Testicular Cancer

A study published in The Lancet (2005;366:293–300) has demonstrated that a single dose of chemotherapy (carboplatin) is as effective and less toxic than three weeks of radiotherapy for Stage I seminoma in testicular cancer. The researchers, led by R. Tim Oliver, MD, for the Medical Research Council TE19 and the European Organization for Research and Treatment of Cancer 30982 studies, decided to investigate this line of treatment because the standard of care for Stage I seminoma for the past 50 years has been hemi-castration followed by three weeks of radiotherapy—a treatment associated with a risk of late non-germ-cell cancer as well as cardiovascular events, the article notes. “Though the study needs longer follow-up and larger numbers, this surprising finding, were it to apply to primary tumors when first diagnosed, is the first hint that it may now be safe to embark on studies of testis conservation instead of hemi-castration.” Between 1996 and 2001, a total of 1,477 patients with Stage I seminoma—from 70 hospitals in 14 countries throughout Europe—were recruited into the trial. The patients, within eight weeks of orchidectomy, were randomly assigned to receive either radiotherapy or one injection of carboplatin—at two trial centers in the UK and Belgium. After a median follow-up of three years, the relapse-free survival rate was found to be similar in the two groups (95.4% for carboplatin, 96.6% for radiotherapy). After five years, it was also found that patients on carboplatin were less likely to develop tumors in their remaining testicle. Editorial: Follow-up Still Short Cancer of the testis is rare and most are primary germ-cell tumors. In an accompanying editorial, Padraig Warde, MD, and Mary Gospodarowicz, MD, from the Department of Radiation Oncology at Princess Margaret Hospital of the University of Toronto, note that 60% of these primary germ-cell tumors are pure seminomas, and that 70% to 89% present with no radiological evidence of disease.Figure: Lead researcher Tim Oliver, MD: “It was very interesting that there was literally no contribution from America, and no American clinical researcher has done any work on reducing the risks of treating seminomas.”With advances in imaging and because of the worry of side effects of radiation therapy, post-orchidectomy surveillance has become the preferred strategy, Drs. Warde and Gospodarowicz said, questioning, therefore, whether adjuvant chemotherapy is the best management. They say that the follow-up period in the Lancet study was short and that further relapses might occur in the patients on carboplatin. The editorial cites a Phase II study with a relapse rate of 8.6%, but patients in this trial were on a lower dose of carboplatin. Drs. Warde and Gospodarowicz add that the long-term side effects of radiation therapy—secondary malignancies and cardiovascular effects mentioned in the study—have been well documented, but point out that the long-term side effects of carboplatin remain unknown.Figure: Padraig Warde, MD (left), and Mary Gospodarowicz, MD, wrote an accompanying editorial in the same issue of Lancet as Professor Oliver's study, and noted that with advances in imaging and because of the concern of radiation therapy side effects, post-orchidectomy surveillance has become the preferred strategy. Since the follow-up period in the study was short, it is possible that further relapses may occur in the patients on carboplatin, especially since a Phase II study of such patients showed a relapse rate of 8.6%, and patients in this trial were treated with a lower dose of carboplatin.Response to Criticism In an interview, Professor Oliver, from the Department of Medical Oncology at St. Bart's and the London Hospital, responded to the criticism in the editorial: “The authors were trying to use an academic argument about the shortness of the follow-up period, meaning that people could still not be confident about carboplatin. “Obviously we still don't know at 20 years whether there might be a risk of second cancers, but we have now used carboplatin for nearly 20 years and cisplatin for nearly 30 years.” Professor Oliver also points out that patients on the new radiotherapy schedules (drawn up as a result of 20-year follow-up data from old radiotherapy schedules) have only been followed for the same period of time as patients in the carboplatin trial. And, there are already some worrying late recurrences, he added. “So they have no more solid evidence for radiotherapy than I have for carboplatin from my trial.” As the Lancet paper notes, Professor Oliver was one of the first researchers to identify the high risk of late-onset non-germ-cell cancers and cardiovascular events from a conventional dose of radiotherapy—“which is why years of research have been spent on trials with a reduced adjuvant radiation dose,” he said. But although these trials have demonstrated no loss of effectiveness with reduced radiation with respect to relapse-free survival, the Lancet paper points out that patients who had para-aortic irradiation only also had a significantly increased rate of pelvic relapse. No Need for Adjuvant Chemotherapy? The authors of the editorial also question whether adjuvant chemotherapy should be given at all. They point out that surveillance data are now mature enough to show that surveillance alone is safe and that 80% to 85% of patients do not require post-orchidectomy treatment. Dr. Oliver said he agrees that the figure for those not needing treatment is high, but he points out that the main disadvantage for surveillance is that relapse can be as late as eight years after diagnosis. Also, very occasionally in the past, “if follow-up has not been optimum, the first thing that can indicate relapse is paralysis of the legs from spread into the spine,” he explained. “The aim must be to reduce this unnecessary treatment by developing better methods of predicting those at risk of recurrence and giving treatment