Cancer Treatment

Capeox (Xelox) for metastatic colon cancer: NCCN Guideline

In 2007, the NCCN  update has added the regimen CapeOx, a combination of capecitabine (Xeloda, Roche) and oxaliplatin (Eloxatin, Sanofi-Aventis), as an alternative to FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) for the treatment of advanced or metastatic colon cancer. The majority of safety and efficacy data for CapeOx have come from Europe, where administration of capecitabine at a starting dose of 1000 mg/m2 twice daily for 14 days, to be repeated every 21 days, is standard. There is some evidence that North American patients may experience greater toxicity with capecitabine, and other fluoropyrimidines, than the Europeans and may require a lower dose. However, because the efficacy of the drug at lower doses has not been evaluated in large, randomized trials, NCCN still recommends a starting dose of 1000 mg/m2 with close monitoring in the first cycle for toxicity and possible dosage adjustments.

Anna Pessino, Alberto Sobrero Optimal treatment of metastatic colorectal cancer Expert Review of Anticancer Therapy 2006 6:5, 801-812

Dan S. Zuckerman, Jeffrey W. Clark Systemic therapy for metastatic colorectal cancer Cancer
112(9), 1879-1891

NCCN.ORG, Colorectal/Colon

Radiofrequency ablation for the liver

Radiofrequency ablation (RFA) is a thermoablative technique which destroys tissue by heating cancer cells to temperatures exceeding 60°C. In RFA, temperature changes are induced using high-frequency alternating current applied via an electrode or electrodes placed within the tissue to generate ionic agitation. RFA can be applied percutaneously, laparoscopically or intraoperatively.

Percutaneous ablation is a commonly used modality of tratment when resection is not possible for HCC. Other local modalities are radiofrequency ablation or chemo embolization. Microwave coagulation therapy, one of the thermal ablation therapies now available, has been used in the treatment of liver metastases. To date, at least seven series have been published in the English-language literature  in which the results of microwave coagulation therapy of hepatic metastases have been described. However, these results were narrowly focused preliminary studies: a few clinical patient trials, principally as assessments of feasibility, safety, and short-term efficacy. Although the preliminary results are promising, few articles concerning the effect of microwave ablation on survival have been published. This is even more true in the setting of metastatic cancer.

A R Gillams
Liver ablation therapy
Br. J. Radiol., September 1, 2004; 77(921): 713 - 723.

P. Liang, B. Dong, X. Yu, Y. Yang, D. Yu, L. Su, Q. Xiao, and L. Sheng
Prognostic Factors for Percutaneous Microwave Coagulation Therapy of Hepatic Metastases
Am. J. Roentgenol., November 1, 2003; 181(5): 1319 - 1325.

http://www.nice.org.uk/nicemedia/pdf/ip/IPG092guidance.pdf

Vectbix in combination

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. The proposed combination is according to an ongoing phase II study, 181. 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.

1.Is there sufficient information to render a conclusive determination?

Yes

2.Is the treatment protocol… in accordance with standards of good medical practice within the organized medical community according to the plan’s definition of medically necessary?

No

3.Based on plan’s definition of experimental is the treatment determined to be experimental?

yes

4.If so, what other options would be generally accepted medical practice?

Vectbix or erbitux alone, Xeloda

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.

Folfox and Folfiri for metastatic colorectal cancer

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.

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

Intrahepatic chemotherapy for colon cancer metastases

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.

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

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 emchanism of action, there is interest in studying it in colorectal and oterh 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.

Maintenance Avastin

The trial that led to the FDA approval of avastin for nonsmall lung cancer was called ECOG 4599 (NEJM abstract here), and in that trial 878 patients with previously untreated advanced NSCLC (limited to those with nonsquamous cancers, no brain metastases, no history of coughing up blood, and not on coumadin or other blood thinners) were randomized to carbo/taxol for six cycles or the same chemo with avastin 15 mg/kg every three weeks.  For the patients who didn’t show progression of their cancer after six cycles of chemo, the protocol had patients stop the chemo and continue on “maintenance” avastin every three weeks, until they showed evidence of progression of their disease. Based on the overall survival benefit, the FDA approved avastin in this particular population, to be given with carbo/taxol, then followed by maintenance avastin.  We don’t have trial results in which avastin is given with chemo but then there’s no maintenance therapy. There was no maintenance in the breast cancer Avastin trials but one colon cancer trial did include it.

http://onctalk.com/2007/08/15/avastin-maintenance/

http://content.nejm.org/cgi/content/abstract/355/24/2542

Vectbix after Erbitux for colon cancer

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. NCCN does not recommend using either of theese two EGFR blockers after the other. This recommendation is based on a lack of studies showing otherwise and the similar mechanism of action of the two drugs.

NCCN.ORG, colon cancer, p.24

Xeloda for adjuvant therapy of breast cancer

yLay Summary: I review suitability of Xeloda for adjuvant therapy of breast cancer.

The proven efficacy of capecitabine (Xeloda(R)) in the metastatic setting, its association with minimal myelosuppression and alopecia, and the lack of increased toxicity when added to taxotere all point to an increasingly important role for capecitabine for early breast cancer, according to an overview of recent, ongoing and future trials.

