Download CLINICAL CANCER ADVANCES 2012 ASCO`s Annual Report on

CLINICAL CANCER ADVANCES 2012
ASCO’s Annual Report on Progress Against Cancer12
GASTROINTESTINAL CANCERS
SPECIALTY EDITOR: FADI BRAITEH, MD,
U.S. Oncology Research, Comprehensive Cancer Centers of Nevada
GI cancers include those of the esophagus, stomach, liver, pancreas, biliary tract, small bowel,
appendix, colon, rectum, and anus. This year, researchers reported important advances in the
treatment of advanced colorectal cancer using new targeted drugs as single agents and new biologics in
combination with cytotoxic therapies (drugs that kill cancer cells). In addition, one study determined
a significant survival benefit using preoperative chemotherapy plus radiation in patients with
esophageal and gastroesophageal junction cancers.
Major Advances
Preoperative chemotherapy and radiation therapy double overall survival for
esophageal and gastroesophageal junction cancers
Esophageal cancer is one of the most deadly cancers, causing more than 400,000 deaths per year
worldwide. Although a cure is possible for patients whose tumors can be removed completely during
surgery, this is not possible for approximately one quarter of patients and leads to poorer outcomes.
On the basis of positive results from an early-phase clinical trial, researchers launched a phase III
clinical trial to determine if treatment with chemotherapy and radiation therapy before surgery would
improve the success of surgery and extend patient survival.1
In the trial, patients with adenocarcinoma, squamous cell carcinoma, and large-cell undifferentiated
carcinoma of the esophagus or gastroesophageal junction were randomly assigned to chemotherapy
(carboplatin and paclitaxel) plus radiation therapy followed by surgery (178 patients) or surgery alone
(188 patients). This year, researchers reported that preoperative treatment yielded substantial
benefits: 29% of patients experienced complete remissions; median overall survival was longer (49 v 24
months)
and the death rate was 35% lower in patients who underwentpreoperative treatment
compared with those who had surgery alone. Toxicities from this additional therapy were minor.
These findings will likely change the standard of care for most patients with esophageal and
gastroesophageal junction cancers, offering the possibility of cure for many
Regorafenib prolongs overall survival in patients with metastatic colorectal cancer
Regorafenib is a multitargeted experimental drug that blocksthe growth of tumor cells and blood
vessels. The drug has shown promising antitumor effects in preclinical studies and is currently being
tested in clinical trials for various cancer types (Sarcoma).
This year, researchers reported results of a phase III clinical tial that sought to determine if
regorafenib would extend overall survival in patients with metastatic colorectal cancer
whose disease had progressed after all approved standard therapies.2
This international clinical trial (CORRECT) randomly assigned patients to receive regorafenib plus best
supportive care (505 patients) or placebo plus best supportive care (255 patients). Results of an
interim analysis of trial data show a notable improvement in median overall survival for regorafenib
versus placebo (6.4 v 5.0 months).
On the basis of these encouraging results, the study was unblinded to allow patients who had been
receiving placebo to switch to regorafenib.
In September this year, the FDA approved regorafenib to treat patients with metastatic colorectal
cancer whose disease had progressed despite standard treatments. 3
Notable Advances
Second-line treatment with bevacizumab extends overall survival in patients with
metastatic colorectal cancer
Bevacizumab added to chemotherapy is a standard first-line treatment for metastatic colorectal
cancer. Bevacizumab isalso used as a second-line treatment for patients who had not been treated with
the drug previously. But before this year, it was unclear if it was beneficial to administer bevacizumab
as a second-line treatment to patients whose disease had progressed after first-line bevacizumab plus
chemotherapy.
To answer this question, researchers conducted a clinical trial in patients with inoperable metastatic
colorectal cancer whose disease had worsened within 3 months of stopping initial treatment with
bevacizumab and chemotherapy.4
In the study, patients were randomly assigned to receive bevacizumab plus chemotherapy (409
patients) or chemotherapy alone (411 patients). This year, investigators reported the first trial
results, finding that the median overall survival was longer with combination treatment compared with
chemotherapy alone (11.2 v 9.8 months). The combination treatment also delayed time to disease
progression. The results of this randomized study support a rationale for continuing bevacizumab in
patients whose disease worsens after first-line treatment with bevacizumab plus chemotherapy. It
remains to be proven if this so-called recycling of bevacizumab after first-line therapy is a costeffective strategy that prolongs survival, with expected differences in application in Europe versus
North America.
