Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors.

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.     

High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors

BACKGROUND: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies. METHODS: To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed. RESULTS: The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria). CONCLUSIONS: HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy.     

Preradiation chemotherapy for newly diagnosed childhood brain tumors. A modified Phase II trial

A poor-risk population of children with primary malignant central nervous system (CNS) tumors, other than gliomas, can be identified by their young age, by the presence of disease dissemination at diagnosis, and possibly by subtotal resection of the primary tumor. These children require at least neuraxis radiation therapy and possibly chemotherapy for disease control. Unfortunately, once neuraxis radiation is administered, tolerance of subsequent chemotherapy is limited. The authors have explored a multimodal treatment approach in 14 poor-risk patients initially consisting of a modified Phase II chemotherapy trial followed by neuraxis radiation. The diagnoses were medulloblastoma (5), pineoblastoma (3), cerebral primitive neuroectodermal tumor (3), germinoma (2), and choroid plexus carcinoma (1). Eleven patients had disseminated CNS disease, and two had bone marrow involvement at diagnosis. Nine patients received 2 courses of intravenous cyclophosphamide (80 mg/kg) alone over 8 weeks, and five others received three daily doses of intrathecal Ara-C (50 mg/m2) and oral hydroxyurea (40 mg/kg) with each course of cyclophosphamide. There were four complete responses (two dysgerminomas, one pineoblastoma, and one primitive neuroectodermal tumor), one partial response (medulloblastoma), and three mixed responses (two medulloblastomas, one pineoblastoma) to chemotherapy alone, for a response rate of 57%. Twelve patients subsequently tolerated the planned dose of neuraxis radiation. The median survival of all patients was 11 months, and seven of eight deaths were related to recurrent disease. The hematologic toxicity was appreciable, and one death resulted from gram-negative septicemia. Through the use of this type of Phase II trial, valuable information can be obtained on the response rates to specific chemotherapy agents administered prior to radiation. Although cyclophosphamide alone was an active agent in this context, these treatment regimens did not have an important affect on survival.     

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.     

Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas

BACKGROUND: The role of high dose chemotherapy (HDC) in patients with pediatric brain tumors currently is ill-defined. The purpose of this pilot study was to assess the feasibility and the benefit of HDC after radiotherapy in a group of children with newly diagnosed diffuse pontine gliomas. METHODS: Patients eligible for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons, who were not treated previously with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, provided clinical findings and magnetic resonance imaging were typical. Patients were given focal radiotherapy followed 2-3 months later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300 mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow transplantation. Survival was the endpoint, and the statistical procedure was based on sequential subgroup analysis. RESULTS: Thirty-six patients were entered on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the time of diagnosis. One patient eventually was excluded due to inappropriate eligibility criteria. All 35 eligible patients received irradiation. Early progression (9 patients) and parental refusal (2 patients) precluded the use of HDC in 11 patients. Three patients died of HDC-related complications. All 21 patients who survived HDC eventually died of disease progression. The median survival time was 10 months for the study group. The median survival time in the subgroup of patients who received HDC was 10 months (range, 3-26 months). Statistical analysis did not suggest any evidence of survival benefit. CONCLUSIONS: For patients with diffuse pontine gliomas, survival using this aggressive treatment modality does not appear to be any better than that reported for conventional radiotherapy.     

Impact of consolidation radiotherapy in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow rescue.

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994,425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT-). The assignment of RT was not randomized. The RT+ and RT- groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT- patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT-groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT- groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.     

High-dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system

BACKGROUND: Embryonal central nervous system (CNS) tumors (medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors) are rare in adults. Recurrent disease has an extremely poor outcome. The use of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has demonstrated promising results in children with recurrent disease, but there are only limited data regarding its role in adults. The purpose of the current study was to evaluate adult patients with embryonal CNS tumors who were treated with HDC with ASCT and compare their outcomes with those of patients who received conventional-dose chemotherapy. METHODS: The authors reviewed the medical records of 23 adult patients (age >or= 18 years) who were treated at the Mayo Clinic for recurrent embryonal CNS tumors between 1976 and 2004. The authors compared treatment with HDC with ASCT (10 patients) with an historic control of patients treated with conventional-dose chemotherapy (nitrosourea based, cisplatin based, or both) (13 patients). RESULTS: HDC with ASCT was associated with increased survival (P= .044) and a longer time to disease progression (TTP) (P= .028). The conventional-dose chemotherapy group had a median TTP of 0.58 years and a median survival of 2.00 years. The HDC with ASCT group had a median TTP of 1.25 years and a median survival of 3.47 years. When restricted to patients receiving ASCT after first disease recurrence, the median TTP was 2.5 years and the median survival was 4.16 years. Toxicities were similar in both groups. CONCLUSIONS: Improvements in the median TTP and survival noted with the administration of HDC with ASCT, as well as the acceptable toxicity of this regimen, supports consideration of its use in adults with recurrent embryonal CNS tumors.     

Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours

We reviewed the European Group for Blood and Marrow Transplantation (EBMT) experience with salvage high-dose chemotherapy (HDC) in paediatric patients with extragonadal germ-cell tumour (GCT). A total of 23 children with extragonadal GCT, median age 12 years (range 1-20), were treated with salvage HDC with haematopoietic progenitor cell support. The GCT primary location was intracranial site in nine cases, sacrococcyx in eight, retroperitoneum in four, and mediastinum in two. In all, 22 patients had a nongerminomatous GCT and one germinoma. Nine patients received HDC in first- and 14 in second- or third-relapse situation. No toxic deaths occurred. Overall, 16 of 23 patients (70%) achieved a complete remission. With a median follow-up of 66 months (range 31-173 months), 10 (43%) are continuously disease-free. Of six patients who had a disease recurrence after HDC, one achieved a disease-free status with surgical resection followed by chemotherapy and radiotherapy. In total, 11 patients (48%) are currently disease-free. Eight of 14 patients (57%) with extracranial primary and three of nine patients (33%) with intracranial primary GCT are currently disease-free. HDC induced impressive long-term remissions as salvage treatment in children with extragonadal extracranial GCTs. Salvage HDC should be investigated in prospective trials in these patients.     

High-dose carboplatin,thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma

Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0–M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m²/day) on days −8 to −6, and thiotepa (300 mg/m²/day) and etoposide (250 mg/m²/day) on days −5 to −3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6–44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3–58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2–201.6 months). The Kaplan–Meier estimate of median overall survival is 26.8 months (95% CI: 11.9–51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%–41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome.     

Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease.

The purpose of this study was to assess the efficacy of high-dose chemotherapy (HDC) with autologous stem cell transplant in stage IV breast cancer patients with minimal metastases. Eligible patients had (a) disease that could be resected en bloc and/or irradiated with curative intent using a single field and could, thus, be rendered as having no evidence of disease (NED); and/or (b) <5% bone marrow involvement. From September 1991 to August 1997, 40 consecutive patients were prospectively entered on the study. Pre-HDC local treatment consisted of surgery (n = 31) and radiotherapy (XRT; n = 3). All patients received HDC with cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea and autologous stem cell transplant, with or without CD34 selection. Following HDC, 22 patients received XRT. Four patients died of treatment-related complications. Eighteen patients developed grade 3 nonhematological toxicities (15 lung, 2 cardiomyopathy, and 1 optic neuritis), which resolved with therapy. Within a median follow-up of 49 (15-91) months, 14 patients had relapsed. Twenty-five patients (62.5%) were alive, and 22 patients (55%) were alive and free of disease. Median event-free and overall survivals were 43 and 77 months, respectively. In the subset of patients with one metastatic site, 17 of 24 (68%) remained relapse free. Grade 2 tumors, a single metastatic site, and delivery of XRT were favorable predictors of relapse-free survival in univariate but not multivariate analyses. Inclusion of HDC, as described, in the multimodal treatment of stage IV breast cancer patients with minimal metastases is promising. These results warrant prospective randomized trials with a HDC-containing arm in this patient population.     

