Cancer Treatment Today » Kidney Cancer

Votrient versus Sutent for renal cell cancer – pro

M Levin, MD — Sun, 21 Apr 2013 21:59:04 +0000

Progress in the treatment of kidney cancer has been nothing short of amazing in the past few years. Many new drugs have been introduced and FDA approved for first line therapy. This significantly expanded our armamentarium against this previously difficult to treat cancer. At the same time, rapid introduction of new agents has led to the situation in which there is there little evidence on how to select which one should be used first. The only the two drugs for which some evidence exists are Votrient(pazopanib) and Sutent(sunitinib). The first attempt to compare them was a patient preference study called PISCES, which showed 70% of patients preferred pazopanib and 22% preferred sunitinib. Presumably, this reflects either a more tolerable spectrum of side effects for pazopanib or or some beneficial, perhaps a mood elevating, effect that pazopanib provides. This is not an idle question, because in actuality the side effects do not appear to differ all that much, certainly not enough to explain the dramatic difference in patients’ preference for Votrient.

The two drugs were directly compared in the COMPARZ trial. In the study, a total of 1,110 patients were randomized to receive treatment with pazopanib at 800 mg/daily or sunitinib at 50 mg/daily for four weeks followed by two weeks off treatment. Treatment continued until disease progression, unacceptable toxicity, voluntary withdrawal, or death due to any cause.

This was a non-inferiority trial. It showed that pazopanib had similar efficacy (i.e non-inferiority) compared to sunitinib in first-line treatment of metastatic renal cell carcinoma. For both drugs, the median progression-free survival by the treating physician’s assessment was slightly more than 10 months. However, the median progression-free survival time in the study (Abstract LBA8), which was funded by GlaxoSmithKline, was 9.5 months for the patients receiving sunitinib compared with 8.4 months for those receiving pazopanib — a nonsignificant difference that fell within the predetermined criteria for showing non-inferiority, but a better result for sunitinib nevertheless.

The most common adverse events (occurring in 30% or more of patients) that were more common with sunitinib were: fatigue (63% vs. 55%) hand-foot syndrome (50% vs. 29%); taste alteration (36% vs. 26%); and thrombocytopenia (34% vs. 10%). Side effects that were more common with pazopanib were ALT increase (31% vs. 18%) and hair whitening (30% vs. 10%). Additionally, 11 of the 14 quality-of-life measures were in favor of pazopanib over sunitinib, he reported. These included measures of fatigue, kidney symptoms, and mouth and throat soreness. A total of 42 percent of patients in the pazopanib arm and 41 percent in the sunitinib arm had serious adverse events. Serious adverse events occurring in three percent or more of patients in the pazopanib arm were ALT increase and AST increase; and serious adverse events occurring in three percent or more of patients in the sunitinib arm were pyrexia and thrombocytopenia. Thirteen patients (2%) in the pazopanib arm and 19 patients in the sunitinib arm (3%) had fatal adverse events.

Strangely, despite patients’ preference for pazopanib, discontinuation rate of sunitinib was less.

Many opinion leaders in GU oncology are inclined to use Votrient first, because the patients prefer it and seem to tolerate it better, leading to fewer discontinuations in their experience. Others are not yet convinced. In any case, the results that these two drugs produce are certainly similar enough so that patient preference should play a major role in therapy selection.

Motzer RJ, Hutson TE, Reeves J, et al: Randomized open-label phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): Results of the COMPARZ trial. 2012 ESMO Congress. Abstract LBA8. Presented October 1, 2012.

Escudier B, et al: Patient preference between pazopanib (Paz) and sunitinib: Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. 2012 ASCO Annual Meeting. Abstract CRA4502. Presented June 2, 2012.

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About Votrient for kidney cancer

Tarceva for papillary renal cell carcinoma – pro

M Levin, MD — Thu, 31 Jan 2013 17:08:30 +0000

Papillary Renal Cell Carcinoma represents approximately 10% to 20% of kidney cancers. These tumors are thought of as being realtively resistant to immunotherapy with TKI and mTOR inhibitors and Tarceva(erlotinib) has been studied in this subgroup. There is a reported response rate in low teens and the disease control rate (defined as stable disease for 6 weeks, or confirmed partial response or complete response using RECIST [Response Evaluation Criteria in Solid Tumors]) was 64% in one study(Gordon et al). The median overall survival was 27 months. This and other studies showed that single-agent erlotinib was associated with disease control and survival outcomes of interest, with an expected toxicity profile. The NCCN has now included erlotinib as a category 3 option for first-line therapy for patients with relapsed or medically unresectable stage IV with non–clear cell histology. Category 3 means that the recommendation is based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D.
Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317.J Clin Oncol. 2009 Dec 1;27(34):5788-93.

