Cancer Treatment Today » Brain Metastases

How to follow brain metastases after radiosurgery – pro

M Levin, MD — Thu, 22 Nov 2012 15:15:17 +0000

How to follow a patient with treated brain metastases is becoming a more and more actual clinical problem as treatments that control systemic disease continue to improve. It is not uncommon now to follow a patient for many months or even years after treatment of metastatic disease without new metastases developing. One study reported a median time of 8.8 months to new metastasis after radiosurgery. Patients with 3 or more lesions and cancer histologies other than NSCLC were more likely to have additional future metastasis. This data produced a recommendation for close surveillance with a 3-month interval between magnetic resonance imaging (MRI), in order to identify new metastasis early to facilitate the most effective treatment. However, the most appropriate frequency and choice of imaging modality following treatment of a patient with brain metastases remain controversial. As the most sensitive current imaging modality for the brain, MRI is the preferred imaging modality, even with an newer applications such as spectroscopy, diffusion-weighted imaging, and perfusion-weighted imaging.

A. Mintz, MD et al, Management of single brain metastasis: a practice guideline. Curr Oncol. 2007 August; 14(4): 131–143.

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]

For Lay version see here

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

Suspected brain metastases: The role of PET – pro

M Levin, MD — Mon, 03 Sep 2012 03:01:20 +0000

Biopsying the primary lesions is technically difficult since it is located in the cerebellum. Studies of PET have focused on the population with a biopsy proven source of metastases. For example, in one study of biopsy proven cancer of unknown origin, a survey on clinical usefulness of PET (response rate 83%) suggested that PET positively contributed to diagnostic understanding in 29 of 52 evaluable cases. It concluded that late in the diagnostic trajectory, approximately four patients need to be scanned by PET in order to find one primary tumour. However, in addition to direct demonstration of unknown primaries, there appears to be a positive effect on the diagnostic work-up of these patients of a similar magnitude.

A 1999 study found that PET identified focal hypermetabolic abnormalities in 19 of 22 intracranial metastases, 2 hypometabolic lesions, and 1 renal cell tumor embolism that hemorrhaged (hypometabolic lesion). It also identified 82% of extracranial primary tumor sites, of which 55% were found only on PET and not on conventional diagnostic tests. Patients did not have a biopsy proven diagnosis in this study. Another study concluded: ” Screening the patients with suspected metastatic brain tumors using whole-body (18)F-FDG PET could be helpful in differentiating metastatic brain tumor from primary brain tumor and in detecting the primary lesion.”

Joshi, U, van der Hoeven, J J M, Comans, E F I, Herder, G J, Teule, G J J, Hoekstra, O S
In search of an unknown primary tumour presenting with extracervical metastases: the diagnostic performance of FDG-PET
Br J Radiol 2004 77: 1000-1006

D. A. Podoloff
PET/CT and Occult Primary Tumors
J Natl Compr Canc Netw, March 1, 2009; 7(3): 239 – 244.

Peter Nicholson et al, FDG-PET in the Staging Work-Up of Patients with Suspected Intracranial Metastatic Tumors, Ann Surg. 1999 August; 230(2): 202.

Jeong HJ, Chung JK, Kim YK, Kim CY, Kim DG, Jeong JM, Lee DS, Jung HW, Lee MC.
Usefulness of whole-body (18)F-FDG PET in patients with suspected metastatic brain tumors.
J Nucl Med. 2002 Nov;43(11):1432-7.

Temodar for brain metastases – pro

admin — Sat, 01 Sep 2012 22:48:20 +0000

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.

Many chemotherapeutic agents do not penetrate the blood-brain barrier. Temozolomide is a chemotherapeutic agent with a good safety profile that crosses the blood-brain barrier and has shown activity against many human solid tumors. 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.

I consider Temodar to be supported since there are two phase II studies. NCCN recommends it for brain metastases without restricting it to specific tumor types.

