Low-dose Oral Etoposide Research Articles

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. ClinicalTrials.gov Identifier: NCT01356290.

Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach.

Simple SummaryAbout 30% of patients with medulloblastoma experience recurrence, which is usually incurable despite intensive chemotherapy. The aim of our retrospective study was to evaluate a novel combinatorial metronomic antiangiogenic approach (“MEMMAT-like”) for recurrent medulloblastoma consisting of five oral drugs, an intravenous antibody against vascular endothelial growth factor, and intrathecal therapy. The study, conducted between 2006 and 2016, included 29 consecutive patients with first or multiple recurrences treated according to this “MEMMAT-like” strategy and confirmed a significantly longer median overall survival than in previously reported studies. As of 07/2022, 9/29 patients are alive 86 to 164 months after recurrence. Treatment was primarily out-patient and well-tolerated. Toxicities did occur but were manageable. The novel combination significantly improved overall and progression-free survival for patients with recurrent medulloblastoma. A formal study (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) has been completed and is currently being evaluated.Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy (“MEMMAT-like”) before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the “MEMMAT-like” therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.

Low-dose oral etoposide is an active option for patients with heavily pre-treated thymic epithelial tumors.

9074 Background: Platinum based regimens are used in the first line setting for advanced Thymic Epithelial Tumors (TETs). Angiogenesis plays an important role in TETs: VEGF is overexpressed in TETs, and associated with aggressiveness and advanced stage. Etoposide inhibits angiogenesis in vitro and in vivo by decreasing VEGF production and microvessel density. The aim of this study is to assess the activity of metronomic oral etoposide, with identification of circulating predictive and pharmacodynamics biomarkers. Methods: Patients with advanced platinum pretreated TET referred from 2014 to 2019 at Rare Tumors Reference Center of Naples, were prospectively enrolled in this study. Oral etoposide 50 mg daily for 3 weeks on and 1 week off every 28 days, has been delivered until progression of disease, complete response or unacceptable toxicity. Response rate (RR), progression free survival (PFS), toxicity and ratio between time to etoposide progression (TTPe) and time to previous best treatment progression (TTPp) were evaluated. Serum samples were prospectively obtained from ten patients with simultaneously radiological assessment. cfDNA quantification was assessed using Qubit Fluorometric Quantitation. Results: 21 patients were enrolled: median age 59 years range (41 - 88); 70% male, 60% T (4 B1, 3 B2, 4 B3, 1 B1-B2); 40% had TC. A median of 5 (range 1-9) prior therapy regimens had been administered. Median follow-up since etoposide was 5 years (range 0.5-5). Obtaining an overall response rate of 85%, 3 patients achieved complete response and 15 partial response. Median PFS was 16 months [95%CI 3-60] with respectively a median PFS of 12 for T (95%CI 3-38) and 19 for TC (95%CI 6-60). No grade 3-4 related events occurred, G1-2 myelotoxicity has been registered in 20% of patients. Therapy is still ongoing for 15 patients and all are still alive. Median TTPe was 16 months, TTPp was 9 months and TTPe / TTPp ratio equal to 1.7. The median cfDNA of 8 responder patients, before starting therapy, was 2.2 ng/μl (0.178-5.24), dropping dramatically at radiological response to 0.5 ng/μl (0.323-2.56). 2 out of 3 non-responder patients had a median baseline value of 2.49 ng/μl, increasing to 4.6 ng/μl at progression. Variation of circulating VEGF correlates with radiological response. Conclusions: Taking into account that other antiangiogenic drugs, showing some activity in second and further lines treatment, are very expensive and associated with several side effects, we suggest that low dose oral etoposide might become the preferred treatment option in heavily pretreated TETs.

Successful treatment of mycosis fungoides (tumor stage) with low-dose oral etoposide in combination with local electron beam radiation therapy : Report of two cases

Successful treatment of mycosis fungoides (tumor stage) with low-dose oral etoposide in combination with local electron beam radiation therapy : Report of two cases

Effectiveness of low-dose oral etoposide treatment in patients with recurrent and platinum-resistant epithelial ovarian cancer

