Metronomic Chemotherapy as a New Strategy for End-stage Pediatric Oncology Patients in Iran (original) (raw)
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Pediatric Blood & Cancer, 2013
Background. Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a "5-drug" oral regimen in children with recurrent or progressive cancer. Procedure. Patients 21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed. Results. One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days-21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/ primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P ¼ 0.009). Conclusion. The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636-642.
Metronomic Chemotherapy vs Best Supportive Care in Progressive Pediatric Solid Malignant Tumors
JAMA Oncology, 2017
IMPORTANCE Although oral metronomic chemotherapy is often used in progressive pediatric solid malignant tumors, a literature review reveals that only small single-arm retrospective or phase 1 and 2 studies have been performed. Skepticism abounds because of the lack of level 1 evidence. OBJECTIVES To compare the effect of metronomic chemotherapy on progression-free survival (PFS) with that of placebo in pediatric patients with primary extracranial, nonhematopoietic solid malignant tumors that progress after at least 2 lines of chemotherapy. DESIGN, SETTING, AND PARTICIPANTS A double-blinded, placebo-controlled randomized clinical trial was conducted from October 1, 2013, through December 31, 2015, at the cancer center at All India Institute of Medical Sciences in children aged 5 to 18 years with primary extracranial, nonhematopoietic solid malignant tumors that progressed after at least 2 lines of chemotherapy and had no further curative options. INTERVENTIONS One arm received a 4-drug oral metronomic regimen of daily celecoxib and thalidomide with alternating periods of etoposide and cyclophosphamide, whereas the other arm received placebo. Disease status was assessed at baseline, 9 weeks, 18 weeks, and 27 weeks or at clinical progression. MAIN OUTCOMES AND MEASURES The primary end point was PFS as defined by the proportion of patients without disease progression at 6 months, and PFS duration and overall survival (OS) were secondary end points. RESULTS A total of 108 of the 123 patients screened were enrolled, with 52 randomized to the placebo group (median age, 15 years; 40 male [76.9%]) and 56 to the metronomic chemotherapy group (median age, 13 years; 42 male [75.0%]). At a median follow-up of 2.9 months, 100% of the patients had disease progression by 6 months in the placebo group vs 96.4% in the metronomic chemotherapy group (P = .24). Median PFS and OS in the 2 groups was similar (hazard ratio [HR], 0.69; 95% CI, 0.47-1.03 [P = .07] for PFS; and HR, 0.74; 95% CI, 0.50-1.09 [P = .13] for OS). In post hoc subgroup analysis, cohorts receiving more than 3 cycles (HR for PFS, 0.46; 95% CI, 0.23-0.93; P = .03) and those without a bone sarcoma (ie, neither primitive neuroectodermal tumor nor osteosarcoma) (HR for PFS, 0.39; 95% CI, 0.18-0.81; P = .01) appeared to benefit from metronomic chemotherapy. CONCLUSIONS AND RELEVANCE Metronomic chemotherapy does not improve 6-month PFS, compared with placebo, among pediatric patients with extracranial progressive solid malignant tumors. However, patients without bone sarcoma and those able to tolerate therapy for more than 3 cycles (9 weeks) benefit. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01858571
Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature
Journal of Clinical Medicine
We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to...
Metronomic antiangiogenic therapy in children with recurrent brain tumours of different histologies
memo - Magazine of European Medical Oncology, 2011
Children with relapsed malignant brain tumours have a poor prognosis despite intensive treatment including high-dose chemotherapy with stem cell rescue [1, 2]. Angiogenesis, the formation of new blood vessels, is an important component of normal physiological processes such as wound healing and development. Moreover, tumour growth and metastasis is closely related to formation of new blood vessels [3, 4]. Antiangiogenic therapy inhibits neovascularization, thereby inhibiting tumour progression indirectly [5]. Th e term metronomic chemotherapy refers to the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and without prolonged drug-free breaks. Beside the antiangiogenic eff ect, metronomic chemotherapy has been shown to modulate anti-tumoural immunity and has the ability to induce tumour dormancy [6]. Th e combination of agents used in our metronomic antiangiogenic therapy is based on a four-drug regimen (thalidomide, celecoxib, etoposide and cyclophosphamide) published by Kieran et al. in 2005 [7]. We augmented this regimen with bevacizumab, fenofi brate, and intrathecal therapy with the goal to improve progression-free survival for patients with recurrent or refractory CNS tumours for whom no curative therapy is available. We report on our experience with an antiangiogenic metronomic chemotherapy for paediatric patients with recurrent CNS tumours of diff erent histologies.
