Clinical trials for new frontline treatments
Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%. A study of 467 intermediate risk patients enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those patients with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.
By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:
- 1982-1985: European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized to melphalan autologous bone marrow transplant or no further therapy (no radiation therapy given to any). Transplant and no-transplant arms each had 65 patients, and recent long-term follow-up report revealed significantly better 5 year event-free survival for stage 4 over 1 year old in melphalan-transplant group versus no further treatment: 33% versus 17% respectively.
- 1990-1999: European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over 1 year old and revealed higher survival rate for rapid sequence induction (10-day cycle) versus standard induction (21-day cycle) with same total dose. Ten-year event free survival was 27% and 18% respectively with non-aggressive surgical approach, no radiotherapy, and melphalan-only autologous bone marrow or stem cell transplant for both groups.
- 1991-1996: Phase III trial with two sequential randomizations for 379 high-risk NB patients was carried out by the Children's Cancer Group (CCG-3891) which demonstrated improved survival with myeloablative therapy (with total body irradiation) and 13-cis-retinoic acid (Accutane) with 50 patients in each of the four arms of the study.,
- 1996-2003: The German (GPOH) study NB97 compared outcomes of 295 high-risk NB patients randomized for stem cell transplant or consolidation chemotherapy. Results showed increased survival with transplant.
- 2000-2006: The recent study (COG-A3973) questioned the need for purged stem cells for CEM-LI (carboplatin, etoposide, melphalan, with local irradiation) transplant, and accrued 486 patients. Purging stem cells was not found to improve survival determined in early review that the antibody ch14.18 with interleukin 2 and GMCSF (studied retrospectively in German GPOH NB90 and NB 97 at a lower dose and without cytokines) improved survival, and will accrue a total of 423 patients.
- 2002-2008: SIOP (International Society of Paediatric Oncology) formed the European SIOP Neuroblastoma Group (ESIOP NB) in 1994 and activated a phase III high-risk NB protocol in 2002 (SIOP-EUROPE-HR-NBL-1) using “rapid” COJEC (8 cycles of chemotherapy given at 10-day intervals) followed by transplant randomization to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan) and then randomization to with or without ch14.18 antibody treatment. This study will evaluate the use of growth factors as well as compare transplant regimens, with or without ch14.18 antibody, and all patients receive retinoic acid. This trial will accrue 1000 patients (175 per year). There are eight arms to this study.
- 2005-2010: The current German NB2004 randomization will include MIBG therapy and randomize topotecan use in up-front therapy and will accrue a total of 642 for all risk groups (roughly half will be high-risk). After transplant, the high-risk protocol includes six months of cis-retinoic acid, a three month break, and another three months of retinoic acid.
- 2007: The COG phase III ANBL0532 trial opened December 2007 for accrual of 495 and will compare single versus tandem transplants, and induction begins with two cycles of topotecan.
In addition to these phase III studies, research institutions such as Baylor College of Medicine/Texas Children's, St. Jude Children's Research Hospital, and Memorial Sloan-Kettering Cancer Center in New York offer unique treatment protocols. Texas Children's uses a novel induction regimen which includes a method of giving chemotherapy called “chemo-switching” where cisplatin is given as high-dose pulse and etoposide is given at low-dose over several weeks for the first two cycles. St Jude's recently finished (2007) testing a new up-front chemotherapy regimen in 23 children which included irinotecan and gefitinib with 16 months of maintenance chemotherapy after stem cell transplant with alternating oral 13-cis-retinoic acid and topotecan. In December 2008 St Jude's opened a new trial using temsirolimus and irinotecan in induction. Sloan-Kettering offers treatment that includes a mouse-derived monoclonal antibody, 3F8, used in protocols since the mid 1980s. This antibody is used for treating minimal residual disease or consolidation instead of stem cell transplant.
Clinical trials for refractory and relapsed neuroblastoma
Some children (particularly in high-risk cases) do not respond completely to frontline treatment (with a complete response or very good partial response) and are labeled refractory. These children are removed from the frontline therapy (clinical trial) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to frontline therapy and achieve a remission, but later the disease recurs (relapse). These children are also eligible for new therapies being tested in clinical trials. The protein p53 is believed to play a role in the development of resistance to chemotherapy.
Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group. Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.
Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are studying targeted therapy, anti-angiogenesis agents, and new monoclonal antibodies such as hu14.18-IL2.
In November 2006, DRAXIS Health received approval from the U.S. Food and Drug Administration (FDA) to run two clinical trials using radioactive Iobenguane I-131 Injection (I-131 MIBG) to treat high-risk neuroblastoma and in May 2008 Molecular Insight Pharmaceuticals announced the opening of a Phase IIa trial of Azedra, the I-131 MIBG molecule radiolabeled using Molecular Insight's proprietary Ultratrace technology, which removes unnecessary nonradioactive molecules, effectively concentrating radiation in the neuroblastoma tumor cells. These trials are coordinated by a group of 11 children’s hospitals and two universities in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium, and are continuations of earlier NANT studies. The NANT consortium is also currently offering trials using a tyrosine kinase inhibitor CEP-701 (lestaurtinib), new oral powder formulation of fenretinide, intravenous fenretinide, and bisphosphonate (Zometa).
In February 2007, a study in Sweden reported that a common painkiller might inhibit the development of neuroblastoma and help make treatment of the disease more effective. Celecoxib, an analgesic, anti-inflammatory agent that inhibits the inflammatory enzyme Cox-2 which is required for neuroblastoma cells growth and proliferation. Clinical studies are now planned; research to date has been done only in animals and cell cultures.
A November 2009 study in mice shows that activating the tumor suppressor p53 with a new drug, nutlin-3, may slow tumor growth.. In this study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and obstructs p53’s ability to trigger programmed cell death. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53.
Further Reading
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