic brain tumors in Japan: results of questionnaire survey of the Japanese Radiation Oncology Study Group (JROSG) working subgroup for neurological tumors.

BACKGROUND: To determine the current practice of stereotactic irradiation (STI) for brain metastases in Japan by a questionnaire survey. METHODS: A questionnaire was distributed to 313 institutions performing STI with one of the following machines: Gamma Knife (GK), CyberKnife (CK), Novalis (Nov), or other linear accelerator (LINAC)-based systems (OLS). The participation was voluntary. RESULTS: There were 163 responding institutions. The total number of STI treatments between April 2013 and March 2014 was 10,684. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) were performed in 8624 (80.7%) and 2060 (19.3%) cases, respectively. Whole-brain radiation therapy (WBRT) was performed for a total of 3515 cases. For a case model of a 1.5-cm solitary brain metastasis in a non-eloquent area, the most common GTV-PTV margin was 2 mm (22 of 114 institutions), and an institutional standard fraction was 1 (75 of 114 institutions). The doses for the model case also varied from 13.0 to 26.0 Gy (Median 20 Gy) when converted to SRS (α/ß = 10). A prescription point was at the PTV margin the most. The median dose constraints which were converted to SRS (α/ß = 3) to organs at risk were 12.2, 12.7, and 13.7 Gy for optic nerves, cavernous sinus, and brainstem, respectively. CONCLUSIONS: STI for brain metastases in current practice varied significantly among institutions. These different strategies relied mostly on the type of treatment machine used. It is thus necessary to establish a common guideline to express dose prescriptions and plan qualities for different STI machines.

Feasibility study of chemoradiotherapy followed by amrubicin and cisplatin for limited-disease small cell lung cancer.

To evaluate the feasibility of amrubicin plus cisplatin (AP) following chemoradiotherapy for limited-disease small-cell lung cancer, chemo-naïve patients aged 20-70 years with a performance status of 0 or 1 and normal organ functions were treated with etoposide 100 mg/m2 on days 1-3, cisplatin 80 mg/m(2) on day 1 and concurrent thoracic radiotherapy at 45 Gy/30 fractions (EP-TRT), followed by three cycles of amrubicin 40 mg/m2 on days 1-3 and cisplatin 60 mg/m2 on day 1 every 3 weeks. The EP-TRT could be completed in 21 patients (15 male and 6 female patients with a median age of 62 years). Of these, 2, 1 and 18 (86%) patients received one, two and three cycles of AP, respectively. Sixteen (76%) patients required granulocyte-colony stimulating factor (G-CSF) support. Grade 3/4 neutropenia occurred in all patients. Grade 3 febrile neutropenia was observed in 9 patients, lasting for 1 day in 5 patients. The incidences of grade 3/4 thrombocytopenia and anemia were 43 and 24%, respectively. Grade 3 infection and anorexia occurred in 2 and 3 patients, respectively. The response rate was 95%. The median (95% confidence interval [CI]) progression-free survival (PFS) was 41.9 (0-102) months, and the 5-year PFS rate (CI) was 41.9% (20.4-63.4%). The median overall survival (OS) has not been reached yet, and the 5-year OS rate (CI) was 57.8% (35.2-80.4%). In conclusion, EP-TRT followed by AP therapy was well-tolerated, although a large number of patients required G-CSF support.

After low and high dose-rate interstitial brachytherapy followed by IMRT radiotherapy for intermediate and high risk prostate cancer.

BACKGROUND: The study aimed to compare urinary symptoms in patients with clinically localized prostate cancer after a combination of either low-dose-rate or high-dose-rate interstitial brachytherapy along with intensity-modulated radiation therapy (LDR-ISBT + IMRT or HDR-ISBT + IMRT). METHODS: From June 2009 to April 2014, 16 and 22 patients were treated with LDR-ISBT + IMRT and HDR-ISBT + IMRT, respectively. No patient from these groups was excluded from this study. The prescribed dose of LDR-ISBT, HDR-ISBT, and IMRT was 115 Gy, 20 Gy in 2 fractions, and 46 Gy in 23 fractions, respectively. Obstructive and irritative urinary symptoms were assessed by the International Prostate Symptom Score (IPSS) examined before and after treatments. After ISBT, IPSS was evaluated in the 1st and 4th weeks, then every 2-3 months for the 1st year, and every 6 months thereafter. RESULTS: The median follow-up of the patients treated with LDR-ISBT + IMRT and HDR-ISBT + IMRT was 1070.5 days and 1048.5 days, respectively (p = 0.321). The IPSS-increment in the LDR-ISBT + IMRT group was greater than that in the HDR-ISBT + IMRT between 91 and 180 days after ISBT (p = 0.015). In the LDR-ISBT + IMRT group, the IPSS took longer time to return to the initial level than in the HDR-ISBT + IMRT group (in LDR-ISBT + IMRT group, the recovery time was 90 days later). The dose to urethra showed a statistically significant association with the IPSS-increment in the irritative urinary symptoms (p = 0.011). Clinical outcomes were comparable between both the groups. CONCLUSIONS: Both therapeutic modalities are safe and well suited for patients with clinically localized prostate cancer; however, it took patients longer to recover from LDR-ISBT + IMRT than from HDR-ISBT + IMRT. It is possible that fast dose delivery induced early symptoms and early recovery, while gradual dose delivery induced late symptoms and late recovery. Urethral dose reductions were associated with small increments in IPSS.

