Cancer Treatment Today » Colon Cancer

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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Colovantage test for colon cancer – pro

M Levin, MD — Sun, 28 Oct 2012 16:09:25 +0000

ColoVantage is a new test available from Quest. It is a screening test that is not meant to be a substitute for colonoscopy. It was approved by NY State in March of 2011. It detects circulating methylated DNA from the SEPT9 gene, which is involved in cytokinesis and cell cycle control. A case-control study performed at Quest Diagnostics showed that the ColoVantage test is 70% sensitive for CRC detection at a specificity of 89%. ColoVantage has successfully detected cancer at all stages; however, the number of patients at each stage of cancer was too small to derive stage-specific sensitivity data. A similar test demonstrated a sensitivity of 67% and a specificity of 88% in a prospective study of almost 8000 people. Unfortinately, at this time, it remains a proprietary test that has not been sufficiently studied. These findings need to be confirmed in larger studies that evaluate the clinical utility of this test. Support for this test in guidelines from professional organizations is lacking.

Rösch T, Church T, Osborn N, et al. Prospective clinical validation of an assay for methylated SEPT9 DNA for colorectal cancer screening in plasma of average risk men and women over the age of 50 [abstract]. Gut. 2010;59(suppl III):A307.

deVos T, Tetzner R, Model F, Weiss G, Schuster M, Distler J, et al. Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clin Chem. 2009 Jul;55(7):1337-46.

Tänzer M, Balluff B, Distler J, Hale K, Leodolter A, Röcken C, et al. Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS One. 2010 Feb 4;5(2):e9061.

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PET to detect recurrence of colon cancer with serially rising CEA levels – pro

M Levin, MD — Sun, 23 Sep 2012 18:34:03 +0000

PET is being more frequenlty used to detect and identify recurrence. More recently NCCN has been more supportive of PET in this setting. It used to support PET only in the situation of rising CEA and no identified recurrence for localization of disease recurrence in patients with rising CEA level and non-diagnostic imaging studies, such as CT scans.However, PET scan can potentially identify occult disease in this setting that CT misses. Therefore, PET scans can led to greater potentially curative resection in patients with elevated CEA and patients who are candidates for resection of isolated colorectal cancer liver metastases. PET scan prior to attempted resection reduces the number of unnecessary laparotomies.

On p. Col-9, 2012 NCCN recommends the use of CT scans of chest and abdomen in the situation of serial CEA elevations but also says “Consider PET/CT scan”.

CMS guidelines state that PET would rarely be used in the diagnosis of colorectal cancer. However, starting July 1, 2001, HCFA, now called the Centers for Medicare and Medicaid Services (CMS), is covering FDG-PET imaging for diagnosis, staging, and restaging of colorectal cancer.

Gade M, Kubik M, Fisker RV, Thorlacius-Ussing O, Petersen LJ. Diagnostic value of (18)F-FDG PET/CT as first choice in the detection of recurrent colorectal cancer due to rising CEA. Cancer Imaging. 2015;15(1):11. Published 2015 Aug 13. doi:10.1186/s40644-015-0048-y

Abdel-Nabi H, Doerr RJ, Lamonica DM, et al. Staging of primary colorectal carcinomas with fluorine-18 fluorodeoxyglucose whole-body PET: correlation with histopathologic and CT findings. Radiology, 1998;206:755-760.

Podoloff DA, Advani RH, Allred C, Benson AB 3rd, Brown E, Burstein HJ, Carlson RW, Coleman RE, Czuczman MS, Delbeke D, Edge SB, Ettinger DS, Grannis FW Jr, Hillner BE, Hoffman JM, Kiel K, Komaki R, Larson SM, Mankoff DA, Rosenzweig KE, Skibber JM, Yahalom J, Yu JM, Zelenetz AD.
NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer.
J Natl Compr Canc Netw. 2007 May;5 Suppl 1:S1-S22; quiz S23-2.

