Stage I Germ Cell Tumours: Achieving Cure at Minimal Cost

Clinical Oncology 22 (2010) 1–5 Contents lists available at ScienceDirect

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Editorial

Stage I Germ Cell Tumours: Achieving Cure at Minimal Cost R.A. Huddart Institute of Cancer Research and Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK Received 5 August 2009; accepted 10 August 2009

Stage I germ cell tumours (tumours that appear clinically to be restricted to the testis) are an oncology success story. As confirmed by the meta-analyses reported in the Cancer Care Ontario guidelines [1], nearly all patients are cured of their cancer, with most series reporting cure rates of over 98%. As diagnoses are being made earlier, and patients tending to present with earlier disease, at least in the UK, the overall prognosis of germ cell tumours has accordingly improved. The latest UK figures suggest that 97.5% of patients now survive 5 years [2]. These results are a cause for celebration, yet this is not necessarily the end of the story. As we celebrate winning the cancer battle, increasingly we are worrying about losing the long-term war. Without treatment, a significant proportion of stage I patients will relapse (about 15–20% of seminomas and 25–30% of non-seminomas). These relapses can be treated when they appear or adjuvant therapies can be applied to minimise the risk of relapse. What has become apparent over the last few years is that these treatments carry with them the risk of long-term life-threatening complications, such as cardiovascular disease or second malignancy. The Cancer Care Ontario guidelines confirm other reviews that initial oncological management does not affect cure rates, but does affect relative treatment burdens. In planning treatment for stage I disease we need to take account of these differences, but need to consider the effect both of the initial treatment and of salvage treatment. We have learnt a lot about treatments and their effects, but this has raised further questions about the long-term effects of treatment. Here I will discuss the issue of late effects and the relative merits of strategies to treat stage I disease.

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What is Known about Late Effects of Treatment? Over recent years a number of studies have investigated the risk of cardiovascular disease and second malignancy. Some of the major studies are summarised in Table 1. In general, these studies have reported an increased second malignancy risk after both chemotherapy and radiotherapy and an increased risk of cardiovascular disease, particularly after chemotherapy. Some, but not all, studies have reported an increased risk of cardiovascular disease after radiotherapy, although this risk is more variable across studies. The absolute risks of these problems are significant, especially in the context of a disease with good prognosis. The largest study of second malignancy by Travis and colleagues [6] reported an absolute increase in second malignancy from 23% to 31% (non-seminomas) and 36% (seminomas) at 40 years after radiotherapy, i.e. an excess risk of 8–13%. A conservative estimate of 50% mortality would suggest that this represents an absolute excess risk of 4–6% mortality from second malignancy. Van den Belt Dusebout [8] reported an increased risk of cardiovascular disease or second malignancy of 1.8 for radiotherapy and 1.9 for chemotherapy. Taken together, the data, in my view, are convincing that these effects are real. However in terms of advising on patient management there are two major issues. First, to have sufficient power the most robust studies are the largest and often registry or multi-institutional and often lack the fine detail of patient treatment; whereas smaller studies with better treatment detail lack power for subgroup analysis. Second, most is known about patients treated the longest time ago and thus as treatments evolve we have less information about recent treatments, e.g. the effect of radiotherapy volume/ dose changes, and the use of low-dose chemotherapy. This inevitably means that we have to extrapolate from available data and in turn clinicians may then draw different conclusions.

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R.A. Huddart / Clinical Oncology 22 (2010) 1–5

Table 1 Summary of major studies of late second malignancy and cardiovascular disease after treatment for germ cell tumours Reference

Criteria

Huddart et al. [3,4] Zagars et al. [5] Travis et al. [6] Robinson et al. [7] van den Belt Dusebout et al. [8] Fossa et al. [9]

Incidencey Mortalityy Incidence* 20þ year mortality* Incidencey (multivariate analysis vs surgery alone) Mortality* (circulatory disease <35)

* y

Relative risk of second malignancy

Relative risk of cardiovascular disease

Overall

Radiotherapy

Chemotherapy

Radiotherapy

Chemotherapy

– – 1.9 2.18 –

2.4 1.91 2.0 – 2.6

1.6 – 1.8 – 2.1

2.4 1.61 – – 1.2

2.59 – – – 1.7

–

–

–

1.7

1.69

Relative risk or odds ratio compared with population norms. Relative risk or odds ratio compared patients treated by surgery alone.

