Balancing oxaliplatin dose with neurological side effects in metastatic colon cancer
The drug oxaliplatin is a major reason the prognosis for metastatic colon cancer has gone from an expected survival of several months to a couple years. Unfortunately, the drug can also carry with it debilitating neurological side effects, which generally start as the sensation of pins and needles in fingers and toes and can leave patients unable to walk or dress independently.
However, “Many patients don’t receive the necessary dose to try to keep their cancer in check, because their symptoms become too debilitating and their quality of life is reduced,” says Andrew Weickhardt, MD, clinical fellow at the University of Colorado Cancer Center.
Weickhardt, along with Keith Wells, MD, and Wells Messersmith, MD, CU Cancer Center investigator and developmental therapeutics program co-leader, recently published a review in the Journal of Oncology that describes how to maximize the positives of this tricky balance between oxaliplatin’s effects and side effects.
“Before, when patients died in a few months, these symptoms were overlooked. Now they’re living two to three years and the symptoms deserve closer attention,” Weickhardt says.
The review recommends two approaches, used alone or simultaneously – what Weickhardt calls a “stop and go” approach, along with supplements that may mitigate the drug’s neurological damage.
In the stop and go approach, a patient starts oxaliplatin along with another drug and takes both for two months. Then, the patient takes a hiatus from oxaliplatin (while continuing the first drug), and reintroduces oxaliplatin two months later or at the point of disease progression, whichever is sooner.
“After about six to nine months of total treatment, metastatic colorectal cancers tend to develop resistance to the drug,” says Weickhardt. “And also, no matter what we do, after this same six to nine months of total treatment, neurological side effects start to rise.” And so stop-and-go oxaliplatin dosing spreads the drug’s effectiveness over the maximum possible time, with the fewest possible side effects.
Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. It is the second most frequently diagnosed malignancy in the United States as well as the second most common cause of cancer death. Surgery is the primary treatment and results in cure in approximately 50% of patients. Recurrence following surgery is a major problem and often is the ultimate cause of death. The prognosis of colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with colon cancer, although most have not been prospectively validated. Age greater than 65 years at presentation is not a contraindication to standard therapies; acceptable morbidity and mortality, as well as long-term survival, are achieved in this patient population.
Because of the frequency of the disease, the identification of high-risk groups, the demonstrated slow growth of primary lesions, the better survival of early-stage lesions, and the relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults starting at age 50 years, especially for those with first-degree relatives with colorectal cancer. There are groups that have a high incidence of colorectal cancer. These groups include those with hereditary conditions, such as familial polyposis, hereditary nonpolyposis colon cancer (HNPCC), Lynch I Syndrome, Lynch II Syndrome, and ulcerative colitis. Together they account for 10% to 15% of colorectal cancers. Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and possibility of selection factors make this observation difficult to interpret. More common conditions with an increased risk include: a personal history of colorectal cancer or adenomas, first degree family history of colorectal cancer or adenomas, and a personal history of ovarian, endometrial, or breast cancer. These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers. For more information on this subject, consult the PDQ summaries on screening for colorectal cancer and prevention of colorectal cancer.
Still, with this regimen, Weickhardt says that one in twenty patients experience significant nerve damage that can last for more than six months. “There’s room for improvement,” he says.
Though to date clinical trials of protective drugs given with oxaliplatin have been small, Weickhardt sees promise in the use of simple calcium and magnesium supplements.
“An infusion of calcium and magnesium should be used as well because they’ve shown some benefit and they don’t do any harm,” Weickhardt says. “They’re popular in the community, and I’d encourage their use.”
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By Garth Sundem