Cancer Treatment Today » Chemotherapy

5 Florouracyl – weekly or every 21 days? – pro

M Levin, MD — Thu, 21 Feb 2013 03:16:15 +0000

Fluoropyrimidine (5-fluorouracil [5-FU] is the oldest chemotherapy drug for colon cancer and it is usually given with leucovorin [LV]. For second or third line therapy, single agents are acceptable and NCCN has a complex schema when to give what for second line and also lists Erbitux and Vectbix. Capecitabine is also FDA approved as a single agent. NCCN does not list 5FU/Leukovorin but it can also be considered appropriate given the long history of its use for colorectal metastatic cancer and support from many older papers.

The issue of the best schedule for 5FU.leukovorin has not been resolved, and with the appearance of many new drugs, has receded into the past and is no longer being investigated. Both high dose leukovorin (Mayo) and low dose leukovorin dosing is effective but the former apears to be more toxic. The Mayo Clinic schedule is 5-FU bolus 425 mg/m2 plus LV 20 mg/m2 daily for 5 days, repeated every 45 weeks for six cycles. This was superior to control in NCCTG Trial 87-46-51 , and at least equivalent to three other regimens in the large US Intergroup trial INT-0089. Older evidence from phase II trials suggests that weekly 5-fluorouracil and leucovorin have lower toxicity(3).

The FDA has not weigned in on the schedule. The indicaiton states that Fluorouracil is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas.

1.Boige V, Mendiboure J, Pignon JP, et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol 2010; 28:2556.
2.Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007; 12:38.
3.K. Patel, D. A. Anthoney, A. M. Crellin, D. Sebag-Montefiore, J. Messruther and M. T. Seymour, Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose-intensity in adjuvant chemotherapy after colorectal cancer resection Ann Oncol (2004) 15 (4): 568-573.
4.Meta-analysis Group in Cancer. Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol1998; 16: 35373541
5.Florouracyo infusion, Prescribing Information, 2012

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Gemzar alone for colorectal cancer – pro

M Levin, MD — Fri, 09 Nov 2012 19:14:35 +0000

The role of gemcitabine for colorectal can has not been defined. Moore et al found that Gemcitabine, at the doses and schedule used in his study, did not demonstrate activity against advanced colorectal adenocarcinoma. A much later study from Columbia University(Saif et al) found that Gemcitabine has a modest activity in heavily pre-treated colorectal cancer patients and may be an option in good performance status patients. There are a number of reports and ongoing studies of gemcitabine in combination for colorectal cancer. A recent study, Gemcitabine in Treating Patients With Advanced Colorectal Cancer,, NCT00007943, was completed in 2009 but not published as of 2012.

MUHAMMAD WASIF SAIF, KRISTIN KALEY, ROBIN PENNEY, SUSAN HOTCHKISS, KOSTAS N. SYRIGOS and ALEXIOS S. STRIMPAKOS, The Efficacy of Gemcitabine as Salvage Treatment in Patients with Refractory Advanced Colorectal Cancer (CRC): A Single Institution Experience Anticancer Research September 2011 vol. 31 no. 9 2971-2974

Dennis F. Moore, Richard Pazdur, Karen Daugherty, Peter Tarassoff and James L. Abbruzzese Phase II study of gemcitabine in advanced colorectal adenocarcinoma Investigational New Drugs
Volume 10, Number 4 (1992), 323-325.

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Sprycel for colon cancer – pro

M Levin, MD — Fri, 02 Nov 2012 12:54:21 +0000

Dasatinib, also known as Sprycel, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. It is a drug that is approved by the FDA for chronic myelogenous leukemia. It has an effect on the Src kinases, which interact with the EGFR receptor. One phase II trial(Nautiyal et al) showed that Dasatinib is inactive in previously treated metastatic colorectal patients patients. There is a trial that is studying this drug: Dasatinib in Treating Patients With Previously Treated Metastatic Colorectal Cancer, NCT00504153. This study is ongoing, but not recruiting participants.

