Cancer Treatment Today » Metastatic Cancer

Extrapulmonary small cell cancers: Role of surveillance – pro

M Levin, MD — Mon, 10 Sep 2012 20:19:54 +0000

Colorectal small cell carcinoma (RESCC) is a rare tumor with an aggressive course. Only case reports exist to guide surveillance approach.Most cases of small cell cancers of organs other than ung are trated as if they were metastatic small cell lung cancer. A recent stuedy showed that of 120 patients with ESCC, in which the most frequent site of origin was the female genital tract (26 percent), followed by gastrointestinal tract (23 percent), genitourinary tract (19 percent), head and neck (16 percent), unknown primary site (13 percent), and other sites (4.3 percent). The repovailing approach of treating extrapulmonary small cell cancers as small cell lung cancer has been questioned and treatmnen results in general are poor. There are no guidelines or reviews that recommend routine surveillance for patients with colonic EPCCC.

Dina El Demellawy et al, Primary colorectal small cell carcinoma: A clinicopathological and immunohistochemical study of 10 cases Diagnostic Pathology 2007, 2:35

Brennan SM, Gregory DL, Stillie A, et al. Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer 2010; 116:888.

Ochsenreither S, Marnitz-Schultze S, Schneider A, et al. Extrapulmonary small cell carcinoma (EPSCC): 10 years’ multi-disciplinary experience at Charité. Anticancer Res 2009; 29:3411.

Wong YN, Jack RH, Mak V, et al. The epidemiology and survival of extrapulmonary small cell carcinoma in South East England, 1970-2004. BMC Cancer 2009; 9:209.

Walenkamp AM, Sonke GS, Sleijfer DT. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat Rev 2009; 35:228.

Jonathan R. Strosberg,The NANETS Consensus Guidelines for the Diagnosis and Management of Poorly Differentiated (High-Grade) Extrapulmonary Neuroendocrine Carcinomas Pancreas. 2010 August; 39(6): 799–800.

Cicin I, Karagol H, Uzunoglu S, Uygun K, Usta U, Kocak Z, Caloglu M, Saynak M, Tokatli F, Uzal C.
Extrapulmonary small-cell carcinoma compared with small-cell lung carcinoma: a retrospective single-center study. Cancer. 2007 Sep 1;110(5):1068-76.

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.

Gliadel for brain mets – pro

M Levin, MD — Wed, 22 Aug 2012 20:48:11 +0000

Gliadel®, followed by standard radiotherapy, is an option for selected patients with newly diagnosed malignant glioma where a near-gross total excision is possible; however, the majority of patients with malignant glioma will not be eligible for various reasons (i.e. non-resectable tumours or contact with the ventricular system). Gliadel® is also an option in patients with surgically resectable recurrent malignant gliomas.

Several studies have looked at the rlol of Gliadel in treating brain metastases. Ninety-three patients with brain metastases (new and recurrent) were studied by three groups In these three studies, 66 patients received WBRT following resection and wafer placement and 27 patients in the PROLONG study received no WBRT. During the follow up, there was no local recurrence reported in 91 patients and only two neurologically related deaths. Therefore, data in these studies show that there may be a benefit for local chemotherapy with Gliadel.

Possible role of Gliadel for metastatic cancer to the brain is being studied: Exploratory Study, Evaluating the Treatment Effect of Surgery Plus GLIADEL® Wafer in Patients With Metastatic Brain Cancer, NCT00525590. Perry J, Chambers A, Spithoff K, Laperriere N, Neuro-oncology Disease Site Group. Gliadel wafers in the treatment of malignant glioma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Aug 15. 19 p. (Evidence-based series; no. 9-7). [12 references]

Brem S, Staller A, Wotoczek-Obadia M, Robb J, Vrionis FD, Pearlman JL, et al: Interstitial chemotherapy for local control of CNS metastases. Neuro-oncol 6:370-371, 2004 (Abstract)

Ewend MG, Elbabaa S, Carey LA: Current treatment paradigms for the management of patients with brain metastases. Neurosurgery 57 (5 Suppl): S66-S77, 2005 of Neurology. Neurology 54:1886-1893, 2000 Golden GA, Meldorf M, PROLONG Study Group: Patients with metastatic brain cancer undergoing resection and Gliadel implantation experienced low local recurrence rates in the PROLONG registry. Neuro-oncol 6:375-376, 2004 (Abstract)

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

Decitabine and epigenetic therapy for solid cancers – pro

M Levin, MD — Wed, 22 Aug 2012 20:41:15 +0000

Lay search: Decitabine is being studies for “epigenetic” therapy of solid cancers.

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 mechanism of action, there is interest in studying it in colorectal and other 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.

Chemotherapy for adrenocortical cancer – pro

M Levin, MD — Sat, 23 Jun 2012 01:24:36 +0000

Adrenocortical cancer is a rare condition and chemotherapy is relatively unexplored. Studies involve small case series, single-patient trials and anecdotal unpublished communications. Compounds that have been used include established chemotherapeutic agents for treatment of other solid tumors, as well as more recent compounds, used in single cases. These agents include streptozotocin, gemcitabine, navelbine, docetaxel and taxol. The best evidence is for streptozotocin. Mitotane is the only FDA approved drug but it has a narrow therapeutic window. Based on the results of a case control study, mitotane is being explored as adjuvant therapy. An ongoing randomized international trial aims to define the best combination chemotherapy plus mitotane regimen. Genetic and biological studies have identified molecular targets for specific targeted drugs such as IGF receptor inhibitors and antiangiogenetic drugs. Phase II trials are exploring the activity of these drugs either alone or in combination with chemotherapy.However, available evidence does not allow for any conclusions on the efficacy of these agents in ACC.