Implications We expect that less than 1% of patients with stage I disease will die of their disease directly from their germ cell tumour. These data on late toxicity would suggest that over the long term they are more likely to die from treatment toxicity than their disease. We do need to manage their germ cell tumour effectively, but we need to take responsibility and use the minimum amount of treatment to achieve cure. This sounds straightforward, but has to take account of the entire treatment burden, including the effects of salvage treatment. It is further complicated as we do not know the relative effects of low-dose treatment in most patients vs more intensive treatment in a subgroup of patients.

Seminoma The meta-analysis presented in the Cancer Care Ontario guidelines [1] identifies the three most commonly used options with similar survival outcomes: adjuvant radiotherapy, adjuvant carboplatin chemotherapy and surveillance. When I trained, the decision and consensus treatment was strongly in favour of adjuvant radiotherapy, which randomised trials had refined to involve treating a para-aortic strip to 20 Gy in 10 fractions. I strongly believe that the data on second malignancy mean that this advice should no longer be given routinely. The Travis et al. [6] data, reviewed above, would suggest an excess cancer risk for patients treated by dogleg radiotherapy of around 8–10%. Although it has been estimated that reducing the field to a para-aortic strip could halve this risk [10], if one assumes a 50% case mortality risk from second malignancy this would suggest a 2–3% mortality referable directly to this, not including any cardiovascular risk. This is higher than the risk of dying directly of seminoma and represents one death for every five recurrences prevented. For my money this is a poor return and I believe can no longer be justified, except in exceptional circumstances. The choice between carboplatin and surveillance is, in my view, more balanced, and perhaps more so than presented in

this meta-analysis. In part, this is because I would give more weight to the well-run Medical Research Council/European Organization for Research and Treatment of Cancer (MRC/ EORTC) randomised trial [11] than is given in the overview, and in part as long-term follow-up has been recently presented confirming the efficacy of this approach [12]. Recently, Horwich and colleagues [13,14] reported on the long-term outcomes of patients managed by surveillance. In this study, the entire treatment usage was tracked from diagnosis to 10 years of follow-up. This has been compared with other strategies on a more theoretical basis (Table 2). This approach suggests that on average the treatment burden for surveillance patients is less than that for patients receiving adjuvant therapy (an average of 0.46 treatments vs 1.06–1.12 for those receiving carboplatin), although the burden is considerably higher for those who relapse. There remains the issues regarding the relative value of different treatments. The treatments given in the surveillance patients (probably a course of radiotherapy or combination chemotherapy) are significantly more intensive than a single course of carboplatin. Thus, the treatments received are not equal and we have no good way of weighting or making a valued judgement. We also have no detailed evidence of the long-term risks of single-agent carboplatin; we would imagine this to be lower than other treatments and data to date have been reassuring, but we cannot be certain [15]. As discussed below for non-seminoma, surveillance is not without its problems. Most data would suggest that seminoma surveillance needs to extend over a number of years, raising issues of compliance, and involved careful follow-up with cross-sectional imaging. This has been successful in large academic centres, but its safety in a wider community setting has not been confirmed and nor has the optimum imaging schedule [16,17]. There is also concern that surveillance schedules that contain significant computed tomography imaging expose patients to significant levels of diagnostic irradiation with attendant long-term risks. The MRC TE24 TRISST trial is addressing these issues, testing a more and less intensive scanning schedule and if magnetic resonance imaging could replace computed tomography, together with assessing surveillance on a multi-centre basis [16].

