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.

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.

Treatment of brain metastases

Lay Summary: We overview treatment options for brain metastases.

Surgical resection should be considered in patients with single brain metastasis in an accessible location, especially when the size is large, the mass effect is considerable and an obstructive hydrocephalus is present (Good Practice Point). Surgery is recommended when the systemic disease is absent/controlled and the Karnofsky Performance score is 70 or more (level A recommendation). When the combined resection of a solitary brain metastasis and a non-small cell lung carcinoma (stage I and II) is feasible, surgery for the brain lesion should come first, with a maximum delay between the two surgeries not exceeding 3 weeks. Patients with disseminated but controllable systemic disease (i.e. bone metastases from breast cancer) or with a radioresistant primary tumor (melanoma, renal cell carcinoma, and colon cancer) may benefit from surgery. Surgery at recurrence is useful in selected patients.

Stereotactic radiosurgery (SRS) should be considered in patients with metastases of a diameter of <3–3.5 cm and/or located in eloquent cortical areas, basal ganglia, brain stem or with comorbidities precluding surgery. Gamma-knife or linear accelerator (Linac) are equally effective. SRS may be effective at recurrence after prior radiation treatment.

The role of adjuvant whole-brain radiotherapy (WBRT) after surgery or radiosurgery remains to be clarified. In case of absent/controlled systemic disease and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT if close follow-up with MRI (every 3 to 4 months) is performed or deliver early WBRT with fractions of 1.8–2 Gy to a total dose of 40–55 Gy to avoid late neurotoxicity. Whole-brain radiotherapy alone is the therapy of choice for patients with active systemic disease and/or poor performance status and should employ hypofractionated regimens such as 30 Gy in 10 fractions or 20 Gy in five fractions. For elderly patients with poor performance status WBRT can be withheld and supportive care only employed .

In patients with up to three brain metastases, good performance status (KPS of 70 or more) and controlled systemic disease, SRS is an alternative to WBRT (level B recommendation), whilst surgical resection is an option when the lesions are in an accessible location (level C recommendation). In patients with more than three brain metastases WBRT with hypofractionated regimens is the treatment of choice (level B recommendation). In bedridden patients it should be considered to withhold active radiation treatment and restrict therapy to supportive care.

There appears to not be a role for IMRT since it is neither a good therapy for overall brain like WBRT not specific enought for the tumor alone, like radiosurgery.

The Role of Chemotherapy

Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors, like small cell lung cancers, lymphomas, germ cell tumors and breast cancers, especially for chemonaive patients or if an effective chemotherapy schedule for the primary is still available (Good Practice Point). Radiation therapy, with or without chemotherapy, is still the treatment of choice for patients needing a palliation of neurological symptoms

Mintz AP, Perry J, Laperriere N, Cairncross G, Chambers A, Spithoff K, Neuro-oncology Disease Site Group. Management of single brain metastases: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Aug 15. 26 p. (Evidence-based series; no. 9-1). [29 references]

Soffietti R, Cornu P, Delattre JY, Grant R, Graus F, Grisold W, Heimans J, Hildebrand J, Hoskin P, Kalljo M, Krauseneck P, Marosi C, Siegal T, Vecht C. EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur J Neurol 2006 Jul;13(7):674-81. [44 references]

Sandostatin for meningioma

Several preclincial reports and a small phase Ii study recently been published suggesting activity of Sandostatin in meningioma.  Somatostatin receptors, especially the sst2A subtype, are present on most meningiomas. The addition of somatostatin inhibits meningioma growth in vitro in some studies. There have been anecdotal reports of octreotide inhibiting growth in meningiomas.

A prospective pilot trial of sustained-release somatostatin (Sandostatin LAR) in 16 patients with recurrent meningiomas was conducted with a primary study objective of progression-free survival at 6 months. Patients received 2 to 15 cycles (median 4.5) of somatostatin with minimal toxicity. Four partial responses, five stable disease, and seven progressive disease patterns were seen. Duration of response ranged from 2 to 20+ months (median 5.0 months). Median survival was 7.5 months (range 3 to 20+). The overall progression-free survival was 44% (seven patients) at 6 months.

In this small trial of patients with recurrent meningiomas shown to overexpress somatostatin receptors by octreotide scintigraphy, long-acting somatostatin (Sandostatin LAR) was administered on a monthly schedule. Thirty-one percent of patients demonstrated a partial radiographic response and 44% achieved progression-free survival at 6 months. Toxicity was minimal, suggesting somatostatin analogues may offer a novel, relatively nontoxic alternative treatment for recurrent meningiomas.

