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Testicular Cancer Survivorship: Looking Back to Move Forward

Publication: Journal of Clinical Oncology
Testicular cancer (TC) is the most common cancer in US men age 18-39 years.1 The global incidence of TC continues to increase, including in the United States2 However, TC mortality has declined since the introduction of cisplatin-based chemotherapy in the 1970s,3 with the relative 10-year relative survival rate reaching 95%.4 Accompanying this success, mortality attributable to treatment-related complications in testicular cancer survivors (TCS) has emerged as a critical survivorship issue.5 Serum platinum remains partially active and is measurable ≥ 10 years after chemotherapy,6 with platinum-DNA adducts detectable in most human organs.6 Radiotherapy (RT) affects organ function by causing short- and long-term normal tissue injury.7 Currently, knowledge gaps exist concerning non-TC mortality according to detailed TC treatment data after 1980, when both modern platinum-based chemotherapy (PBCT)8 and reductions in both RT fields (ipsilateral para-aortic lymphatics) and doses (20 Gy) for adjuvant treatment of stage I seminoma were adopted.8

The Takeaway

In the article that accompanies this editorial, Hellesnes et al9 examined the impact of testicular cancer (TC) management on non-TC mortality in relation to TC treatment after 1980.
In the article that accompanies this editorial, Hellesnes et al9 examined the impact of TC management on non-TC mortality in relation to TC treatment after 1980. An overall significant 23% excess of non-TC mortality existed compared with the general population, with significantly elevated risks after PBCT (standardized mortality ratio [SMR] = 1.23) and RT (SMR = 1.28), but not after surgery. The non-TC mortality was highest among survivors diagnosed with TC < 20 years of age, with a 2.27-fold significantly increased risk (absolute excess risk = 14.42/10,000 person-years). These findings are consistent with an international population-based study10 that reported an overall significant 34% excess deaths from noncancer causes among 38,907 1-year TCS given chemotherapy (with or without RT) in 1975 or later. A Dutch hospital-based investigation (1976-2006)11 similarly reported a 40% significant excess of non-TC mortality among 6,042 TCS versus the general population, with a cumulative mortality of 9.6% 25 years after treatment.
In the past 25 years, our understanding of second malignant neoplasms (SMN) in TCS has expanded. There is increasing evidence supporting the roles of both PBCT and RT in SMN development. In 1997, an international population-based investigation of nearly 29,000 TCS (1935-1993) reported a significantly increased 1.4-fold risk of SMNs for more than two decades following TC diagnosis.12 A subsequent study of > 18,000 TCS (1970-1993) demonstrated a significant dose-response relationship between cumulative cisplatin amount and leukemia risk after RT dose adjustment (Ptrend = .001).13 In 2005, an international population-based study of 40,576 TCS (1943-2001)14 confirmed significantly increased risks of solid cancers following chemotherapy alone (relative risk = 1.8) among 10-year TCS. To characterize SMN risks because of TC treatments after 1980, three studies15-17 showed significantly elevated 1.4- to 2.4-fold risks among TCS given PBCT versus those who did not. A Dutch hospital-based study16 specifically reported a dose-dependent relationship between PBCT and solid tumors, with significant linear dose-dependent increases in gastrointestinal cancer risk by 53% with each additional 100 mg/m2 of PBCT (Ptrend < .001).
RT is another etiologic factor for SMN.14,16,18,19 An international population-based investigation of 40,576 TCS (1943-2001) reported a significantly increased 2.7-fold solid cancer risk in locations within infradiaphragmatic RT fields compared with non-RT exposed sites, with risks remaining elevated for > 35 years.14 A multicenter hospital-based study16 similarly showed that the hazard ratio (HR) of an infradiaphragmatic SMN increased by 8%/Gy of administered RT (P < .001) compared with TCS who received no para-aortic RT. Two other studies confirmed significant dose-dependent relationships between RT and subsequent cancers of pancreas (linear increase in odds ratio by 0.12/Gy; Ptrend < .001)18 and stomach (> 20-fold elevated risks with gastric RT dose ≥ 50 Gy v < 10Gy; Ptrend < .001).19
Hellesnes et al9 confirmed that the increased SMN incidence among TCS after PBCT or RT led to significant excess SMN mortality. These colleagues reported that SMN were the most important cause of non-TC mortality (SMR = 1.53) with 43% and 59% significant excess deaths after PBCT and RT, respectively. In multivariable analyses, both four and > 4 cycles of cisplatin-based chemotherapy were associated with significant excess SMN deaths (HR = 1.79 and 2.87, respectively). These findings are consistent with the Dutch hospital-based investigation (1976-2006)11 that demonstrated that the HR for SMN mortality increased 0.29 per 100 mg/m2 of administered platinum (Ptrend < .001). Importantly, Hellesnes et al9 found no significant SMN mortality risk after carboplatin, a chemotherapy agent used for adjuvant treatment of stage I seminoma,8 but future research is required to definitively address this issue given the sparse number of exposed patients (N = 315). Hellesnes et al9 also showed significantly increased SMN mortality after RT doses ≥ 20 Gy compared with surgery, with significantly increased 2.75- to 4.96-fold risks after para-aortic and supradiaphragmatic or infradiaphragmatic RT.
Evidence exists that TC treatments are associated with increased cardiovascular disease (CVD) mortality.10,11,20 An international population-based investigation (1943-2002) reported a significant 60% excess mortality because of circulatory disease among TCS given chemotherapy after 1975.10 A Dutch hospital-based TCS study (median follow-up = 17.6 years)11 showed a significantly increased overall 2.1-fold risk of ischemic heart disease mortality after PBCT compared to patients without platinum exposure. However, a population-based study20 of 15,006 TCS who received initial chemotherapy or surgery alone without RT (1980-2010) reported that significantly increased 4.8-fold risk of CVD mortality after chemotherapy was restricted to the first year, likely explained in part by acute direct vascular injury and endothelial dysfunction induced by cisplatin.21 Similarly, Hellesnes et al9 showed significant excess CVD deaths within the first year of follow-up (SMR = 3.90), albeit based on small numbers (n = 3), but did not report an overall increased CVD mortality. Recent advances in CVD management, as reflected in steady declines in European22 CVD death rates into the 2010s, may account for this observation.
Hellesnes et al9 reported significant excess mortality because of infections after surgery (SMR = 3.73), genitourinary diseases after PBCT (SMR = 3.29), and digestive diseases after RT (SMR = 2.46). These significantly increased overall mortality risks from noncancer causes highlight the importance of quantifying the cumulative burden of morbidity (CBM) attributable to TC treatments and accounting for how adverse health outcomes (AHOs) impact overall health. To examine the type and prevalence of AHOs among TCS after PBCT, a North American multi-institutional study23 showed that approximately one third of TCS reported ≥ three AHOs. To characterize the CBM, a follow-up investigation24 used a score that incorporated both AHO number and severity, reporting that approximately 20% of TCS had a CBM score of high (15%) or very high or severe (4.1%), with close to 80% scoring medium (30%) or low or very low (47%).
Many TCS experience anxiety and depression. A systematic review25 reported that TCS experience more clinically significant anxiety (approximately 20%) than the general population (approximately 12.5%). Approximately 7.9%-9.7% of TCS reported depression in prior studies,26,27 but it remains uncertain if TCS have significantly increased risks of depression compared with the general population. A US population–based study of 23,381 TCS showed a 20% increase in suicide risk, with higher rates among races other than White or Black (SMR = 1.8) and age < 30 years (SMR = 1.5).28 Similarly, Hellesnes et al9 confirmed significant 1.65-fold excess suicides among TCS after PBCT.
Because of their young age at diagnosis and long-term survival, the study of TCS has emerged as a valuable paradigm for adult-onset cancer survivorship research. During the past two decades, TC survivorship research has provided health care providers with important information to counsel TCS about types and risks of AHOs after treatment, including adherence to lifestyle changes (e.g. tobacco cessation and exercise) and adoption of cancer screening programs to mitigate risks. To further advance TC survivorship research, we propose that future research focus on the following four areas.
First, it will be important to develop precision medicine approaches to individualize TC treatment to the extent possible by identifying novel biomarkers for better risk stratification. The goal is to minimize the number of PBCT cycles and both RT field size and dose needed to cure TC. The identification of microRNA (miR)371a-3p as a potential TC tumor marker is a recent breakthrough. A prospective study29 showed that miR-371a-3p has a sensitivity of 90.1%, specificity of 94.0%, and an area under the curve of 0.966 for detecting TC, outperforming classic serum markers. A prospective trial (NCT04435756) is ongoing to evaluate serum miR-371a-3p in patients with TC.
Second, it will be critical to identify genetic variants that predispose TCS to acute and long-term AHOs. Elucidation of etiopathogenetic mechanisms will provide a critical step for developing risk-based, targeted prevention and intervention approaches. During the past two decades, investigations have identified germline mutations that are significantly associated with platinum-related ototoxicity (megalin [rs2085252], COMT [rs9332377], TPMT [rs12201199], and ACYP2 [rs1872328])]; cisplatin-induced hearing loss (WFS1 [rs62283056]); cisplatin-induced tinnitus (OTOS [rs7606353]); and cisplatin-induced neuropathy (GST P1 and RPRD1B), as reviewed by Fung et al.5
Third, understanding how aging interacts with the development and progression of AHOs after TC treatment is another important research area. Expanding evidence now suggests childhood cancer survivors develop premature physiologic aging after cytotoxic therapies.30 Accelerated cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity are five major hypothesized mechanisms.30 Finally, establishment of longitudinal TCS cohort studies that follow survivors for life to examine CBM and latency trends of AHOs according to treatment types will continue to be critical.31 In particular, it is important that these cohorts include TCS cured with surgical approaches alone, so that the overall survivorship of these patients is comprehensively characterized with the same due diligence afforded patients given cytotoxic treatment.
See accompanying article on page 3561