Erratum in:
J Natl Compr Canc Netw. 2007 Aug;5(7)

Sobhani I, Tiret E, Lebtahi R, Aparicio T, Itti E, Montravers F, Vaylet C, Rougier P, AndréT, Gornet JM,
Cherqui D, Delbaldo C, Panis Y, Talbot JN, Meignan M, Le Guludec D, Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer.
Br J Cancer. 2008;98(5): 875.

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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:

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). Zaltrap was recenlty(2012) also approved.

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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Afinitor for colon cancer – pro

M Levin, MD — Fri, 21 Sep 2012 18:05:46 +0000

Evidence for using Afinitor for colorectal cancer is weak – one small trial with weak results. There is some evidence from a small trial ( Altomare et al) reported in ASCO 2012 that some colorectal cancer patients whose tumors had gotten worse on all standard treatments can benefit from a combination of Afinitor® (everolimus) and Avastin® (bevacizumab). This was a small trial in 50 patients. It showed a tumor control rate of 47%. Median progression-free survival time was 2.28 months, median overall survival time was 7.87 months. 46 percent of patients had disease control that lasted a median of 6.1 months. There were no complete or partial responses. 8 had a minor response lasting median 4.1 months. 15 had stable disease lasting median 6.7 months.

Altomare et al., 2010 ASCO Annual Meeting Abstracts, Abstract # 3535, Phase II trial of bevacizumab (B) plus everolimus (E) for refractory metastatic colorectal cancer (mCRC).

nccn. colorectal cancer 2012

Afinitor, Prescribing Information 2012.

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Nexavar for colon cancer – pro

M Levin, MD — Thu, 06 Sep 2012 16:17:04 +0000

Nexavar is currently in a phase II clinical trial for colorectal cancer. In this trial, researchers are combining the targeted monoclonal antibody cetuximab (Erbitux) with another targeted drug called sorafenib (Nexavar) to treat patients with metastatic colorectal cancer whose tumors show epidermal growth factor receptor (EGFR) activity. I was not able to find any other published liteature on the use of Nexavar for colon cancer. Sorafenib works by inhibiting the action of various kinase enzymes. This stops the signals that tell the cancer cells to grow and multiply. It also stops blood vessels growing into the tumour. This reduces the tumour’s blood supply and with it, its supply of oxygen and nutrients. Both these effects stop the tumour from growing. it is currently FDA approved for renal cell cancer and for hepatocellular carcinoma. Plan language considers this an ivestigational agent because it is in a phase II trial, there are no studies of single agent use, and the expert consensus is that more studies are needed.

Nexavar, Prescribing information
NCCN.ORG, Colorectal cancer

PET for colon cancer staging – pro

M Levin, MD — Wed, 05 Sep 2012 18:48:42 +0000

Lay Summary: PET is an acceptable way to stage colon cancer, although some resistance remains.

More recently NCCN has been more supportive of PET in colorectal cancer staging. It supports PET in the situation of rising CEA and no identified recurrence but also in some other settings (p.13). CMS guidelines state that PET would rarely be used in the diagnosis of colorectal cancer. However, starting July 1, 2001, HCFA, now called the Centers for Medicare and Medicaid Services (CMS), is covering FDG-PET imaging for diagnosis, staging, and restaging of colorectal cancer.