An interesting report suggested that curcumin, a turmeric derivative, can increase the effectiveness of Sprycel in colon cancer but this needs to be proven in large, prospective trials.

G. Somlo, F. Atzori, L. Strauss, A. Rybicki, X. Wu, W. Gradishar, J. Specht;Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004.J Clin Oncol 27:15s, 2009 (suppl; abstr 1012)

Lisa Hutchinson Targeted therapies: Dasatinib sensitizes KRAS-mutant colorectal cancer tumors to cetuximab Nature Reviews Clinical Oncology 8, 193 (April 2011)

Nautiyal J, Banerjee S, Kanwar SS, Yu Y, Patel BB, Sarkar FH, Majumdar AP. Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells.Int J Cancer. 2011 Feb 15;128(4):951-61.

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Xeliri second line for metastatic colorectal cancer – pro

M Levin, MD — Sun, 23 Sep 2012 17:48:36 +0000

The issue that we will discuss is Xeliri (Xeloda and irinotecan) in second or later line of therapy. It is a tempting regimen because Xeldoa is an generally effective drug for colorectal cancer and it is oral. We start by pointing out that there are now six different classes of drugs with significant antitumor activity in colon cancer:

The best way to combine and sequence all of these drugs to optimize treatment is not yet established, although for intial treatment of metasatic colorectal cancer NCCN recommends combinations of 5FU and Lekovorin with oxaliplatin or irinotecan with or without Avastin, CAPEOX, 5FU/Leukovorin, Xeloda and Avastin or Folfoxiri.

For second or third line therapy, single agents are acceptable and NCCN lists irinotecan as a single agent. It also lists combinations, see p. COL-C of the NCCN guideline for colon cancer. NCCN has a complex schema when to give what for second line and also lists irinnotecan or Folfiri with Erbitux, Zaltrap or Vectbix. However, it does not list irinotecan with Xeloda.

NCCN, Colon cancer 2012

Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29:2011.

Ogino S, Shima K, Meyerhardt JA, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 2012; 18:890.

Bokemeyer C, Cutsem EV, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012.

Braun MS, Richman SD, Quirke P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008; 26:2690.

Boige V, Mendiboure J, Pignon JP, et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol 2010; 28:2556.

Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007; 12:38.

Masi G, Vasile E, Loupakis F, et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst 2011; 103:21.

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Folfox and Folfiri for metastatic colorectal cancer – pro

M Levin, MD — Wed, 05 Sep 2012 12:20:21 +0000

Currently, there are seven active and approved chemotherapy drugs for patients with metastatic colorectal cancer: 5-FU, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab. Among the best studied ways of putting some of these drugs together are the regimen Folfox and Folfiri. Three randomized studies demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin. Intergroup study N9741 then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced an improved PFS (median, 6.9 months vs. 8.7 months; P = .014; HR = 0.74; 95% CI, 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR = 0.66; 95% CI, 0.54–0.82) compared with patients randomized to IFL. Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over upon progression on first-line therapy, respectively. PFS and OS were identical between the treatment arms in both studies. Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.Avastin is also approved with 5FU containing regimens for first line. Forfiri is FDA approved also with Erbitux.

The Folfox regimen includes a 22 hour continuous infusion of 5FU. While this can be done through a pump on the outpatient basis, it is often delivered inpatient. The FLOX regimen eliminates the infusion part and is slowly gaining on the Folfox because it is more convenient. However, at the present time, Folfox has more supporting studies and is more widely used than FLOX. Flox is quoted in NCCN, COL-F, 2 2017.
Tournigand, C, Andre, T, Achille, E, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J Clin Oncol 2004; 22:229.