Use of liposomal doxorubicin–cyclophosphamide combination in breast cancer patients with brain metastases: a monocentric retrospective study

Brain metastases (BM) can affect up to 45 % of a high-risk breast cancer (BC) population. Liposomal doxorubicin (LD)-based chemotherapy has demonstrated efficacy in the treatment of BC and LD crosses the blood–brain barrier. The aim of this retrospective study is to evaluate the efficacy of the LD–cyclophosphamide (CTX) combination in BM related to BC. Patients diagnosed with BM related to BC and treated with the LD–CTX combination were eligible. BM objective response rate (BM-ORR), BM disease control rate (BM-DCR), BM progression-free survival, overall survival (OS) and safety were analyzed. 29 patients were eligible. The median time from metastatic diagnosis to brain involvement was 12 months. BM was more frequently observed in HER2+ patients. On average, three courses of chemotherapy were administered without grade 3–4 limiting adverse events. After three cycles, BM-ORR and BM-DCR were 41.4 and 58.6 % respectively versus 50 and 62.5 % when no prior radiotherapy was administered. From BM diagnosis, OS was 23 months. A high BM-ORR is observed with the LD–CTX combination in patients with BM related to BC. This is an attractive therapeutic option for these patients, especially when no prior whole brain radiotherapy has been administered.     

Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma

Summary Purpose We performed a retrospective study of patients with diffuse pontine glioma (DPG) who suffered neuraxis metastasis (NM) and characterized the incidence, clinical features, radiologic findings, and patterns of disease dissemination. Methods Magnetic resonance imaging (MRI) of brain and spine was used to assess NM. Some patients also underwent magnetic resonance spectroscopy (MRS) (6 patients) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans (13 patients) to further evaluate areas of metastatic disease. Three patients had histologic confirmation of disease at the site of NM. Results Between 1986 and 2003, 18 of 96 patients (17.3%) with DPG developed NM. The median age at diagnosis was 8 years (range, 4–17). All patients had adjuvant chemotherapy and/or focal radiotherapy at diagnosis. The NM occurred at a median of 15 months from diagnosis of DPG (range, 3–96). Three patterns of NM were seen on MRI of brain and spine in these patients; 8 (39%) had parenchymal (PM), 4 (22%) leptomeningeal (PM), 2 (11%) subependymal, and in 5 a combination of two or more patterns. The MRS and FDG-PET scan of suspected areas of metastatic disease was consistent with tumor in 6 of 6 and 12 of 13 patients who underwent these procedures respectively. Three patients also had histologic confirmation of malignant glioma at the site of NM. Despite salvage therapy, all 18 patients have died of disease at a median of 5 months (range, 0.5–20) from diagnosis of neuraxis spread. Conclusion Our study emphasizes the need for screening patients with DPG for NM at the time of recurrence. ^★Presented in part at the International Society of Pediatric Neuro-Oncology Meeting held in Boston, MA June 13–16, 2004.     

Patterns of failure in relation to radiotherapy fields in supratentorial primitive neuroectodermal tumor

PURPOSE: Supratentorial primitive neuroectodermal tumor (PNET) accounts for 2-3% of all pediatric brain tumors. We retrospectively reviewed all supratentorial PNET cases treated with radiotherapy (RT) at our institutions. METHODS AND MATERIALS: A total of 25 patients (17 males and 8 females, median age 9 years) were treated with RT between 1980 and 2001. The primary site location was the pineal region in 7 (28%), temporal lobe in 5 (20%), thalamus in 5 (20%), frontal lobe in 4 (16%), parietal lobe in 2 (8%), and suprasellar region in 2 (8%). Five patients (20%) had neuraxis dissemination (M+ disease) at initial diagnosis. The RT treatment volumes were craniospinal (CS) in 17 (68%), whole brain (WB) followed by a boost in 2 (8%), and primary site (PS) alone in 6 (24%). The median dose to the primary site was 54 Gy (range, 31-55.8 Gy). The median dose to patients receiving WB and spinal fields was 36 Gy (range, 23.4-39.6 Gy). Sixteen patients (64%) received chemotherapy; the most common type was the "8 in 1" chemotherapy regimen in 9 children. The median follow-up of surviving patients was 70 months (range, 34-251 months). RESULTS: The 5-year and 10-year progression-free survival rate was 36% and 27%, respectively, and the median time to progression was 22 months. The 5-year and 10-year progression-free survival rate was 47.1% and 47.1% for those receiving CSRT and 12.5% and 0% for those receiving WBRT or PSRT, respectively. The 5-year and 10-year progression-free survival rate for those with M0 disease was 40.0% and 30.0%, respectively; for those with M+ disease, the corresponding figures were 20.0% and 0%. On multivariate analysis, only M status (p = 0.01) and RT volume (p = 0.02) were statistically significant according to the Cox proportional hazards model. The primary site control rate at 5 and 10 years was 62%. Failure at nontreated neuraxis sites was a common cause of progression in patients receiving WBRT or PSRT, as seen in 6 (75%) of 8 cases. Of the 17 patients undergoing CSRT, 8 had no recurrence. Eight of the nine CSRT relapses had a leptomeningeal component. Four (80%) of 5 M+ children and 4 (33%) of 12 M0 children who underwent CSRT developed recurrence in the neuraxis (p = 0.1, Fisher's exact test). CONCLUSION: The craniospinal axis is the standard volume that needs to be treated in supratentorial PNET. Leptomeningeal dissemination was the main obstacle for cure even in patients receiving CSRT, regardless of M status.     

