Management of Stage I Testicular Cancer

Jerusha Padayachee; Roderick Clark; Padraig Warde; Robert J. Hamilton

Disclosures

Curr Opin Urol. 2022;32(1):17-23. 

In This Article

Adjuvant Approaches in Stage I Testis Cancer

The options for treatment post radical orchiectomy in both seminoma and nonseminoma include adjuvant therapy [radiotherapy, chemotherapy and retroperitoneal lymph node dissection (RPLND)], and active surveillance. In both patient groups, there has been an increasing propensity towards employing an approach of active surveillance and this is supported by multiple current guidelines.[6–9]

Seminoma

Active Surveillance. Previous estimates have suggested that irrespective of risk profile, 80–85% of CSI seminoma patients are cured by radical orchiectomy alone.[10] Therefore, it is felt that an active surveillance approach would avoid unnecessary toxicities of adjuvant therapy in a large proportion of patients. In one of the most comprehensive population-based studies to date, Milano et al.[11] recently reported on a US population-based study of 24 900 testicular cancer survivors. They reported a statistically significant excess of solid-second malignant neoplasms affecting one in six testicular cancer patients treated with radiotherapy, and one in 10 in patients receiving chemotherapy, 30 years after treatment. In addition, they found a 2.7-fold increased risk of leukaemia after chemotherapy. The safety of active surveillance is supported by a meta-analysis by Petrelli et al.,[12] which showed no difference in overall survival between adjuvant treatment and active surveillance. Similarly, in a more recent systematic review by Pierorazio et al.[13] median cancer-specific survival in early stage seminoma patients was 99.7, 99.5 and 100% for active surveillance, radiotherapy and chemotherapy, respectively; with less toxicities with an active surveillance approach.

Active Surveillance Protocol.Table 1 presents the active surveillance protocol at Princess Margaret Cancer Centre. A computed tomography (CT) abdomen and pelvis is undertaken every 6 months for 3 years after diagnosis and less frequently thereafter; recognizing that the median time to relapse is 14 months.[14] Our approach is to continue surveillance for 9 years, as local data have shown that 8% of relapsed cases occurred beyond 5 years.[15] We do not routinely do chest radiographs (or CT Thorax) or measure serum tumour markers as we have not found these to be helpful in the early detection of relapse.[14,16]

Concerns have been raised on the frequency of CT-imaging while on the surveillance program, given the potential risks associated with radiation exposure. We currently use low-dose CT scans, which entail 50% of the radiation dose of a typical CT. With this approach, the overall radiation exposure during active surveillance is substantially reduced, without compromise to the detection of relapses.[17] An additional strategy being considered is the use of MRI imaging for surveillance. The TRISST trial was recently presented at GU ASCO 2021.[18] This randomized phase III trial compared the use of CT and MRI in active surveillance of CSI seminoma patients, as well as evaluated the surveillance schedule. Presented in abstract form, the data suggest noninferiority of MRI-imaging in this setting, although further study is necessary before this approach can be recommended.

Relapsed Stage I Seminoma. Seminomas, unlike NSGCTs, present with a very predictable pattern of relapse. Virtually all patients present with retroperitoneal lymphadenopathy as the first site of relapse, with previous reports showing this to be as high as 98%.[10] Options of treatment in this setting include salvage radiotherapy and salvage chemotherapy, and the selection of treatment is determined by the risk of second relapse and the need to minimize treatment-related toxicity.