Adding cetuximab to standard adjuvant chemotherapy does not improve outcomes
in stage III colon cancer
Approximately half of patients with stage III colon cancer (cancer that has spread to the lymph nodes
surrounding the colon but not to other parts of the body) are cured by surgery and postoperative
(adjuvant) chemotherapy, and efforts are ongoing to elevate such cure rates.
Postoperative FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy has been shown to
reduce recurrence rates and improve overall survival in those patients.
This year, researchers reported results of a phase III studyevaluating whether adding the targeted
drug cetuximab to FOLFOX improves outcomes for those patients. Cetuximab was previously approved
to treat patients with metastatic colon cancer who do not carry alterations in the KRAS gene, as a
single agent or in combination with irinotecan in previously treated patients with metastatic disease.
In July 2012, the FDA granted its approval in combination with FOLFIRI (fluorouracil, leucovorin, and
irinotecan) as a first-line treatment for patients with metastatic disease without KRAS alterations
as well. This trial—involving 2,686 patients with stage III colon cancer—found that survival rates for
FOLFOX alone were 74.6% versus 71.5% for FOLFOX plus cetuximab in patients without KRAS
alterations and 67% versus 65% in those with KRAS alterations.5
The results suggest that cetuximab should not be used in patients with stage III colon cancer after
surgery and underscore the need for a better understanding of the distinct tumor biology in advanced
colon cancers.
Study identifies factors that predict which patients with metastatic colorectal
cancer might benefit from chemotherapy
Patients with advanced colorectal cancer typically undergo surgery to remove cancerous tissue that
has spread to the liver. A recent clinical trial showed that patients who were treated with FOLFOX
chemotherapy around the time of surgery (so-called perioperative chemotherapy) had a prolonged time
to cancer progression compared with those who had undergone surgery alone.
A retrospective analysis of clinical data from 342 patients who participated in that trial revealed that
FOLFOX seems to benefit a particular subset of patients with liver metastases from colorectal
cancer—those who have increased levels of a marker called carcinoembryonic antigen (CEA), have a
body mass index lower than 30, and are fully active (performance status,0).6
Among patients with increased CEA levels, the rates of disease progression at 3 years were 35% for
those who received perioperative chemotherapy versus 20% for those who underwent surgery alone.
FDA approves cetuximab in combination with FOLFIRI chemotherapy for patients
with metastatic colorectal cancer
In July, the FDA approved cetuximab for use in combination with FOLFIRI chemotherapy for firstline treatment of patients with KRAS mutation–negative, epidermal growth factor receptor (EGFR)–
expressing metastatic colorectal cancer. 7
Adding cetuximab to chemotherapy results in improved overall and progression-free survival for this
group of patients.
FDA approves ziv-aflibercept injection in combination with FOLFIRI
chemotherapy for patients with metastatic colorectal cancer
In August, the FDA approved the biologic ziv-aflibercept injection for use in combination with
FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has
progressed after an oxaliplatin-containing regimen. This new targeted treatment offers the possibility
of slowing disease progression in this subset of patients. 8
REFERENCES
1. van Hagen P, Hulshof MC, Lanschot JJ, et al: Preoperative chemoradiotherapy for esophageal or
junctional cancer. N Engl J Med 366:2074-2084, 2012
2. Grothey A, Sobrero AF, Siena S, et al: Results of a phase III randomized, double-blind, placebocontrolled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo
plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after
standard therapies. J Clin Oncol 30: 2012 (suppl; abstr LBA385)
3. US Food and Drug Administration: FDA approves new treatment for advanced colorectal cancer.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321271.htm
4. Arnold D, Andre T, Bennouna J, et al: Bevacizumab (BEV) plus chemotherapy (CT) continued beyond
first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV
plus CT: Results of a randomized phase III intergroup study (TML study). J Clin Oncol 30:203s, 2012
(suppl; abstr CRA3503)
5. Alberts SR, Sargent DJ, Nair S, et al: Effect of oxaliplatin, fluorouracil, and leucovorin with or
without cetuximab on survival among patients with resected stage III colon cancer: A randomized
trial. JAMA 307:1383-1393, 2012
6. Sorbye H, Mauer M, Gruenberger T, et al: Predictive factors for the benefit of perioperative
FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial
40983). Ann Surg 255:534-539, 2012
7. US Food and Drug Administration: Cetuximab in combination with Folfiri/Therascreen
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm310933.htm
8. US Food and Drug Administration: FDA Approves Zaltrap for metastatic colorectal cancer.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncemen