Surgical Removal of the Primary Tumor Not Immediately Needed in Patients with Metastatic Colorectal Cancer

New research shows that patients who are newly diagnosed with metastatic, surgically incurable, colorectal cancer (mCRC) do not need immediate surgery to remove their primary tumor unless the tumor is causing complications.

Surgical removal of the primary tumor at the time of diagnosis was once standard practice and is still common in patients with metastatic colorectal cancer. Because cancer has already spread to other parts of the body by this stage, the purpose of this surgery is not to extend survival, but to prevent future complications, such as intestinal blockage, perforation of the bowel, and severe bleeding. However, over the past decade several new effective chemotherapy drugs for colorectal cancer have been introduced and until now there has been little data to assess whether this pre-emptive surgery is still warranted.

The research will be presented on Monday, June 1, by Philip B. Paty, MD, Memorial Sloan-Kettering Cancer Center, New York, NY, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida.

Incidence of metastatic Colorectal Cancer (mCRC)
According to GLOBOCAN 2002, a cancer incidence database produced by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO), the worldwide incidence of colorectal cancer is approximately one million cases per year. The National Cancer Institute (NCI) reports that approximately 50 percent of patients diagnosed with colorectal cancer will suffer from advanced disease that has metastasized to other parts of the body, most commonly to the liver.

Uncertain benefit
The researchers rationale is that in the absence of symptoms (bleeding, perforation, obstruction) or resectable metastatic disease, primary tumor resection in patients who present with synchronous metastatic colorectal cancer (mCRC) is of uncertain benefit.

The purpose of their study was to describe the frequency of intervention necessary to palliate the intact primary tumor in patients who present with synchronous stage IV CRC and receive up-front modern combination chemotherapy without prophylactic surgery.

“In this era of modern chemotherapy, routine surgery to remove the primary tumor in patients with unresectable metastases is no longer supported by the data,” explained Philip Paty, MD, an attending surgeon and vice chairman of clinical research at Memorial Sloan-Kettering Cancer Center (MSKCC) and the study’s senior author. “In addition to being an unnecessary procedure that carries its own risks of morbidity and mortality, surgery delays the start of chemotherapy for several weeks, and in some cases may make the patient less fit for and less tolerant of chemotherapy. Unless there is an immediate need for surgery, patients should begin chemotherapy first.”

FOLFOX, IFL and FOLFIRI
This retrospective study identified 233 consecutive patients who presented with metastatic colorectal cancer between 2000 and 2006, and were treated with chemotherapy at MSKCC, but had no serious symptoms to prompt immediate surgery. The patients received one of three triple-drug chemotherapy combinations as their initial treatment (the regimens known as FOLFOX, IFL, and FOLFIRI).

Some were also treated with the targeted therapy bevacizumab (Avastin, Roche).

Investigators determined that 217 (93%) patients never developed complications that required removal of their tumor. For the 16 patients (7%) who did eventually need surgery, the vast majority (14/16) had successful operations.

10 patients (4%) required nonoperative intervention (stent or radiotherapy), whereas 213 (89%) never required any direct symptomatic management for their intact primary. Of those, 47 (20%) ultimately underwent elective colon resection at the time of metastasectomy and 8 (3%) during laparotomy for hepatic artery infusion pump placement. Neither use of bevacizumab, location of the primary tumor in the rectum, or metastatic disease burden was associated with increased intervention rate. In addition, when included as a time-varying covariate in a Cox regression model, the need for emergent intervention did not correlate with overall survival.

Most patients with synchronous stage IV CRC who receive up-front modern combination chemotherapy never required palliative surgery for their intact primary. The data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

Overall, the researchers concluded that the mortality attributable to surgery was very low (0.8 percent), suggesting that this approach, by avoiding unnecessary surgery, improves the overall safety of treatment.