only to them. Such an approach has recently been reported by a group from Spain.” (see box) Dr. Oliver points out that the Spanish researchers were able to target two thirds of their patients with a higher than average risk of relapse and treat just them, and in this group they reduced the risk of relapse from 20% to 4%. Carboplatin & Fertility The other disadvantage to surveillance is that subfertility is common in up to two thirds of patients, and “these patients might benefit from the unexpected finding of the Lancet study of the reduction in occurrence of second tumors,” he said. “This is thought to be due to the carboplatin improving the fertility of the remaining testis, resulting in it becoming less susceptible to becoming malignant. Clearly so far we can only say this for five years of follow-up, and there remains a risk for up to 20 years. “However, even though it may only be in the short term, this does mean five more years of keeping your testicle—and it is very traumatic losing both. And HRT [hormone-replacement therapy] in men is not nearly so developed as in women. That result in itself has turned out to be a considerable bonus.” But Dr. Oliver says that ultimately “the most lasting legacy of this trial may be the opening up of greater understanding of how testis cancer develops and the making of testis conservation as much an everyday treatment of testis cancer as [conservation] is of breast cancer today.” Treatment Change in UK? Professor Oliver said he is convinced that his study will change the management of Stage 1 seminoma in the UK: In fact, “it already has, as carboplatin is quicker to get than radiotherapy. “What happens is that the waiting times to get the radiotherapy were very much an inhibition, so using carboplatin was getting people through more quickly and thus shortening the waiting times,” he said. It is clearly a more straightforward and shorter treatment than radiotherapy: as Professor Oliver explains, it is easy to do and has no complications—“and now with this study, people are more confident to use it.” In a situation like this where the results for radiation therapy were already so good, the results of the study had to be equally as good, he said—“you couldn't afford to have the alternative 5% or 10% worse”—so that people would get a lot of confidence from them. Professor Oliver added that the practice had been changing during the course of the trial at least in the UK since most of the people who treat this type of patient entered the trial—“we attracted something between 40% and 50% of the patients with that condition into the trial. After a median follow-up of three years, the relapse-free survival rate was similar—95% for patients receiving carboplatin and 97% for those given radiotherapy. After five years, the results showed that patients on carboplatin were less likely to develop tumors in their remaining testicle. “Between a third and a half of the doctors who treat this condition in this country [the UK] were involved in the trial, and we had contributions from most European countries and Australasia—whereas from the US we had none. “It was very interesting that there was literally no contribution from America, and no American clinical researcher has done any work on reducing the risks of treating seminomas.” He said he is not sure why this might be, but points out that in the British system, “any innovation that diminishes the pressure on resources by reducing the cost or speeding up treatment—if proven safe—is taken up much more quickly in the NHS than things which increase costs. It is the reverse of this in America, where risking less treatment in situations with a high cure rate is more difficult to implement.” However, he stressed, the fact is that the Lancet study has shown that people whose disease recurred after treatment with carboplatin were more easy to cure than people who developed recurrence after radiation—“so that should diminish some of the Americans' worries.” What the Patient Has to Decide Professor Oliver said that now that the two treatments—i.e., a single dose of chemotherapy or three weeks of radiotherapy—have been proven to be equal, in the future a patient is faced with a choice: treatment now or later. “The patient will need to decide whether the risks of recurrence and needing three months more intense chemotherapy are such that one day's treatment [on carboplatin] and two to three weeks off work now—for the gain of less trouble and dependence on hospitals in the future—are worth taking,” Professor Oliver said. “Or, the patient will have to decide whether he has a low enough risk and/or important events in his life, like promotion or competing in a sporting event, to need to commit to them in the short term and take the risk later.” And if the patient decides that he or she wants preventive treatment now, there are two clear points in carboplatin's favor over radiation, Dr. Oliver explained: First, “carboplatin is certainly less acutely toxic over the first four to six weeks. Patients get back to work more quickly and they feel more normal.” And secondly, there is the unexpected finding that treatment is proven against second germ cell tumors in the other testicle—“so they have a good chance of surviving longer with their other testes intact. And this is with just one day's treatment—whereas it takes 10 years of treatment to show the same thing for tamoxifen for women with breast cancer. “Though needing longer follow-up and larger numbers to be sure, this surprising finding, were it to apply to primary tumors when first diagnosed, is the first hint that it may now be safe to embark on studies of testis conservation instead of hemi-castration.” No Comments from US Oncologists Five US oncologists were approached for their opinions for this article, but all were either unavailable or said they were too busy to comment. Mary Fogarty is Editor of OT's UK Edition.

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