Biopsy targeting with dynamic contrast-enhanced versus standard neuronavigation MRI in glioma: a prospective double-blinded evaluation of selection benefits

While 2/3 of patients with ATRT are less than 3 years at diagnosis, the literature suggests younger children present with more aggressive disease and poorer outcome. However, little data exist on characteristics and outcome of patients diagnosed with ATRT in the first year of life. In particular, it is unclear whether they access similar treatments as do older children. We compared the cohort of patients?≤12 months from the Canadian ATRT registry to all cases extracted from the literature reported between 1996 and 2014 to describe their clinical and treatment characteristics, and potential prognostic factors. Twenty-six (33.7%) patients from the Canadian registry were ≤12 months at diagnosis as were 120 cases identified in the literature. Post-operatively, 46% of the registry’s patients underwent palliation as opposed to 10.8% in the literature cohort. Palliative patients were significantly younger than those who received active therapy (3.3 vs. 6.6 months). While the use of high-dose chemotherapy (HDC) was relatively similar in both cohorts (42.9 and 35.5% respectively), radiotherapy (RT) use was significantly lower in the Canadian cohort (14.3 vs 44.9%). Children?≤6 months, who received active therapy, had a worst outcome than older ones. Gross total resection, HDC and adjuvant RT were associated with better outcomes. Eighty percent of the tested patients had evidence of germline mutation of INI1. While 1/3 of ATRT occurs within the first year of life, a large proportion only received palliative therapy. Even when actively treated, children?≤6 months fare worse. Some selected patients benefit from HDC.     

Cyclophosphamide, adriamycin and vincristine (CAV) in the treatment of small cell lung cancer

Thirty-nine previously untreated small cell lung cancer patients received cyclophosphamide (CTX) + adriamycin (ADM) + vincristine (VCR) (CAV). The doses initially used were CTX 1,000 mg/body day 1, ADM 50 mg/body day, VCR 1 mg/body day, 8, 15 or 2 mg/body day(group A). Later, CTX 1,000 mg/m2 day, ADM 60 mg/m2 day, VCR 1.4 mg/m2 day were used. All patients had PS 0-3, 24 had limited disease (LD) and 15, extensive disease (ED). The overall response rate and the complete response (CR) rates were 63% (15/24) and 21% (5/24) for LD, and 21% (3/14) and 0% (0/14) for ED, respectively. The median response durations were 22 weeks for LD and 33 weeks for ED. The median CR duration in LD patients was 23 weeks. Twelve LD and 1 ED patient received thoracic radiotherapy (RT) optionally after 2-4 courses of CAV therapy. Eventually, 8 patients achieved CR. The median survival for LD, ED and all cases were 43 weeks, 37 weeks and 41 weeks, respectively. The 1, 2 and 3-year survival rates were 42, 25 and 21% for LD, and 40, 7 and 0% for ED. Three patients were long-term disease-free survivors (greater than 3 years), and these had LD and received RT. There were 3 chemotherapy-related deaths (2 patients with leukopenia + infection, 1 patient with drug-induced pneumonitis). The survival results of CAV therapy in our hospital were comparable with the recent results of chemotherapies available against small cell lung cancer.     

