Chemotherapy and Second Cancers

The drugs that work by damaging DNA in cancer cells can damage DNA in healthy cells too. The US National Toxicology Program publishes a Report on Carcinogens. Its Fifteenth Edition names several of these drugs one by one, as known to be a human carcinogen.

That listing is not based on animal studies alone. For each of the drugs below, the RoC profile says the classification rests on sufficient evidence of carcinogenicity from studies in humans.

• Cyclophosphamide was first listed in 1980. Its profile cites studies that found excesses of bladder cancer and leukemia in people treated with it.
• Melphalan was first listed in 1980. Patients treated for breast cancer, ovarian cancer, or myeloma had a leukemia risk more than 100 times higher.
• Chlorambucil was first listed in 1981. The cancer linked to it is mainly acute nonlymphocytic leukemia.
• Thiotepa was first listed in 1981 on animal evidence, then reclassified as known to be a human carcinogen in 1998. Its human evidence is specifically leukemia.

None of that changes the arithmetic of treatment. It does mean the risk is specific and measured rather than vague.

Every one of these listings carries a dose relationship, which is the strongest signal that the drug, and not something else, is doing the damage.

For cyclophosphamide, the RoC profile cites a German case-control study. In it, leukemia risk rose as the dose rose. It also cites a nested case-control study in non-Hodgkin lymphoma patients. There, bladder cancer risk rose as the total dose rose.

For melphalan, the profile says leukemia risk increased with increasing dose, and was not affected by co-exposure to radiation therapy.

For chlorambucil, the profile describes a randomized trial in 431 patients with polycythemia vera. Acute nonlymphocytic leukemia was 13 times more common with chlorambucil plus phlebotomy than with phlebotomy alone. Risk rose with both dose and duration.

NCI's PDQ summary on late effects of childhood cancer treatment separates therapy-related blood cancers into two types, and the difference is practical.

The alkylating agent type. PDQ names eight drugs here. They are cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, the nitrosoureas, chlorambucil, and dacarbazine. Risk is dose dependent. Latency runs 3 to 5 years after exposure. It is tied to changes in chromosomes 5 and 7.

The topoisomerase II inhibitor type. PDQ names etoposide, teniposide, and drugs related to the anthracyclines. This type shows up as overt leukemia after 6 months to 3 years. It is tied to balanced translocations at chromosome bands 11q23 or 21q22.

PDQ adds that the names have changed. These are now called myelodysplastic syndrome post-cytotoxic therapy, and acute myeloid leukemia post-cytotoxic therapy. The older labels were therapy-related MDS and therapy-related AML.

PDQ gives a shape to the risk over time that is more reassuring than most people expect.

The short latency is under 10 years from the primary cancer diagnosis. Risk then plateaus after 10 to 15 years.

Beyond 15 years, PDQ says the risk of a later leukemia stays significantly raised. The standardized incidence ratio is 3.5. But PDQ puts that in absolute terms right away. These events are rare, with an excess risk of 0.02 cases per 1,000 person-years.

A large pooled analysis puts numbers on the chemo side. It drew on studies of children diagnosed between 1930 and 2000. In it, 147 cases of second primary leukemia were matched to 522 controls. Other treatments were controlled for. A topoisomerase II inhibitor dose above 2,500 mg/m², with no radiation, carried an odds ratio of 14.3 for second AML. The confidence interval was wide, from 2.7 to 75.1.

PDQ notes that second primary leukemias were most likely in the first decade after treatment.

PDQ makes a distinction worth carrying into any survivorship visit.

Therapy-related solid second cancers make up 80% of all subsequent neoplasms. They track strongly with radiation exposure, not with chemo. Their latency exceeds 10 years. PDQ says the risk keeps rising with longer follow-up.

Three factors raise that risk: younger age at the time of radiation, a higher total radiation dose, and a longer period of follow-up afterward.

The clinical implication is direct. The drug question and the radiation question have different answers and different timelines.

The Childhood Cancer Survivor Study reported 30-year figures. Any subsequent neoplasm came to 20.5%. Nonmelanoma skin cancer made up 9.1%. Later cancers with malignant histology, leaving out that skin cancer, came to 7.9%. Meningioma came to 3.1%.

PDQ calls that a sixfold increased risk against the general population. It also defines the term. A subsequent neoplasm is a histologically distinct growth. It develops at least 2 months after treatment for the first cancer ends. And it may be benign or malignant.

PDQ notes these subsequent neoplasms are the leading cause of late mortality unrelated to relapse.

These figures come from childhood cancer survivors, followed for decades. They should not be read across to an adult treated once with a short course of chemotherapy.

NCI defines late effects as problems that may not appear for months or years after treatment ends. They differ from side effects that ease once treatment stops.

Where the drugs above were used, four concrete questions matter. Which agents were given. What the total dose was, in mg/m². Whether radiation was part of the plan. And what the radiation field covered. Those four answers decide which timeline on this page applies.

A therapy-related leukemia or myelodysplastic syndrome shows itself through the blood, so the signs are bleeding, infection and breathlessness rather than a lump.

• Call 911 or go to an emergency department if bleeding will not stop, you are coughing or vomiting blood, or breathlessness comes on suddenly. If you are still on chemotherapy, a temperature of 100.4°F (38°C) or higher belongs here too: CDC calls fever during chemotherapy a medical emergency.
• Call your care team the same day if bruises appear where nothing hit you, small red dots spread over your skin, your gums bleed when you brush, or you keep picking up infections.
• Call your care team within a day or two if tiredness has deepened without explanation, you are short of breath on stairs you used to manage, or night sweats and unexplained weight loss have set in.

The wider category of long-term monitoring is covered in survivorship. The blood cancer most often involved is described in leukemia. The difference between a classification and a personal probability is set out in hazard versus risk.

• NTP RoC profile: cyclophosphamide
• NTP RoC profile: melphalan
• NTP RoC profile: chlorambucil
• NTP RoC profile: thiotepa
• NCI PDQ: late effects, HP version
• NCI: late effects
• CDC: fever and cancer treatment