Studies bring clarity to combination therapies for colorectal cancer

Todd S. Crocenzi, M.D.
Medical director, Gastrointestinal Cancer Research Program, Robert W. Franz Cancer Research Center
in the Earle A. Chiles Research Institute

March was colorectal cancer awareness month. Although such designations impact us all differently, I saw it as an opportunity for reflection and ultimately a call to action.


Perhaps the dust has settled a bit since January’s annual 2010 Gastrointestinal Cancers Symposium (aka “ASCO GI”), a consistently informative meeting co-sponsored by the American Gastroenterological Association, American Society of Clinical Oncology, American Society of Therapeutic Radiology and Oncology, and the Society of Surgical Oncology.

This annual meeting provides a “pulse check” of the year’s progress in gastrointestinal oncology, and it typically yields a few pearls of practice-altering information.

Inconsistencies bother me to no end. Ever since the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial was halted in early 2007, questions have persisted about the potential hazards of combining panitumumab with cytotoxic therapy. This had been done successfully with the other anti-EGFR antibody cetuximab in the years prior for the treatment of metastatic colorectal cancer.

There are exceptions, but generally class effects of pharmaceuticals are a good bet. There were complexities to the PACCE trial that limited too many conclusions. This trial, ultimately published by J.R. Hecht, et al (Journal of Clinical Oncology, Feb. 10, 2009; 27(5):672-80), randomized 1,053 patients to either chemotherapy (oxaliplatin or irinotecan-based) and anti-VEGF antibody bevacizumab with or without panitumumab.

The interim analysis revealed a statistically significant superiority in progression-free survival and overall survival for the chemotherapy and bevacizumab arm vs. that combination with panitumumab.

The final assessment: Stick with what had been shown to be helpful, using panitumumab alone until we figure out what’s going on. Was the problem combining panitumumab with chemotherapy? Was it combining anti-EGFR antibody with anti-VEGF antibody?

More data to suggest the latter came with presentation of the CAIRO-2 trial data at ASCO 2008 annual meeting. The core chemotherapy regimen in this trial was doublet capecitabine and oxaliplatin.

All patients received bevacizumab as well and randomized to this three-drug combination with or without cetuximab. The cetuximab-included arm carried an inferior progression-free survival and no benefits in response rate or other clinical endpoints. Perhaps the combined antibody approach was the problem.

These accumulating data had significant reverberations, including a revision of the large CALGB-sponsored trial in metastatic colorectal cancer that heretofore had included a combined targeted therapy arm (bevacizumab + cetuximab).

Large randomized trials then continued exploring chemotherapy with and without panitumumab. Perhaps a similar beneficial effect of this combination was still possible. In parallel, KRAS mutational status evolved as the real “target” rather than the assumed target of EGFR to predict efficacy of the EGFR antagonists.

Although questions remained on how to combine EGFR antagonists with other chemotherapeutics, personalization of therapy evolved with the use of these agents only in non-mutated KRAS patients.

Symposium sheds new light

This brings us to this year’s Gastrointestinal Cancers Symposium. Two large randomized trials of chemotherapy with or without panitumumab were reported: PRIME, or 203 trial, and the 181 trial.

PRIME, a first-line study, had been reported at the November 2009 ECCO/ESMO annual meeting in terms of its primary endpoint progression-free survival. It was positive in favor of leucovorin-modulated 5-FU + oxaliplatin (FOLFOX) + panitumumab vs. FOLFOX alone (PFS=9.6 mos vs. 8.0 mos, hazard ratio [HR]=0.80; P=.02).

The same study was reported at the 2010 GI Cancers Symposium, including an overall survival analysis (S. Siena et al, 2010 GI Cancers Symposium, abstract No. 283). This secondary endpoint favored FOLFOX + panitumumab over FOLFOX but was not statistically significant (23.9 mos vs. 19.7 mos; HR=0.83, P=0.07).

The 181 trial explored a second line leucovorin-modulated 5-FU + irinotecan (FOLFIRI) with or without panitumumab. This study was also reported at the fall 2009 ECCO/ESMO meeting where FOLFIRI + panitumumab was superior to FOLFIRI by the primary endpoint of progression-free survival in patients with wild-type KRAS tumors (5.9 mos vs. 3.9 mos (HR=0.73; P=.004)).

Response rate also was superior for the FOLFIRI + panitumumab arm (ORR=35 percent vs. 10 percent). Given the more common toxicities of acneiform rash and diarrhea with the EGFR antagonists like panitumumab, patient-reported outcomes of overall health assessment were reported at the 2010 GI Cancers Symposium (M. Peeters, et al. abstract No. 282).

Although panitumumab is a fully human antibody different from the chimeric antibody cetuximab, it remains unclear if the theoretical lower risk of infusion reactions is clinically meaningful. Panitumumab does offer the patient additional convenience with every-two-week administration, different from weekly cetuximab infusions.

In my view, the PRIME and 181 trial studies have brought some consistency back to integrating EGFR antagonists in the treatment of metastatic colorectal cancer as we craft rational polypharmacy for our patients. We have data to support the use of panitumumab in a manner analogous to the current clinical use of cetuximab and with perhaps some added patient convenience.

It remains to be seen whether payors will scrutinize the use of panitumumab in combination with chemotherapy while drug label indications are expanded.

Improvements continue in the duration and quality of life of our patients with incurable, metastatic colorectal cancer. It’s been nearly 50 years since the approval in 1962 of fluorouracil for the treatment of advanced colorectal cancer. Median survival for this disease has improved from approximately six months to 24 months in that time, with several drug therapies in our armamentarium.

Although such progress in this disease would be considered a success by most in the oncologic community, the general public would view this as not enough and not soon enough. If costs were more transparent, perhaps many would be objecting with “at what cost?”

Although gradual progress continues in extending lifespan in metastatic colorectal cancer, the median survivals derived from the trials reviewed and most other modern systemic therapy trials typically range from 20 to 24 months.

Many with a diagnosis will take this option heartily over median survivals of six months with supportive care alone. Two years is still a lot shorter than the actuarial survivals (perhaps a few decades) for many of the patients we encounter with this stage of disease.

In addition, as we add complexity to our regimens, we demand more time and effort from our patients, which takes away from time otherwise enjoyed with their loved ones. Justified or not, the field of oncology is criticized at times for not working harder on prevention. Getting smarter about treating advanced colorectal cancer is important in moving the field of oncology forward, while early detection and prevention efforts give us hope to make the field of oncology go away.

Clinical articles by Todd S. Crocenzi, M.D.