Colucci G, Gebbia V, Paoletti G, et al.: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23 (22): 4866-75, 2005.
Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (23): 2335-42, 2004.
Giantonio BJ, Catalano PJ, Meropol NJ, et al.: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 23 (Suppl 16): A-2, 1s, 2005.
Rothenberg ML, Eckardt JR, Kuhn JG, et al.: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14 (4): 1128-35, 1996.
nccn.org, colorectal 2014

Daniela R. Nebuloni Milena P. Mak Fabiano Hahn Souza Daniel F. Saragiotto Thiago Júlio Gilberto De Castro Jr Jorge Sabbaga Paulo M. Hoff, Modified FLOX as first-line chemotherapy for metastatic colorectal cancer patients in the public health system in Brazil: Effectiveness and cost-utility analysis Mol CLin Oncol January 2013 Volume 1 Issue 1

Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007:25:21982204.

Intrahepatic chemotherapy for colon cancer metastases – pro

M Levin, MD — Tue, 28 Aug 2012 01:01:19 +0000

The potential value of hepatic intra-arterial chemotherapy (HIAC) can be considered from several different perspectives. A fundamental assumption for this discourse requires that, in this evaluation, HIAC is being provided with the intent of providing regional hepatic therapy for metastatic hepatic disease. Despite advances in colon cancer (CRC) screening, surgical techniques, and several novel adjuvant agents, CRC continues to be a significant medical challenge. In the United States, approximately 130,000 cases of colon cancer are diagnosed annually. Of these patients, approximately 60% will ultimately develop metastatic disease, and <30% of the initial patient population will have disease confined to the liver.

Ample evidence exists in support of HIAC as the preferred route of administration of regional hepatic chemotherapy: it achieves higher intrahepatic drug concentrations and excellent tumor response rates when compared with other routes of administration. HIAC is an effective form of regional chemotherapy for hepatic metastases. Nearly all studies demonstrate a tendency toward or a significant decrease in hepatic tumor progression when HIAC is used. It is also clear from the data reviewed that regional control of hepatic disease without or independent of systemic disease control does not confer a survival advantage.

To date, the QOL of patients undergoing HIAC has not been adequately evaluated or compared with other treatment modalities. The studies available do not permit any conclusions about the QOL of patients receiving HIAC. Future studies should include QOL among the secondary outcomes in evaluating HIAC.

To date, 10 RCTs have been published, for a total of 1,277 patients enrolled. For tumor response rates, relative risks (RR) and their 95% CIs were obtained from raw data; for OS, hazard ratios (HRs) and their 95% CIs were extrapolated from the Kaplan-Meier survival curves.

Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.

Going to a different setting, the use of HAI of FUDR and systemic 5-FU/LV following resection of hepatic metastases clearly decreases local recurrence and can improve 2-year survival, and further study of HAI in this setting is warranted. Both hepatic and extrahepatic relapses remain a problem and, therefore, initial studies combining HAI with newer systemic agents, such as irinotecan and oxaliplatin, are under way. These should provide a framework to guide us as to which combination regimens are the most effective and well-tolerated. Ultimately, this should lead to randomized trials of HAI therapy plus systemic chemotherapy versus our most active systemic chemotherapy alone in order to determine the best approach to treating hepatic CRC metastases.

http://www.annalssurgicaloncology.org/cgi/reprint/13/2/142.pdf

Evan S. Ong, MD, Madeleine Poirier, MDCM, MSc, FRCS(C) and N. Joseph Espat, MD, MS, FACS
Hepatic Intra-Arterial Chemotherapy Annals of Surgical Oncology 13:142-149 (2006)

S. Mocellin, P. Pilati, M. Lise, and D. Nitti
Meta-Analysis of Hepatic Arterial Infusion for Unresectable Liver Metastases From Colorectal Cancer: The End of an Era?
J. Clin. Oncol., December 10, 2007; 25(35): 5649 – 5654.