R.A. Huddart / Clinical Oncology 22 (2010) 1–5

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Table 2 Treatment burden in the management of stage I seminoma Treatment

n

Initial treatment Chemotherapy

Surveillance All [Relapsed patients] Radiotherapy* theoretical Radiotherapyy theoretical Carboplatinz theoretical Carboplatinx theoretical * y z x

Assumes Assumes Assumes Assumes

after after after after

164 [22] 164 164 164 164

25

Second and subsequent treatment Radiotherapy

Total treatments

Chemotherapy

Radiotherapy

19

25

7

76

164 164

29 19 14 7

4 4

193 183 182 175

164 164

Burden per patient

0.46 [3.45] 1.18 1.12 1.12 1.06

radiotherapy, relapses in 4.5% þ salvage therapies in 2. radiotherapy, relapses in 3% and 1, respectively. carboplatin, relapses in 3.5% þ salvage therapies in 2. carboplatin, relapses in 3% and 1, respectively.

One way forward is to undertake a risk-adapted strategy. A prognostic factor analysis has been published [18], but has to date not been formally confirmed. However, it represents the best available data. At this point in time I would concur with the conclusions of the Cancer Care Ontario guidelines and offer surveillance to all patients, but were I would differ is that I would offer patients, especially those at higher risk, the option of adjuvant carboplatin, emphasising the unknowns about long-term risks.

Non-seminoma The options for the treatment of stage I non-seminoma consist of surveillance [19], retroperitoneal lymph node dissection (RPLND) with or without adjuvant chemotherapy [20,21] or adjuvant chemotherapy with two cycles of Bleomycin, Etoposide, Cisplatin (BEP) chemotherapy [22].

Most studies have shown that the presence or absence of vessel (lymphatic or venous) invasion is a robust predictor of recurrence risk [23]. Those with no invasion have an approximate risk of 15–20% of relapse, whereas those with vessel invasion have a 40–50% risk of relapse. Some studies have suggested that the proportion of embyronal carcinoma could further modify these risks, but a robust way of using this information has not been identified to date [23]. As highlighted in the Cancer Care Ontario guidelines, there is no difference in the cure rate of any of these approaches and again I believe decisions need to be made in consideration of the overall treatment burden. A theoretical exercise demonstrating these differences is given in Table 3. This analysis, the Cancer Care Ontario meta-analysis and most consensus statements would agree that for those in low-risk groups the most appropriate management with the lowest burden of treatment would be a policy of surveillance. This does need to be undertaken in a well-structured environment and the risk

Table 3 Theoretical effect of different strategies on relapses and chemotherapy and surgery in stage I non-seminomatous germ cell tumours Group

No. in group

No. of relapses

Courses of BEP/group

Total courses chemotherapy

Surveillance for all patients

100

30

90

90

10

Adjuvant BEP (2) high risk Surveillance low risk

50 50

0 10

100 30

130

3

Adjuvant BEP (1) high risk Surveillance low risk

50 50

2 10

56 30

86

4

100

15

45

45

100

Routine RPLND plus: Surveillance (node negative) Adjuvant BEP (node positive)

85 15

10 0

30 30

60

100

Surveillance low risk RPLND high risk

50 50

10 11

22.5 33

55.5

Routine RPLND

Total RPLND

53

BEP, RPLND, retroperitoneal lymph node dissection. The outcome of treating 100 patients in terms of relapse and chemotherapy or surgery usage associated with different current treatment policies. The following assumptions are made: (a) a 30% overall risk of relapse in the surveillance group with 20% low risk patients and 40% for high risk (assumed 50% in each group); (b) 12% of pstage A and 34% pstage B patients will relapse after RPLND; (c) 33% of patients will require RPLND after chemotherapy; (d) patients relapsing from surveillance will receive three cycles of BEP; (e) treatment of postchemotherapy relapses is not included (assumed same in all groups).

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R.A. Huddart / Clinical Oncology 22 (2010) 1–5

Table 4 Outcome of treatment using one cycle of adjuvant BEP chemotherapy Reference

Eligibility

n

No. relapses

Relapse TD

Relapse non-TD

Predicted relapse rate

Tandstad et al. [29]

VIþ VI One or two MRC risk factors VIþ EC Any

157 155 22

5 (3.2%) 2 (1.3%) 1

1

6

1

1

41.7* 13.5 20y

66 21 4

17 23 174

1z

0

1

12

2

0

2

41y 20y 27x

548

11 (2.0%)