[Radiation Therapy for Management of Soft Tissue Sarcomas].

Soft tissue sarcomas (STS) are rare malignancies. STS represent a heterogeneous group of tumors, with many of them posing a high risk of local recurrence and distant metastasis. The major therapeutic goals of treating STS are to maximize local tumor control using minimal surgery and to improve survival. The ability of radiation therapy (RT) to improve local control has made it a cornerstone in the multimodality treatment of STS. Koshy reported survival benefit of RT in patients undergoing limbsparing surgery for soft tissue sarcomas of the extremities. A retrospective study from the Surveillance, Epidemiology, and End Results (SEER) database that included data from 6,960 patients. They reports that radiation was associated with improved survival in patients with high-grade tumors. The randomized study of preoperative versus postoperative radiation therapy conducted by the National Cancer Institute of Canada (NCIC). The radiation therapy techniques consisted of 50 Gy in the preoperative setting and 66 Gy given postoperatively. Patients treated with postoperative radiation therapy tended to have greater fibrosis. Fibrosis, joint stiffness and edema adversely affect patient function. Haas reported the proposed consensus guidelines on target volume delineation with RT for STS in 2012. Particle therapy, intensity-modulated RT (IMRT) and image-guided RT (IGRT) offers the opportunity to reduce the normal tissue morbidity of RT while maintaining local tumor control. In conclusion, the precision with which the radiation dose is distributed with advanced RT has a beneficial effect in sparing normal tissue with improved local control over that achieved with conventional RT.

Impact of KRAS mutation on response and outcome of patients with stage III non-squamous non-small cell lung cancer.

The frequency and clinical profile of patients with stage III non-small cell lung cancer harboring KRAS mutations have not yet been well documented. Here, we analyzed hotspot KRAS mutations using high-resolution melting analyses in tumor specimens from patients who received chemoradiotherapy between January 2001 and December 2010 at the National Cancer Center Hospital. The associations between the presence of KRAS mutations and the response rate, relapse-free survival, first relapse sites, survival post-progression and overall survival were investigated. A total of 274 non-squamous non-small cell lung cancer patients received chemoradiotherapy at our hospital. After excluding 121 patients for whom tumor specimens were not available and 34 patients with EGFR mutations, the remaining 119 patients were included in the analysis. KRAS mutations were found at a frequency of 13%. Patients with KRAS mutations had a shorter median relapse-free survival (6.1 vs 10.9 months) and a lower response rate (63% vs 81%). As for the first relapse site, patients with KRAS mutations had fewer local relapses (8% vs 23%) and more brain metastases (46% vs 12%). After disease progression, patients with KRAS mutations had a significantly shorter median survival post-progression (2.5 vs 7.3 months, P = 0.028) and median overall survival (15.1 vs 29.1 months, P = 0.022). Our results suggested that KRAS mutation could be associated with a reduced efficacy of chemoradiotherapy and a shortened survival time.

CT based three dimensional dose-volume evaluations for high-dose rate intracavitary brachytherapy for cervical cancer.

BACKGROUND: In this study, high risk clinical target volumes (HR-CTVs) according to GEC-ESTRO guideline were contoured retrospectively based on CT images taken at the time of high-dose rate intracavitary brachytherapy (HDR-ICBT) and correlation between clinical outcome and dose of HR-CTV were analyzed. METHODS: Our study population consists of 51 patients with cervical cancer (Stages IB-IVA) treated with 50 Gy external beam radiotherapy (EBRT) using central shield combined with 2-5 times of 6 Gy HDR-ICBT with or without weekly cisplatin. Dose calculation was based on Manchester system and prescribed dose of 6 Gy were delivered for point A. CT images taken at the time of each HDR-ICBT were reviewed and HR-CTVs were contoured. Doses were converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model (α/ß = 10 Gy). RESULTS: Three-year overall survival, Progression-free survival, and local control rate was 82.4%, 85.3% and 91.7%, respectively. Median cumulative dose of HR-CTV D90 was 65.0 Gy (52.7-101.7 Gy). Median length from tandem to the most lateral edge of HR-CTV at the first ICBT was 29.2 mm (range, 18.0-51.9 mm). On univariate analysis, both LCR and PFS was significantly favorable in those patients D90 for HR-CTV was 60 Gy or greater (p = 0.001 and 0.03, respectively). PFS was significantly favorable in those patients maximum length from tandem to edge of HR-CTV at first ICBT was shorter than 3.5 cm (p = 0.042). CONCLUSION: Volume-dose showed a relationship to the clinical outcome in CT based brachytherapy for cervical carcinoma.

