Solid Tumors Incidence And Risk Factors

The risk of solid tumors after treatment of lymphoma is most established in Hodgkin's lymphoma. However, as therapies for NHL improve and result in more survivors, it is expected that risks and risk factors for the development of solid tumors in this setting will be similar to those in Hodgkin's lymphoma. In the modern Hodgkin's lymphoma therapeutic era (post-mechlorethamine), lung and breast cancer, often appearing 15 or more years after completion of lymphoma therapy, have emerged as the most significant subtypes of second malignancy, accounting for the majority of cases.2 Table 78.1 shows the types of solid tumors observed in a cohort of patients treated for Hodgkin's lymphoma at a single institution, representative of published experiences.

A recent study analyzed data from 32,591 patients with Hodgkin's lymphoma reported to 16 registries in North America and Europe.3 Importantly, this included 1111 25-year survivors. In this series, there were 1726 solid tumors, with cancers of the lung, digestive tract, and

Figure 78.1 Cumulative incidence of second tumors among patients with Hodgkin's lymphoma (N = 1319) treated at the Joint Center for Radiation Therapy, and the expected cumulative incidence of tumors among a matched population breast the most common. After a progressive rise in relative risk of all solid tumors over time, there was an apparent downturn in risk at 25 years, emphasizing the importance of long-term surveillance in this population.

Radiation therapy is the most significant risk factor for developing solid tumors after lymphoma, with the majority of second cancers arising either within or at the edges of radiation fields. In the aforementioned series, temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, breast, bladder, and thyroid all suggested a radiogenic effect. Three case-control studies have carefully evaluated the dose-response relationship between exposure to radiation therapies and the development of breast cancer and lung cancer, and demonstrated a significant trend of increasing risk of tumor development with increasing radiation dose.4-6

The contribution of chemotherapy alone to the risk of solid tumor development is less clear. In a cohort of patients with Hodgkin's lymphoma from the British Lymphoma Investigation Group, 31% of the population was treated with chemotherapy alone (predominantly with alkylating agents), and the relative risks of developing lung cancer after radiation therapy alone or chemotherapy alone were both significantly increased at 2.9 and 3.3, respectively.7 A nested case-control study of lung cancer after Hodgkin's lymphoma was subsequently performed, comparing 88 cases of lung cancer with 176 matched controls.8 Patients with a history of mechlorethamine treatment were at a significantly higher risk of developing lung cancer (RR = 1.69).

Two case-control studies on breast cancer after Hodgkin's lymphoma, however, showed a significantly decreased risk of breast cancer after alkylating chemotherapy exposure.45 The relationship was dose related, with decreasing breast cancer risk with additional cycles of chemotherapy. Other data suggest the risk of breast cancer is significantly reduced in women who had premature menopause: the younger the age at menopause, the lower the risk of breast cancer.4 These studies do report that the radiation-related risk of breast cancer, however, does not diminish in the longest follow-up, again suggesting a need for lifetime surveillance and programs of patient and physician awareness.

Table 78.1 Tumor-type distribution of the 142 solid tumors observed in 1319 patients treated for Hodgkin's disease at the Joint Center for Radiation Therapy at a median of 12 years of follow-up

Solid tumor type (N = 142)

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