Cancer Treatment

Sutent for lung cancer

 Sunitinib (marketed as Sutent by Pfizer, and previously known as SU11248) is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). After activity was found in cell cultures, a Phase II study of refractory non-small-cell lung cancer found that “Sunitinib has provocative single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents.

 Socinski MA et al. (2006). "Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): preliminary results of a multicenter phase II trial". Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I 24 (18S (June 20 suppl)). However, in August 2010, Pfizer halted a study with Sutent. The trial looked at Sutent as an add-on therapy to Roche's Tarceva, comparing the two-drug regimen with Tarceva alone. The combo didn't extend patients' lives any longer than Tarceva did by itself.

Cardiac function and stem cell transplantation

It is a generally accepted tenet that Ejection Fraction of below 45% exposes a stem cell transplant candidate to excess cardiac risk. A recent study questioned this but clearly more studies are needed before this standard can be changed.

 That study evaluated the frequency of cardiac complications and 100-day nonrelapse mortality (NRM) in 56 patients with a LVEF of ≤45%, who received allo HCT at one institution. The results were retrospectively compared with a matched control group with LVEF of ≥50%, which received an allogeneic stem cell transplantation (allo-SCT). After a median follow-up of 29 months in the study group, grade ≥2 cardiac complications were seen in 7 of 56 (12.5%) patients and cumulative incidence of 100-day NRM was 12.5% with no deaths from cardiac causes. In contrast, after a median follow-up of 49 months in the control group, grade >2 cardiac complications were seen in 19 of 161 patients (11.8%; P = 1.00) and cumulative incidence of 100-day NRM was 14.9% (P = .82). The presence of at least 1 of the 7 pretransplant cardiac risk factors (past history of smoking, hypertension, hyperlipidemia, coronary artery disease, arrhythmia, prior myocardial infarction, and congestive heart failure) was associated with a higher cardiac complication rate in the study group (P = .03). The authors concluded that selected patients with a LVEF of ≤45% can safely receive allo-HCT without a significant increase in cardiac toxicity or NRM.

 Sakata-Yanagimoto M, Kanda Y & Nakagawa M et al.. Predictors for severe cardiac complications after hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 33: 1043−1047. |

Warfarin Sensitivity Test

Warfarin (Coumadin®) dose is sometimes difficult to adjust. The labeling for a popular formulation of warfarin was revised in August 2007 and February 2010 to include information about how the three most widely studied pharmacogenetic mutations (CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A) affect dose requirements (NDA 9-218/S-105). The Warfarin-Sensitivity test idendifies that most common mutations that affect warfarin metabolism. ?CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing
?VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing
?Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing.

Approval was based on a study involved 896 participants with an average age of 65 who were members of prescription benefit plans managed by Medco. Hospitalization rates for this group were matched against a historical control group of 2,688 individuals. Researchers collected DNA from either blood or buccal cells and determined patients’ genotypes for the CYP2C9 and VKORC genetic variants. Mutations in the CYP2C9 gene have been associated with decreased warfarin metabolism, while mutations in the VKORC1 gene are associated with warfarin sensitivity. Based on each individual’s genotype, clinicians used a dosing algorithm to determine that person’s initial dose. The study followed patients for 6 months after the start of their treatment. Compared with the control group, the genotyped patients had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism during the follow-up period. The study results were first reported at the American College of Cardiology’s annual meeting in March of 2010 and are available online: J Am Coll Cardiol (doi:10.1016/j.jacc.2010.03.009).

This is the relevant information form the label for Warfarin: "

The dose of COUMADIN must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by:

• Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and
• Genetic factors (CYP2C9 and VKORC1 genotypes).

Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients. (See CLINICAL PHARMACOLOGY and PRECAUTIONS).

The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose."

 

Food and Drug Administration. New labeling information for Coumadin. Approved 1/22/2010.

Anderson JL, Horne BD, Stevens SM et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563-70.

The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data.
N Engl J Med 2009;360:753-64.