Risk factors for early death after surgery in patients with brain metastases: reevaluation of the indications for and role of surgery.

Surgical resection remains an important option for the treatment of brain metastases despite recent advancements in radiotherapy and systemic therapy. When selecting surgical candidates, it is important to exclude terminal cases who will receive neither a survival benefit nor an improvement in their quality of life. We reviewed a total of 264 surgical cases of brain metastases and analyzed the clinical characteristics of early death in order to clarify the indication for and the role of surgery. The median survival time (MST) after surgery in all cases was 12.4 months. Early death was defined as death within 6 months, and 23% (62 cases) of this series were succumbed to this. A decrease in postoperative Karnofsky performance status (KPS) (<70) (P = 0.041), lack of systemic therapy after surgery (P < 0.0001), and uncontrolled extracranial malignancies (P = 0.0022) were significantly related to early death in multivariate analysis, while preoperative KPS (<70) and recursive partitioning analysis (RPA) class were related to early death only in univariate analysis (P < 0.05). When analyzing patients with uncontrolled extracranial malignancies and those with a postoperative KPS score of 70 or greater (who were generally candidates for systemic therapy), the MST was significantly longer in the systemic therapy (+) group compared with the systemic therapy (-) group (12.5 vs. 5.6 months; P = 0.0026). Our data indicate that the postoperative RPA class and treatment strategy were associated with early death. Deterioration of patients by surgery should be avoided in the treatment of brain metastases.

Japanese structure survey of high-precision radiotherapy in 2012 based on institutional questionnaire about the patterns of care.

OBJECTIVE: The purpose of this study was to clarify operational situations, treatment planning and processes, quality assurance and quality control with relevance to stereotactic radiotherapy, intensity-modulated radiotherapy and image-guided radiotherapy in Japan. METHODS: We adopted 109 items as the quality indicators of high-precision radiotherapy to prepare a questionnaire. In April 2012, we started to publicly open the questionnaire on the website, requesting every institution with radiotherapy machines for response. The response ratio was 62.1% (490 out of 789 institutions responded). RESULTS: Two or more radiotherapy technologists per linear accelerator managed linear accelerator operation in ∼90% of the responded institutions while medical physicists/radiotherapy quality managers were engaged in the operation in only 64.9% of the institutions. Radiotherapy certified nurses also worked in only 18.4% of the institutions. The ratios of the institutions equipped for stereotactic radiotherapy of lung tumor, intensity-modulated radiotherapy and image-guided radiotherapy were 43.3, 32.6 and 46.8%, respectively. In intensity-modulated radiotherapy planning, radiation oncologists were usually responsible for delineation while medical physicists/radiotherapy quality managers or radiotherapy technologists set up beam in 33.3% of the institutions. The median time required for quality assurance of intensity-modulated radiotherapy at any site of brain, head and neck and prostate was 4 h. Intensity-modulated radiotherapy quality assurance activity had to be started after clinical hours in >60% of the institutions. CONCLUSIONS: This study clarified one major issue in the current high-precision radiotherapy in Japan. A manpower shortage should be corrected for high-precision radiotherapy, especially in the area relevant to quality assurance/quality control.

Secondary osteosarcoma developing 10 years after chemoradiotherapy for non-small-cell lung cancer.

A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor.

Primary CNS lymphoma treated with radiotherapy in Japan: a survey of patients treated in 2005-2009 and a comparison with those treated in 1985-2004.

