Cancer Treatment

Chemotherapy for ependymoma

Ependymoma is a primarily pediatric cancer and the role of chemotherapy is not well defined. In 1998, an extensive review and analysis of all published literature on the topic of intracranial ependymoma highlighted the difficulty associated with extrapolating data from single-institution studies.
Forty-five series were reviewed, including more than 1400 children. The largest series reported on 92 patients, and the accrual rate ranged from 0.32-12 patients per year. Notably, the extent of surgical resection was the only reported prognostic factor in these series that was consistently found to be a valid predictor of outcome.
These findings were confirmed by a prospectively randomized trial published that same year evaluating Children's Cancer Group Protocol 921. Predictors of long-term survival included an estimate of the extent of resection made at surgery (total compared with less than total, P=0.0001) and the amount of residual tumor on postoperative imaging as verified by centralized radiologic review. Other factors, including centrally reviewed tumor histopathologic type, location, metastasis, and tumor (M and T) stages, patient age, race, gender, and chemotherapy treatment regimen were not found to be correlated significantly with long-term survival.Currently, no role exists for adjuvant therapy of spinal ependymoma after complete surgical resection. For patients who have postoperative residual tumor or early recurrence, radiation is considered on the basis of the individual patient's medical condition and neurological status.

In a 2001 abstract, the authors conclude, "a significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy." The conclusion of this abstract and article gives an impression that chemotherapy can be used so that irradiation can be avoided. In their study, the authors documented that 40% and 23% of children were spared from radiotherapy at 2 and 4 years, respectively, from the initiation of chemotherapy. This has engendered a lively debate that has not ended. NCCN does nto recommed adjuvant chemotherapy and for recurrence or anaplastic disease recommends, CPTII, temozolamide, notrosoureas, PCV or paltinum based regimens for 2nd or 3rd line therapy.

Avastin is in a pahse II study for this condition, with CPT-11.

Magnetic resonance spectroscopy for brain cancers

Proton MR spectroscopy (1H-MR spectroscopy, MRS) is a potentially useful adjunct to anatomic MR imaging in the characterization of brain tumors. Proton MR spectroscopy (1H-MR spectroscopy) provides additional information on the metabolic composition within an area of tissue. In August 2002, the American College of Radiology requested that the Center for Medicare and Medicaid Services (CMS) reconsider the 1994 noncoverage decision for 1H-MR spectroscopy. In September 2004, based in large part on 2 technology assessments CMS reaffirmed the existing noncoverage policy, concluding that "... the evidence is not adequate to conclude that 1H-MR spectroscopy is reasonable and necessary... for use in the diagnosis of brain tumors." Several subsidiaries of large managed care organizations have reached similar noncoverage decisions, though this is far from universal and many carriers have made ad ecision to cover MRS.

Of the 22 studies that measured diagnostic performance, the largest head-to-head comparison of MR imaging alone versus MR imaging and 1H-MR spectroscopy provided encouraging findings that 1H-MR spectroscopy can make a significant contribution to diagnosis for patients with indeterminate brain lesions.
A number of large diagnostic performance studies have demonstrated that 1H-MR spectroscopy can accurately distinguish between high- and low-grade astrocytomas. This work now needs to be extended to demonstrate: (1) diagnostic thresholds selected a priori, rather than post hoc, can achieve similar diagnostic accuracy, (2) the incremental diagnostic yield of 1H-MR spectroscopy compared with anatomic MR imaging, and (3) that any improvement in tumor grading by 1H-MR spectroscopy leads to a reduction in biopsy rates or changes in therapy. Evidence in other clinical subgroups, such as the use of 1H-MR spectroscopy to distinguish neoplastic and non-neoplastic lesions or to differentiate recurrent tumors from radiation necrosis, is limited by the small number of studies.

W. Hollingwortha, L.S. Medinac, R.E. Lenkinskid, D.K. Shibataa, B. Bernalc, D. Zurakowskie, B. Comstockb and J.G. Jarvika A Systematic Literature Review of Magnetic Resonance Spectroscopy for the Characterization of Brain Tumors American Journal of Neuroradiology 27:1404-1411, August 2006

Moller-Hartmann W, Herminghaus S, Krings T, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002;44:371–81

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2´-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth.