New drug: Zaltrap – pro

M Levin, MD — Fri, 24 Aug 2012 16:52:25 +0000

Zaltrap was approved by the FDA in the beginning of August 2012 for patients who fail oxaliplatin. It is also known as aflibercept, VEGF trap or, when used for macular degeneration, Eylea. It is a recombinant fusion protein between the Fc portion of human IgG1 and the extracellular domains of VEGF receptor 1 & 2 (VEGFR 1 & VEGFR 2), which binds VEGF-A and VEGF-B (vascular endothelial growth factor), as well as PLGF (placental growth factor). By binding to and inhibiting these angiogenic growth factors, their neovascular activity, and vascular permeability, ziv-aflibercept inhibits tumor angiogenesis.

Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. The approval for colon cancer was based on a phase III trial. ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Aflibercept failed its primary endpoint of overall survival in the Vital phase III trial for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), although it improved the secondary endpoint of progression-free survival. It is also in trials for prostate cancer.

J. Tabernero, E. Van Cutsem, R. Lakomy, J. Prausova, P. Ruff, G. Van Hazel, V. Moiseyenko, D. Ferry, J. McKendrick, K. Soussan-Lazard, E. Boelle, C. Allegra. VELOUR, a Phase 3 Study of Aflibercept (A) Versus Placebo (pbo) in Combination with FOLFIRI for the Treatment of Patients (pt) with Previously Treated Metastatic Colorectal Cancer (MCRC). 2011 European Multidisciplinary Congress. Abstract 6LBA. Presented September 25, 2011.

Tzu-Fei Wang and Albert Craig Lockhart Aflibercept in the Treatment of Metastatic Colorectal Cancer Clin Med Insights Oncol. 2012; 6: 19–30.

Tang P, Cohen SJ, Bjarnason GA. Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer (MCRC): a PMH phase II consortium trial. J Clin Oncol. 2008;(Suppl 26):Abstr 4027.

Teng LS, Jin KT, He KF, Zhang J, Wang HH, Cao J. Clinical applications of VEGF-trap (aflibercept) in cancer treatment. J Chin Med Assoc. 2010;73:449–56.

Please see the Lay version here

Chemo Options for Later Lines of Therapy for Metastatic Colon Cancer – pro

M Levin, MD — Sat, 04 Aug 2012 19:25:40 +0000

There are now five different classes of drugs with significant antitumor activity in colon cancer:

Fluoropyrimidine (5-fluorouracil [5-FU] which is usually given with leucovorin [LV], capecitabine, tegafur plus uracil [UFT]). Irinotecan, Oxaliplatin, Cetuximab and panitumumab. The latter two are monoclonal antibodies (MoAbs) directed against the epidermal growth factor receptor (EGFR), and bevacizumab, is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Recently another antibody was approved for colon cancer - Zaltrap, as well as the drug Stivarga. The best way to combine and sequence all of these drugs to optimize treatment is not yet established, although for intial treatment of metasatic colorectal cancer NCCN recommends combinations of 5FU and Lekovorin with oxaliplatin or irinotecan with or without Avastin, CAPEOX, 5FU/Leukovorin, Xeloda and Avastin or Folfoxiri.

For second or third line therapy, single agents are acceptable but NCCN lists only irinotecan as a single agent. It also lists combinations of these drugs, Erbitux and Vectbix(for wild type KRA patients), see p. COL-C of the NCCN guideline for colon cancer. NCCN has a complex schema when to give what for second line and also lists Erbitux and Vectbix. However, capecitabine is also FDA approved as a single agent. NCCN does not list 5FU/Leikovorin but it can also be considered appropriate given the long history of its use for colorectal metastatic cancer and support from many older papers.

Recently, Stivarga was also approved. STIVARGA® (regorafenib) is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy.

NCCN, Colon cancer 2013

STIVARGA Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013.

Grothey A, Sobrero A, Siena S, et al; CORRECT Study Team. Results of a phase III randomized, double-blind, placebo-controlled multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Poster presented at: American Society of Clinical Oncology 2012 Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA.

Read the Layperson version here.