Support

Supported by the National Cancer Institute: 2 R01 CA 157823, Genetic Susceptibility and Biomarkers of Platinum-Related Toxicity (L.B.T.).

Authors' Disclosures of Potential Conflicts of Interest

Testicular Cancer Survivorship: Looking Back to Move Forward

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Chunkit Fung

Consulting or Advisory Role: Novartis, Exelixis
Research Funding: Astellas Pharma (Inst)
No other potential conflicts of interest were reported.

References

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Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3531 - 3534
PubMed: 34591594

History

Published online: September 30, 2021
Published in print: November 10, 2021

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Authors

Affiliations

Division of Hematology and Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, James P. Wilmot Cancer Institute, Rochester, NY
Department of Medicine, Indiana University School of Medicine, Department of Epidemiology Fairbanks School of Public Health, Indianapolis, IN

Notes

Lois B. Travis, MD, SCD, Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine and Department of Epidemiology Fairbanks School of Public Health, 535 Barnhill Dr, RT 433, Indianapolis, IN 46202; e-mail: [email protected].

Author Contributions

Conception and design: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

Disclosures

Chunkit Fung
Consulting or Advisory Role: Novartis, Exelixis
Research Funding: Astellas Pharma (Inst)
No other potential conflicts of interest were reported.

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Chunkit Fung, Lois B. Travis
Journal of Clinical Oncology 2021 39:32, 3531-3534

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