Radiotherapy improves survival for patients with stage IIa testicular seminoma

Patients with stage IIa testicular seminoma experienced prolonged OS when they received radiotherapy rather than multi-agent chemotherapy, according to an analysis using the National Cancer Data Base presented at the European Society for Therapeutic Radiology and Oncology conference.

Perspective from David I. Quinn, MBBS, PhD

However, this benefit did not persist for patients with stage IIb disease, results showed.

“Testicular seminoma is a rare disease, [so] there is a lack of randomized data to guide treatment and many prior studies have been limited by small sample sizes,” Scott Glaser, MD, resident physician at University of Pittsburgh Cancer Institute, said in a press release. “It has, therefore, been difficult to tease out small differences in efficacy of radiation therapy versus chemotherapy.”

The National Comprehensive Cancer Network recommends radiotherapy for stage IIa disease, whereas the European Association of Urology guidelines recommend radiation or multi-agent chemotherapy. Both guidelines call for radiation or multi-agent chemotherapy for stage IIb disease and multi-agent chemotherapy for stage IIc disease.

In general, stage II testicular seminoma is highly curable with multi-agent chemotherapy or radiation, but the two modalities have never been prospectively compared.

“The trend away from radiation therapy may be due to a misperception that it is more toxic than three or four cycles of multi-agent chemotherapy,” Glaser said. “Across this large, national dataset, radiation therapy was associated with a better outcome for stage IIa patients and equivalent outcomes for stage IIb patients. However, potential explanations for these improved outcomes are less clear.”

Researchers used the National Cancer Data Base to analyze predictive factors for the use of radiation vs. multi-agent chemotherapy and determine their corresponding OS among 2,437 patients diagnosed between 1998 and 2012 with stage II testicular seminoma (IIa, n = 960; IIb, n = 812; IIIc, n = 665).

Median follow-up was 65 months.

Rates of radiation usage were higher than those of multi-agent chemotherapy among patients with stage IIa disease (78.1% vs. 21.9%) and stage IIb disease (54.4% vs. 45.6%), but lower among patients with stage IIc disease (4.2% vs. 95.8%).

Use of radiation decreased over time for patients with stage IIa (P = .0001) and IIb disease (P = .016), whereas use of multi-agent chemotherapy increased.

Among patients with IIa or IIb disease, those who were diagnosed in a later year, were treated at an academic facility, or underwent pathologic assessment of lymph nodes were more likely to receive multi-agent chemotherapy.

Charlson-Deyo comorbidity scores of 1 or higher and having non-private insurance also increased likelihood of receiving multi-agent chemotherapy among patients with stage IIa disease, whereas a T stage of 2 or higher increased the likelihood for patients with stage IIb disease.

Rates of unadjusted 5-year OS were 97.1% (95% CI, 96.1-98.1) for stage IIa disease, 93.9% (95% CI, 92.1-95.7) for stage IIb disease, and 92.6% (95% CI, 90.6-95.6) for stage IIc disease (P = .006).

Five-year OS was higher among patients with stage IIa disease treated with radiation vs. multi-agent chemotherapy (99% vs. 93%).

The data also showed a radiation advantage on multivariable analysis (HR = 0.22; 95% CI, 0.08-0.64) and propensity-adjusted analysis (HR = 0.28; 95% CI, 0.09-0.88).

Among patients with stage IIb disease, 5-year OS rates were 95.2% (95% CI, 92.8-97.6) for those who received radiation and 92.4% (95% CI, 89.2-95.6) for those who received multi-agent chemotherapy (P = .04).

However, multivariable (HR = 0.74; 95% CI, 0.32-1.7) and propensity-adjusted analyses (HR = 0.77; 95% CI, 0.33-1.8) were not statistically significant.

The researchers acknowledged that their analysis may be limited due to the lack of data on staging workup, specific chemotherapy regimen, number cycles for chemotherapy and nonadherence.

“We would advocate for radiotherapy continuing to be the preferred treatment for stage IIa patients and for a risk-adapted approach for stage IIb patients,” Glaser and colleagues wrote.

These data need confirmation, Philip Poortmans, MD, PhD, head of department of radiation oncology at Radboud University Medical Center in Nijmegen, the Netherlands and president of ESTRO, said in the press release.

