Testicular Cancer Survivors Have Increased Risk of Developing Subsequent Malignant Neoplasms in the Platinum Era

Treatment advances have resulted a better cure rate for testicular cancer but also carry an elevated risk of developing neoplasms after treatment

While the introduction of platinum-based chemotherapy and radiotherapy have greatly improved cure rates in patients with germ cell testicular cancer over surgery alone, these treatments also result in increased risk of subsequent malignant neoplasms (SMNs), according to an article currently appearing in the Journal of Clinical Oncology. 

Lead author Harmke J. Groot of the Netherlands Cancer Institute in Amsterdam, the Netherlands and colleagues assessed the risk associated with receipt of platinum-containing chemotherapy or radiotherapy and the development of a subsequent SMN in this retrospective analysis. The investigators evaluated the long-term treatment-specific solid SMN risk in a large cohort of patients treated between 1976 and 2007 for testicular cancer in the Netherlands as compared with the overall incidence of cancer in the general Dutch population. 

The multicentre cohort comprised 5,838 patients who received standard treatment for testicular cancer prior to the age of 50 years and survived for one year. Standard treatment consisted of unilateral orchiectomy followed by elective nodal radiotherapy for patients with stage I or II seminoma or combination chemotherapy for those with disseminated seminoma or non-seminoma. 

Treatment-specific risks were assessed between cases and controls using multivariable regression and within cohort assessments were also done to determine whether an excess hazard ratio (HR) existed for treatment dose. 

Cumulative incidence of SMNs is higher in survivors of testicular cancer than in the general population 

In the testicular cancer cohort, one-year survivors subsequently developed 350 solid SMNs during a median follow-up of 14.1 years. The 25-year cumulative incidence of solid SMNs was 10.3% (95% confidence interval [CI] 9.0% to 11.6%). 

The median time to development of the first solid SMN was 16.9 years (interquartile range, 10.5 to 23.1 years) in the overall cohort. Compared to the general population, one-year testicular cancer survivors had a 1.8-fold increased risk (95% CI 1.6, 2.0). 

Patients treated for non-seminoma more likely to experience SMNs 

Following orchiectomy, most (82.4%) patients with seminoma (n=2817) were treated with radiotherapy, whereas 57.9% of the patients with non-seminoma (n=3021) received platinum-based chemotherapy. The risk of developing a solid SMN was 1.52 in patients with seminoma and 2.21 in those with non-seminoma. 

Patients with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder, while the risk of SMNs of the thyroid, lung, stomach, pancreas, colon, bladder, and of melanoma and soft tissue sarcoma was increased in one-year survivors with non-seminoma. 

Risk of SMN increased with higher radiation doses and more chemotherapy cycles 

By multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (HR 2.40; 95% CI 1.58, 3.62). Per receipt of 100 mg/m2 of platinum-containing chemotherapy the HR of developing a gastrointestinal SMN was increased by 53% (95% CI 26%, 80%). 

After receiving platinum-based chemotherapy, the risk of a non-colorectal gastrointestinal SMN was highest (HR 5.00; 95% CI 2.28, 10.95), followed by colorectal SMN (HR, 3.85; 95% CI 1.67, 8.92). 

The risk of a solid SMN increased with the receipt of platinum at doses of 400 to 499 and ≥ 500 mg/m2 following surgery compared to treatment by surgery alone (HR 2.43; 95% CI 1.40, 4.23 and HR 2.42; 95% CI 1.50, 3.90), respectively. 

However, lower doses of platinum did not significantly increase the risk of a solid SMN compared to surgery alone (HR 1.75; 95% CI 0.90,3.43). 

In one-year survivors treated with radiotherapy, the HR of a subsequent infradiaphragmatic SMN significantly increased by 8% per Gy of radiation dose received (95% CI 6%, 9%; p = 0.001), and the HR for gastrointestinal SMNs increased by 9% per Gy (95% CI 7%, 11%; p trend = 0.001) for gastrointestinal SMNs. 

The risk of infradiaphragmatic SMN associated with receiving 26 Gy to the para-aortic field alone, which was administered most often in the later years evaluated, was HR 1.88 (95% CI 0.90, 3.92) compared with no radiotherapy. Patients treated with similar doses of radiotherapy administered to a dog-leg field, which was standard in the earlier years of this analysis, experienced a 4.04-fold increased risk (95% CI 2.27, 7.18; p heterogeneity = 0.001; adjusted for age and chemotherapy dose). 

Conclusions 

The authors concluded that this study has important implications for both survivors of testicular cancer and patients with newly diagnosed testicular cancer. 

They pointed out that lower risk of a subsequent SMN was observed with treatment consisting of lower infradiaphragmatic radiation doses and fewer cycles of chemotherapy. This analysis demonstrated that increased risks of developing various solid SMNs associated with exposure to platinum-based chemotherapy and radiotherapy and also provided evidence of a dose-response relationship between platinum-containing chemotherapy and solid SMN risk that was particularly strong for gastrointestinal SMNs. 

The investigators advise that efforts should be made to reduce treatment intensity and to increase awareness of these late effects. They suggest that screening patients following treatment for testicular cancer may provide early detection if reliable screening tools are available. 

The study was supported by Dutch Cancer Society Grant No. 2011-5209. 

Reference 

Groot HJ, Lubberts S, de Wit R, et al. Risk of Solid Cancer After Treatment of Testicular Germ Cell Cancer in the Platinum Era. JCO 2018; Jul 10:JCO2017774174. doi: 10.1200/JCO.2017.77.4174. [Epub ahead of print].