Treatment of Hodgkin's disease in children with or without radiotherapy

From 1975 until 1984 37 children with newly diagnosed Hodgkin's disease were treated with six mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) courses with or without involved field radiotherapy (25 Gy) independent of the stage of their disease. Patients with small lymph node tumors (less than 4 cm) received only six MOPP-courses. Patients with large lymph node tumors (greater than 4 cm) received involved field radiotherapy, 25 Gy to the large tumor masses, between the third and fourth MOPP-course. For the 21 patients with "small" tumors, the disease-free survival (DFS) rate is 90%. In this group two patients with clinical stage (CS) III disease have relapsed but both are alive after successful salvage treatment. The median follow-up time is 69.7+ months. For the 16 patients with larger tumor masses (greater than 4 cm) the DFS rate is 87.5%. In this group one patient with CS II relapsed and died of Hodgkin's disease, and one with CS III relapsed after 37 months, but is now without evidence of disease, 61 months from diagnosis. The median follow-up time is 62+ months. Most of the children with Hodgkin's disease diagnosed before or during puberty can be cured with chemotherapy alone, and thus will not suffer from the damaging late effects of radiotherapy.     

21例原发乳腺淋巴瘤临床分析并文献复习

目的:探讨原发乳腺淋巴瘤(primary breast lymphoma,PBL)的临床、病理特点、诊断、治疗方法及预后.方法:回顾性分析中山大学附属肿瘤医院1998年至2015年收治的21例PBL住院患者一般病例资料、分析其疾病特征、治疗及预后等情况.结果:21例中患者均为女性,年龄13~78岁,中位年龄41岁.ⅠE期12例、ⅡE期4例、ⅣE期5例,病理类型以弥漫大B细胞淋巴瘤为主(17/21例),治疗及预后:全组患者9例(42.9%)接受联合化放疗,11例(52.4%)单纯化疗,化疗方案以CHOP(7例)和RCHOP(11例)为主.中位随访42个月(3~126月),全组中位生存期56月,3年总生存率为84%,5年总生存率为78%.化疗联合靶向与单纯化疗相比、化疗联合放疗与单纯化疗相比,5年总生存率均无显著差异(88.2%和76.5%,P=0.77;84.3%和72.6%,P=0.38).结论:PBL接受以化疗为主的治疗,总体预后较好.     

Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial

Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90–100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.     

Salvage high-dose chemotherapy in female patients with relapsed/refractory germ-cell tumors: a retrospective analysis of the European Group for Blood and Marrow Transplantation (EBMT)

BackgroundHigh-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation.Patients and methodsBetween 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15–48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%).ResultsNine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm−), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1–219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm− following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3–219 months).ConclusionsSalvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.     

Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin's disease.

The risk of idiopathic pneumonia syndrome (IPS) in patients with Hodgkin''s disease (HD) undergoing high-dose chemotherapy (HDC) is significant, and once developed IPS is potentially fatal. The aim of this study was to quantify this risk accurately and determine prognostic factors for its development and course. Using a computerized database, all patients with HD treated with BCNU (carmustine) containing HDC and haematopoietic support at The Royal Marsden between November 1985 and March 1994 were identified. Patient characteristics, previous treatments, disease status at HDC, dose of BCNU, incidence and severity of IPS and survival were all determined and analysed. During the study period, 94 patients received HDC, of whom 26 (28%) had a first episode of IPS within a year of HDC and 23 within 6 months. The median time to presentation after HDC was 93 days (range 12-336 days). The only factors that significantly increased the risk of developing IPS on multivariate analysis were dose of BCNU (P for trend = 0.03) and female sex (P = 0.04). Of these 26 patients, 14 had complete resolution of all symptoms, three had persisting pulmonary symptoms at 6 months and the remaining nine died of IPS at a median of 74 days (19-418 days). All the patients who died from IPS had the first symptoms within 6 months of HDC and all received doses of BCNU > 475 mg m(-2) (P for trend = 0.001). For women receiving > 475 mg m(-2) the risk of death was significantly higher than for men (P = 0.035) but not for those receiving < 475 mg m(-2). Previous lung disease, persisting residual disease before HDC, previous bleomycin or previous mantle radiotherapy did not increase either the incidence of IPS or risk of a fatal outcome. We conclude that the main avoidable risk factor for fatal IPS after HDC is dose of BCNU, and this is especially true for women. If < 475 mg m(-2) is given, even patients with previous mantle radiotherapy and/or previous bleomycin have a very low risk of developing fatal lung toxicity if lung function tests are normal.