“The movement away from radiation therapy in favor of chemotherapy, induced by the fear of a higher rate of late toxicity, is now suggested to be probably not the right one for patients with stage IIa testicular seminoma, with an OS benefit in favor of radiation therapy up to at least 10 years after treatment,” Poortmans said. “Ideally, these results should be confirmed in a prospective trial with a very long-term follow-up, including a thorough analysis of side effects. However, this might be difficult to achieve.” – by Nick Andrews

References :

Glaser SM, et al. Clin Oncol.2016; doi:10.1016/j.clon.2016.02.008.

Glaser SM, et al. Abstract E35-0121. Presented at: ESTRO 35 Conference; April 29-May 3, 2016; Turin, Italy.

Disclosure : HemOnc Today was unable to confirm the researchers’ relevant financial disclosures at the time of reporting.

Perspective

David I. Quinn, MBBS, PhD

Seminoma is generally exquisitely sensitive to radiation and chemotherapy, often to curative effect. In stage II lymph node-positive seminoma there has been relative equipoise as to whether chemotherapy or radiation therapy is preferred. The data from Glaser and colleagues — which examine the outcomes for a large number of stage II patients treated with different modalities of therapy — run against the current presumptive paradigm of moving away from radiation therapy as the primary option in early-stage disease.

In stage I seminoma, the transition has been from traditional para-aortic adjuvant radiation to close surveillance or, if surveillance is not an option, one or two doses of adjuvant high-dose carboplatin. There is no difference in OS when starting with any of these three approaches, but surveillance eliminates the use of radiation or chemotherapy in 75% of these patients who do not need it. In stage II seminoma, the evidence from phase 2 trials suggests similar outcomes with radiation and chemotherapy, but there is no level-one data for one over the other.

Despite a deficit of high-level evidence, there has been a transition from radiation therapy as the primary therapy in stage II seminoma toward multiple-agent cisplatin-based chemotherapy. The report by Glaser and colleagues confirms this trend, which may be based on several assumptions or presumptions:

Outcome measured by OS is not influenced by the initial modality used.
Radiation will cure around 90% of stage IIA or IIB cases, with the remaining 10% relapsing. These relapses mostly occur outside the radiation field due to growth of micrometastases, usually in the thorax, and are cured with chemotherapy.
Primary chemotherapy with multiple-agent therapy will cure 90% or more of the patients without the need for further therapy.

The data from Glaser and colleagues question the move toward chemotherapy as the preferred primary therapy in stage IIA seminomas and suggest we should continue to consider radiation therapy, where it may be superior to chemotherapy. The study is probably underpowered to determine such a difference in outcome in stage IIB seminoma based on choice of initial therapy. Stage IIC patients are far more likely to have occult metastatic cancer distant to the retroperitoneal lymph nodes and to have volumes of cancer in the lymph nodes, meaning that radiation therapy is less likely to have definitive efficacy. On that basis, one can solidly argue for chemotherapy in stage IIC seminoma patients, and the data from the Glaser study will not change that.

Overall, most experts use a risk-adapted therapeutic selection paradigm for stage II seminoma with radiation therapy being preferred for IIA but with more multiple-agent chemotherapy used in stages IIB and IIC seminoma.

Can we avoid chemotherapy and radiation in any stage II patients?

Retrospective and case series data suggest that some of these patients may be curable with primary surgery in the form of retroperitoneal lymph node dissection. This is being tested in a phase 2 trial led by University of Southern California with 2-year RFS as the primary endpoint (NCT02537548). If the results of this trial are promising, we may need to consider the three different treatment modalities in patients with stage IIA seminoma.

In the meantime, we need to discuss a risk-adapted treatment strategy with input from multiple disciplines.

References:

Classen J, et al. J Clin Oncol. 2003;21:1101-1106.

Domont J, et al. Urol Oncol. 2013;doi:10.1016/j.urolonc.2011.04.004.

Garcia-del-Muro X, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2007.15.9103.

Hu B, et al. Clin Genitourin Cancer. 2015;doi:10.1016/j.clgc.2015.01.002.

Mead GM, et al. J Natl Cancer Inst. 2011;doi:10.1093/jnci/djq525.

Motzer RJ, et al. J Natl Compr Canc Netw. 2015;13(6):772-799.

Nichols CR, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.47.6010.

David I. Quinn, MBBS, PhD

University of Southern California Norris Comprehensive Cancer Center

Disclosures: Quinn reports no relevant financial disclosures.