Cancer Treatment Today » New Drugs

Tamoxifen side effects and treatment – pro

M Levin, MD — Fri, 05 Apr 2013 10:40:13 +0000

Tamoxifen is a venerable drug that revolutionized breast cancer care when it was first introduced. More recently, it has been largely supplanted by aromatase inhibitors(AI), but tamoxifen is still useful in pre-menopausal women, in whom AIs do not work.

Tamoxifen has a variety of bothersome side effects, related mostly to forced early menopause. In the trials reviewed by Kennecke al, hot flushes were commonly reported (40% to 60%).In the MA 17 trial, even women who were on no hormonal treatment after 5 years of tamoxifen had a 54% incidence of low-grade hot flushes. A;so gynecological side effects (such as vaginal discharge or bleeding) are common with tamoxifen. Rates of vaginal bleeding of 10% and hysterectomy at 5% were noted. Gynecological side effects tend to decrease and were less apparent after 2 years of tamoxifen use, as tamoxifen-induced gynecological symptoms predominate in the initial years of therapy. Although low, there is a significant risk of thromboembolic events and small risk of uterine cancer, which is usually noticed in early stages because of the bleeding and successfully treated. here is small increase in the risk of cataracts. On the other hand, proestrogenic effects of tamoxifen decrease fracture rate and may stave off dementia and cardiac problems.

Much work has been done on this. Cuzick et aldid a meta-analysis of the tamoxifen trials to examine both risks and benefits. Braithwaite et al conducted a meta-analysis of vascular and neoplastic events associated with tamoxifen use in 32 randomized controlled trials, which included the four tamoxifen risk reduction trials. In this meta-analysis, subanalyses were performed on the risk reduction trials alone. Bushnell and Goldstein conducted a meta-analysis on nine randomized trials, including the four tamoxifen risk reduction trials, to examine the association between ischemic strokes and tamoxifen use.

A variety of symptomatic approaches have been employed but none have been rigorously assessed(http://mydoctor.kaiserpermanente.org/ncal/Images/tamoxifen_tcm28-15153.pdf_). Pharmacologic treatments that are used for menopause symptoms management are also used for tamoxifen induced menopause.

H.F. Kennecke,New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors, BCMJ, Vol. 48, No. 3, April 2006, 121-126

Kala Visvanathanet al, American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction, JCO July 1, 2009 vol. 27 no. 19 3235-3258

Cuzick Jet al,(2003) Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296–300.21.↵

Braithwaite RS at al, (2003) Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 18:937–947

Bushnell CD wt al, (2004) Risk of ischemic stroke with tamoxifen treatment for breast cancer: A meta-analysis. Neurology 63:1230–1233.

For Lay version see here

Zoladex and tamoxifen for premanopausal women

Aromatase inhibitors

Votrient for GIST – pro

M Levin, MD — Thu, 29 Nov 2012 15:48:21 +0000

Pazopanib(Votrient) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and KIT. These are important pathways for GIST tumors and several trials looked into using pazopanib for GIST. Although initial studies suggested that the drug is not effective for GIST, more recently a phase II study of 25 patients and a randomized study of 86 patients suggest that it is.The results of PAZOGIST, a randomised phase II study of pazopanib plus best supportive care (BSC) vs BSC alone in patients with unresectable metastatic and/or locally-advanced gastrointestinal stromal tumours (GIST), who are resistant or experienced toxicity to previous treatments with standard doses of imatinib and sunitinib, show an improvement in progression-free survival (PFS) in favour of pazopanib arm. The study was presented by Prof. Jean-Yves Blay of the University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France during the Proffered Paper session in Sarcoma at ESMO Congress 2014 in Madrid, Spain. The primary endpoint was PFS. It was planned to include 80 patients to detect an improvement in the 4-month PFS rate from 15% in the BSC arm alone to 45% in the pazopanib plus BSC with 5% two-sided α error and 80% power. Secondary objectives included overall survival (OS), objective response rate at 4 months, best response rate and tolerance.

P. G. Casali & J.-Y. Blay,Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnnals of Oncology 21 (Supplement 5): v98–v102, 2010

nccn, GIST 2012

Nishida T, Hirota S, Yanagisawa A, Sugino Y, Minami M, Yamamura Y, Otani Y, Shimada Y, Takahashi F, Kubota T; GIST Guideline Subcommittee.
Clinical practice guidelines for gastrointestinal stromal tumor (GIST) in Japan: English version.Int J Clin Oncol. 2008 Oct;13(5):416-30.