The aim of this study was to evaluate the efficacy and toxicity profile of oral etoposide (50 mg/day, days 1–14, every 3 weeks) in recurrent platinum-resistant epithelial ovarian cancer (EOC). 52 recurrent platinum-resistant EOC patients followed up in four centres between April 2000 and December 2013 were analysed retrospectively. There was response in a total of 21 patients [partial response (PR) and stable disease (SD)], 12 of them used etoposide in second and third, and 9 of them used it in fourth- to fifth-lines of treatment. The overall response rate was 19.2% and clinical benefit rate was 40.4% [PR (19.2%), SD (21.2%)]. Median overall survival (OS) and progression-free survival (PFS) was 9.95 months (95%CI, 0.2–19.7 months) and 3.2 months (95%CI 2.6–3.8 months), respectively. Grade III–IV haematologic and non-haematologic adverse events were observed in 7 (13.4%) patients. We consider that oral etoposide (50 mg/day, days 1–14, every 3 weeks) is an effective treatment with a manageable adverse effect profile in recurrent platinum-resistant EOC patients.Impact statementWhat is already known on this subject: Oral etoposide is an effective option for recurrent EOC patients at a dose of 50–100 mg/m2/day (1–21 days, every 28 days) regimen. However, it has a high toxicity rate.What the results of this study add: Oral etoposide at a dose of 50 mg/kg (1–14 days, every 21 days) is an effective treatment with a manageable toxicity profile in platinum- resistant ovarian cancer patients when it is used as ≤4th-line palliative setting.What the implications are of these findings for clinical practice and/or further research: We need trials evaluating the effect of low-dose oral etoposide combination with bevacizumab or other chemotherapy agents (irinotecan and gemcitabine) in platinum-resistant EOC patients.

Oral etoposide in relapsed or refractory Ewing sarcoma: a monoinstitutional experience in children and adolescents.

To assess the efficacy and toxicity of low-dose oral etoposide (VP) 16 in relapsing/refractory Ewing sarcoma. The records of all patients treated at our department between 1989 and 2012 for relapsing/refractory Ewing sarcoma who received oral VP-16 were analyzed. The dose was 40 mg/m2 daily for 21 consecutive days in every 28. Response was assessed after 2/3 cycles according to Response Evaluation Criteria in Solid Tumors 1.0. A total of 46 of 58 patients completed at least 2 cycles; 12 suspended the treatment earlier due to rapid disease progression. The patients' median age at diagnosis was 14 years and 25/58 had metastatic disease. All patients received intensive polychemotherapy including VP-16 IV as first- (n = 53) or second-line (n = 5) treatment; 21/58 had myeloablative regimens with peripheral blood stem cell rescue, and 1 underwent allogeneic stem cell transplantation. Oral VP-16 was prescribed as 2nd-, 3rd-, and 4th-line treatment for 19, 27, and 12 patients, respectively. The cycles administered totaled 241 (median 3, mean 4 per patient; range 1-14). A total of 46 of 58 patients were evaluable: 11 responded (9 partial remission, 1 very good partial remission, 1 complete remission) and 10 were stable, the response lasting a mean of 8 months. Hematologic toxicity G3/G4 (in 164/241 evaluable cycles) occurred in 15%, 16%, and 11% of cycles for leukocytes, hemoglobin, and platelets, respectively. There were 5 cases of pneumonia. Two patients developed secondary leukemia after receiving 12 and 14 cycles. Low-dose oral VP-16 may be suitable in a palliative setting with an acceptable toxicity. The risk of secondary leukemia is in line with reports in the literature.

Human herpesvirus 8-negative primary effusion lymphoma-like lymphoma with t(8;14)(q24;q32)

Primary effusion lymphoma (PEL) is a large B-cell lymphoma proliferating only in the body cavity effusion. It often occurs in advanced AIDS patients and is associated with human herpesvirus 8 (HHV-8). On the other hand, HHV-8 negative effusion lymphoma, which is different from PEL in many ways, has also been reported and is referred to as HHV8-unrelated PEL-like lymphoma. This lymphoma is very rare and its clinical characteristics have not yet been fully clarified. We therefore report an HIV seronegative elderly patient with HHV8-unrelated PEL-like lymphoma. An 89-year-old woman was admitted to our hospital due to general fatigue and dyspnea. The patient presented with left pleural effusion in the absence of lymphadenopathy and tumor masses. The pathological examination of the pleural effusion showed proliferation of atypical large lymphoid cells, which were positive for CD19, CD20, CD10, CD38, CD7, BCL2 and BCL6 but negative for CD5, CD30, MUM1, surface immunoglobulin, HHV-8 and EBV. Cytogenetic analysis showed a complex karyotype including t(8;14)(q24;q32). The pleural effusion decreased in response to monotherapy with oral low-dose etoposide, but recurrence was detected 7 months later. Rituximab was transiently effective for the recurrent pleural effusion, but the patient died of lymphoma exacerbation 13 months after the diagnosis.

