Radiotherapy versus carboplatin for Stage I seminoma: Updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214)

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2008

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Presenter: R. T. Oliver
Presenter's Affiliation: St. Bartholomew’s Hospital, London, United Kingdom
Type of Session: Plenary

Background

  • Seminonas are the most common subtype of testicular cancers, accounting for about 40% of cases. Stage I seminomas are limited to the testis. 
  • Since the 1950s, the standard of care for treatment of Stage I seminomas has been orchiectomy followed by adjuvant irradiation of the pelvic and para-aortic notes. The relapse rate for this treatment is nearly 5%.
  • However, studies in the 1980’s and 1990’s have shown that patients with adjuvant RT had a 20% excess mortality when compared to matched controls, and randomized trials have shown efficacy of decreased RT exposure. 
  • It has also been noted that about 80% of these patients are cured by orchiectomy alone, but  when stratified by risk factors, there are some patients who can be defined as having an increased risk of relapse. 
  • Since surveillance is not always an optimal method, and irradiation was found to be associated with a higher risk of mortality, secondary malignancies, and cardiovascular events, the UK Medical Research Council has conducted 2 studies to examine a reduction in the amount of radiation and the extent of the radiation field. 
    • The TE 10 study compared para-aortic (PA) strip with dog-leg (DL) field irradiation (ie, PA strip plus ipsilateral iliac and inguinal fields) and found a significantly increased rate of pelvic relapse in the PA only group. The TE 18 studied compared 30 Gy vs. 20 Gy for the total dose, and did not see a difference in relapse-free survival (RFS).
  • It has also been seen that metastatic seminomas have an increased sensitivity to single agent platinum-based chemotherapy compared with non-seminomas. 
    • It was thus hypothesized that treatment with carboplatin may be a possible alternative to radiation. 
  • The present study is a randomized, collaborative trial to compare 1 course of carboplatin with radiotherapy following orchiectomy in stage I seminoma patients. The initial results of this study were presented by the authors at ASCO 2004 with a median follow up on 4 years. The authors are now presenting the updated results with a 6.5 year median follow-up.

Materials and Methods

  • Between 1996 and 2001, 1,477 patients with Stage I seminoma s/p orchiectomy were randomized to radiation therapy (RT) at 20-30 Gy (n=904) vs. 1 injection of carboplatin (C).
  • C was dosed at 7x(GFR+25) if EDTA was used (n=357) and 90% of this dose if creatinine clearance was used (n=202). 
  • The randomization was 3C:5RT.
  • This study has a non-inferiority design, and is powered to exclude a 3% difference with 90% certainty. 
  • The primary endpoint was RFS, and this was determined using a Kaplan-Meier method and hazard ratios from the Cox regression model.
  • In this update, an analysis of RFS for the variation of dose of C (based on which renal function parameter was used) was also performed, however this was a non-randomized comparison.

Results

  • Patient characteristics were balanced and there were no significant differences between the groups. 
  • Median follow up for this update is 6.5 years, and 78% (n=1148) of patients have a documented minimum 5-year follow up (previously, it was only 23%). 
  • The RFS rate for the RT group was 96.0% and in the C group was 94.7%, and the HR was 1.25 (0.83, 1.89). 
  • There was, however, a significant difference in the rate of 2nd primary germ cell tumors (GCT).      It was 2 (0.3%) for C and 15 (1.7%) on RT, with a HR of 0.22 (0.05, 0.95), p=0.03.  
  • When comparing the 2 C doses, no significant difference was seen between the groups (92.6% vs. 96.1%).  
  • In terms of toxicity, patients were scored based on percentage of patients able to work at 4 weeks and 12 weeks. There was a significant difference at week 4 between C and RT (19% vs. 38%, p<0.05), however this difference was not present at 12 weeks. There was increased grade 2 and 3 thrombocytopenia in the C group compared to the RT group. Other toxicities were not mentioned.

Author's Conclusions

  • One course of carboplatin is safe, is less acutely toxic, and is as effective as RT for stage I seminoma. 
    With longer follow up, this report confirms the previously presented results.
  • There is a reduced risk of 2nd GCT in the C arm compared to the RT arm.
  • Longer follow up, close to 20 years, is needed to examine death rates from non-germ cell secondary cancers and heart disease between the 2 groups. 

Clinical/Scientific Implications

  • Seminomas are the most common testicular germ cell tumor, and usually affect young men. Although the cure rate is close to 99% in these patients, the risk of relapse and secondary toxicities of treatments are of great concern, since these patients often survive for many years. 
  • This prospective, randomized non-inferiority trial demonstrates that carboplatin is not less effective than RT as adjuvant treatment for Stage I seminoma. Since this is not a superiority trial, one cannot conclude that one treatment is more effective than the other, but that carboplatin may be an alternative to RT. 
  • In addition, since the survival rate of these patients is so high, it would not be meaningful to look at differences in overall survival in these patients. 
  • In terms of the clinical implications of these results, the big question becomes, which alternative should I choose for my patients? The goal when choosing treatments for patients is to maximize cure rate with the least toxicity possible. We need to focus on a relative risk/benefit ratio for the patient population we are treating. 
  • The authors report that carboplatin was associated with fewer toxic effects and a more rapid return to work than radiotherapy, as well as a reduced incidence of secondary GCTs compared to RT. However, it is unclear how detrimental a secondary GCT is to a patient, since its cure rate is so high. Data on risks of late non-germ cell secondary malignancies and cardiovascular toxicity between the 2 groups would be more beneficial in choosing an optimal therapy. Extended long-term follow-up is needed to determine these risks. 
  • Based on these results, we should understand that carboplatin is an effective alternative to RT in terms of RFS and is an option.
  • However, we do not have enough longer-term follow up data to change our current standard of care of orchiectomy followed by RT. 

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