Currenlty Decitabine is FDA approved for myedlodysplaisa. Because of the aforementioned emchanism of action, there is interest in studying it in colorectal and oterh solid cancers. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies.

Robert Brown, Jane A Plumb Demethylation of DNA by decitabine in cancer chemotherapyExpert Review of Anticancer Therapy August 2004, Vol. 4, No. 4, Pages 501-510

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O'Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

http://jco.ascopubs.org/cgi/reprint/JCO.2004.01.947v1.pdf

Adis Decitabine: 2'-Deoxy-5-azacytidine, Aza dC, DAC, Dezocitidine, NSC 127716. R&D Profile Drugs in R & D. 4(6):352-358, 2003.

Jean-Pierre J. Issa DNA Methylation as a Therapeutic Target in Cancer Clinical Cancer Research 13, 1634-1637, March 15, 2007.

Xeloda for glioblastoma

Lay Summary: Xeloda is being investigated for GBM.

Capecitabine (Xeloda) is a drug that damages the DNA (deoxyribonucleic acid) of tumor cells and blocks the function of DNA and RNA (ribonucleic acid) of tumor cells. These actions help to kill the tumor cells. Celecoxib is a drug that may help to prevent the development of some types of cancer by blocking a type of enzyme (COX-2) that is found in tumor cells. Temozolomide and CCNU are the current standard treatment for malignant brain tumors. Both drugs work by damaging the DNA (deoxyribonucleic acid) of tumor cells to kill these tumor cells. 6-Thioguanine is a drug that helps to increase the effects of Temozolomide and CCNU on tumor cells.

This study, NCT00504660, has the following objectives:
Primary Objectives:

To determine the efficacy, as measured by 12 month progression-free survival, of Temozolomide or CCNU with 6-Thioguanine followed by Capecitabine and Celecoxib in the treatment of patients with recurrent and/or progressive anaplastic gliomas or glioblastoma multiforme.
To determine the long-term toxicity of Temozolomide or CCNU with 6-Thioguanine followed by Capecitabine and Celecoxib in recurrent anaplastic glioma or glioblastoma multiforme patients treated in this manner.
To determine the clinical relevance of genetic subtyping tumors as a predictor of response to this chemotherapy and long term survival.

However, the question is about Xeloda alone. I understand that the otehr drugs have been approved.

Xeloda is also being investigated with radiation and in combination with other chemotherapy drugs for glioblastoma. Several trials are lsited on: http://clinicaltrials.gov/ct2/results?recr=Open&term=glioma

http://clinicaltrials.gov/ct2/show/NCT00504660?term=glioma&recr=Open&rank=12

nccn.org, brain cancer

A. Reardon, Patrick Y. Wen Therapeutic Advances in the Treatment of Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Gleevec for glioblastoma and astrocytoma

Lay Summary: Gleevec is not active in glioblastoma but may have promise in combination with other drugs.

Despite optimal treatment, the prognosis of patients with malignant gliomas remains poor. Patients with glioblastoma multiforme have a median survival of 9 to 14 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months. Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks. There is a need for more effective therapies.
Tyrosine kinases play a fundamental role in signal transduction, and deregulated activity of these enzymes has been observed in an increasing number of cancers. There is growing evidence that specific inhibitors of these tyrosine kinases have potential therapeutic applications in oncology and Gleevec is being actively investigated in this disease.  in one phase II component, the 6M-PFS for glioblastoma multiforme patients was 3%, whereas that for anaplastic glioma was 10%. In comparison, a retrospective review of negative phase II trials in recurrent malignant gliomas from the M.D. Anderson Cancer Center found a 6M-PFS of 15% for glioblastoma multiforme and 31% for anaplastic glioma (2). The results are especially disappointing for anaplastic gliomas where the relative importance of PDGF raised the possibility of potential benefit from imatinib.