BACKGROUND: The aim of our study was to analyze changes over time in the characteristics, treatment, and outcome of patients with primary central nervous system lymphoma (PCNSL). METHODS: Data on 315 patients with histologically proven PCNSL undergoing radiotherapy between 2005 and 2009 were collected from 20 Japanese institutions using a questionnaire. These data were then compared with data on 273 patients treated during the period 1995-2004 and those on 466 patients treated during the period 1985-1994. RESULTS: In terms of patient and tumor characteristics, we found a significant increase in mean patient age in the 2005-2009 period compared to the 1985-2004 period (63 vs. 58-59 years, respectively) and in the percentage of patients with better performance status (PS) during the 2005-2009 period compared with the 1995-2004 period (World Health Organization PS 0-2: 73 vs. 65 %, respectively). Regarding treatment, relative to the 1995-2004 period, significant changes in the 2005-2009 period were (1) decreased rate of attempting tumor resection (23 vs. 44 %); (2) increased use of chemotherapy (78 vs. 68 %), and (3) increased use of methotrexate (MTX)-containing regimens (84 vs. 53 %). The 5-year overall survival rates were 15.3, 30.1, and 36.5 % for patients seen during the 1985-1994, 1995-2004, and 2005-2009 periods, respectively, but relapse-free survival did not improve between the 1995-2004 and 2005-2009 periods (26.7 vs. 25.7 % at 5 years, respectively). Patients receiving MTX-containing chemotherapy had 5-year survival rates of 19, 50, and 44 % during these three periods, respectively. CONCLUSIONS: Although patient backgrounds differed among the study periods, recent trends were a high patient age, better PS, avoidance of extensive tumor resection, more frequent use of chemotherapy, and improved survival. The recent improvement in survival may be due to improvements in second-line treatment and supportive care.

Long-term results of concurrent chemoradiotherapy using cisplatin and vinorelbine for stage III non-small-cell lung cancer.

Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). The long-term feasibility and efficacy of vinorelbine and cisplatin with concurrent thoracic radiotherapy were investigated. Eighteen patients received cisplatin (80 mg/m(2)) on day 1 and vinorelbine (20 mg/m(2) in level 1, and 25 mg/m(2) in level 2) on days 1 and 8 every 4 weeks for four cycles in a phase I trial. Ninety-three patients received the same chemotherapy regimen except for the fixed vinorelbine (20 mg/m(2)) dosage and consolidation therapy with docetaxel (60 mg/m(2), every 3 weeks). The thoracic radiotherapy consisted of a single dose of 2 Gy once daily to a total dose of 60 Gy. A total of 111 patients were analyzed in the present study: male/female, 91/20; median age, 60 years; stage IIIA/IIIB, 50/61; and squamous/non-squamous histology, 26/85. The 3-, 5-, and 7-year overall survival rates (95% CI) were 43.2% (33.9-52.2), 25.2% (17.6-33.5), and 23.2% (15.8-31.4), respectively. The median progression-free survival and median survival time (95% CI) were 13.5 (10.1-16.7) months and 30.0 (24.3-38.8) months, respectively. Four patients (4%) experienced Grade 5 pulmonary toxicities from 4.4 to 9.4 months after the start of treatment. In conclusion, approximately 15% of patients with unresectable stage III NSCLC could be cured with chemoradiotherapy without severe late toxicities after 10 months of follow-up. Although based on the data from highly selected population participated in phase I and phase II trial, this analysis would strengthen and confirm the previous reports concerning concurrent chemoradiotherapy with third generation cytotoxic agents.

Increased risk of gastric adenocarcinoma after treatment of primary gastric diffuse large B-cell lymphoma.

BACKGROUND: There have been sporadic reports about synchronous as well as metachronous gastric adenocarcinoma and primary gastric lymphoma. Many reports have dealt with metachronous gastric adenocarcinoma in mucosa-associated lymphoid tissue lymphoma of stomach. But to our knowledge, there have been no reports that document the increased incidence of metachronous gastric adenocarcinoma in patients with gastric diffuse large B-cell lymphoma. This retrospective study was conducted to estimate the incidence of metachronous gastric adenocarcinoma after primary gastric lymphoma treatment, especially in diffuse large B-cell lymphoma. METHODS: The retrospective cohort study of 139 primary gastric lymphoma patients treated with radiotherapy at our hospital. Mean observation period was 61.5 months (range: 3.7-124.6 months). Patients profile, characteristics of primary gastric lymphoma and metachronous gastric adenocarcinoma were retrieved from medical records. The risk of metachronous gastric adenocarcinoma was compared with the risk of gastric adenocarcinoma in Japanese population. RESULTS: There were 10 (7.2%) metachronous gastric adenocarcinoma patients after treatment of primary gastric lymphomas. It was quite high risk compared with the risk of gastric carcinoma in Japanese population of 54.7/100,000. Seven patients of 10 were diffuse large B-cell lymphoma and other 3 patients were mixed type of diffuse large B-cell lymphoma and mucosa associated lymphoid tissue lymphoma. Four patients of 10 metachronous gastric adenocarcinomas were signet-ring cell carcinoma and two patients died of gastric adenocarcinoma. Metachronous gastric adenocarcinoma may have a more malignant potential than sporadic gastric adenocarcinoma. Old age, Helicobacter pylori infection and gastric mucosal change of chronic gastritis and intestinal metaplasia were possible risk factors for metachronous gastric adenocarcinoma. CONCLUSION: There was an increased risk of gastric adenocarcinoma after treatment of primary gastric lymphoma, especially of diffuse large B-cell lymphoma.