Continuous low-dose oral chemotherapy in recurrent and persistent carcinoma of cervix following chemoradiation: a comparative study between prolonged oral cyclophosphamide and oral Etoposide.

Aim:To compare the efficacy and toxicities of low-dose oral cyclophosphamide and oral etoposide in patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy.Materials and Methods:30 patients with recurrent and persistent cervical cancer with gross pelvic disease were enrolled in this trial. The patients were randomly divided into two groups of 15 patients each with one group receiving low dose oral cyclophosphamide (100 mg/day) and the other group receiving low-dose oral etoposide (50 mg/day). Results were statistically analysed by IBM SPSS Statistics 19.Results:Oral etoposide was not well tolerated with grade 2 neutropenia occurring in 33.3% and grade 3 neutropenia in 6.6% and thrombocytopenia occurring in 13.3%. Oral cyclophosphamide group on the other hand was better tolerated with none of the patients having thrombocytopenia and 6.6% patients having grade 2 neutropenia. There were two complete response (15.38%) and one partial response at the end of study (7.6%) in the cyclophosphamide group whereas there was no complete response and two partial response (16.6%) in the oral etoposide group.Conclusion:Long-term, low-dose oral etoposide was found to be less tolerated without any significant effect with patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy in contrast to oral cyclophosphamide which was found to be effective and well-tolerated by the patients.

Oral Etoposide for Platinum-Resistant and Recurrent Epithelial Ovarian Cancer: a Study by the Anatolian Society of Medical Oncology

The aim of this study was to evaluate the efficacy and toxicity of long-term, low-dose oral etoposide as an advanced treatment option in patients with platinum resistant epithelial ovarian cancer. For the purposes of this study, 51 patients with histologically-confirmed, recurrent or metastatic platinum-resistant epithelial ovarian cancer (EOC) treated at six different centers between January 2006 and January 2011 were retrospectively evaluated. Patients were treated with oral etoposide (50 mg/day for a cycle of 14 days, repeated every 21 days). Among the 51 platinum-resistant patients, 17.6% demonstrated a partial response and 25.5% a stable response. The median progression-free survival (PFS) was 3.9 months (95% CI, 2.1-5.7), while the median overall survival was 16.4 months (11.8-20.9). No significant relationship was observed between the pre-treatment CA 125 levels, post-treatment CA-125 levels and the treatment response rates (p=0.21). Among the 51 patients who were evaluated in terms of toxicity, grade 1 or 4 hematologic toxicity was observed in 19 (37.3%); and grade 1-4 gastrointestinal toxicity occurred in 15 patients (29.4%). Chronic low-dose oral etoposide treatment is generally effective and well-tolerated in platinum-resistant ovarian cancer patients.

Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors

Median survival time of recurrent embryonal brain tumors is short regardless of salvage chemotherapy used. An evolving alternative approach to conventional chemotherapy is to target neovascularization by interfering with tumor angiogenesis at various levels. From November 2006 to December 2010, 16 patients (median age: 9 years) with recurrent (9 first, 7 multiple) embryonal brain tumors were treated with an antiangiogenic multidrug combination regimen (bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intraventricular therapy (etoposide and liposomal cytarabine). At a median of 33 months, 10/16 patients are alive. 4/4 patients with CNS primitive neuroectodermal tumors (CNS PNET) and 1/7 patients with medulloblastoma (MB) died of tumor progression during the first year. Another patient with MB died of an accident after 23 months, the remaining five patients with MB are alive for 12, 33, 33, 37, and 58 months. For the seven patients with MB, both overall survival (OS) and event free survival (EFS) after 6 months was 100%, after 12 months 85.7 ± 13%, and after 24 months 68.6 ± 19%. In contrast, for patients with CNS PNET, both OS and EFS after 6 months was 75.0 ± 22% and 0.0% and all patients had died by 12 months. Low-dose oral etoposide and cyclophosphamide was reduced after a median of 2 months and discontinued after a median of 11 months. Toxicities were manageable and therapy was generally well tolerated. Our results suggest that the chosen antiangiogenic drug combination is particularly beneficial for patients with MB and warrants further investigation.