The European Organization for Research and Treatment of Cancer and the North Central Cancer Treatment Group are also conducting phase II studies of imatinib in recurrent gliomas. In the European Organization for Research and Treatment of Cancer study, glioblastoma multiforme and anaplastic glioma patients were initially treated with imatinib at a dose of 300 mg twice daily, increasing after 8 weeks to 400 mg twice daily if no grade II toxicity was observed. Subsequently, the protocol was amended to treat patients initially with 400 mg imatinib twice daily, increasing to 500 mg twice daily if no toxicity was observed after 8 weeks. The majority of these patients were on EIAED, and there was no attempt to adjust the dose according to the type of AED. Preliminary results of the European Organization for Research and Treatment of Cancer phase II study in glioblastoma multiforme patients showed 3 partial response and 5 stable disease over 6 months in 51 patients, with a 6M-PFS of 15.7%. In anaplastic glioma patients, there was only 1 partial response in 36 anaplastic oligodendroglioma/anaplastic oligoastrocytoma patients and 1 partial response in 25 anaplastic astrocytoma patients. These results are consistent and suggest that imatinib has minimal single-agent activity in malignant gliomas.

The next step was studying Gleevec in combiantion with other drugs. As an example of the trend, I will focus on Gleevec and Hyrea data. Researchers from Germany have reported clinical benefit in 57% of patients with refractory glioblastoma multiforme treated with Gleevec (imatinib) and hydroxyurea. The details of this phase II study appeared in the September 2005 issue of Annals of Oncology. The current trial included 30 patients with progressive glioblastoma multiforme refractory to chemotherapy and radiation therapy. The combination of Gleevec and hydroxyurea led to a 20% response rate and a disease stabilization rate of 37%. The median time to disease progression was 10 weeks and the overall survival was 19 weeks. Three patients continue on therapy for 106 or more weeks. The two-year progression-free survival was 16% with 32% of patients surviving at least six months. These authors suggest that this combination shows promise. Clearly much more investigtion needs to be done before this combination can be routinely prescribed.

Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Annals of Oncology. 2005;16:1702-1708.
McLaughlin ME, Robson CD, Kieran MW, et al. Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (ST0571), Gleevec: a case report and laboratory investigation. Journal of Pediatric Hematology and Oncology . 25:644-648.
Patrick Y. Wen et al, Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08 Clinical Cancer Research Vol. 12, 4899-4907, August 15, 2006
. M.P. Omuro, S. Faivre, and E. Raymond
Lessons learned in the development of targeted therapy for malignant gliomas
Mol. Cancer Ther., July 1, 2007; 6(7): 1909 - 1919.

Octreotide for maningioma

Lay Summary: Case reports usggest that octreotide may casue regression of some meningiomas.

For more than a decade, In-111 octreotide has been known to accumulate in meningiomas as a result of the expression of subtype 2 somatostatin receptors. Improved imaging characteristics can be expected with the recently developed radiotracer Tc-99m depreotide, which also binds to subtype 2 somatostatin receptors. SPECT with Tc-99m depreotide and orm In-111 octreotide imaging are both useful.
Therapeutically, octreotide has also been reported to cause regressions. The first report was in 1993. Garcia-Luna et al reported on the clinical use ofoctreotide, a long-acting somatostatin agonist, in 3patients with unresectable meningiomas. Doses usedwere gradually increased up to 1000, 900, and 1500µg/24 hours during 16, 6, and 7 weeks, respectively.Patient tolerance to the drug was excellent, withabdominal discomfort and diarrhea observed in only 1patient. Findings included the subjective improvementof headache in 2 patients and objective transientimprovement in ocular movements in 1 patient. In allcases, computed tomography scans observed nochange in meningioma size. This report confirms thesafety of octreotide but was too small to draw any mean-ingful conclusions. Since then a number of other case reports have appeard but no prospsective studies have been published.

