SLIDES & TRANSCRIPTS
Saturday, December 14, 2002

Surveillance for Testicular Cancer in 2002/Seminoma/Non-Seminoma

Mary Gospodarowicz, M.D.

I would like to do this presentation on behalf of the whole PMH testis group. As you see, we have a big, multidisciplinary group that has been looking after patients with testicular tumors.

TOP

My colleagues were so worried about this presentation that they thought that I should illustrate it better. So I would like to thank Mike Jewett for giving me a slide with pictures.

The situation with testicular tumor patients is different to what we have had in other cancers. These patients present at a very young age, and have potential for a very long survival, with a very good prognosis. And because of this good prognosis, survival is no longer the only outcome for the majority of patients that we are concerned with. And the goal of treatment, beside cure, is to minimize the morbidity.

TOP

When we talk about surveillance, people think of surveillance as a treatment modality of stage 1 cancer, but actually there are other modes of surveillance, and I won't discuss them all. One is surveillance in patients with partial orchiectomy, where one is concerned about local tumor recurrence. The classical surveillance after orchiectomy is mostly for regional or distant failure.

Patients who have adjuvant therapy are at low risk for distant failure. And we have patients with residual masses post-treatment, for example, patients with seminoma who have a residual mass. They can also be surveyed for local failure. And then most of the patients who undergo treatment are at the risk of second testicular tumor, and some are at risk of complications. So this is all a form of surveillance.

TOP

Surveillance in the stage 1 testicular tumors was not practiced before the 1970’[s. In fact, most of the audience probably doesn't know, but before our time, most of the patients with stage 1 testicular cancer were actually treated with radiotherapy. And the retroperitoneal lymph node dissection for non-seminoma was really adopted as an effective modality of management in the 1970’s.

The surveillance for testicular tumors was pioneered by Mike Peckham in Royal Marsden Hospital in London, as the first report was published in 1979. It was a very novel strategy at the time, thought to be a fairly dangerous attempt in management of patients with testicular tumors.

It took over a decade for results of the only phase III trial of surveillance in non-seminoma. This was done by the Danish testicular cancer group, who randomized non-seminoma patients between surveillance and radiation therapy. It was not a very popular trial, because radiation therapy has largely been abandoned for non-seminoma in the early eighties.

This trial did show that radiotherapy reduced the risk of the abdominal relapse in stage 1 non-seminoma, but there was no difference survival, and it didn't do anything to the risk of distant relapse, so this treatment was abandoned.

It took almost a decade after the first report of surveillance for non-seminoma for the first published report of seminoma surveillance, which was also done by the Royal Marsden Hospital group.

TOP

And just to summarize what I'm going to be talking about, in non-seminoma, approximately 40-60 percent of patients present with stage 1 disease. Surveillance is now a widely accepted treatment option, with the failure rate ranging between 25-30 percent, survival that approaches 99-100 percent. And there are alternative treatment options that will be discussed, and they include retroperitoneal lymph node dissection, or adjuvant chemotherapy in patients who are high-risk.

TOP

In contrast, seminoma stage 1 disease is even more common, with currently 70-80 percent of patients presenting with stage 1 disease. Surveillance is still a poorly accepted treatment option; however, there is now solid evidence that the risk of recurrence is probably no more than 15 percent. Survival again, approaches 100 percent.

And there are well-described alternative treatment options. The popular classical treatment, which is adjuvant retroperitoneal radiation therapy, and the newer form of treatment, which is adjuvant single-agent carboplatin chemotherapy.

TOP

So let's go on and discuss non-seminoma - the three treatment options are surveillance, lymph node dissection, and chemotherapy. Surveillance shows us that we only need to observe patients with non-seminoma for five years. Relapse in non-seminoma on surveillance after two years are distinctly uncommon.

The overall risk of recurrence is around 30 percent, somewhere around 25-35 percent. Good co-specific survival. With retroperitoneal lymph node dissection, approximately 70 percent of patients have pathologic stage 1 disease. Of those, less than 10 percent recur. The patient with pathologic stage 2 disease and clinical stage 1 disease have approximately a 30 percent risk of recurrence treated with surgery.

Chemotherapy to date has been used only in high-risk patients, and there is still a risk of recurrence following chemotherapy, but this is usually quite low.

TOP

This is a picture of retroperitoneal lymph node dissection. Mike said that I had to put it in. And it sort of occurred to me why the surgeons always have to put in these pictures. I think it's because they are so proud of what they can do,

TOP

that you need to illustrate it.

So I thought that radiation oncologists also have pictures that they are proud of. But just because you can do it, doesn't mean you should be doing it all the time.

TOP

The surveillance theories in non-seminoma show there has now been a lot of literature, large numbers of patients that have been followed without treatment after orchiectomy. This is the risk of relapse, as I said, 25-35 percent. And this is survival that approaches 100 percent. It depends on whether you report the overall or cause-specific survival.

TOP

We also know the pattern of failure pretty well. Initially, when we started, people thought that the major pattern of failure would be distant. However, 50-70 percent of patients actually do recur in retroperitoneal lymph nodes, but there is also a failure pattern only in supradiaphragmatic sites from other series.

TOP

I'm just going to show you the Prince Margaret Hospital, Torontro (PMH) non-seminoma surveillance series between 1981-96, of 170 patients. Our failure rate was 28.2 percent,which ranged 2-21 months after diagnosis. There were no failures after two years. All but one are alive and free of disease. And we found that the majority of patients fail in the retroperitoneal or with markers only. Most of them had both. Again, distant failure alone was distinctly uncommon.

TOP

The prognostic factors that lead us to predict who is likely to recur have also been studied. The biggest and probably most comprehensive analysis was done by the MRC-UK study, where in the multivariate analysis they found that four factors: vascular invasion, lymphatic invasion, absence of yolk sac elements, and presence of embryonal carcinoma predicted failure.

