Secondary Malignancies

Several international studies have used information from tumor registries in an attempt to determine whether there is an increased incidence of secondary malignancies in patients with testicular cancer and,

Figure 28-5. Audiometry assessment of a patient after cisplatin-based chemotherapy, demonstrating bilateral hearing impairment, most notably at higher frequencies. O = right ear; X = left ear.

specifically, whether radiotherapy and/or chemotherapy increases the incidence. Several tumor types have been identified in this context, including second primary testicular cancer (probably unrelated to treatment), soft-tissue sarcomas or neuroendocrine carcinomas (especially associated with prior radiotherapy or chemotherapy and sometimes arising from unre-sected immature teratoma), malignant melanoma (perhaps associated with the syndrome of multiple atypical nevi), and acute myelomonocytic leukemia (associated with etoposide).

However, the situation is complex. As outlined by Nichols and Loehrer,34 two issues have to be considered when attempting to assess the prevalence and causes of second malignancies in patients treated for germ cell tumors. First, when the incidence in a treatment group is being determined, a valid judgment can be made only when that group is compared with a group of patients who have the same characteristics but who did not receive that treatment (eg, as previously noted, patients treated for stage II disease with chemotherapy or radiotherapy should be compared only with those treated for stage II disease with surgery alone). This is an important issue as it is likely that common factors such as genetic risks or prenatal exposures pertain to all treatment groups. Second, patients treated with dose-intense chemotherapy regimens from the early years (in which alkylating agents such as cyclophos-phamide were often used), often with maintenance regimens of up to 2 years, appear to constitute a different cohort from those treated in the current era; however, they are often analyzed as one group.

With these concerns in mind, the following studies, although not perfect, point to a slight increase in malignancies in certain subgroups. Van Leeuwen and colleagues estimated the risk of secondary cancers in 1,909 patients with testicular cancer from 1971 to 1985, with a median follow-up of 7.7 years.35 In this cohort, 78 patients developed a secondary cancer, compared with the 47.6 expected cancers in the general population. This resulted in a relative risk (RR) of 1.6. On closer analysis, it was noted that the cancers were predominantly gastrointestinal (RR, 2.6) (particularly stomach cancer [RR, 3.7], contralateral testicular cancer [RR, 35.7], and leukemia [RR, 5.1]).

Patients who received radiation therapy had a RR of 6.9 for developing stomach cancer whereas those who received chemotherapy had no increased risk of solid malignancies (RR, 0.83).

Moreover, patients who underwent surgery as sole treatment had an increased risk of contralateral testicular cancer, and those who had chemotherapy had no increased risk when compared with the general population. The latter finding was postulated to be due to the elimination of carcinoma in situ. In those who received chemotherapy, the observed-to-expected ratio (O/E) of leukemia was 1:0.05, with an RR of 20 and a 95% confidence interval (CI) of 0.51-111, and was not statistically significant. This cohort did not receive etoposide. However, the risk of leukemia was significantly increased in the radiation therapy group (O/E = 3:0.58; RR, 5.2; 95% CI, 1.1-15.1).

A similar study by Travis and colleagues evaluated 28,843 patients with a history of testicular cancer between 1935 to 1993 from 16 different tumor registries in North America and Europe.36 There were 1,406 cancers (excluding contralateral testicular cancer) and an RR of 1.43. In this cohort, 64 leukemias were identified, with a fourfold risk overall and an 11- to 15-fold increase when associated with chemotherapy. Acute nonlymphoblastic and lymphoblastic leukemias were both identified and also found to be associated with radiation therapy. The risk of solid tumors was noted to be increased, especially after 20 years, in a 3,330-patient cohort, with an RR of 1.54. Excess cancers of the bladder, stomach, and pancreas were mainly associated with radiotherapy. Other cancers with an increased incidence were colon cancer, rectal cancer, melanoma, prostate cancer, kidney cancer, thyroid cancer, and sarcomas. Further to this, Jacob-sen and colleagues found that of 6,187 men with testicular cancer, 10 patients developed sarcoma, 8 of these 10 having received radiation therapy and 2 having had unknown therapy.37 The relative risk was approximately threefold.

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