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Cyclophosphamide is one of the few cancer drugs that has been shown to cause a specific solid cancer, in the bladder, and the risk depends steeply on the total dose given. Blood in the urine years after treatment with it is a reason to be investigated rather than reassured, and the cumulative dose on your treatment summary is what tells you where you sit.
What to do about it. There is no bladder screening programme for people who have had cyclophosphamide anywhere. Visible blood in the urine, or blood found on a dip test, at any point after treatment, is the signal, and it should be investigated as it would be in anyone else rather than attributed to old treatment. During treatment, generous hydration and the protective drug mesna reduce the acute bladder injury; whether they reduce the later cancer risk has not been shown.
The dose relationship, measured. Within a cohort of 6,171 people who survived at least two years after non-Hodgkin lymphoma, 48 who developed a second cancer of the urinary tract were matched to 136 controls with lymphoma who did not. Cyclophosphamide therapy carried a 4.5-fold risk of bladder cancer (95% CI 1.5 to 13.6), and the risk depended on the cumulative dose. Below 20 g in total, the risk was 2.4-fold and not statistically significant. At 20 to 49 g it was 6.0-fold (1.3 to 29) and at 50 g or more it was 14.5-fold (2.3 to 94), with a trend across dose groups at P = .004.
In absolute terms. The same analysis put it in a form a person can use: for patients given cumulative doses between 20 and 49 g, "the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients after 15 years of follow-up", and at 50 g or more "the excess risk increases to approximately seven excess bladder cancers per 100 NHL patients". Radiotherapy given without cyclophosphamide carried a non-significant increase, and the risk from both together was as expected if the individual excesses were added. Neither radiotherapy nor cyclophosphamide was associated with any excess of kidney cancer.
Why the bladder in particular. Cyclophosphamide is broken down to acrolein, which concentrates in urine and injures the bladder lining; this is the same mechanism as the haemorrhagic cystitis seen acutely at high doses. The mutation pattern in cyclophosphamide-associated bladder tumours differs from that in smoking-related and in schistosomiasis-related bladder cancer, which is one line of evidence that the drug and not a shared cause is responsible.
What the authors asked for. The paper's conclusion goes beyond its own data in a way worth reproducing: "The strong dose-response relationship and high absolute risk of bladder cancer underscore the importance of limiting the cumulative dose of cyclophosphamide to what is required to achieve therapeutic end points", and "long-term side effects of therapy that might be acceptable in cancer treatment may need to be re-evaluated for patients with non-neoplastic disorders". Cyclophosphamide is used in lupus, vasculitis and nephrotic syndrome as well as in cancer, and the dose relationship does not change when the indication does.
Where the dose comes from. Standard adjuvant breast cancer regimens give cumulative cyclophosphamide well below the 20 g threshold in this study; prolonged use in lymphoma, in autoimmune disease or in older regimens can exceed it. A treatment summary that records the regimen, the number of cycles and the dose per cycle is what allows that to be worked out, and a late-effects clinic or the treating centre can usually reconstruct it from the records.
Showing the molecule this term concerns: Cyclophosphamide.
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