Abdel-Nabi and coworkers evaluated 48 patients with either biopsy-proven (44 patients) or a high clinical suspicion for colorectal cancer. These patients were scheduled to undergo exploratory laparotomy. FDG-PET detected all intraluminal carcinomas, and false-positive results were obtained in 4 of 7 patients who did not have cancer. Three of the 4 patients with false-positive results had inflammatory bowel disease, and 1 patient had undergone a polypectomy. Lymph node metastases were identified by PET in 4 of 14 patients who had lymph node involvement. CT had a similar sensitivity for detection of lymph node metastases. PET was superior to CT in identifying metastases to the liver — 7 of 8 patients had documented hepatic metastases detected by PET and only in 3 patients were these metastases detected by CT. Filmont and colleagues at UCLA evaluated the impact of FDG-PET imaging on the clinical stage determined by conventional imaging in the restaging of patients with colorectal cancer. In a population of 127 patients undergoing studies for restaging, PET downstaged 15 patients (12%), upstaged 18 patients (14%), and assigned the same stage in 94 patients (74%) compared with conventional imaging. Thus, whole-body FDG-PET had an impact on the clinical stage in 26% of colorectal cancer patients being restaged after treatment. The same group evaluated the prognostic value of FDG-PET in patients being restaged for colorectal cancer, comparing the prognostic value of FDG-PET and conventional imaging. The mean duration of follow-up was 61 +/- 29 weeks. Nine (16%) of the 55 patients had no evidence for residual/recurrent disease, whereas 46 (84%) had evidence for residual/recurrent disease. The positive and negative predictive values for PET were 95% and 59%, respectively. Conventional imaging had a positive predictive value of 89% and negative predictive value of 29%. The prognostic accuracy of PET was superior to that of conventional imaging (87% vs 71%). These data demonstrate that whole-body PET imaging predicts the outcome of colorectal cancer patients with high accuracy, and the high negative predictive value is superior to that of conventional imaging.

However, the real question is if it can supplant CT with contrast and that is not resolved.

NCCN on p.COL-2 says that PET/CT should not routinely be done for staging and should only be used to clarify an equivocal finding on a contrast enchanced CT. It recommends Chest/abdominal/pelvic CT annually for upto 5 y for patients at high risk forrecurrence.

The field is definitely moving toward accepting PET in various situation in colon cancer but not universally.

NCCN 2014 on p. COL-3 and REC-3 says that PET is not routinely recommended for surveillance. NCCN in its guideline on p. COL-3says that use of PET for restaging is not recommended.

Filmont JE, Vranjesevic D, Meta J, et al. Restaging of colorectal cancer patients: impact of FDG-PET on clinical stage by conventional imaging. Program and abstracts of the Society of Nuclear Medicine 48th Annual Meeting; June 23-27, 2001; Toronto, Ontario, Canada. J Nucl Med. 2001;42(suppl):123P. Abstract 461.

Filmont J, Vranjesevic D, Meta J, et al: Prognostic value of FDG-PET for predicting the outcome of re-staged colorectal cancer patients. Program and abstracts of the Society of Nuclear Medicine 48th Annual Meeting; June 23-27, 2001; Toronto, Ontario, Canada. J Nucl Med. 2001;42(suppl):124P. Abstract 464.

Podoloff DA, Advani RH, Allred C, Benson AB 3rd, Brown E, Burstein HJ, Carlson RW, Coleman RE, Czuczman MS, Delbeke D, Edge SB, Ettinger DS, Grannis FW Jr, Hillner BE, Hoffman JM, Kiel K, Komaki R, Larson SM, Mankoff DA, Rosenzweig KE, Skibber JM, Yahalom J, Yu JM, Zelenetz AD.NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer.J Natl Compr Canc Netw. 2007 May;5 Suppl 1:S1-S22; quiz S23-2.

Erratum in:: J Natl Compr Canc Netw. 2007 Aug;5(7); R. Labianca et al, Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow-up Ann Oncol (2010) 21 (suppl 5): v70-v77.; Dewhurst C, Rosen MP, Blake MA, Baker ME, Cash BD, Fidler JL, Greene FL, Hindman NM, Jones B, Katz DS, Lalani T, Miller FH, Small WC, Sudakoff GS, Tulchinsky M, Yaghmai V, Yee J, Expert Panel on Gastrointestinal Imaging. ACR Appropriateness Criteria® pretreatment staging of colorectal cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2011. 7 p. [62 references]

Vectibix in combination – pro

M Levin, MD — Wed, 05 Sep 2012 18:32:28 +0000

Panitumumab (Vectibix, Amgen) was approved by the FDA for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, or irinotecan-containing regimens. The NCCN Colon Cancer panel added panitumumab as alternate option to cetuximab after first or second progression on previous therapy. This addition came with a recommendation that patients should not be excluded from therapy on the basis of EGFR results.