For more information:

• American Society for Clinical Oncology (ASCO)
• Poultsides GA , Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG, Weiser M, Temple LK, Wong W, Paty PB. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial Treatment. CRA4030

PubMed abstracts:

• Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009 Apr 30. [Epub ahead of print].
• Dy GK, Hobday TJ, Nelson G, Windschitl HE, O'Connell MJ, et al. Long-term survivors of metastatic colorectal cancer treated with systemic chemotherapy alone: a north central cancer treatment group review of 3811 patients, n0144. Clin Colorectal Cancer. 2009 Mar;8(2):88-93.
• Tamandl D, Gruenberger B, Herberger B, Kaczirek K, Gruenberger T. Surgery after neoadjuvant chemotherapy for colorectal liver metastases is safe and feasible in elderly patients. J Surg Oncol. 2009 Feb 20. [Epub ahead of print]
• Cao Y, Liao C, Tan A, Liu L, Mo Z, Gao F. Capecitabine plus oxaliplatin versu fluorouracil plus oxaliplatin as first line treatment for metastatic colorectal caner - meta-analysis of six randomized trials. Colorectal Dis. 2009 Feb 7. [Epub ahead of print]

Other ASCO 2009 abstracts:

• A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08.
  Meeting:2009 ASCO Annual Meeting Abstract No: LBA4 First Author: N. Wolmark Category: Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4000 First Author: D. KerrCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial).
  Meeting:2009 ASCO Annual Meeting Abstract No: 4001 First Author: S. TejparCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)

Illustration courtesy of the American Society of Clinical Oncology.

Bevacizumab study does not meet primary endpoint, but results suggest future trials may hold promise for early-stage colon cancer treatment

Adding bevacizumab to standard adjuvant chemotherapy does not improve disease-free survival for early-stage colon cancer. This is the primary conclusion from the complete results from the first, randomized phase III trial of bevacizumab (Avastin, Roche) in early-stage colon cancer, known as NSABP C-08, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between Genentech and NCI, and will be presented on Sunday, May 31, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida.

NSABP C-08 was the first study to report results on the use of bevacizumab as an adjuvant treatment. Bevacizumab targets the vascular endothelial growth factor (VEGF) receptor, a key driver of tumor angiogenesis – an essential process in the development and maintenance of blood vessels which is required for a tumor to grow and to spread (metastasize) to other parts of the body.

The results of the NSABP C-08 trial have found that adding bevacizumab to standard adjuvant chemotherapy did not improve disease-free survival (the time that patients are free of tumor recurrence) in early-stage colon cancer

The current study enrolled 2,710 patients who were randomized to receive six months of standard adjuvant chemotherapy or six months of adjuvant chemotherapy combined with bevacizumab plus an additional six months of bevacizumab after the chemotherapy had ended.

All patients in the study had stage II or stage III disease and first had surgery to remove their tumors. After a median follow-up of three years, the investigators found that 77.4 percent of patients in the experimental group (bevacizumab) were alive and free of disease, compared with 75.5 percent of patients in the control group, a difference that was not statistically significant. There were no unexpected side effects in either arm and the toxicities from bevacizumab were well tolerated.

“One interesting effect was that during the year that patients were receiving bevacizumab we saw a benefit in disease-free survival (DFS) that subsequently diminished when follow-up was completed,” said Norman Wolmark, MD, chairman of the Department of Human Oncology at Allegheny General Hospital and the study’s lead author. Patients receiving bevacizumab treatment had a 40 percent lower risk of cancer returning, however, this initial improvement over chemotherapy alone gradually diminished over time.

Commenting on the trial, Walmark continued “Our overall conclusion is that bevacizumab was not effective as an adjuvant treatment for early-stage colon cancer, but the transient benefit we saw in patients who received bevacizumab illustrates that we have more to learn about how this reagent works, and we need to design more clinical trials to determine how it can be used most effectively.”

No new safety signals for bevacizumab were observed in the study and careful review of the data did not provide evidence that cancer returns faster or more aggressively after bevacizumab therapy was stopped.

“These results are encouraging and suggest that Avastin may have an important role in early cancer treatment. We are committed to the ongoing program of Avastin in early-stage cancers and believe that these results could help us optimize the use of Avastin for the benefit of patients,’’ noted William M. Burns, CEO of the pharmaceutical division of Roche, a leader in research-focused healthcare.

Study Results
The NSABP C-08, a two-arm randomized prospective multi-center Phase III study evaluated the use of bevacizumab plus chemotherapy (mFolfox6 + bevacizumab/mFF6+B) for the treatment of Stage II or III adenocarcinoma immediately following surgery (adjuvant therapy) compared to chemotherapy alone (mFolfox6/mFF6). The study showed the addition of one year of bevacizumab to chemotherapy did not result in a statistically significant improvement in overall disease-free survival (DFS). However, during the year of bevacizumab treatment there was an early and significant improvement in disease-free survival that diminished over the course of the study.