And if you had zero to one adverse factors, you had low risk of relapse; with two adverse factors about a quarter of patients relapsed. With three to four of these factors, 58 percent of patients relapsed. So we can actually stratify patients who are at a high-risk for relapse. But unfortunately, with all the investigations over the years, to my knowledge, no one has actually shown a group of patients that is at 80 or 90 percent risk of relapse. So it's solely the high-risk group, about a 50-60 percent at the most.

TOP

So in summary, non-seminoma surveillance is now a well-accepted safe management strategy. Nearly all patients who relapse are cured with chemotherapy. High-risk patients may receive adjuvant chemotherapy. It has been shown that if you have a strategy where you observe low risk patients, and give adjuvant chemotherapy to high risk patients, you can actually reduce your failure rate in non-seminoma surveillance to about 15-20 percent.

TOP

And I just put this in, because the slides are going on the Web. This is the surveillance protocol. We give these protocols to the patients when they go on surveillance, so that they can be informed when their follow-up is due.

TOP

Moving on to the seminoma surveillance, the three treatment options in stage 1 seminoma include adjuvant radiotherapy to retroperitoneal lymph node dissection. At the present time there is a choice of treating paraaortic and pelvic nodes, or treating paraaortic lymph nodes alone.

The failure rate is less than 5 percent, with almost 100 percent cause-specific survival rate. Surveillance series show an approximate failure rate of 15 percent, and again, very good survival.

In newer treatment methods, I think there is enough literature now to say that adjuvant single agent carboplatin(one course) has a failure rate of less than 5 percent. The data on follow-up is not as mature, with a median follow-up of 3-4 years, and we all know that late relapse is more common with seminoma than in non-seminoma.

TOP

One of my colleague, Park Ward, did a pooled analysis of the four largest seminoma surveillance series that amounted to 638 patients, with a median follow-up now of 7 years. The risk of relapse was about 17.7 percent at 5 years. Although the patients with seminoma are at the risk for late failures, 70 percent of them recurred with 2 years, and very few died of disease.

TOP

The prognostic factors for relapse in seminoma are more difficult to identify. The two that were significant in this pooled analysis were tumor site and testis invasion.

TOP

At Princess Margaret Hospital, we reviewed all our patients with stage 1 seminoma who were treated in the last 20 years; 627 cases with now a median follow-up of close to 9 years. And 345 of those patients had surveillance. I didn't put the slide in, but the patients' characteristics were actually quite similar as far as the size of the tumor and patient's age.

TOP

And on surveillance, 290 patients have never relapsed. We have 55 relapses for an overall relapse-free rate of 85 percent.

The sites of relapse in seminoma are much more predictable. The vast majority of patients do relapse in paraaortic lymph nodes. A few of them have pelvic lymph nodes, and very few have relapsed in pelvic lymph nodes alone, and an occasional patient had relapse in the abdomen and in the mediastinum.

TOP

In our series, patients who recurred in retroperitoneal were treated by and large, with radiation therapy, and 5 of those patients, about 10 percent had a second relapse in supradiaphragmatic region or mediastinum - all of these were salvaged. Thirteen patients had chemotherapy either because they relapsed fairly promptly, or had larger nodes at the time, or multiple at the time of relapse. And two had surgery. These two patients were the patients who had prior radiation for a previous testicular tumor, and the tumor that was surveyed was the second tumor. One patient who relapsed very quickly on surveillance was treated with chemotherapy, did not respond, and failed salvage treatment and died.

TOP

The frequently asked question is: will the patients who are surveyed and relapse need more treatment? And when you look at the patients at PMH who were treated either with surveillance or radiation, the relapse-free rate on patients with surveillance was 85 percent. It was 95 percent, not 5 percent on the radiation, with the same cause-specific survival. Five percent of patients who were surveyed required chemotherapy, and 3.5 percent of those with radiation. So there is no significant difference in the number of patients who eventually require chemotherapy because they have systemic disease.

However, obviously, all the patients who received adjuvant radiation had some adjuvant treatment, while 85 percent of patients who were on surveillance never needed any treatment other than orchiectomy.

TOP

And this is our schema for seminoma surveillance. It goes on longer. We follow patients for a long time, because this is our investigational protocol. So if we are going to learn what is the risk of late relapse, we have to follow patients for a long period of time.

We have minimized the number of CT scans now to cue four months for the first three years, twice a year, and then one a year. But we think that with further follow-up we probably could reduce the follow-up investigations even further.

TOP

Why do we survey patients? The treatment with radiation or chemotherapy or surgery in stage 1 testicular tumors is very safe. And for a long time it's been said that low dose retroperitoneal radiation is not associated with any toxicity. However, there are studies of the risk of second malignancy in germ cell testicular tumors.

TOP

And because the biggest study has been done by Lois Travis here at NCI, with 28,000 patients from 16 population-based registries that actually shows an increased risk of second cancer in patients who were treated for germ cell testicular tumors. And this toxicity is not only related to the use of radiation, but also to the use of chemotherapy.

TOP

And this is the overall look at second malignancy risk after diagnosis of seminoma. This is the population expected-risk. As you can see, there is excess risk in seminoma of second cancers.

TOP

And if you want to read further about it, there is a very nice review by Lois Travis of therapy-associated solid tumors.

TOP

So in summary, the surveillance in stage 1 germ cell tumors is very safe, yet it continues to be controversial. Cure is no longer an issue. The traditional endpoints such as survival or relapse and toxicity are important, but also relevant are issues of late mortality, quality of life, and overall cost of treatment.

Thank you very much.

TOP