Michael S. Gordon, Michael Hussey, Raymond B. Nagle, Primo N. Lara Jr, Philip C. Mack, Janice Dutcher, Wolfram Samlowski, Joseph I. Clark, David I. Quinn, Chong-Xian Pan and David Crawfor Phase II Study of Erlotinib in Patients With Locally Advanced or Metastatic Papillary Histology Renal Cell Cancer: SWOG S0317
JCO Dec 1, 2009:5788-5793

Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol 2009;27:5788–5793.

Robert J. Motzer, MD, Neeraj Agarwal, MD, Clair Beard, MD, Sam Bhayani, MD, Graeme B. Bolger, MD, Michael A. Carducci, MD, Sam S. Chang, MD, Toni K. Choueiri, MD, Steven L. Hancock, MD, Gary R. Hudes, MD, Eric Jonasch, MD, David Josephson, MD, Timothy M. Kuzel, MD, Ellis G. Levine, MD, Daniel W. Lin, MD, Kim A. Margolin, MD, M. Dror Michaelson, MD, PhD, Thomas Olencki, DO, Roberto Pili, MD, Thomas W. Ratliff, MD, Bruce G. Redman, DO, Cary N. Robertson, MD, Charles J. Ryan, MD, Joel Sheinfeld, MD, Philippe E. Spiess, MD, Jue Wang, MD and Richard B. Wilder, MD Kidney Cancer J Natl Compr Canc Netw 2011;9:960-977

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Temodar for renal cell carcinoma – pro

M Levin, MD — Wed, 21 Nov 2012 19:47:43 +0000

Personalized medicine approach relies heavily on chemosensitivity testing and genetic profiling of individual cancers. Temodar is one of the drugs that is usually included in chemosensitivity panels. Unfortunately, the new paradigm does not “fit” well with the existing approaches and methods for weighing and evaluating evidence supporting cancer treatments, and new approaches to do so have not yet been developed.

Temodar has some supporting, albeit conflicting evidence in renal cancer, if you follow the “old” paradigm. Park et al found it have no activity in kidney cancer, whereas Ozgur et al found it to have minimal side effects and a total response rate of 60%. Bex et al found no objective responses in a group of previosuly treated patients. Temozolamide. Sakura found Temodar and interferon to be inactive.
E. Özgür, C. H. Ohlmann, U. H. Engelmann, G. Haupt, A. Heidenreich Temozolomide in the management of progressive metastatic renal cell cancer (RCC) following immunotherapy Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 4600

Bex A, Kerst J, Mallo H, Van Tinteren H, Horenblas S, De Gast GC. Extended continuous oral temozolomide in patients with progressive metastatic renal cell carcinoma not responding to interferon alpha 2b.J Chemother. 2005 Dec;17(6):674-8.

D. Park, C. Ryan, M. Dolan, N. Vogelzang and W. Stadler A phase II trial of oral temozolomide in patients with metastatic renal cell cancer Cancer Chemotherapy and Pharmacology Volume 50, Number 2 (2002), 160-162

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Cryoablation for renal cell cancer – pro

M Levin, MD — Wed, 12 Sep 2012 21:41:41 +0000

Cryoablation is not well supported by the medical literature for renal cell cancer. There are mostly case reprots adns eries, although soem of tehm are large and there are no comparative tirals. The procedure has some theoretical disadvantages. For one, it leaves no pathology, so that prognostication becomes difficult. Other limitations of percutaneous cryoablation include the inability to control hemorrhage without intra-arterial access and a lack of long-term follow-up data. Perioperative complications and renal functional outcomes of laparoscopic cryoablation and open partial nephrectomy are similar; however, laparoscopic cryoablation confers a substantially higher local recurrence risk of about 15% after 3 years. There are no formal guidelines but some experts believe that laparoscopic renal cryoablation should be reserved for high risk patients with decreased life expectancy.