Disease-Free Survival was measured from the date of randomization to the date of any type of cancer recurrence or death from any cause. Patients enrolled in the study were randomized after surgery to receive either FOLFOX chemotherapy alone for six months or FOLFOX in combination with bevacizumab (intravenously every two weeks) for six months, followed by an additional six months of bevacizumab monotherapy. Patients continue to be followed for overall survival, a secondary endpoint of the study.

Overall in the study, there was 12 percent improvement in DFS that was not statistically significant (hazard ratio=0.89, p=0.15; risk reduction 11 percent). In the first year of the study, while patients received bevacizumab in addition to a standard six-months of adjuvant chemotherapy, disease-free survival improved by 67 percent compared to chemotherapy alone (hazard ratio=0.60; risk reduction of 40 percent). However, this early improvement in DFS began to diminish after the first year, and overall DFS was not improved.

NSABP C-08 included a comprehensive safety analysis that showed no new or unexpected safety events related to bevacizumab in the study. Specific severe (Grade 3 or greater) adverse events (AEs) that occurred with increased frequency in patients who received bevacizumab versus chemotherapy alone were: hypertension (12 percent vs. 1.8 percent), pain (11.1 percent vs. 6.3 percent), proteinuria (2.7 percent vs. 0.8 percent) and wound-healing complications (1.7 percent vs. 0.3 percent).

Other trials and standard of care
Bevacizumab is currently approved for metastatic colorectal, breast, and lung cancers and other trials are ongoing to evaluate it as an adjuvant treatment for a variety of solid tumors. Therapy with bevacizumab is the standard of care in advanced colon cancer treatment which will be further confirmed throughout the ASCO meeting with 53 efficacy and safety data presentations including more than 6,000 patients.

In addition to early-stage colon cancer, bevacizumab is being studied as an adjuvant treatment in other early-stage diseases: HER2-negative breast cancer, HER2-positive breast cancer, and non-squamous, non-small cell lung cancer. Approximately 26,000 people are expected to participate in bevacizumab based adjuvant studies, making the bevacizumab development program one of the most comprehensive undertakings in cancer research since chemotherapy. The Avastin (bevacizumab) development program includes more than 450 clinical trials worldwide in approximately 30 different tumor types.

More than 500,000 patients have been treated with bevacizumab so far. A comprehensive clinical program with more than 450 clinical trials is investigating the use of bevacizumab in various tumor types (including colorectal, breast, lung, brain, gastric, ovarian, prostate and others) and different settings (advanced or early stage disease).

Mode of Action
The precise mode of action of bevacizumab helps control tumor growth and metastases with only a limited impact on side effects of chemotherapy.

The drug has proven survival benefits across multiple tumor types and is approved in Europe for the treatment of the advanced stages of four common types of cancer, including colorectal cancer, breast cancer, lung cancer and kidney cancer. These types of cancer collectively cause nearly 3 million deaths each year in the US alone.

In the US, bevacizumab was the first anti-angiogenesis therapy approved by the FDA and is now approved for the treatment of four tumor types: breast, colorectal, glioblastoma, and non-small cell lung cancer (NSCLC).

For further information:

• American Society for Clinical Oncology
• Wolmark, G. Yothers, M. J. O’Connell, S. Sharif, J. N. et al. A phase III trial comparing mFolfox6 to mFolfox6 + bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 N. Plenary presentation, Sunday, May 31, 3:15 PM EDT, Level 2, West Hall D2. Plenary Session, Lead Author: Norman Wolmark, MD, Allegheny General Hospital Pittsburgh, Pa. Abstract No# LBA4

Other, related, abstracts

• A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4000 First Author: D. KerrCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial).
  Meeting:2009 ASCO Annual Meeting Abstract No: 4001 First Author: S. TejparCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4002 First Author: A. D. RothCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)

Folfox Background information:

• Wikipedia (Definition)
• Cancer Research UK
• NCI – National cancer Institute

Colorectal Cancer:

• Medical Oncology (at Boomja.com)
• Goldberg RM, Therapy for Metastatic Colorectal Cancer The Oncologist Vol. 11, No. 9, 981-987, October 2006

Pharmaceutical information:

• EMEA - European Public Assessment Report (bevacizumab)
• Highlights of Prescribing Information USA (bevacizumab)
  

New studies answer key questions about the treatment of gastrointestinal cancers

Findings from a number of large clinical trials of new treatment regimens for gastrointestinal cancers were released today at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held in Orlando, May 29 - June 2, 2009 and will be highlighted in Onco’Zine – The international Cancer Blog.

“The studies presented today answer many important questions about the best care for people with gastrointestinal cancers,” said Nicholas Petrelli, MD, medical director of the Helen F. Graham Cancer Center in Wilmington, Delaware. “These large, conclusive trials tell us what works, and importantly, tell us what doesn’t work. Some settle long-time debates in the field, others demonstrate that the current standard of care is actually superior to experimental treatments, and others will allow patients to avoid unnecessary side effects or surgery.”

The results presented include:

• First-ever data on bevacizumab as adjuvant therapy finds no benefit in colon cancer: A phase III trial finds that adding the targeted therapy bevacizumab (Avastin, Roche), to standard adjuvant chemotherapy did not improve disease free survival for patients with locally advanced colon cancer.
• Surgery unnecessary for majority of patients with advanced colorectal cancer: Most patients with metastatic colorectal cancer can safely avoid surgery on their primary tumors.
• A trial compares common adjuvant treatments for pancreatic cancer: A phase III trial comparing the adjuvant treatments most commonly used for pancreatic cancer in the United States and Europe, gemcitabine (Gemzar, Eli Lilly and Company) and 5-FU/FA, respectively, found that there is no difference in survival between the two regimens, though gemcitabine was associated with fewer side effects.
• The largest study to date on anal cancer supports the current standard: A phase III study finds that the current standard of care for anal cancer should not be changed, and that ongoing maintenance therapy after initial treatment is not effective.
• Oxaliplatin does not improve outcomes for rectal cancer: Adding oxaliplatin (Eloxatin, Sanofi-Aventis) to standard treatment in patients with locally advanced rectal cancer does not improve tumor response. However, a preliminary analysis seems to suggests that the treatment may reduce distant metastases.

For more information:

• American Society of Clinical Oncology
• 2009 ASCO annual meeting abstracts

Reference:

• Medical-Oncology (at Boomja.com)

Relative risk similarly increased for low and high dose of bevacizumab

Vascular complications, including venous thromboembolism (VTE) are one of the leading causes of morbidity and mortality in patients with cancer. A variety of antineoplastic agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have received for clinical use while others have entered clinical trials.

Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, researchers observed a variety of vascular complications, including venous or arterial thromboembolism and hemorrhage, as relevant toxicities with the use of angiogenesis inhibitors. Concerns were especially alarming with bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in venous thromboembolism is controversial.

Bloomberg and HealthDay News both reported on a meta-analysis recently published in the Journal of American Medical Association (JAMA).

To assess the overall risk of venous thromboembolism associated with the use of bevacizumab, Dr Nalluri and his team of researchers from the Division of Medical Oncology, Department of Medicine, Stony Brook University, Stony Brook, New York, NY 11794, systematic reviewed and analyzed a number of randomized controlled trials.Eligible studies included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab for which data on venous thromboembolism were available.

Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies.

The researchers found 15 randomized controlled trials and identified a total of 7956 patients with a variety of advanced solid tumors. Among those patients receiving bevacizumab, the summary incidences of all-grade and high-grade venous thromboembolism were 11.9% (95% CI, 6.8%-19.9%) and 6.3% (95% CI, 4.8%-8.3%), respectively.

Patients treated with bevacizumab had a significantly increased risk of venous thromboembolism with a relative risk of 1.33 (95% CI, 1.13-1.56; P < .001) compared with controls. The risk was significantly increased for both all-grade and high-grade venous thromboembolism. In addition, the relative risk was similarly increased for bevacizumab at 2.5 mg/kg per week (low dose; RR, 1.31 [95% CI, 1.08-1.60]; P = .007) and 5 mg/kg per week (high dose; RR, 1.31 [95% CI, 1.02-1.68]; P = .04).

The authors of the meta-analysis concluded that the use of bevacizumab in cancer patients was associated with an increased risk of developing venous thromboembolism.

In an unrelated study published in American Journal of Hematology, Dr Francesca Elice and her team of researchers from Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy, concluded that careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs, including bevacizumab, is warranted and that further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.

PubMed abstracts:

• Nalluri SR., Chu D., Keresztes R., Zhu X., Wu S., Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008 Nov 19;300(19):2277-85.
• Elice F, Jacoub J, Rickles FR Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008 Nov;83(11):862-70.