M. E. Trudeau et al, Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG) Ann Oncol (June 2006) 17 (6): 952-956.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. (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.Semin Oncol. 2001 Aug;28(4 Suppl 13):34-42.
Temozolomide for treating brain metastases.Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. May 5, 2014 (early release online).
2. Brastianos PK, Curry WT, Oh KS: Clinical discussion and review of the management of brain metastases. J Natl Compr Canc Netw 11:1153-1164, 2013.
NCCN BRAIN-D, 3 2017

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

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]

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.

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.

Temodar for small cell lung cancer – pro

M Levin, MD — Fri, 24 Aug 2012 17:37:49 +0000

Several phase II trials have been reported using Temodar(TEM) for patients with brain metastases from solid tumors, including SCLC. In one study, two out of five patients with SCLC pretreated with whole brain radiation therapy showed disease stabilization with TEM. A second study explored the use of whole-brain radiation therapy with concurrent and adjuvant TEM in patients with metastatic cancer and three patients with SCLC were included in this study, two of whom demonstrated a complete response in the brain. Anecdotally, single-agent TEM has been used in patients with SCLC with response. Memorial Sloan-Kettering Cancer Center has an ongoing phase II study using TEM in second- or third-line treatment of SCLC: Temozolomide for Relapsed Sensitive or Refractory Small Cell Lung Cancer, NCT00740636. Most of this work appears to have been done by one investigator in a single institution, Dr. Pietanza in Memorial, who is also the author on the two reported phase II trials, which seem based on the same body of experience.

For second line, NCCN recommends many single agents on SCL-B,1, including paclitaxel, etoposide, irinotecan, topotecan, ifosfamide and others.

Lee M. Krug, MD, and Maria C. Pietanza, MD Emerging Therapies in Small Cell Lung Cancer
http://www.spom.com.py/Content/Manuscripts/C15_S60_M75.pdf, 2009

M. Catherine Pietanza Et aL, Phase II Trial of Temozolomide in Patients with Relapsed Sensitive or Refractory Small Cell Lung Cancer, with Assessment of Methylguanine-DNA Methyltransferase as a Potential Biomarker Clin Cancer Res February 15, 2012 18; 1138

Read the Layperson version here.

RTA-477 for glioblastoma and brain metastases – pro

M Levin, MD — Wed, 22 Aug 2012 20:45:03 +0000

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

Brain MRI: Routine for All Cancers? – pro

M Levin, MD — Tue, 19 Jun 2012 16:02:46 +0000

In adults the primary tumors most likely to metastatize to the brain are located, in decreasing order, in the lung (minimum 50%), breast (15–25%), skin (melanoma) (5–20%), colon–rectum and kidney, but in general any malignant tumor is able to metastatize to the brain. The primary site is unknown in up to 15% of patients. Brain metastases are more often diagnosed in patients with known malignancy, when they present with neurological findings or complaints. In some cancers with a high risk of brain mets, such as small cell lung cancer, CT of head with contrast or brain MRI are recommended at the initial staging. A non-contrast CAT scan is not considered adequate to completely rule out brain metastasis. Therefore, an MRI or contrast CT is medically necessary at initial staging for small cell lung cancer but not in other cancers, unless there are signs or symptoms suggesting brain metastases.

R. Soffietti et al, EFNS Guidelines on diagnosis and treatment of brain metastases: report
of an EFNS Task Force European Journal of Neurology 2006, 13: 674–681

Videtic GM, Gasper LE, Aref AM, Germano I, Goldsmith BJ, Imperato JP, Marcus KJ, McDermott MW, McDonald MW, Patchell RA, Robins HI, Rogers CL, Suh JH, Wolfson AH, Wippold FJ II, Expert Panel on Radiation Oncology-Brain Metastases. ACR Appropriateness Criteria® multiple brain metastases. [online publication]. Reston (VA): American College of Radiology (ACR); 2009. 9 p. [37 references]

A. Mintz, MD. Management of single brain metastasis: a practice guideline Curr Oncol. 2007 August; 14(4): 131–143.

Read the Layperson version here.