Experts Agree That Optimal Treatment for Metastatic Colorectal Cancer Remains a Moving Target

For most colorectal cancer patients, their main concerns are quite straightforward: gaining time and maintaining qualify of life. For oncologists, offering the appropriate continuum of care means juggling multiple issues at once:
• Identifying the goal of treatment;
• Considering the clinical and molecular features of the disease;
• Assessing which treatment approach to adopt for each patient throughout the course of disease; and
• Assessing the efficacy and side effects of different treatments.

With the availability of multiple chemotherapy agents that have improved outcomes over the past couple of decades and the combination of chemotherapy with biologic agents, several treatment paradigms have emerged, according to Axel Grothey, MD, a professor of oncology and a consultant at Mayo Clinic in Rochester, Minn. Dr. Grothey outlined some of the pros and cons of the current treatment paradigms and assessed whether the latest study results will change the standard of care.

Selecting a treatment strategy

An ongoing area of investigation is the optimal integration of targeted therapies for first-line and maintenance treatment of patients with advanced disease. Currently, evidence supports the efficacy of bevacizumab (Avastin) added to one of the commonly used chemotherapy regimens as first-line treatment for patients with advanced disease. These regimens include FOLFOX, FOLFIRI, and XELOX (see Table).

For patients receiving palliative care, Dr. Grothey said he supports a combination treatment strategy. "Start with a combination regimen plus bevacizumab, and then use phases of maintenance treatments," he said. "Reintroduce chemotherapy and introduce potentially active new agents in a continuum of care."

One major issue with a combination protocol is the need to recognize and manage toxicities. Dr. Grothey pointed to a study led by Leonard B. Saltz, MD, that showed the addition of bevacizumab to FOLFOX produced only a minor effect on progression-free survival (PFS; J Clin Oncol 26:2013-2019, 2008).

Dr. Grothey suggested that the lack of improvement in PFS with this regimen was most likely because in most patients all drugs were stopped when neurotoxicity manifested. An alternative strategy would be to discontinue oxaliplatin before neurotoxicity becomes apparent and continue with fluoropyrimidine and bevacizumab instead.

TABLE

Regimens for advanced colon cancer

FOLFOX = oxaliplatin + 5-fluorouracil (5-FU) and leucovorin

FOLFIRI = irinotecan (Camptosar) + 5-FU and leucovorin

XELOX = oxaliplatin + capecitabine

For maintenance therapy, a number of studies are looking at the efficacy of single-agent bevacizumab aft er induction therapy. Results from the recent MACRO study indicated that this strategy is feasible. The phase III trial included 480 patients with metastatic colorectal cancer randomized to first-line XELOX plus bevacizumab for six cycles followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy. The study found no difference in PFS between the two arms and acceptable toxicity in both arms (American Society of Clinical Oncology [ASCO] abstract 3501).

According to Josep Tabernero, MD, the leader of MACRO, the study showed that "continuation treatment with singleagent bevacizumab aft er induction treatment of a combination of cytotoxins, oxaliplatin, and capecitabine (Xeloda), (with bevacizumab) seems to be an alternative treatment option compared with the more standard one, which consists of continuing all the cytotoxic drugs with bevacizumab until progression of the disease and/or unacceptable toxicity." Dr. Tabernero is from the medical oncology department at Vall d'Hebron University Hospital in Barcelona, Spain.

But Dr. Grothey said that data from the MACRO study were weak and that it would not have much influence on clinical practice. Instead, the ongoing CAIRO3 study, by the Dutch Colorectal Cancer Group, should provide more definitive answers. In that study, patients with stable disease aft er induction therapy for advanced colorectal cancer are being randomized to observation or maintenance therapy with low-dose capecitabine and bevacizumab.

Another major area of investigation is the role of therapies that target the epidermal growth factor receptor (EGFR). Recent studies looking at the addition of either cetuximab (Erbitux) with FOLFOX (OPUS study) or panitumumab (Vectibix) with FOLFOX (PRIME study) have indicated a significant improvement in survival and response rates with the addition of the EGFR inhibitor to the combination chemotherapy regimen.

However, the most recent results of the UK's Medical Research Council COIN study, which looked at the benefit of adding cetuximab to either continuous or intermittent XELOX or FOLFOX, found no benefit to survival with the addition of cetuximab (see A Second Opinion).

A second opinion

Results from the COIN study raise questions about the use of cetuximab in combination with oxaliplatinbased chemotherapy in the first-line management of colorectal cancer, said lead author Tim Maughan, MD, consultant clinical oncologist at Velindre Hospital in Cardiff , UK.

While Dr. Maughan agreed with Dr. Grothey that the goal of therapy for most patients with metastatic disease is to gain time and maintain quality of life, Dr. Maughan disagreed with the need to treat patients until progression.

The COIN trial found that, although patients with raised platelets at baseline had a shorter survival when given intermittent chemotherapy, patients with normal platelets who receive intermittent chemotherapy had no loss in overall survival.

"The COIN trial raises the hypothesis that patients with normal platelets at baseline could be considered for chemotherapy-free intervals, with no loss in overall survival, improved quality of life, and less chemotherapy and less toxicity," Dr. Maughan said.

An additional finding in COIN that contradicted prior studies on cetuximab in this setting was a lack of benefit even in patients with KRAS wild-type disease. Prior data from the OPUS study showed a strong biological effect of cetuximab in patients with KRAS wild-type disease, indicated by significantly greater survival and response rates. Similar findings were reported in the PRIME study with the addition of panitumumab (ASCO abstracts 3502 and 3525).

For Dr. Grothey, the results of the COIN study are difficult to interpret. "I think that in KRAS wild-type [disease], EGFR antibodies add activity to FOLFOX [as shown in the OPUS and PRIME studies]," he said.

Dr. Grothey recommended adding cetuximab or panitumumab in patients with KRAS wild-type disease.

Full exposure to active agents

Dr. Grothey said the take-home message for oncologists from the current data is the importance of exposing metastatic colon cancer patients to all potentially active agents.

"These agents are the oncologist's tools to keep patients alive," he emphasized, adding oncologists should reuse chemotherapeutic agents in different combinations in the course of therapy rather than take a treatment approach that focuses on distinct lines of therapy.

He also stressed that fluoropyrimidine-based combination regimens should be the default backbone of treatment options and that sequential single-agent therapy should be reserved for select patients. Finally, Dr. Grothey said that keeping patients on therapy long-term and treating to progression should be the default strategy, but oncologists need to be aware of toxicities, particularly neurotoxicity associated with oxaliplatin.

Source: ASCO 2010 education session.