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Oral vascular endothelial growth factor receptor (VEGFR) inhibitors have become the most commonly used front-line agents for advanced renal cell carcinoma (RCC) based on reported overall response rates as high as 40% and median time-to-progression of greater than 8 months.¹ A number of new novel agents for RCC have already, or are currently completing phase III trials, and may receive approval for use in RCC within the next year.

If you were to alter your current choice of first-line agents in RCC which of the following novel agent descriptions would you find most compelling?

1. An oral anti-VEGFR tyrosine kinase inhibitor of similar efficacy as currently available agents, but with a more favorable adverse event profile.
2. An intravenous anti-angiogenic agent with proven efficacy primarily in combination with an established cytokine.
3. An oral m-TOR inhibitor with clinical trial demonstrated efficacy as second-line therapy in patients whose disease has progressed on an anti-VEGFR tyrosine kinase inhibitor (TKI).
4. Any or all of the above
5. None of the above

Notification of Publication Correction
Imedex strives to provide accurate information in our publications and correct published errors of fact. The following publication recently required corrections or clarifications.

PUBLICATION TITLE: OncoFacts February 2009 Issue
PUBLICATION TYPE: Online: OncoFacts summaries of abstracts from the 31st Annual San Antonio Breast Cancer Symposium (SABCS) conference
CORRECTION : Abstract 78, paragraph 2, lines 1-2. FEC should have been 5-fluorouracil, epirubicin, and cyclophosphamide, not fludarabine, epirubicin and cyclophosphamide.
The corrected sentence is as follows: 1. 5- fluorouracil, epirubicin, and cyclophosphamide (FEC [500/100/500 mg/m²]) q 3 weeks x 6

This month we will be focusing on data from the recent 2009 Gastrointestinal Cancers Symposium. This multidisciplinary meeting was held in San Francisco in mid-January. The program included a number of didactic presentations as well as 563 abstracts, both oral, poster and published. Nearly 3000 attendees were present at this year’s meeting, including a large international contingent of attendees.

In this issue:

Additional Colorectal Cancer Data

Abstract 295: Effect of extended preoperative chemotherapy on pathologic response and postoperative liver insufficient after hepatic resection for colorectal liver metastases
Dr Daria Zorzi presented a retrospective review of 219 patients with liver metastases from colorectal cancer who received pre-operative FOLFOX with or without bevacizumab prior to hepatic resection in an attempt to determine if there were differences in efficacy and toxicity parameters between those who received less than 9 cycles versus 9 or more cycles of chemotherapy prior to surgery. There was no difference in the proportion of patients who achieve a complete or major pathologic response between the 2 duration-of-treatment groups. But the combination of FOLFOX-bevacizumab resulted in a significantly higher frequency of complete and major pathologic responses than the FOLFOX alone treatment arm in both groups. The incidences of sinusoidal injury and liver insufficiency were significantly higher in the group that received >9 cycles of chemotherapy. Interestingly, the incidence of liver injury among the >9 cycles-group was somewhat lower among those receiving bevacizumab than among those receiving FOLFOX alone, but the incidence of postoperative liver insufficiency was higher. The bottom line conclusion was that pushing pre-operative chemotherapy beyond 8 cycles did not improve response, but did increase toxicity.

Abstract 296: Cetuximab plus FOLFOX6 or cetuximab plus FOLFIRI as neoadjuvant treatment of nonresectable colorectal liver metastases: A randomized multicenter study (CELIM-study)
Dr Gunnar Folprecht presented the results of a randomized phase II study of neoadjuvant therapy for patients with nonresectable liver metastases from colorectal cancer. In this trial, 106 evaluable patients were randomized to FOLFOX-cetuximab versus FOLFIRI-cetuximab. Patients were stratified by their disease being technically nonresectable (55%) versus having >5 liver metastases (44%). Seventy-three percent were EGFR positive by IHC, and 71% were K-ras wild-type. A median of 8 cycles was delivered, though most resections were performed after 4-6 cycles. Forty-two percent of patients had a liver resection, and 35% had an R-0 resection.

Efficacy according to treatment arm
	FOLFOX-Cetuximab	FOLFIRI-Cetuximab	All patients
PR+CR	85% / 68%	66% / 57%	75% / 62%
(95% CI)	71.9% to 93.1%	51.7% to 78.5%	65.9% to 83.1%
Resection	40%	43%	42%
R0-resection	37%	34%	35%
Responses are unconfirmed / confirmed

Seventy-nine percent of patients with K-ras wild-type achieved a confirmed PR or CR from therapy. Forty-three percent of Kras mutated patients responded. Peri-operative morbidity was seen in 36% of those resected. There were 2 peri-operative deaths. The authors concluded that both regimens were effective with high efficacy in K-ras wild-type cancers and had an encouraging rate of liver resections.

David Ryan, MD from Massachusetts General Hospital presented an excellent discussion of a number of the colorectal cancer abstracts that were presented Saturday afternoon at the symposium.

He began by listing the things that we already know about colorectal cancer.

Resection of liver-only metastases from colorectal cancer can cure approximately 30% of patients.
Patients who have unresectable disease can occasionally become resectable after pre-operative chemotherapy. This amounts to about 10% of patients with nonresectable disease patients in the US.
Conversion to resectability leads to a 5-year survival similar to that seen with patients who were initially resectable.
The role of post-resection adjuvant multi-agent chemotherapy remains uncertain.
The EORTC 40983 study of peri-operative FOLFOX versus surgery alone demonstrated a statistically insignificant trend towards improved PFS, but there did appear to be a significant benefit for those patients who were eligible and underwent resection.
Peri-operative chemotherapy has been associated with certain types of hepatic injury and increased peri-operative morbidity.
Pathologic CR may be a good endpoint for overall survival but needs validation in large randomized studies.

Dr Ryan then went on to discuss what we don’t know.

Does postoperative multi-agent adjuvant chemotherapy improve survival in patients with liver metastases from colorectal cancer?
Is postoperative chemotherapy the equivalent of peri-operative chemotherapy?
What is the role of bevacizumab, cetuximab and panitumumab in these patients?
What is the optimal grouping and staging of patients with isolated liver metastases?
Finally, how do we define unresectability in patients with isolated liver metastases?

David Ryan then laid out what he felt were the take home points of the bevacizumab and cetuximab trials in isolated liver metastatic colorectal cancer.

Longer chemotherapy is NOT associated with improved outcome.
Bevacizumab may alter the liver injury pattern - less sinusoidal injury, but a trend towards increased liver insufficiency.
Bevacizumab increases the pathologic major response rate, but does it matter?
Grouping high risk and technically unresectable patients is feasible.
Cetuximab is active and safe in this patient population.
Liver injury rate was similar with FOLFOX and FOLFIRI.

Then Dr Ryan remarked on what needs to be considered in clinical trials planning for the future.

We need a consensus on staging of patients with liver-only metastatic colorectal cancer, and what constitutes clearly resectable, technically unresectable and high-risk.
A consensus is needed on the definition of technically unresectable.
Phase III trials are needed to evaluate peri-operative versus postoperative multi-agent chemotherapy in clearly resectable patients.
Phase III trials are needed to evaluate the relative role of cetuximab or panitumumab in K-ras wild-type versus bevacizumab particularly in high-risk patients.
There is an ongoing randomized phase II trial in patients with metastatic colorectal cancers who relapse following oxaliplatin-bevacizumab based front-line therapy. In the SPIRITT trial, patients whose tumors are K-ras wild-type are randomized to FOLFIRI with either panitumumab or bevacizumab.

OncoFacts™ Editor:

JEpstein

James Epstein, MD

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