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