Of the newer drugs, there is a case report, one for Nexavar and one for Sutent. This clearly is insufficient to consider these agents to be adequately supported.

Alfredo Berruti et al, Emerging drugs for adrenocortical carcinoma Expert Opinion on Emerging Drugs

September 2008, Vol. 13, No. 3, Pages 497-509 , DOI 10.1517/14728214.13.3.497

Chemoembolization for liver metastases – pro

M Levin, MD — Tue, 19 Jun 2012 14:39:10 +0000

Transcatheter arterial chemoembolization (TACE) of the liver is a proposed alternative to conventional systemic or intra-arterial chemotherapy, and to various nonsurgical ablative techniques, to treat resectable and nonresectable tumors. The rationale for TACE is that infusions of viscous material containing one or more antineoplastic agents may exert synergistic effects: cytotoxicity from the chemotherapy, potentiated by anoxia in the infarcted region. The beneficial effect of chemoembolization may be further potentiated by labeling the infusate with radioactive isotopes for localized radiotherapy. The liver is especially amenable to such an approach, given its distinct lobular anatomy, the existence of two (2) independent blood supplies, and the ability of healthy hepatic tissue to grow and thus compensate for tissue mass lost during chemoembolization. Another rationale is that TACE delivers effective local doses, while possibly minimizing systemic toxicities associated with oral or intravenous chemotherapy.

Chemoembolization is often used for hepatocellular carcinoma and neuroendocrine cancers of the liver. According to available literature, chemoembolization (TACE) may be indicated for symptomatic treatment of functional neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver, in persons with adequate hepatic function (bilirubin < 2 mg/dl, absence of ascites; no portal vein occlusion; and tumor involvement of < 65 % of liver). For carcinoid tumors, TACE is indicated only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea). The safety and effectiveness of chemoembolization for breast cancer metastases is unknown as only case reports and series have so far been reported. The largest series reported in a 2008 abstract was of 217 patients but this as not a prospective study.

In a comparative study with the three drugs versus mitomycin and doxorubicin for HCC, no advantage was found for the three drugs. For neuroendocrine carcnoma, a comparative study found that: “Chemoembolization was not associated with a higher degree of toxicity than bland embolization. Chemoembolization demonstrated trends toward improvement in TTP, symptom control, and survival. Based on these results, a multicenter prospective randomized trial is warranted.”

The Society of Interventional Radiology (SIR, 2009) states that chemoembolization has shown promising early results with some types of metastatic tumors. The evidence in the current medical literature is insufficient to demonstrate the efficacy of TACE or TAE for the treatment of liver metastases from other primary tumors, including but not limited to breast cancer, colorectal cancer, and other tumors of unknown primary sites. Metastatic disease to the liver from tumors other than primary neuroendocrine tumors is generally treated with surgery, chemotherapy, or both. First-line therapy for colorectal hepatic metastasis is treatment with systemic chemotherapy followed by radiofrequency ablation (RFA) or cryosurgical ablation if systemic therapy fails or is not an option.

For NET there is a trial: Best Therapy for Patients With Neuroendocrine Tumors (BESTTHERAPYNET) in Germany. It is a prospective observational study containing three arms comprising different therapeutic measures to treat patients with neuroendocrine tumors in advanced stages. The therapy arms include local ablative therapy such as TACE or SIRT, surgery and RFA with peptide receptor radiotherapy. This is not a randomized study. Observationsl studies are not phase I or II. It is a research method designed to draw inferences about the possible effect of exposure on an established outcome (e.g. a disease, a therapy) without the investigator’s intervention.

Nabil M, Gruber T, Yakoub D, Ackermann H, Zangos S, Vogl TJ. Repetitive transarterial chemoembolization (TACE) of liver metastases from renal cell carcinoma: local control and survival results. Eur Radiol. 2008 Jul;18(7):1456-63

M . Giroux , R . Baum , M . Soulen. Chemoembolization of Liver Metastasis from Breast Carcinoma .
Journal of Vascular and Interventional Radiology , Volume 15 , Issue 3 , Pages 289 – 291, 2004

Brown DB, Geschwind JF, Soulen M, et al. Society of Interventional Radiology (SIR) position statement on chemoembolization of hepatic malignancies. Society of Interventional Radiology. J Vasc Interv Radiol. 2006; 17(2):217-223.

Alexander T. Ruutiainen et al, Chemoembolization and Bland Embolization of Neuroendocrine Tumor Metastases to the Liver Journal of Vascular and Interventional Radiology
Volume 18, Issue 7, July 2007, Pages 847-855

Society of Interventional Radiology (SIR). Interventional radiology treatments for liver cancer. 2009. Available at: http://www.sirweb.org/patients/liver-cancer/