The following requiremetns of teh policy are not met: For more than a decade, In-111 octreotide has been known to accumulate in meningiomas as a result of the expression of subtype 2 somatostatin receptors. Improved imaging characteristics can be expected with the recently developed radiotracer Tc-99m depreotide, which also binds to subtype 2 somatostatin receptors. SPECT with Tc-99m depreotide and orm In-111 octreotide imaging are both useful.
Therapeutically, octreotide has also been reported to cause regressions. The first report was in 1993. Garcia-Luna et al reported on the clinical use ofoctreotide, a long-acting somatostatin agonist, in 3patients with unresectable meningiomas. Doses usedwere gradually increased up to 1000, 900, and 1500µg/24 hours during 16, 6, and 7 weeks, respectively.Patient tolerance to the drug was excellent, withabdominal discomfort and diarrhea observed in only 1patient. Findings included the subjective improvementof headache in 2 patients and objective transientimprovement in ocular movements in 1 patient. In allcases, computed tomography scans observed nochange in meningioma size. This report confirms thesafety of octreotide but was too small to draw any mean-ingful conclusions. Since then a number of other case reports have appeard but no prospective studies have been published.

Jaffrain-Rea ML, Minniti G, Santoro A, et al. Visual improvement during octreotide therapy in a case of episellar meningioma. Clin Neurol Neurosurg. Mar 1998;100(1):40-3.

Garcia-Luna PP, Relimpio F, Pumar A, et al. Clinical use of octreotide in unresectable meningiomas: a report of three cases. J Neurosurg Sci. 1993;37:237-241.

Marc C. Chamberlain, MD, Michael J. Glantz, MD and Camilo E. Fadul, MDRecurrent meningioma
Salvage therapy with long-acting somatostatin analogue NEUROLOGY 2007;69:969-973

Motefaxin gadollinium for brain metstases and gliblastoma

Motexafin gadolinium is a member of a class of rationally designed porphyrin-like molecules called texaphyrins. The rationale for its use in cancer therapy is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells and it has a novel mechanism of action as it induces redox stress, triggering apoptosis in a broad range of cancers. RECENT FINDINGS: In vitro studies have shown that motexafin gadolinium is synergistic with radiation and varied chemotherapeutic agents. A phase III international study has shown that the onset of neurologic progression is significantly delayed in patients with brain metastases from lung cancer treated with whole-brain radiation and motexafin gadolinium (compared with radiation alone). Recent preclinical data have shown that motexafin gadolinium alone is cytotoxic to cancers such as multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia through redox and apoptotic pathways. Multiple clinical trials examining motexafin gadolinium as a single agent and in combination with radiation and/or chemotherapy for the treatment of solid and hematopoietic tumors are underway. SUMMARY: Motexafin gadolinium is a novel tumor-targeted agent that disrupts redox balance in cancer cells by futile redox cycling. Motexafin gadolinium is currently in numerous hematology/oncology clinical trials for use as a single agent and in combination with chemotherapy and/or radiation therapy. Most of the reprots ahve been in the treatment of brain metastases. Trials for brain mets and gliomas are ongoing.

nccn.org, brain cancers

GM, Khuntia D, Mehta MPMotexafin gadolinium: a novel radiosensitizer for brain tumors.Forouzannia A, Richards.Expert Rev Anticancer Ther. 2007 Jun;7(6):785-94.

D. R. Miles, J. A. Smith, S.-C. Phan, S. J. Hutcheson, M. F. Renschler, J. M. Ford, and G. W. Boswell
Population Pharmacokinetics of Motexafin Gadolinium in Adults With Brain Metastases or Glioblastoma Multiforme
J. Clin. Pharmacol., March 1, 2005; 45(3): 299 - 312.