K. N. Ganjoo et al, A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol (2014) 25 (1): 236-240.

ESMO Abstract LBA45 – A randomized multicentre phase II study of pazopanib plus best supportive care (BSC) vs BSC alone in metastatic gastroIntestinal stromal tumors (GIST) resistant to imatinib and sunitinib, 2014.

For Lay version see here

Lyrica for neuropathic pain of chemotherapy – pro

admin — Sat, 01 Sep 2012 22:21:24 +0000

Lyrica was designed as a more potent successor to gabapentin. It is indicated for treating neuropathic pain from diabetes or post herpetic neuralgia. There is not enough reported data to state that it should be used in all neuropathic pain. Still, there are guideliens that recommend it for treatment of neuropathic pain other than from diabetes. The NICE guidelines on neuropathic pain (1,2) recommend amitriptyline or pregabalin first line. The Drug and Therapeutics Bulletin (DTB) questions the recommendation in the recent guideline and noted that pregabalin is still a black triangle drug and this too should be considered in any comparison with the much longer established gabapentin. The DTB concludes: “the guideline’s promotion of pregabalin creates a dilemma for those who know from the published data that gabapentin remains an effective treatment option for neuropathic pain. Gabapentin is by far the cheaper of the two drugs and therefore for the same level of investment, the NHS faces the choice of treating more patients with a cheaper but (on indirect evidence) slightly less effective drug, or fewer patients with a more expensive, seemingly more effective one.”

However, other guidelines made the same recommendation. For example, Attal etal says, “Treatments with established efficacy on the basis of class I trials in painful polyneuropathy (PPN) (with the exception of human immunodeficiency virus (HIV)-associated polyneuropathy) are tricyclic antidepressants (TCAs), duloxetine, venlafaxine, gabapentin (GBP), pregabalin, opioids and tramadol (level A).”

REFERENCES

Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P, EFNS Task Force. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006 Nov;13(11):1153-69. [147 references]

J. Mark Wallace Update on pharmacotherapy guidelines for treatment of neuropathic pain Current Pain and Headache Reports Volume 11, Number 3, 208-214

NICE March 2010: CG96 Neuropathic pain – pharmacological management: quick reference guide

MTUS Chronic Pain 2009, o. 16

New Drug: Votrient for renal cell cancer – pro

admin — Sat, 01 Sep 2012 22:20:31 +0000

Votrient(pazopanib) is a multi-targeted tyrosine kinase inhibitor and it is currently approved for renal cell carcinoma. VOTRIENT® is indicated for the treatment of patients with advanced renal cell carcinoma(RCC).

Pazopanib has not been compared to other agents for the treatment of RCC in clinical trials. Two published clinical trials have evaluated pazopanib in RCC. In one randomized, double-blind trial, median progression free survival was improved with pazopanib (9.2 months) compared to placebo (4.2 months, p<0.0001); more patients experienced a complete or partial response with pazopanib (30%) compared to placebo (3%, p<0.001). In one open-label trial, 35% of patients experienced a complete or partial response. Median progression free survival was 52 weeks. The median duration of response ranged from 58.7 to 68 weeks.
The National Comprehensive Cancer Network (NCCN) recommends Votrient for RCC as follows:
• First-line therapy as a single agent for relapsed or medically unresectable stage IV disease with predominant clear cell histology in selected patients (grade 1)
• Subsequent therapy as a single agent for relapsed or medically unresectable stage IV disease with predominant clear cell histology in patients who have progressed on prior first-line therapy (grade 1)
This drug is also recommended by NICE.

Bible KC, Smallridge R, Maples W, et al. Phase II trial of pazopanib in progressive, metastatic, iodine-insensitive differentiated thyroid cancers [Abstract 3521]. Journal of Clinical Oncology. 2009;27(15S).
GlaxoSmithKline. Votrient (pazopanib tablets) [product information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.
McEvoy GK, ed. AHFS 2010 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists, Inc. 2010.
NCCN Drugs & Biologics Compendium™. Votrient™ (pazopanib). Copyright 20109, National Comprehensive Cancer Network (NCCN).