低用量エトポシド内服療法が有効であったanaplastic large cell lymphomaの１例

低用量エトポシド内服療法が有効であったanaplastic large cell lymphomaの１例

Inhibition of tumor angiogenesis by oral etoposide

The chemotherapeutic agent etoposide is a topoisomerase II inhibitor widely used for cancer therapy. Low-dose oral etoposide, administered at close regular intervals, has potent anti-tumor activity in patients who are refractory to intravenous etoposide; however, the mechanism remains unclear. Since endothelial cells may be more sensitive than tumor cells to chemotherapy agents, we determined the effects of etoposide alone and in combination with oral cyclooxygenase-2 inhibitors and peroxisome-proliferator activated receptor γ ligands on angiogenesis and tumor growth in xenograft tumor models. Optimal anti-angiogenic (metronomic) and anti-tumor doses of etoposide on angiogenesis, primary tumor growth and metastasis were established alone and in combination therapy. Etoposide inhibited endothelial and tumor cell proliferation, decreased vascular endothelial growth factor (VEGF) production by tumor cells and suppressed endothelial tube formation at non-cytotoxic concentrations. In our in vivo studies, oral etoposide inhibited fibroblast growth factor 2 and VEGF-induced corneal neovascularization, VEGF-induced vascular permeability and increased levels of the endogenous angiogenesis inhibitor endostatin in mice. In addition, etoposide inhibited Lewis lung carcinoma (LLC) and human glioblastoma (U87) primary tumor growth as well as spontaneous lung metastasis in a LLC resection model. Furthermore, etoposide had synergistic anti-tumor activity in combination with celecoxib and rosiglitazone, which are also oral anti-angiogenic and anti-tumor agents. Etoposide inhibits angiogenesis in vitro and in vivo by indirect and direct mechanisms of action. Combining etoposide with celecoxib and rosiglitazone increases its efficacy and merits further investigation in future clinical trials to determine the potential usefulness of etoposide in combinatory anti-angiogenic chemotherapy.

Primary cutaneous CD30+ anaplastic large-cell lymphoma with generalized skin involvement and involvement of one peripheral lymph node, successfully treated with low-dose oral etoposide

Primary cutaneous CD30+ anaplastic large-cell lymphoma (PCALCL) in adults is rare, and the prognosis is generally excellent. Multifocal PCALCL tends to relapse after multiagent chemotherapy and is generally considered more prone to progress to extracutaneous involvement than is the localized disease. We report a 43-year-old woman with PCALCL who had generalized skin involvement accompanied by involvement of one peripheral draining lymph-node region. Although the disease relapsed after multiagent chemotherapy regimens, the disease was successfully treated with low-dose etoposide. We reviewed the previously reported cases of PCALCL treated with low-dose etoposide. We suggest that oral etoposide might be a useful effective treatment for treatment of relapsed multifocal PCALCL.

Intracavitary chemotherapy (Gliadel®) and oral low-dose etoposide for recurrent anaplastic ependymoma

Anaplastic ependymoma is associated with a higher incidence of tumor recurrence and its prognosis still remains unsatisfactory. Consolidated therapy for ependymoma includes surgery followed by focal radiotherapy when resection is incomplete. In the case of relapse treatment, options are limited especially for patients who have already received radiotherapy. We sought to establish the feasibility of administering low-dose oral etoposide (50 mg/m(2)/day for 21 days) in combination with the implantation of intracavitary carmustine (BCNU) wafers (Gliadel) at the gross total resection for achieving synergistic treatment in three children affected by recurrent anaplastic ependymoma. All patients had Karnofsky performance scale (KPS) scores >80%. The therapy was tolerated safely and well in all patients without any post-surgery complications. After BCNU wafer implantation, all patients achieved radiological and clinical stabilization for an average period of 3 months. Two patients relapsed after 4 months as shown in brain MRIs. The other patient went to progression two months after the Gliadel implantation. This multimodal approach was not effective for the treatment of refractory anaplastic ependymoma and further studies are required in order to define the role of the combination of multidrug systemic chemotherapy with BCNU wafer implantation in children with high-risk brain tumors.

PET Scintigraphy of Etoposide-Induced Pulmonary Toxicity

A patient with chronic myelomonocytic leukemia developed drug-induced pulmonary toxicity after using low dose oral etoposide. Because etoposide-induced pulmonary toxicity is an uncommon but serious adverse event, clinicians must be vigilant about the possibility of it, so that the optimal treatment can start as soon as possible. This report demonstrates that PET scintigraphy might be a helpful tool in the early diagnosis of drug-induced pulmonary toxicity.