This a prelimianry study that needs repeatition and validation. Numerous treatmetn alternaives formeingioma are available. To date, surgical resection is the mainstay of meningioma therapy. The completeness of the resection is the single most important prognostic factor for recurrence. In case of incomplete resection or recurrence, radiation therapy with 54 Gy (1.8 to 2 Gy/fraction) yields comparable results to total resection. Radiosurgery is a valuable alternative to radiotherapy (RT), maybe in the future also for surgery, as recently demonstrated. In the rare meningioma patients, that have exhausted the possibilities of surgery and RT, there have been some successful small series using hydroxyurea or interferon alpha.

Future therapeutic options might consist in octreotide isotopic therapy or targeted therapy directed against tumour neo-angiogenesis or other proliferation associated markers in meningiomas. However, at this time it should be considered investigational.Marc C. Chamberlain, MD, Michael J. Glantz, MD and Camilo E. Fadul, MD
Salvage therapy with long-acting somatostatin analogue NEUROLOGY 2007;69:969-973

C  Marosi, M  Hassler, K  R ssler
Guidelines for treatment of meningioma, Forum (Genoa, Italy) Vol. 13 Issue 1 Pg. 76-89    2003

McMullen KP, Stieber VW. Meningioma: current treatment options and future directions.
Curr Treat Options Oncol. 2004 Dec;5(6):499-509.

Isotretinoin for glioblastomas

Isotretinoin is a promising agent for glioblastoma. 13-cis-Retinoic acid (cRA) is a synthetic analog of vitamin A, which binds to all three subtypes of retinoic acid receptors (RARα, β, and γ) and retinoid X receptors (RXRα, β, and γ). RAR and RXR are members of the nuclear steroid receptor family, bind as homodimers or heterodimers to specific DNA response elements, and influence the transcription of relevant genes. Retinoids have diverse biologic effects in malignant conditions, including regulating the synthesis of enzymes, growth factors, and binding proteins. Retinoids also modulate genomic and postgenomic expression, exert antiangiogenic effects, and interact with protein kinase-C pathways. The retinoic acid receptor and its ligand mediate trans- repression of activating-protein-1, which is a heterodimeric transcription factor composed of fos- and jun-related proteins. Retinoids also protect the regulatory domain of protein kinase-C from modification induced by oxidant tumor promoters. In hematologic and nonhematologic (skin and head and neck) tumors, treatment with retinoids has demonstrated some efficacy. A phase 2 pilot study of cRA given to patients with progressive or recurrent glioma after failing radiation and conventional chemotherapy demonstrated encouraging results in 1996 and 1999 (Yung et al). Since then, other reports were published. It is not to the point of being combined with various other active drugs in phase II studies.

Siew-Ju See, Victor A. Levin, W.-K. Alfred Yung, Kenneth R. Hess, and Morris D. Groves
13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme Neuro-oncol. 2004 July; 6(3): 253–258.

Yung WK, Kyritsis AP, Gleason MJ, Levin VA.Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid. Clin Cancer Res. 1996 Dec;2(12):1931-5.

PET for brain cancer/ necrosis versus progression

For PET brain cancers are not inlcuded in guidelines and CMS does not cover PET for this diangosis. Occasionally, PET can provide information to differntiate tumor necrosis from tumor progression. The sensitivity of PET for differentiating necrosis and tumor progression is 80%–90% and the specificity is 50%–90%. Causes of false-negative PET results include recent radiation therapy, low histologic grade, and small tumor volume. FDG PET may be false positive in nonmalignant inflammatory processes and subclinical seizure activity. The question of hypermetabolic foci of radiation injury as a cause of false-positive scans requires further investigation. Other issues requiring further study are the optimal timing of FDG PET after radiation and chemotherapy and the accuracy of FDG PET in tumors other than high-grade gliomas.

W.-Y. Guo
Is Current Imaging Good Enough to Differentiate Radiation-Induced Brain Injury from Tumor Recurrence?
AJNR Am. J. Neuroradiol., June 1, 2005; 26(6): 1305 - 1305.

Daniel D. Langleben and George M. Segall PET in Differentiation of Recurrent Brain Tumor from Radiation Injury The Journal of Nuclear Medicine Vol. 41 No. 11 1861-1867

Tarceva for GBM

Lay Summary: Tarceva is a promising new drug for GBM.

There are a number of phase II trials of Tarceva. Researchers from the Cleveland Clinic Brain Tumor Institute have reported that Tarceva® (erlotinib) produced responses in more than 40% of patients with glioblastoma multiforme. These results were presented at the 29th European Society of Medical Oncology (ESMO) Congress held in Vienna, Austria, October 29 – November 3, 2004. Another  phase II trial, evaluating efficacy and tolerability of gefitinib in 53 recurrent glioblastoma patients not selected for any biologic characteristic showed that the drug may have modest activity. Haas-Kogan et al. reported their experience in 41 glioma patients treated with erlotinib within a phase I study. Erlotinib was administered alone or in combination with the alkylating agent temozolomide. All of these studies showed activity comparable or better than other available options.

