A recent editorial entitled "More Proof That Less Chemo is Best in Elderly Colorectal Cancer Patients" (David Kerr, Medscape, January 24, 2019) examined the benefits of Oxaliplatin-based therapy in older patients from a study in The Annals of Oncology (Hofheinz, R. D., et al, Annals of Oncology, 2018).
This study showed that the addition of Oxaliplatin to 5-FU in patients over 70 did not provide significant benefit.
Some years earlier we had examined a related topic in our laboratory.
A colleague traveling to France to participate in a geriatric oncology meeting posed the question, "Does age affect sensitivity to chemotherapy drugs?"
To answer the question, we examined 293 patients with untreated cancer of the breast, colon, lung and lymphoma and compared relative sensitivity by age.
We found that younger and older patients have comparable sensitivities to chemotherapy suggesting that, on a pharmacologic basis, there is no reason to withhold cytotoxic drugs from older patients with good performance status.
Case of 83-Year-Old Male with Neuroendocrine Cancer
This came to mind when I was asked to see an 83-year-old gentleman with a history of both prostate and colon cancer, who presented with a new mass in the abdomen.
With his prostate cancer in good control, I was concerned that this might be a return of his colon cancer.
Indeed his CEA, a marker for colon cancer, was elevated.
A CT-guided biopsy provided tissue for our laboratory analysis. Expecting colon cancer, we focused primarily upon drugs used in that disease.
The final diagnosis however was a neuroendocrine cancer.
Although there are variants of prostate cancer with neuroendocrine features, his molecular profile did not support a prostatic origin. It appeared that we had a new and unrelated neuroendocrine tumor.
Among the colon cancer agents tested were Irinotecan plus platinum-based drugs which proved to be the most active of all the drug combinations. Once the pathology findings confirmed a neuroendocrine tumor, all of this began to come into focus.
Neuroendocrine tumors are usually treated with the combination of Cisplatin plus Etoposide. While we did not test Etoposide, as it is never given in colon cancer, Etoposide and Irinotecan share activity by inhibiting closely related DNA repair enzymes.
For many neuroendocrine tumors these drugs are almost interchangeable.
Which Drugs to Treat With?
The dilemma: This was an 83 year old with his third cancer.
It was difficult to imagine giving him the standard Cisplatin plus Etoposide, or even the somewhat milder Carboplatin plus Etoposide, as they are associated with rather significant toxicities that include hair loss and bone marrow suppression. Both of these sounded distinctly unappealing to this handsome, well-coiffed gentleman with a full head of hair and his longtime girlfriend.
I had studied the topoisomerase 1 and 2 inhibitors extensively and had published an in-depth analysis on Topotecan, one of the widely used topoisomerase-1 inhibitors, some years earlier (Nagourney RA. et al Br J of Cancer, 2003).
Being aware of the synergy between Cisplatin and Irinotecan, I decided to go back to my published data and selected a Cisplatin plus Topotecan combination, but to avoid Cisplatin’s toxicity, substituted Carboplatin due to its related activity but milder toxicity.
Low Doses Selected Due to Known Sensitivity
With foreknowledge that he was sensitive to the combination I had the luxury of using low doses. Remembering from my earlier work that older patients can be as responsive as younger patients, I reasoned that the right drugs, even at very low doses, would work.
After only one cycle of therapy, the patient's tumor markers plummeted by over 50% and all of his symptoms resolved. He returned for cycle 2, the picture of health.
Now, as he completes his second cycle, we feel confident enough to allow him to take his long-planned (but until recently uncertain) one-month fishing trip to New Zealand.
Recognizing that older patients can respond extremely well to therapy, it may not be a matter of dose intensity or dose density but instead the intelligent selection of drugs that leads to successful outcomes.
Further, with a working knowledge of pharmacology one can craft novel drug combinations at tolerable schedules. I am delighted with his progress and look forward to seeing him upon his return from down-under.
It was one of the Seven Sages of Greece, the Greek poet Cleobulus (600-500 BC), who is quoted in the name of Hygeia, Goddess of Health, that life should be led “All in Good Measure”. That same good measure has allowed this charming 83-year-old to enjoy the trip of a lifetime. No doubt he’ll return with many good fish stories to tell.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com