TDM1- 2012 update -pro

M Levin, MD — Thu, 30 Aug 2012 12:59:35 +0000

Trastuzumab emtansine (INN), variously called L trastuzumab-DM1 or trastuzumab-MCC-DM1, or T-DM1 is an antibody-drug conjugate consisting of the antibody trastuzumab (Herceptin) linked to a cytotoxic agent that is a derivative of maytansine (DM1). Is is promising drug and it is in several studies. EMILIA, a phase III trial of 991 people with HER2-positive unresectable locally advanced or metastatic breast cancer, comparing T-DM1 versus capecitabine plus lapatanib in patients previously treated with trastuzumab and a taxane chemotherapy, showed improved progression free survival in patients treated with T-DM1 (median 9.6 vs. 6.4 months) with an improved safety profile.

The study sponsor reported in August 2012 that T-DM1 significantly improved survival. Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

There is also the MARIANNE study, which compares taxane (docetaxel or paclitaxel) plus trastuzumab vs T-DM1 vs T-DM1 plus pertuzumab as first-line treatment for people with HER2 positive unresectable locally advanced or metastatic breast cancer and the TH3RESA stud, which is comparing T-DM1 vs treatment of physician’s choice for people with HER2 positive metastatic breast cancer previously treated with trastuzumab and lapatinib.

Niculescu-Duvaz I (June 2010). “Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer”. Curr. Opin. Mol. Ther. 12 (3): 350–60.

Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012 Mar 22;12(4):278-87.

See the Lay version here

Pertuzumab, Herceptin, docetaxel for later stage metastatic breast cancer – pro

M Levin, MD — Thu, 23 Aug 2012 10:21:19 +0000

On June 11, 2012, U.S. Food and Drug Administration (FDA) has approved PerjetaTM (pertuzumab). Perjeta is approved in combination with Herceptin® (trastuzumab) and docetaxel chemotherapy for the treatment of people with HER2-positive metastatic breast cancer (mBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval is based on data from a Phase III study which showed that people with previously untreated HER2-positive mBC who received the combination of Perjeta, Herceptin and docetaxel chemotherapy lived a median of 6.1 months longer without their cancer getting worse (progression-free survival, or PFS) compared to Herceptin plus docetaxel chemotherapy (median PFS 18.5 vs. 12.4 months).

This is an exciting development. It must be kept in mind that the study was first line. It is not known how this regimen would work in patients who already failed Herceptin and other agents in the past and it would be premature to view it as a powerful salvage regimen. Baselga et al (2010) did find that the combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy. However, how it compares to other available and active therapies is not known.

Intravenous pertuzumab is currently being evaluated in patients with breast cancer in the following trials: MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breats cancer) and APHINITY (HER2-positive nonmetastatic breast cancer).

Baselga J, Cortes J, Sung-Bae K, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.2012; 366:109–119.

José Baselga, Karen A. Gelmon, Shailendra Verma, Andrew Wardley, PierFranco Conte, David Miles, Giulia Bianchi, Javier Cortes, Virginia A. McNally, Graham A. Ross, Pierre Fumoleau and Luca Gianni Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy JCO March 1, 2010 vol. 28 no. 7 1138-1144

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Gemcitabine for Adjuvant Therapy of Breast Cancer – pro

M Levin, MD — Tue, 19 Jun 2012 10:09:21 +0000

Unlike for pancreatic cancer, there is not much literature regarding the use of gemcitabine for adjuvant therapy of breast cancer. One exception is the tANGo trial. The tAnGo trial was a randomized, open-label, multicenter phase III trial examining adjuvant treatment with epirubicin (Ellence)/cyclophosphamide (Cytoxan, Neosar) for four cycles followed by paclitaxel alone or combined with gemcitabine (Gemzar) for four cycles in patients with early-stage breast cancer. Gemcitabine has been included as a partner for paclitaxel in the tAnGo trial based on high response rates, including high complete response rates, observed in phase II trials of the combination in more advanced disease and based on the tolerability and safety of the combination compared with those of other taxane-containing two-drug combinations. It was not clear how much gemcitabine added to other drugs.

At this time gemcitabine is not well supported, alone or in combination for adjuvant therapy of breast cancer.

Wardley AM, Hiller L, Howard HC, Dunn JA, Bowman A, Coleman RE, Fernando IN, Ritchie DM, Earl HM, Poole CJ; tAnGo Trial Collaborators. tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation. Br J Cancer. 2008 Aug 19;99(4):597-603. Epub 2008 Jul 29.

Chéreau E, Coutant C, Gligorov J, Lesieur B, Antoine M, Daraï E, Uzan S, Rouzier R. Discordance with local guidelines for adjuvant chemotherapy in breast cancer: reasons and effect on survival. Clin Breast Cancer. 2011 Mar;11(1):46-51.

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