There are two phase II trials and a phase I trial as well as the orphan drug designation by the FDA. This meets Caremark criteria for considering the therapy not to be investigational but most toerh palns would still consider it currenlty to be investigational.

Vogelbaum MA, Peereboom D, Stevens GH, et al. Phase II study of single agent therapy with the EGFR tyrosine kinase inhibitor erlotinib in recurrent glioblastoma multiforme. Proceedings from the 29th ESMO Congress, Vienna, Austria, October 29 – November 3, 2004; Annals of Oncology 2004;15, supplement 3:iii206, Abstract #783.

Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22:133–42.

Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005;97:880–7

Sports for hemophiliacs

Regular exercise strengthens muscles and protects joints, which can help reduce spontaneous bleeding. Some recommended activities include swimming, bicycling, walking, jogging, tennis, golfing, dancing, fishing, sailing and bowling. Most experts recommend that children with hemophilia avoid contact sports - such as football, hockey, boxing and wrestling. This information can be found in the Ntional Hemophilia Foundation publication "Hemophilia, Sports and Exercise, 1966", see http://www.hemophilia.org/resources/handi_pubs.htm#bdr. Thus, basketball as a contact sport should not be encouraged for a child with hemophilia, on medical grounds. The Canadian Hemophilia Foundation considers backetball to be a low to medium risk activity. It is my opinion that encouraging a child to engage in contact sports with support of high doses of factors with their own side effect risks may not be wise. Traditionally, swimming, golf, and table tennis were recommended by doctors, whereas most contact sports, including football, were discouraged. However, there had been an emerging trend to allow more and more activities in the recent years and this trend is reflected by the literature. Medical advise should be individualized and it is not possible to speak of a standard of care in this evolving area.

McLain, Larry G.; Heldrich, Fred T. Physician and Sportsmedicine V18 n11 p73-74,76-77,80 Nov 1990 Hemophilia and Sports: Guidelines for Participation. Case Report.

Buzzard BM. Sports and hemophilia: antagonist or protagonist.Clin Orthop Relat Res. 1996 Jul;(328):25-30

Kelly A. Fiala, Sandra J. Hoffmann, and Donna M. Ritenour,
A Survey of Team Physicians on the Participation Status of Hemophilic Athletes in National Collegiate Athletic Association Division I Athletics, J Athl Train. 2003 Jul–Sep; 38(3): 245–251.

http://www.wfh.org/2/docs/Publications/Diagnosis_and_Treatment/Gudelines_Mng_Hemophilia.pdf#search=%22hemophilia%2C%20sports%2C%20guidelines%22

Accutane and Temodar for glioblastoma

Not many options are available for progressive gliomas. Among them is Accutane, studied most in combination with temazolamide. A phase II trial (Radiation Therapy Oncology Group 91–13) of all-trans-retinoic acid in 30 patients with recurrent malignant glioma disclosed minor activity, with tolerable side effects; a response rate of 12% was observed, with a median time to progression of 3.8 months and a median OS of 5.7 months. A similar single-institution phase II trial of all-trans-retinoic acid in 36 patients with recurrent glioma did not show much evidence of activity, with a 3% minor response rate, and median time to progression of only 8 weeks. A recent phase II trial of the combination of radiotherapy and cRA plus interferon alfa-2a in patients with newly diagnosed high-grade glioma did not show an improvement in survival as compared with historical controls. Yung et al conducted a phase II prospective study of 43 patients with recurrent malignant glioma treated with cRA as a single agent, administered at a daily oral dose of 60 to 100 mg/m2/d for 3 weeks, followed by 1 week of rest every 28 days. A response rate of 23% (PR, 7%; minor response, 16%) was observed, with median time to progression of 16 weeks and median survival of 58 weeks for GM and 34 weeks for AA. In another study, for all patients, the PFS 6 was 43%. PFS 6 was 32% for GM and 50% for all AG combined (46% for the non-AO AG subset and 61% for pure AO subset). These results, as compared with the PFS 6 observed in the database (GM, 15%; AG, 31%), met the criteria for PFS 6 success, exceeding the 20% improvement for both the GM and AG strata. At the time of design of the current protocol, the PFS 6 for TMZ alone was not yet reported; subsequent clinical trials of single-agent TMZ reported a PFS 6 of 21% for GM and 44% for AA.

Kurt A. Jaeckle, Kenneth R. Hess, W.K. Alfred Yung, Harry Greenberg, Howard Fine, David Schiff, Ian F. Pollack, John Kuhn, Karen Fink, Minesh Mehta, Timothy Cloughesy, M. Kelly Nicholas, Susan Chang, Michael Prados Journal of Clinical Oncology, Vol 21, Issue 12 (June), 2003: 2305-2311

Groves, M. D., et al. Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. Journal of Clinical Oncology, 2002, 20, 1383-1388