Secondary polycythemia in a sarcoma patient: a commentary about cediranib

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Disease definition

Secondary polycythemia is an elevated absolute red blood cell mass caused by enhanced stimulation of red blood cell production by an otherwise normal erythroid lineage that may be congenital or acquired (congenital secondary polycythemia and acquired secondary polycythemia; see these terms).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380644/

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After hearing of the Nobel prize in medicine , I was curious of what these researchers had found in low oxygen environments, as it is my understanding that is some of the reason that ASPS is slow growing and radio/chemo resistant as well is so incredibly vascular .

https://www.nytimes.com/2019/10/07/heal ... e.amp.html

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William G. Kaelin Jr., professor of medicine at Dana-Farber Cancer Institute and Brigham & Women’s Hospital Harvard Medical School, was drawn to science for its objectivity.
“Like any scientist, I like solving puzzles,” he said in an interview this morning.

But he had an unprepossessing start. When he was a pre-med student hoping to become a physician researcher, a professor wrote, “Mr. Kaelin appears to be a bright young man whose future lies outside of the laboratory.”

Eventually he became intrigued by a rare, genetic cancer, von Hippel-Lindau disease, that is characterized by a profusion of extra blood vessels and overproduction of erythropoietin, or EPO, a hormone that stimulates production of the red blood cells that carry oxygen.”

The cancer “was really fascinating,” Dr. Kaelin said. It had unusual features, like causing the body to make a substance, vegF, that stimulates the formation of blood vessels. And the cancer can cause the body to make too many red blood cells by increasing the production of EPO.

He had a hunch about what was going awry: “I thought it had something to do with oxygen sensing.”

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DISCUSSION

At core of this commentary is the issue of attributing a clinical complication, secondary polycythemia, to one of three possibilities: rare manifestation of a rare disease (asps), rare adverse effect of a rarely used medication (cediranib), or occurrence of another disease. The rare soft-tissue sarcoma subtype of asps, representing 1% of all sarcomas, presents clinically as a deep-seated painless soft-tissue mass that is often metastatic upfront. Although typically indolent, it is often lethal, with a reported 5-year survival rate of 61% at the metastatic stage. We have not been able to find any report of polycythemia as a manifestation of asps, or of paraneoplastic secretion of erythropoietin in that disease.

Alveolar soft part sarcoma is refractory to cytotoxic chemotherapy, but vegf inhibitors have been used with some success. More specifically, an encouraging response rate of 35% has been seen with cediranib2, and that drug is now being studied in randomized phase II trials compared with sunitinib or a placebo.

Inhibitors of vegf such as sunitinib, sorafenib, axitinib, and bevacizumab have been associated with subtle increases in hemoglobin4. It has been demonstrated in preclinical models that vegf inhibition results in erythropoiesis through synthesis of hepatic erythropoietin5. Cediranib has high potency for vegf receptor inhibition, and the dramatic rise in our patient’s hemoglobin is, to our knowledge, the highest hemoglobin rise reported in the literature for any vegf inhibitor. Our extensive work-up did not point to the occurrence of a separate disease process, although such an occurrence cannot be definitively excluded. Our patient developed a long-lasting partial response that has been maintained even with a cediranib dose reduction. We suggest formal prospective assessment of hemoglobin as a potential biomarker for cediranib in clinical trials.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380644