The Risk of Surveillance vs Lymph Node Dissection in Germ Cell Cancer: The Occurrence of Second Malignancy

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In an epidemiologic analysis of SEER data, middle-aged patients with early-stage disease who opted for active surveillance rather than retroperitoneal lymph node dissection experienced a greater rate of second malignancy. The investigators speculate that this may relate to increased radiation exposure (multiple CT scans) and a greater likelihood of subsequent chemotherapy use.

Source: Chamie K, et al. Secondary malignancies among nonseminomatous germ cell tumor cancer survivors. Cancer 2011;117: 4219-4230.

For patients who present with stage I nonseminomatous germ cell tumor (NSGCT) there is an approximate 70% cure rate by orchiectomy alone.1 The implication is that the initial staging evaluation under-stages approximately 30% and therein lies the rationale for retroperitoneal lymph node dissection (RPLND). However, RPLND has been associated with long-term consequences impinging upon quality of life, and for the past two decades approximately one-half of patients with stage I disease elect to pursue a course of active surveillance rather than undergo immediate surgery.2 In recognition of this, the National Comprehensive Cancer Network (NCCN) recommends that early-stage NSGCT patients who forego RPLND have CT imaging every 2-3 months for the first year, every 3-4 months for the second year, every 4 months for the third year, every 6 months for the fourth year, and annually thereafter. Compliance with this recommendation translates into an average of 13-15 CT scans in the first 5 years, thereby realizing a not inconsequential cumulative radiation exposure of over 200 millisieverts (20 rem). This exposure may result in long-term sequelae, most notably the occurrence of second malignancy. In the current study, Chamie and co-investigators sought to identify whether there was an increased risk of second cancers among patients who chose initial surveillance for NSGCT.

The authors utilized data from the Surveillance, Epidemiology, and End Results (SEER) program and stratified the cohort based on whether they underwent RPLND. Within the SEER database they were able to identify 7301 men with NSGCT (all stages) diagnosed between 1988 and 2006. In that cohort, 84 men developed second malignancy. A propensity-score model was used to adjust for covariates, and a competing risks regression analysis was performed to estimate cumulative incidence rates of second malignancy. Incidence risk ratios were predicted by using the cumulative incidence rates per 10,000 patients.

There was no statistically significant increase in the incidence of a secondary malignancy for the entire cohort of testicular cancer survivors. However, when the analysis was restricted only to stage I patients older than 45 years, nonsurgical management was an independent predictor of developing a second malignancy. Extrapolation of these data would allow the prediction that for every 10,000 patients with stage I NSGCT who chose to forego RPLND, an absolute excess incidence of 22, 52, and 73 secondary malignancies would be diagnosed at 5 years, 10 years, and 15 years, respectively.

Commentary

The current results indicated that patients aged > 45 years who forego RPLND for stage I NSGCT are more likely to develop a second malignancy than those who undergo RPLND. Whether this is the result of exposure to radiation (multiple CTs) or a greater exposure to chemotherapy among those who choose initial nonsurgical approach, to both, or to neither remains to be clarified. It is curious that these differences were not apparent for younger patients. Possibly low levels of radiation have less carcinogenic effect when exposed at a younger age, although it is also possible that second cancers will occur over a longer time period than that encompassed in this study. Nonetheless, it is not unheard of to observe different age-associated risks to radiation exposure. For example, in an analysis of close to 50,000 atomic bomb survivors, for those exposed to 0.5-1.0 grays, peak cancer incidence was observed to be highest in those exposed between the ages of 20-29.3 There are a number of variables that may be at play that could not be accounted for using the SEER data alone. For example, what percentage of those under surveillance actually complied with the CT scanning schedule, how many in each group received chemotherapy and with what agents, and were there risk factors or comorbitities that pertained to the decision to forego initial surgery that might portend second malignancy? Were there more cigarette smokers with lung disease who opted for surveillance who subsequently developed lung cancer catalogued as a second malignancy? Finally, with regard to radiation exposure, the question arises whether newer machines with exposure to lower doses will be equally effective as instruments of surveillance and whether such will reduce risk for second cancers.

Nonetheless, what is presented is provocative. The findings raise the specter of concern that nonsurgical management of NSGCT may, in the long run, be associated with more health risks than primary RPLND.

References

1. Koch MO. Cost-effective strategies for the follow-up of patients with germ cell tumors. Urol Clin North Am 1998;25:495-502.

2. Osswald M, et al. Treatment of a population based sample of men diagnosed with testicular cancer in the United States. Urol Oncol 2009;27:604-610.

3. Preston DL, et al. Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res 2007;168:1-64.