Drug side effects can limit the usefulness of even the most powerful drugs in medicine. However, there are certain situations in Oncology where the occurrence of certain drug side effects predicts better outcomes for the patient...eventually, if the side effect is recognised and treated.
An example of this can be found in the treatment of metastatic colorectal carcinoma with monoclonal antobodies to EGFR receptors, namely cetuximab and panatumimab. These two agents commonly cause a generalised papulopustular rash resembling acne. However, the rash doesn't occur in all patients, and when it does occur, can be of varying severity. Subjects who develop the rash, or those who have a more severe form of the rash, are likely to have longer progression free survival from cancer.
There is one caveat however. The rash only predicts longer survival in subjects who do not have mutations in the KRAS oncogene, i.e. have wild type KRAS. In subjects with mutated KRAS, the acneiform rash caused by monoclonal antibodies to EGFR does not portend a better outcome. Therefore, in subjects with wild type KRAS, increasing the dose of cetuximab or panitumumab to the point that the rash appears can be a powerful strategy to improve progression free survival.
Another example of this slightly non-intuitive phenomenon of a serious side effect being the harbinger of an eventually better outcome can be observed in patients with malignant melanoma treated with the ipilimumab. Ipilimumab is a monoclonal antibody to CTLA-4 (also called CD152), a receptor found on activated T-cells. CTLA-4 is a "negative" receptor. When stimulated by its ligands, namely B7-1 (also called CD80) or B7-2 (also called CD86) it inhibits the function of the activated T cell. Thus CTLA-4 exists to provide a counterbalance to CD28, the "positive" receptor on T cells, stimulated by the very same ligands that bind to CTLA-4, and thus stop the T cells from running amok.
By inhibiting the inhibitory receptor CTLA-4, ipilimumab therefore stimulates the T cells to seek out and destroy the cancer cells. This strategy works spectacularly well for melanoma, but unfortunately not so well for most other tumours. However, activated T-cells are like a loaded gun. They will attack cancerous cells, but might also harm innocent bystanders and thus cause colitis, dermatitis, hepatitis, neuropathies, or endocrinopathies, such as hypophysitis.
Hypophysitis can be troublesome, particularly by affecting the adrenocortical and thyroid axes. Severe fatigue and headache culminating in life threatening adrenocortical insufficiency may occur in approximately 1.5% of treated patients. However, this autoimmune side effect is now well recognised and can be managed effectively with replacement doses of hydrocortisone (and thyroxine and sex hormones, where applicable, although these other anterior pituitary hormone deficiencies tend to be self limited). Paradoxically, the development of hypophysitis predicts improved survival following ipilimumab therapy. Nowhere is the old adage, "if it doesn't kill you, it makes you stronger" better epitomised than with these agents used by oncologists.
An example of this can be found in the treatment of metastatic colorectal carcinoma with monoclonal antobodies to EGFR receptors, namely cetuximab and panatumimab. These two agents commonly cause a generalised papulopustular rash resembling acne. However, the rash doesn't occur in all patients, and when it does occur, can be of varying severity. Subjects who develop the rash, or those who have a more severe form of the rash, are likely to have longer progression free survival from cancer.
There is one caveat however. The rash only predicts longer survival in subjects who do not have mutations in the KRAS oncogene, i.e. have wild type KRAS. In subjects with mutated KRAS, the acneiform rash caused by monoclonal antibodies to EGFR does not portend a better outcome. Therefore, in subjects with wild type KRAS, increasing the dose of cetuximab or panitumumab to the point that the rash appears can be a powerful strategy to improve progression free survival.
Another example of this slightly non-intuitive phenomenon of a serious side effect being the harbinger of an eventually better outcome can be observed in patients with malignant melanoma treated with the ipilimumab. Ipilimumab is a monoclonal antibody to CTLA-4 (also called CD152), a receptor found on activated T-cells. CTLA-4 is a "negative" receptor. When stimulated by its ligands, namely B7-1 (also called CD80) or B7-2 (also called CD86) it inhibits the function of the activated T cell. Thus CTLA-4 exists to provide a counterbalance to CD28, the "positive" receptor on T cells, stimulated by the very same ligands that bind to CTLA-4, and thus stop the T cells from running amok.
By inhibiting the inhibitory receptor CTLA-4, ipilimumab therefore stimulates the T cells to seek out and destroy the cancer cells. This strategy works spectacularly well for melanoma, but unfortunately not so well for most other tumours. However, activated T-cells are like a loaded gun. They will attack cancerous cells, but might also harm innocent bystanders and thus cause colitis, dermatitis, hepatitis, neuropathies, or endocrinopathies, such as hypophysitis.
Hypophysitis can be troublesome, particularly by affecting the adrenocortical and thyroid axes. Severe fatigue and headache culminating in life threatening adrenocortical insufficiency may occur in approximately 1.5% of treated patients. However, this autoimmune side effect is now well recognised and can be managed effectively with replacement doses of hydrocortisone (and thyroxine and sex hormones, where applicable, although these other anterior pituitary hormone deficiencies tend to be self limited). Paradoxically, the development of hypophysitis predicts improved survival following ipilimumab therapy. Nowhere is the old adage, "if it doesn't kill you, it makes you stronger" better epitomised than with these agents used by oncologists.
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