Brian C. Allen, and Erick M. Remer, Percutaneous Cryoablation of Renal Tumors: Patient Selection, Technique, and Postprocedural Imaging July 2010 RadioGraphics, 30, 887-900.

Tracy CR, Raman JD, Donnally C, et al. Durable oncologic outcomes after radiofrequency ablation: experience from treating 243 small renal masses over 7.5 years. Cancer 2010; 116:3135.

Stein RJ, Kaouk JH. Renal cryotherapy: a detailed review including a 5-year follow-up. BJU Int 2007; 99:1265.

For Lay version see here.

Bortezomib for renal cell cancer – pro

M Levin, MD — Fri, 31 Aug 2012 13:26:43 +0000

Lay Summary: Velcade, a myeloma drug, has activity in kidney cancer

Few treatment options exist for the patient with metastatic RCC. The majority of patients with metastatic RCC will die from their disease within 12 to 16 months of diagnosis, despite treatment with standard immune modulation. New agents with novel mechanisms are urgently needed for this clinical situation. Laboratory and preclinical studies have identified the proteasome as a potential target in solid tumor therapy , and this unique mechanism suggested that PS-341 may be efficacious in patients with RCC refractory to other therapies. There was a small phase II trial of PS-341 in patients with metastatic RCC. This study was closed after a planned analysis revealed only one objective response. These observations suggest that a subset of patients with RCC may be responsive to proteasome inhibition. Unfortunately, have been dissapointing with that study having one response in 21 patients. In a similar study from the Memorial Sloan-Kettering Cancer Institute, four of 37 patients with metastatic RCC responded to PS-341. Of the 37 assessable patients, the best response was a partial response in four patients (11%; 95% CI, 3% to 25%) and stable disease in 14 patients (38%; 95% CI, 23% to 55%). The four patients with partial response experienced response durations of 8, 8+, 15+, and 20+ months.

Drucker BJ, Schwartz L, Bacik J, et al: Phase II trial of PS-341 shows response in patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 22:386, 2003 (abstr 1550)

Nancy B. Davis, David A. Taber, Rafat H. Ansari, Christopher W. Ryan, Christopher George, Everett E. Vokes, Nicholas J. Vogelzang, Walter M. Stadler Phase II Trial of PS-341 in Patients With Renal Cell Cancer: A University of Chicago Phase II Consortium Study Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 115-119

G. Varuni Kondagunta, Beverly Drucker, Lawrence Schwartz, Jennifer Bacik, Stephanie Marion, Paul Russo, Madhu Mazumdar, Robert J. Motzer Phase II Trial of Bortezomib for Patients With Advanced Renal Cell Carcinoma Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3720-3725

Afinitor and Nexavar or Votrient – pro

M Levin, MD — Fri, 31 Aug 2012 13:19:12 +0000

Everolimus has been approved by the US Food and Drug Administration (FDA) as the first oral, daily therapy (5 mg and 10 mg tablets) to treat advanced kidney cancer after failure of treatment with sunitinib or sorafenib. The NCCN lists it for both first and second line therapy. The approach of tailoring treatment with this drug in combination with other biologicals based on molecular profiles is potentially promising but it is not supported by the literature.

Afinitor was studied in several combination trials. AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. The RECORD-1 trial included only renal cell carcinoma histology

Afinitor, Prescribing Information 2016

P. Cen, A. Daleiden, G. Doshi, R. Amato; A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 27, 2009 (suppl; abstr e16056)

nccn.org, kidney cancer 2016

B. Escudier et al, Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†Ann Oncol (2012) 23 (suppl 7): vii65-vii71.

I had not been able to find any published studies of the combination of Votrient and Afinitor. I found one study: Pazopanib and Everolimus in Patients With Advanced Solid Tumors and Previously Treated Kidney Cancer, NCT01184326. This research study is evaluating the combination of pazopanib and everolimus in patients that have a malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or metastatic or locally advanced unresectable kidney cancer. In this research study the investigators are testing the safety of the combination of pazopanib and everolimus as well as to find the appropriate dose to use for further studies.

Afinitor, Prescribing Information

P. Cen, A. Daleiden, G. Doshi, R. Amato; A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 27, 2009 (suppl; abstr e16056)

nccn.org, kidney cancer 2012

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.