Adjuvant radiotherapy to the regional lymph nodes following orchiectomy has been the standard of care for seminoma for over 50 years. The ipsilateral hemipelvis, retroperitoneum, and mediastinum were all regions thought to be important for reducing the risk of recurrence.
This comprehensive approach to adjuvant therapy, while highly effective in reducing the risk of recurrence and death from seminoma, has taught an important lesson about the long-term toxicity of radiotherapy for young men. With time, these men were found to be at excess risk of death from cardiovascular disease and secondary malignancy, which has been the motivating factor to better define: (1) who needs treatment, (2) what radiation dose is necessary, and (3)what regional lymph node regions require treatment.
Patient Selection for Radiotherapy
Reserving treatment for patients at highest risk for recurrence should limit the burden of treatment. The best evidence for stratifying risk of recurrence in stage I seminoma results from a pooled multi-institutional analysis that identified the presence of rete testis invasion and large tumor size (≥ 4 cm) as the most important factors for assigning risk of recurrence.[1] The presence of both factors portends the highest risk of recurrence—approximately 30%—and enables better patient selection for adjuvant treatment. Surveillance Epidemiology and End Results data suggest more judicious use of radiotherapy in recent years; adjuvant radiotherapy recommendations were significantly lower during the period from 2000 to 2004 compared to 1990 to 1994 (78.7% vs 85.3%, P < .001).[2] There is a need, however, to identify additional risk factors to help close the gap between the proportion at risk and the proportion receiving treatment.
Then vs Now
Zagars et al[3] have shown that radiotherapy increases the risk of cardiovascular mortality. However, it is important to keep in mind that the prevailing radiotherapy technique and dose during the 40 years studied were very different from those used today. The greatest contributing factor to the excess risk of cardiovascular death in men treated for seminoma was the use of large radiation portals. The retroperitoneal field traditionally extended to the top of the 10th thoracic vertebra, including a portion of the heart. In addition, a prophylactic field directly targeting the mediastinum was used during the early 1950s and 1960s. These methods have been abandoned.
Retroperitoneal fields now extend no further than the level of the 11th thoracic vertebra, and mediastinal fields are not used. This is expected to produce a significant reduction in the risk of cardiovascular mortality in the modern era.
Additional reductions in radiotherapy field size and dose may also have a positive impact on long-term toxicity, for example, in the risk for secondary malignancy. Seminoma is one of the most radiosensitive malignancies. No excess risk of recurrence was seen with a lower 20-Gy dose (vs 30 Gy) in the European Organisation for Research and Treatment of Cancer randomized trial that defines the current standard of care,[4] and further reductions may be possible. Ipsilateral hemipelvic radiation can also be avoided, in the absence of previous surgeries that may alter the lymphatics, based on results from the Medical Research Council randomized trial.[5]
Surveillance Concerns
Ideally, to minimize the risk of secondary malignancy, we might want to use no radiation at all. However, that is simply not possible. Even surveillance demands some radiation dose for computed tomography scans and chest x-rays. While efforts have been made to optimize their use to detect recurrence,[6] evidence shows that as few as two or three scans increase the risk of secondary malignancy.[7] The other concern regarding surveillance includes the sometimes elusive pattern of recurrence that may dictate more intensive salvage treatment.
Combination chemotherapy for salvage carries a significant increased risk of cardiovascular disease such as myocardial infarction.[8] Or if the recurrence is locoregional and radiotherapy is used, the radiation field is larger and dose higher compared to adjuvant treatment. Whether outcomes with a routine observational approach will reduce long-term toxicity compared to risk-based use of adjuvant radiotherapy will require further study.
In the meanwhile, risk assessment for recurrence based on rete testis involvement and tumor size should be practiced routinely. In the context of potential risks and benefits of treatment, physicians should consult with the patient, and family if necessary, to determine the willingness and ability to adhere to a surveillance program. Patients and families should also be informed of the salvage treatment options and their potential risks as they relate to adjuvant treatment.
The goal of this activity is to clarify challenging treatment issues of HER2+ breast cancer including incorporation of predictive and prognostic biomarker tests and evidence-based data into practice when determining individualized strategies that improve patient survival and quality of life.