9 (1.6%){

Gilbert et al. [30] Westermann et al. [31] Albers et al. [26] Totals

Predicted no. relapses

47 150{

VIþ, vascular invasion present; VI, vascular invasion absent; MRC, Medical Research Council; EC, embryonal carcinoma present; TD, teratoma differentiated. * Calculated from relapse rate in patients treated by surveillance in study. y VIþ estimate based on data in [29], VI estimate based on surveillance literature. z Plus two contralateral primaries. x Calculated from patients pNþ plus relapses in pN0 patients. { 9/150 or 6% of predicted relapses.

of non-compliance is real and needs to be managed. Unfortunately, it is very difficult to indentify non-compliers at the outset. In a recent Royal Marsden Hospital study, the only factor predicting for compliance was the quality of the doctor–patient relationship, which is difficult to use when setting out management policy [24]. For higher risk patients with vascular invasion, the appropriate treatment policy is perhaps more debateable. The approach with the lowest use of chemotherapy might be to undertake a RPLND and follow on with surveillance. There is good evidence that a proportion of patients with positive retroperitoneal lymph nodes can be cured by this approach [21,25], but there remains a significant risk of subsequent relapse, both in those who are pNþ (relapse risk w 30%) and pN0 (relapse risk w 10%). The cost of this would be that all patients undergo a major surgical procedure with defined toxicity. A recent randomised trial has also shown that even when combined with adjuvant chemotherapy this approach has inferior results to using adjuvant chemotherapy alone [26]. For these reasons the use of RPLND has never been favoured in the UK and is losing popularity elsewhere. The most frequently used adjuvant treatment use in the UK is adjuvant BEP chemotherapy. Two cycles of treatment, as shown in the meta-analysis, results in recurrence rates under 4% and probably under 1–2% [22,26]. It is thus an effective strategy in reducing the risk of recurrence, and is an attractive option to many patients. It does, however, on a population basis, utilise more cycles of chemotherapy per 100 patients than a strategy of surveillance, exposes all patients to this intensive chemotherapy schedule and uses two-thirds of the chemotherapy a patient would currently receive for good prognosis metastatic relapse. There is no doubt that some toxicities (although not all, e.g. risk of neutropenic sepsis) are dose-dependent. The question is whether it is worth trying to avoid chemotherapy altogether against the risk of needing an extra cycle of BEP? Surveillance in this highest risk group might still be a preferred option.

Management could be improved if we could better identify those at highest risk. Functional imaging (18FDG positron emission tomography) has been used to try to identify patients with subclinical disease. Although it could identify some patients with disease, the risk of relapse for those with a negative scan remained high (w35%) [27]. Biological prognostic factors, such as Ki67/MiB-1, have not added significantly to management [23], although a new marker, CXCR4, has recently been reported to be able to stratify high-risk patients into a group with a 70% risk of relapse and a group with 30% risk [28]. This is promising, but awaits further evaluation. Management might also be affected if one cycle of BEP could be used. Modelling (Table 3) would suggest that this would use fewer overall courses of chemotherapy and using one-third of the dose for metastatic disease might be a real saving. A few studies have reported reasonable results with this approach, but the recurrence rate will probably be a little higher than after two cycles of BEP (Table 4). This approach is to be studied in the UK 111 trial, which is due to start in 2009. Summary The prognosis of stage I germ cell tumour remains excellent and cancer cure end points are indistinguishable between the major strategies to manage the disease. The meta-analyses presented here provide a comprehensive summary of the available data and a base from which to decide the options for the management of our patients. The guidance from this document, for both seminoma and nonseminoma, is that a choice needs to be made between an initial surveillance strategy and the use of adjuvant treatment, usually chemotherapy. Patients should be carefully counselled regarding these choices and an individual decision made on consideration of prognostic factors, treatment burden, immediate and late treatment effects and the patients’ wishes and personal preference.

R.A. Huddart / Clinical Oncology 22 (2010) 1–5

Acknowledgement This work was undertaken at The Royal Marsden NHS Foundation Trust, who received a proportion of its funding from the National Health Service Executive; the views expressed in this publication are those of the author and not necessarily those of the National Health Service Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust and Cancer Research UK Section of Radiotherapy [CUK] grant number C46/A3970. We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre.

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