Intensive chemotherapy for metastatic neuroblastoma: A southwest oncology group study
Medical and Pediatric Oncology, 1980
Thirty-three children with Evans stage IV neuroblastoma were treated with an intensive chemotherapy regimen reported by Helson t o be highly effective. The purpose of the study was to determine whether the toxic regimen was manageable by different investigators and t o increase the sample of patients. Remission induction therapy consisted of courses repeated every four weeks: Cyclophosphamide (CTX) 80 mg/kg IV, with IV fluids and furosemide on days 1 and 2; vincristine (VCR) 0.03 mg/kg IV 12 hours after cyclophosphamide; trifluorc-methyl-2-deoxyridine (F3TdR) 45 mg/kg IV push, and papaverine (PAP) 45 mg/kg (1 2-hour infusion) under cardiac monitoring on days 3 and 4. Initially during maintenance, courses of therapy were reduced t o two days. Because this was found t o be ineffective therapy, the courses were extended t o four days. Some of the patients who achieved response were removed from the protocol and placed on different maintenance therapy. Seventeen of 2 1 children newly diagnosed and 6/12 children previously treated for metastatic neuroblastoma achieved partial or complete remissions. Eight of 16 newly diagnosed patients achieving response are still alive, six without evidence of disease for periods of time ranging from 20 t o 41 months. The median of the administered drug dosages was 100% of the recommended dosages. Seventy percent of the 229 courses given were initiated at correct interval. Therapy had t o be delayed on the others because of toxicity. The value of the four-drug combination is limited because of side effects related t o myelosuppression which resulted in severe complications and frequent hospitalizations.
Onkologie, 2006
Antiangiogenese · Therapie, metronomische · Studie, klinische · Kind Zusammenfassung Hintergrund: Mit dem Ziel der Etablierung einer ambulanten Behandlungsstrategie für intensiv vorbehandelte Kinder mit refraktären soliden Tumoren wurde ein 4 Medikamente umfassendes Therapieprotokoll, genannt COMBAT (combined oral maintenance biodifferentiating and antiangiogenic therapy), erstellt. Im Rahmen einer Pilotstudie wurde die Anwendbarkeit der Therapie bei Kindern mit soliden Tumoren, die refraktär und/oder mit einem hohen Risiko verbundenen sind, durchgeführt. Patienten und Methoden: 22 Kinder wurden nach dem COMBAT-Protokoll behandelt. Die Therapie bestand aus täglichen Gaben von Celecoxib und 13-cis-Retinoinsäure (2 Wochen Behandlung / 2 Wochen Pause) sowie Behandlungszyklen mit metronomischem Temozolomid (90 mg/m 2 für 42 Tage) und niedrig dosiertem Etoposid (21 Tage). Die Behandlung erfolgte über einen Zeitraum von 1 Jahr. Ergebnisse: 9 der 14 bezüglich des Ansprechens beurteilbaren Patienten zeigten einen Behandlungsvorteil (längere Krankheitsstabilisation oder Ansprechen). Alle Medikamente waren gut verträglich, und die Patientencompliance war gut. Die beobachteten Nebenwirkungen waren minimal und konnten durch Dosismodifikationen oder lokale Behandlung behoben werden. Schlussfolgerungen: Das COMBAT-Regime ist für intensiv vorbehandelte Patienten auch nach myeloablativer Therapie gut verträglich. Das in dieser Studie beobachtete positive Ansprechen unterstützt die weitere Untersuchung dieses und/oder ähnlicher Behandlungsstrategien für solide Tumoren bei Kindern.
Pediatric Neurology, 2015
Background-The primary goals of the CCG-99703 study were to assess the feasibility and tolerability of, as well as the response rate to, a novel dose-intensive chemotherapy regimen. Methods-Between March 1998 and October 2004, 92 eligible patients were enrolled. Following biopsy/resection, patients received three identical cycles of Induction chemotherapy (vincristine, cyclophosphamide, etoposide and cisplatin) administered every 21-28 days. Patients without tumor progression then received three Consolidation cycles of marrow-ablative chemotherapy (thiotepa and carboplatin) followed by autologous hematopoietic cell rescue. Results-The Maximum Tolerated Dose (MTD) of thiotepa was 10mg/kg/day x 2 days per cycle. The toxic mortality rate was zero during Induction and 2.6% during Consolidation. Centrally evaluated response rates to Induction and Consolidation in evaluable patients with residual tumor were 73.3% and 66.7% respectively. Disease progression rates on Induction and Consolidation were 4%. Five-year EFS and OS were 43.9±5.2% and 63.6±5% respectively. Gross total resection (GTR) versus <GTR were the only significant outcome comparisons: 5-year EFS and OS of 54.4±7% versus 28.9±7% (p= .0065) and 75.9±8% versus 48.7±8% (p= .0034) respectively. The 5-year EFS for localized (M0) versus metastatic (M1+) medulloblastoma was 67.5+/−9.5% versus 30+/−14.5% (p= .007). The 5-year EFS and OS for desmoplastic medulloblastoma patients versus other medulloblastoma were 78.6+/−11% versus 50.5+/−12% (p= .038) and 85.7±9.4% versus 60.6±11.6% (p= .046) respectively. Conclusions-This phase I dose-escalation study of marrow-ablative thiotepa regimen determined an MTD that had acceptable toxicity. Overall survival data justify this strategy for current COG studies.