Vectbix is FDA approved as a single agent. It is experimental in combination. I briefly review the combination Vectbix and chemotherapy studies presented in ASCO GI 2008.

The first is an interim pooled, blinded

safety data from two Phase 3 trials examining Vectibix(TM)

(panitumumab) in combination with chemotherapy in first- and

second-lines of metastatic colorectal cancer (mCRC) treatment. The

respective independent Data Monitoring Committee's reviews of the

pooled, or combined, safety data from both arms of these randomized,

multi-center trials endorsed the continuation of these studies per

protocol.

   PRIME (203) Study

   The "PRIME" (Panitumumab Randomized trial In combination with

chemotherapy for Metastatic colorectal cancer to determine Efficacy)

or "203" trial is a global Phase 3 study investigating Vectibix in

combination with FOLFOX chemotherapy as a first-line treatment for

patients with mCRC. Patients enrolled in the study were randomized to

receive either 6.0 mg/kg of Vectibix and FOLFOX4 once every two weeks

(Q2W) or FOLFOX4 alone Q2W. The primary endpoint is progression-free

survival and other endpoints include overall survival, objective

response rate, time to progression, duration of response and safety.

   A pooled interim safety review of 601 patients (302 Vectibix plus

FOLFOX; 299 FOLFOX only) of which 99 percent received at least one

cycle of therapy showed the following grade 3/4 adverse events:

neutropenia (25 percent), diarrhea (10 percent), fatigue (four

percent), nausea and pulmonary embolism (three percent, respectively),

febrile neutropenia, hypomagnesemia, dehydration and deep vein

thrombosis (two percent, respectively). Fifty-four percent of the

pooled patient population had a skin reaction with 11 percent of

patients having a grade three and less than one percent experiencing a

grade four. PRIME study's target accrual goal of approximately 1,150

patients was reached in January 2008.

   181 Study

   The "181" trial is a global Phase 3 study investigating Vectibix

in combination with FOLFIRI chemotherapy as a second-line treatment

for patients with mCRC. Patients enrolled in the study were randomized

to receive either 6.0 mg/kg of Vectibix and FOLFIRI Q2W or FOLFIRI Q2W

alone. The co-primary endpoints are progression-free survival and

overall survival, other endpoints include objective response rate,

time to progression, duration of response and safety.

   A pooled interim safety review for 701 patients (352 Vectibix plus

FOLFIRI; 349 FOLFIRI only) of which 99 percent received at least one

cycle of therapy showed the following grade 3/4 adverse events:

neutropenia (15 percent), diarrhea (9 percent), fatigue (four

percent), febrile neutropenia, nausea, dehydration, pulmonary embolism

(two percent, respectively), hypomagnesemia and deep vein thrombosis

(one percent, respectively) and infection (less than one percent).

Sixty-one percent of the pooled patient population had a skin reaction

with 12 percent experiencing a grade three and less than one percent

experiencing a grade four. Target accrual for this study is

approximately 1,100 patients and enrollment is anticipated to be

complete by Q1 2008.

   In both arms of each trial KRAS mutational status in patients'

tumors will be studied as a biomarker for Vectibix activity. Recent

data indicate that KRAS gene status may predict efficacy and could

potentially serve as a patient selection biomarker for Vectibix

monotherapy.

In conclusion, this is an investigational treatment still in an ongoing study.

NCCN.ORG, colon cancer, p.24

Wainberg Z, Hecht JR Panitumumab in colon cancer: a review and summary of ongoing trials. Expert opinion on biological therapy. 2006 Nov;6(11):1229-35.

Saif MW, Cohenuram M Role of panitumumab in the management of metastatic colorectal cancer. Clinical Colorectal Cancer 2006 Jul;6(2):118-24

Gibson TB, Ranganathan A, Grothey A Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clinical colorectal cancer 2006 May;6(1):29-31.

Tyagi P Recent results and ongoing trials with panitumumab (ABX-EGF), a fully human anti-epidermal growth factor receptor antibody, in metastatic colorectal cancer Clinical colorectal cancer 2005 May;5(1):21-3.