Oral Low Dose Etoposide in the Treatment of Macrophage Activation Syndrome.

Background: Macrophage activation syndrome (MAS) in adults, also called reactive haemophagocytic syndrome or haemophagocytic lymphohistiocytosis, is the result of inappropriate proliferation and activation of the mononuclear phagocytic system secondary to an underlying disease. Persistent high levels of inflammatory cytokines with impaired cytotoxic capacity of T-lymphocytes and natural killer cells seem to be the main trigger of the syndrome. There are a variety of diseases that can lead to fulminant uncontrolled MAS, mainly viral infections and conditions of immunologic dysregulation such as Systemic Lupus Erythematodes, Morbus Still and neoplastic disorders. Despite the variety of associated diseases, the clinical presentation is uniform with high fever, splenomegaly, lymphadenopathy, hepatomegaly, rash and neurologic abnormalities. MAS is associated with substantial morbidity and mortality. Beside the clinical presentation, extreme elevation of plasma markers for macrophage hyperactivation are mandatory in diagnosing and monitoring MAS (hyperferritinemia, and extreme elevation of neopterin and sIL2R), whereas the phenomenon of hemophagocytosis (±cytopenias) is more variable. Different therapeutic strategies including high-dose steroids, intravenous immunoglobulin (IVIG) [Emmenegger U, et al. American Journal of Haematology 2001; 68:4–10] and intravenous etoposide (VP16)[Imashuku S, et al. Journal of Clinical Oncology 2001; 19:2665–267] have been reported to induce remissions, but tend to be incomplete and of short duration. These treatments are mainly based on studies in children with familial haemophagocytic lymphohistiocytosis and have considerable side-effects. The optimal treatment-approach in adults with MAS remains unclear. Faced with high mortality of MAS at our institution, we accepted VP16 as a paticularly important component of therapy but were struck by fast and live threatening relapses during neutropenic episodes following classical pulse-application of VP16 (2x150mg/m²/d x 2/week). We initiated oral low dose VP16 in refractory RHS and observed substantial effects.Methods and Patients: Our treatment concept was that of uninterrupted macrophage mitigation by continuous low-dose oral VP16 after a first un- or only partially successful episode of high-dose methylprednisolone or IVIG. In the present study we describe the effect of low dose oral VP16 after a first episode treated with high-dose methylprednisolone or IVIG in 3 patients with relapsing or resistant RHS. Close monitoring of cytokine activation was performed by serial measurements of ferritin, sIL2R, transcobalamin II and neopterin (at least twice weekly). 2 of our patients suffered from recurrent MAS in the context of chronic active Epstein-Barr virus infection, 1 patient showed 2 episodes of MAS secondary to Morbus Still. VP16-treatment was dosed at diurnal 50mg for 3 days followed by 15–20mg daily avoiding neutropenic episodes.Results: During the time of observation (4 years) we have ascertained a total of 9 episodes of MAS, 3 of them classified as severe (admission to intensive care unit). 4 episodes of MAS have been managed by oral VP16 exclusively. Decrease of cytokine activation and clinical outcome in episodes treated with oral VP16 proofed to be superior to the other treatment-strategies.Conclusion:Compared to steroids and IVIG, strictly monitored long-term low-dose oral VP16 (for several weeks to months) seems to be a safe and most effective treatment strategy in patients with life-threatening reactive MAS.

Neuroblastoma in adolescents and adults: the Memorial Sloan-Kettering experience.