Temodar and radiation for Oligodendroglioma

Although not receommended by NCCN, or for that matter any study, most neuro-oncologists are now using combined TEmodar and radiation posotperatively for anaplastic oligodendroglioma. Regardless of molecular genetic status, the most commonly recommended treatment in a questinnaire study was the use of concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (18%-34%). The role of chemotherapy for the treatment of oligodendroglioma was well established by several studies using nitrosourea-based therapy. Most used procarbazine, lomustine (CCNU), and vincristine, a combination chemotherapy regimen (ie, PCV) developed by Levin and coworkers. Patients with pure and mixed oligoastrocytic tumors, newly diagnosed, and recurrent mixed tumors responded to this therapy before receiving radiotherapy. Despite prolonged responses, most patients experience disease relapse and ultimately die of progressive disease. The median time for recurrence was at least 16 months in partial responders and at least 25 months in complete responders. Recurrent tumors are not cured by PCV, and the intensity of treatment may be limited by the bone marrow reserve.
Several recent studies evaluated the role of temozolomide as second-line chemotherapy for recurrent oligodendroglioma and showed a response rate of about 25% for patients relapsing after PCV therapy. The EORTC study evaluated temozolomide as a first-line chemotherapy for recurrent OD and showed a response rate of 54%, with 39% of patients remaining free from progression at 12 months.

A phase III study preliminary findings reported by Cairncross et al, comparing radiation therapy versus chemotherapy plus radiation in patients with newly diagnosed anaplastic OD and mixed OD, showed overall similar survival in both groups (4.8 y for radiotherapy plus chemotherapy group vs 4.5 y for radiotherapy alone). However, disease progression-free interval was longer for the combined therapy group (2.6 y vs 1.9 y for radiotherapy alone group). Thus it is not yet a standard of care.

RTA-477 for glioblastoma and brain metastases

Lay Summary: RTA-477 is a promising but experimental treatment at this time.

  RTA 744 is a novel anthracycline that is completing Phase 1 testing. This agent has been well tolerated and has demonstrated excellent activity against brain tumors. Advanced clinical trials of RTA 744 in both primary and secondary (metastatic) brain cancers will be initiated during the second half of 2007. The FDA has granted Orphan Drug designation to RTA 744 for the treatment of brain tumors.

  Thise compounds is a potent inhibitors of topoisomerase II, a DNA repair enzyme. RTA 744 has been studied in a a Phase 1 trial in patients with recurrent primary brain tumors at the University of Texas M. D. Anderson Cancer Center, the University of Texas Southwestern Medical Center at Dallas and the UCLA School of Medicine. As reported at the Society for Neuro-Oncology annual meeting in November 2006, RTA 744 demonstrated appropriate pharmacokinetics and a safety profile consistent with or somewhat better than other drugs in its class. 

Most importantly, RTA 744 has produced positive signs of anti-cancer activity in multiple patients with recurrent GBM.  In particular, one patient who began receiving RTA 744 in January 2006 experienced complete tumor abrogation as measured by repeated MRI imaging (known as a “Complete Response”) and remains tumor free as of April, 2007. Complete Responses are exceedingly rare in this patient population, and indicate that a drug is highly active against this particularly deadly and debilitating form of cancer. Several other patients have also seen their tumors shrink or stabilize upon treatment with RTA 744.

Based on the encouraging results seen to date, Reata started clinical trials of RTA 744 in patients with GBM and brain metastases during the second half of 2007.

C. A. Conrad et al, Survival study of RTA 744 (currently a single agent phase I study) alone and in combination with temozolomide in orthotopic model of glioma
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 1577

R. Kazerooni et al, Phase I clinical pharmacokinetics of RTA 744: A blood brain barrier penetrating anthracycline active against high-grade glioma
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 2045

nccn.org, brain cancer

Chemotehrapy for medulloblastoma in adults

Medulloblastoma is treated primarily with surgical excision followed by radiation therapy and chemotherapy. When there is spinal extension, craniospinal radiation is standard.

Inoperable medulloblastomas are often treated iwth chemotherapy but there is no randomized prospective evidence to support this. This is especially so in adults, in whom this disease is much less common and in whom it appears to behave distinctly differently. 30% of cases occur in adults. Recent therapeutic advances in the treatment of average-risk childhood medulloblastoma have emphasized the reduction of treatment-related toxicity while improving progression-free survival and high dose therapy. However, lessons learned from the pediatric experience have not been widely applied to the adult population in Phase II or randomized clinical trials.

nccn.org, brain cancer

David D Eisenstat Clinical management of medulloblastoma in adults
Expert Review of Anticancer Therapy October 2004, Vol. 4, No. 5, Pages 795-802

http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/NeuroOncology/ManagementPolicies/Medulloblastoma.htm