Cancer Treatment Today » Neuro-oncology

Irinotecan for brain metastases of breast and lung cancer -pro

M Levin, MD — Fri, 09 Nov 2012 15:34:51 +0000

Because irinotecan penetrates the brain-blood barrier and has an effect in primary brain cancer, there is some interest in using it for brain metastasis, especially for lung cancer and breast cancer. Most studies of irinotecan had been for brain mets of small(SCLC) and non-small cell lung cancer(NSMCLC) and not breast cancer and have had mixed results. One study reported complete responses with irinotecan-based chemotherapy for brain metastases in three patients with SCLC, parotid cancer, and esophageal adenocarcinoma. The combination of cisplatin, ifosfamide and irinotecan in treatment-naive patients with NSCLC led to an intracranial response rate of 50%. A study of temozolomide (200 mg/m²) on days 1 to 5 and irinotecan (200 mg/m²) on days 1 to 5 every 4 weeks in previously untreated patients with NSCLC brain metastases reported no responses.

There are several ongoing studies for lung cancer. For breast cancer, there is also a study: Irinotecan and Temozolomide in Treating Patients With Breast Cancer Who Have Received Previous Treatment for Brain Metastases, NCT00617539.

nccn.org, brain cancers, p.38

Chou R, Chen A, Lau D.Complete response of brain metastases to irinotecan-based chemotherapy.ONCOLOGY. Vol. 22 No. 2

Yun Oh, MD et al, Systemic Therapy for Lung Cancer Brain Metastases: A Rationale for Clinical Trials

J Clin Neurosci. 2005 Apr;12(3):242-5.ONCOLOGY. Vol. 22 No. 2

Chou R, Chen A, Lau D: Complete response of brain metastases to irinotecan-based chemotherapy. J Clin Neurosci 12:242-245, 2005. Fujita A, Fukuoka S, Takabatake H, et al: Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology 59:291-295, 2000.For Lay version see here

Accutane and Temodar for glioblastoma – pro

admin — Sat, 01 Sep 2012 20:57:58 +0000

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

Sports for hemophiliacs – pro

admin — Sat, 01 Sep 2012 20:57:09 +0000

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″, seehttp://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#s

Tarceva for GBM – pro

admin — Sat, 01 Sep 2012 20:56:22 +0000

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.

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

Fine HA. J Clin Oncol. 2004;doi:10.1200/JCO.2004.06.927.

PET for brain cancer/ necrosis versus progression – pro

admin — Sat, 01 Sep 2012 20:54:49 +0000

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

Isotretinoin for glioblastomas – pro

admin — Sat, 01 Sep 2012 20:53:47 +0000

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.

Sandostatin for meningioma – pro

admin — Sat, 01 Sep 2012 20:53:00 +0000

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.

Treatment of brain metastases – pro

admin — Sat, 01 Sep 2012 20:51:52 +0000

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. 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. Radiation therapy, with or without chemotherapy, is still the treatment of choice for patients needing a palliation of neurological symptoms

In two phase II trials of temozolomide in heavily pretreated patients with various solid tumor brain metastases, temozolomide was safe and generally well tolerated and showed clinical activity, with three partial responses and 19 disease stabilizations. Results of a third randomized phase II trial of concurrent administration of temozolomide and radiation therapy followed by adjuvant temozolomide therapy compared with radiation alone showed a higher rate of complete and partial responses (objective response of 96% v 67%) and significantly more complete responses (38% v 33%, P =.017), primarily in patients with newly diagnosed brain and lung metastases.

While Avastin does penetrate the blood brain barrier, it’s use specifically to treat brain metastasis is largely unexplored. A 2010 Cochrane panel considered Avastin and did not recommend it. A recent study presented at the ASCO Annual Meeting investigated the use of carboplatin and bevacizumab (Avastin) in progressive brain metastases (including HER2-positive and HER2-negative patients), demonstrating a very promising response rate of 63% in the central nervous system. 3 This remains something that needs to be confirmed.

In terms of surveillance, both NCCN and ACR recommend MRI imaging every three months for one year and no systemic surveillance imaging.

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]

Abrey LE, Christodoulou C. Temozolomide for treating brain metastases.Semin Oncol. 2001 Aug;28(4 Suppl 13):34-42.

Olson JJ, Paleologos NA, Gaspar LE, Robinson PD, Morris RE, Ammirati M, Andrews DW, Asher AL, Burri SH, Cobbs CS, Kondziolka D, Linskey ME, Loeffler JS, McDermott M, Mehta MP, Mikkelsen T, Patchell RA, Ryken TC, Kalkanis SN. The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics. J Neurooncol. 2010 Jan;96(1):115-42. [78 references]

Patel SH, Robbins JR, Videtic GM, Gore EM, Bradley JD, Gaspar LE, Germano I, Ghafoori P, Henderson MA, Lutz ST, McDermott MW, Patchell RA, Robins HI, Vassil AD, Wippold FJ II, Expert Panel on Radiation Oncology-Brain Metastases. ACR Appropriateness Criteria® follow-up and retreatment of brain metastases. [online publication]. Reston (VA): American College of Radiology (ACR); 2011. 8 p. [33 references]

Lin NU, Gelman RS, Younger J, et al: Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). J Clin Oncol 31(suppl):Abstract 513, 2013.

Temodar and radiation for Oligodendroglioma – pro

admin — Sat, 01 Sep 2012 20:50:27 +0000

Although not recommended by NCCN, or for that matter any study, most neuro-oncologists are now using combined Temodar and radiation postoperatively for anaplastic oligodendroglioma. Regardless of molecular genetic status, the most commonly recommended treatment in a questinnaire survey of neuro-oncologists was the use of concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (18%-34%).

The role of chemotherapy for the treatment of oligodendroglioma is 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.

Motefaxin gadollinium for brain metastases and gliblastoma – pro

admin — Sat, 01 Sep 2012 20:49:31 +0000

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.