We reviewed the utility of different treatment modalities in a large series of adolescents/adults with neuroblastoma (NB). The 30 adolescents/adults (median age, 19 years) had stage 2B (n = 1), 3 (n = 2), or 4 (n = 27) NB. Treatments included conventional and myeloablative therapy; local radiotherapy (RT); immunotherapy with anti-G(D2) 3F8 monoclonal antibody +/- granulocyte-macrophage colony-stimulating factor (GM-CSF); and 3F8 alternating with low-dose oral etoposide. Seven patients are in first (n = 4) or second (n = 3) complete/very good partial remission (CR/VGPR) at 9+ to 181+ (median, 45+) months. Among 13 newly diagnosed or minimally prior-treated patients, no major responses were seen in 4/4 treated with N4/N5 chemotherapy, but 6/9 treated with the higher dose N6/N7 regimens and surgery had major responses, and immunotherapy produced CR in BM in three patients. Among 17 patients referred because of resistant NB, favorable responses occurred in 6/12 treated with high-dose cyclophosphamide-based salvage therapy, including one patient who is in CR 170+ months after myeloablative consolidation and five patients who achieved CR/VGPR after 3F8/GM-CSF (n = 4) or 3F8/oral etoposide (n = 1). With a median follow-up of 32+ months post-RT, no local relapses occurred in 10/10 patients who received hyperfractionated 21 Gy RT to prevent regrowth of soft tissue masses that had been resected. High-dose chemotherapy and surgery can achieve a minimal disease state in >50% of newly diagnosed older NB patients. In that setting, local RT, and the use of agents with recently confirmed anti-NB activity, including anti-G(D2) antibodies, and cis-retinoic acid, may improve the poor prognosis of these patients reported to date.

乳房外Ｐａｇｅｔ病 両側鼠径リンパ節転移とパンツ型浸潤をきたした乳房外Ｐａｇｅｔ病の１例

A 75-year-old man visited our hospital because of bilateral inguinal lymphadenopathy and purpuric erythema on the lower abdomen. He had erythematous plaque on the scrotum. Skin biopsy revealed Paget cells in the epidermis of the scrotum and lymph duct's ectasis containing aggregated Paget cells in the lower abdomen. Radiotherapy was performed with considerable effect. Ten weeks later, however, purpuric erythema recurred on his left buttock. Following oral low-dose Etoposide therapy, the purpuric erythema regressed gradually and disappeared. The serum CEA level decreased concomitantly and normalized. Despite fairly good response to oral low dose Etoposide therapy, the patient died of the disease 16 months after the initial admission. [SkinCancer (Japan) 2002; 17: 161-165]

エトポシド少量投与が奏効した乳房外Ｐａｇｅｔ病の１例

We report a case of extramammary Paget's disease in which metastatic skin lesions were treated successfully with low-dose Etoposide administered orally over a 12-week period. The patient, an 84-year-old male, visited us because of a tumor and erythema of the scrotum in June 2000. At presentation, he had a tumor measuring 56×30mm on the scrotum and erythema measuring 12×7cm around the tumor. ACT scan revealed swollen lymph nodes in the bilateral groin. Surgery and lymph node biopsy were carried out in July 2000. Infiltration of tumor cells was revealed microscopically in the bilateral inguinal lymph nodes. Metastatic skin lesions developed on the abdomen two months after the operation, but the tumors regressed gradually and disappeared seven weeks after the introduction of oral low-dose Etoposide (25mg/day) in October 2000. The serum level of carcinoembryonic antigen (CEA) decreased and was normalized 12 weeks after the start of administration. Because of the onset of interstitial pneumonia, administration of Etoposide was stopped in December 2000.Although Etretinate was introduced after the pneumonia was resolved by steroid pulse therapy, metastatic skin lesions gradually developed and the patient died 11 months after the operation. Although Etoposide caused interstitial pneumonia in this patient, we conclude that its oral long-term use at a low dose is worth considering in patients with advanced extramammary Paget's disease. [Skin Cancer (Japan) 2001; 16: 376-381]

Effect of Low-Dose Oral Etoposide on Serum CA-125 in Patients with Advanced Epithelial Ovarian Cancer

The effect of oral etoposide on CA-125 serum levels was evaluated in 17 patients with epithelial ovarian cancer and progressive disease during, or relapsing after, prior chemotherapy. Only three patients had measurable lesions at extraperitoneal sites. Five had no measurable lesions. The oral etoposide dose was 50 mg b.d. for 7 days every 3 weeks, escalating to 10 or 14 days and continued until clinical progression. CA-125 after 4 courses was compared to baseline (CA-125 ratio). The rate of change of CA-125 (s,slope of the exponential regression curve) during the first 4 courses was compared tosover a similar period before treatment. One patient had a clinical partial response. Two other patients had a biochemical response (CA-125 ratio <0.5). Although the biochemical response rate was modest (12.5%), a decrease ofswas observed in 14/16 patients (P= 0.02). The mean change ofsrepresented an increase of mean doubling time from 52 to 693 days. No patients were withdrawn because of toxicity. General malaise, nausea, diarrhea, and anemia were the most important side effects. At the given dose schedule, oral etoposide shows activity in advanced ovarian cancer if the rate of change of CA-125 is used as a measure of activity.