Gage B, Eby C, Johnson J, Deych E et al. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin.  Clinical Pharmacology & Therapeutics 2008: 84, 326–331

Pathwork Tissue of Origin Test

The Pathwork Tissue of Origin Test for FFPE is a microarray-based gene expression test that aids in the diagnosis of poorly differentiated and metastatic tumors. A recent study of 284 clinical samples with Tissue of Origin Test results were categorized according to the clinician's pretest diagnosis, using ICD-9 codes and the biopsy site. The test predicted either a change from nonspecific to a specific site or a change from one primary site to another in 81% of cases. For 15% of cases, the Tissue of Origin Test confirmed the submitted diagnosis. Overall, based on test prediction and the NCCN guidelines, first-line chemotherapy treatment would change for 63% of the cases.

This test is FDA approved but how to use it is not clear. There are several other validation studies but clinical impact must be proven before it is accepted for wider use. On p. MS4 of its Occult Primary Guideline the NCCN does not recommend GEP (Genetic Expression Profiling) for routine evaluation.

At this time, it should still be considered investigational.

Laouri, M., Nystrom, J. S., Halks-Miller, M., Henner, W. D.
Impact of a gene expression-based tissue of origin test on diagnosis and recommendations for first-line chemotherapy.
J Clin Oncol (Meeting Abstracts) 2010 28: 10579

Bridgewater J, van Laar R, Floore A et al. Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer 2008; 98(8):1425-30.

Monzon FA, Lyons-Weiler M, Buturovic LJ et al. Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue origin. J Clin Oncol 2009; 27(15):2503-08.

Adjuvant chemotherapy after Whipple's for cholangiocarcinoma.

 

The role of adjuvant chemothhapy after complete resection of cholangiocarcinoma is changing. The cancer have a high incidence of local failure after surgical resection reaching 52%, a locoregional adjuvant treatment may be considered. Several retrospective reports on adjuvant and recently also on neoadjuvant (chemo)radiotherapy suggest survival benefit in both gallbladder and biliary duct cancer and postoperative chemoirradiation may be considered as an option. Fluorouracil was mostly used for chemoradiotherapy in biliary cancers. Recently concomitant gemcitabine with or without oxaliplatin has shown feasibility with radiotherapy in this disease." In contrast, a 2008 guideline does not support adjuvant chemo outside of clincal trials.

For extrahepatinc cholangiocarcinoma, NCCN recommend chemoradiation with floropyrimidines and then adjvant chemo with the same or gemcitabine based. It does the same or a clincal trial for clean margins, excluding the chemoradiation. It does not mention oxaliplatin.

F. Eckel, T. Brunner S. Jelicand On behalf of the ESMO Guidelines Working Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol (2010) 21 (suppl 5): v65-v69.

Junji Furuse, Tadahiro Takada, Masaru Miyazaki, Shuichi Miyakawa, Kazuhiro Tsukada, Masato Nagino, Satoshi Kondo, Hiroya Saito, Toshio Tsuyuguchi and Koichi Hirata, et al.
Guidelines for chemotherapy of biliary tract and ampullary carcinomas,
Jrnal of Hepato-Biliary-Pancreatic Surgery
Volume 15, Number 1, 55-62

nccn.org, chalngiocarcinoma,

Tazorac for CTCL

CTCL includes a number of clinical syndromes, the most common of which are mycosis fungoides and the Sézary syndrome. Mycosis fungoides presents with patches, plaques, or tumors. In the initial stages disease is confined to the skin. Sézary syndrome is a leukemic variant of CTCL, characterized by erythroderma (stage T4), lymphadenopathy, pruritus and circulating neoplastic (Sézary) cells (stage B1).
Bexarotene is FDA approved for this disease whereas the very similar gel Tazoratene is not. The latter has only one study to support it. A 20 patient pilto study concluded that tazarotene 0.1% gel was a well-tolerated and effective adjuvant topical for the treatment of refractory MF lesions.
 It is currenlty in a clinical trial: Tazarotene 0.1% Cream For the Treatment of Cutaneous T-Cell Lymphoma: A Prospective Study,  NCT00779896 and despite the analogy with bexarotene is still experimental.

Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003 Dec;149(6):1095-107. [67 references]

Apisarnthanarax N, Talpur R, Ward S, Ni X, Kim HW, Duvic M.
Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot study.J Am Acad Dermatol. 2004 Apr;50(4):600-7.