I cite the US Oncology Adjuvant Capecitabine and Docetaxel trial (US Oncology; n = 2610) which is evaluating capecitabine/taxotere in sequential adjuvant treatment; the Trial of Accelerated Adjuvant Chemotherapy with Capecitabine in Early Breast Cancer (TACT2; n = 4400); alternative combination therapy to taxotere in adjuvant breast cancer by the Grupo Español de Investigación en Cáncer de Mama (GEICAM; n = 1302); maintenance capecitabine after adjuvant anthracyclines (GEICAM-CIBOMA; n = 3538); alternative adjuvant combination (AGO GAIN; n = 3130); alternative sequential combination by the Cancer and Leukemia Group B (CALGB; n = 600); ibandronate with or without capecitabine by the Breast International Group (BIG; n = 1394); and sequential capecitabine-based combinations in the Phase III Adjuvant Study (FinXX; n = 1500).

There is also a study looking at doxorubicin/ cyclophosphamide (AC) versus capecitabine plus taxotere (XT) in adjuvant node-negative breast cancer being conducted by the European Organisation for Research and Treatment of Cancer/Breast International Group/Microarray for Node-Negative Disease may Avoid Chemotherapy Trial (EORTC-BIG MINDACT). This study will also have a double-risk evaluation with a 5-year disease-free survival primary endpoint.
O'Shaughnessy JA.The evolving role of capecitabine in breast cancer.Clin Breast Cancer. 2003 Apr;4 Suppl 1:S20-5.

Walko CM, Lindley C.Capecitabine: a review.Clin Ther. 2005 Jan;27(1):23-44.

William B. Ershler Capecitabine Monotherapy: Safe and Effective Treatment for Metastatic Breast Cancer The Oncologist, Vol. 11, No. 4, 325-335, April 2006;

Folfox for adjuvant therapy of colon cancer

Lay Summary: Folfox is a standard of care treatment for stage III and probably stage II colon cancer.

Approximately 80,000 patients will be diagnosed with either stage II or stage III colon cancer in 2007. Although some controversy still exists regarding the role of adjuvant therapy for patients with stage II disease (but newer studies are beginning to show benefit even is stage II), studies have confirmed the benefits of treatment for those with stage III disease.

The use of DFS as a primary endpoint in colon cancer adjuvant trials was further demonstrated by the updated results of the MOSAIC [Multi-center International Study of Oxaliplain/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer] trial, which compared the benefit of adding oxaliplatin to 5-FU/leucovorin (LV) (FOLFOX 4) as adjuvant treatment compared with 5-FU/LV alone. The 3-year DFS with FOLFOX 4 was 78.2% vs 72.9% for 5-FU/LV alone (hazard ratio [HR] = 0.77; P = .002). At 5 years, overall survival remained superior with FOLFOX 4 (73.3% vs 67.4%; HR = 0.80; P = .03). The survival benefit (82.1% vs 74.9 %; HR = 0.74) was seen primarily in "high-risk" patients with stage II disease (ie, T4, bowel obstruction/perforation, poorly differentiated tumors, venous invasion, or fewer than 10 examined nodes) and in those with stage III disease (66.4% vs 58.9%; HR = 0.78; P = .005). The addition of oxaliplatin did not appear to benefit patients with low-risk stage II disease. Median follow-up at 6 years revealed that the benefit of FOLFOX 4 was confined to patients with stage III disease: 73.0% vs 68.6%; HR = 0.8; P = .029. For those with stage II disease, survival at 6 years was equivalent, nearly 87% with either 5-FU/LV or FOLFOX 4.

Toxicities associated with oxaliplatin, such as neutropenia, were common (41%), but febrile neutropenia was uncommon (1.8%). Peripheral neuropathy developed in approximately 15% of patients, but grade 3 neuropathy was seen in only 0.7%, indicating significant recovery from the neurosensory effects of oxaliplatin in the vast majority of patients.

These data clearly support the treatment of patients with stage III colorectal cancer with FOLFOX-based adjuvant regimens as an acceptable standard of practice. These results are consistent with those of the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial, which demonstrated efficacy with addition of oxaliplatin to bolus 5-FU/LV as adjuvant treatment. Oral fluoropyrimidines such as capecitabine have been tested in the adjuvant treatment of patients with stage III disease, and the combination with oxaliplatin appears to have acceptable toxicities. Efficacy data are not yet available and are reviewed under Xelox.

1. Sargent DJ, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. Time dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer. Lessons from the 20,800 patient ACCENT dataset. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4008.
2. O'Connell MJ, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. Survival following recurrence in patients with adjuvant colon cancer: findings from the 20,800 patient ACCENT dataset. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4009.
3. de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with median follow up of six years. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4007.
4. Wolmark N, Wieand S, Kuebler JP, Colangelo L, Smith RE. A phase III trial comparing 5FU/LV to 5FU/LV and oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP protocol C07. Proc Am Soc Clin Oncol. 2005;25:264s. Abstract LBA3500.
5. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696-2704