Chemotherapy is standard approach for patients presenting with large volume (≥5 cm lymph node metastases), due to the risk of occult wide-spread disease. In patients presenting with smaller volume disease, both chemotherapy and radiotherapy are appropriate management options. At Princess Margaret Cancer Centre, radiotherapy is generally favoured in this setting, while taking into account patient's age, comorbid conditions (e.g. inflammatory bowel disease), location of disease (central vs adjacent to kidney parenchyma), and patient preference. Historically, an argument for the use of chemotherapy in this setting was to avoid the risk of secondary malignancy associated with irradiation. Recent data, though, has shown that cisplatin-based chemotherapy carry similar risks of secondary malignancy, as highlighted by Dutch and Norway population-based studies (2.5 and 2.0–3.7-fold increased risk observed, respectively).[19,20] In addition, late chemotherapy-related toxicities must also be taken into account; including peripheral neuropathy, hearing loss, tinnitus, renal disease, and metabolic syndrome. It is also necessary to consider the acute toxicity of chemotherapy including the risk of treatment-related mortality – previously reported as ~3%,[21] and likely related to the fact that more than 25% of patients were over 40 years of age.

In an effort to reduce toxicities of irradiation, there has been increased interest in the use of proton therapy, with recent reports showing gains in dose sparing to organs at risk (kidney, liver, stomach, bowel, bladder), without compromising dose to the target volume.[22,23] As proton therapy becomes more established, it would certainly be worth studying prospectively its application in seminoma patients.

In our experience, with a policy of radiotherapy wherever possible (taking into consideration the aforementioned factors and where nodal volume is <5 cm), we have a 10% risk of second relapse in this setting,[24] and all patients have been salvaged with systemic treatment. However, this approach does mean that some patients have a more prolonged treatment course, and the use of both radiotherapy and chemotherapy does significantly increase the risk of second malignancies.[25] The pros and cons of both strategies need to need discussed with patients.

There are ongoing studies investigating alternative treatment approaches to minimize treatment-related toxicities including de-escalating chemotherapy following an interim PET-CT,[26] single-dose carboplatin with involved node radiotherapy,[27] RPLND,[28,29] and minimally invasive RPLND with single-dose carboplatin.[30] In particular, RPLND presents an attractive alternative, eliminating the risk of second malignancies in this young population; however, robust data are awaited, and in our view should be confined to study protocols and only performed in tertiary centres.

Risk-adapted Approach. The Spanish Germ Cell Cancer Group previously proposed a risk adapted approach for patients with CSI seminoma, using parameters of rete testis invasion and tumour size greater than 4 cm, which was based on a single multiinstitutional study.[31] However, in a recent analysis, Chung et al.[32] failed to validate this prognostic model. With a risk-adapted approach, a significant proportion of patients are unnecessarily treated and we feel there is no role currently for a risk-adapted approach except on clinical trial. This standpoint is supported by a recent systematic review by the European Testicular Cancer Guidelines Panel.[33]

There is increasing interest in the use of biomarkers to better risk stratify patients, particularly in the setting of CSI disease when considering active surveillance. In particular, circulating microRNA testing appears promising. Prospective studies in this area are ongoing and will be discussed separately in this publication.

Adjuvant Radiotherapy. Historically, adjuvant radiotherapy to the para-aortic and pelvic nodal regions was offered following radical orchiectomy in CSI seminoma patients. However, the general trend over time has become to avoid adjuvant radiotherapy. The predominant concern with irradiation is the risk of second malignancy, more so, in a clinical scenario where 85% of patients would be unnecessarily treated. Updated data from Milano et al.[11] reported lower incidences of late second malignancies compared with the historical Travis et al. data;[34] however, the increased risk of second malignancies remains a concern in this young group of patients.

Adjuvant treatment may be indicated when compliance with an active surveillance protocol is a major concern, and radiotherapy is preferred in this scenario.[35] We do not recommend para-aortic nodal irradiation alone as this is associated with a small but definite risk of pelvic nodal failure.[36] We have never seen relapses within the retroperitoneum following adjuvant radiotherapy and therefore follow-up imaging is confined to chest radiographs only.

Adjuvant Chemotherapy. Use of adjuvant chemotherapy for CSI seminoma became more widely adopted following publication of the MRC TE19 trial in 2005 comparing adjuvant radiotherapy with single-dose carboplatin (AUC7).[37] There has been a perception of minimal toxicities with the use of carboplatin, and chemotherapy continues to be widely utilized in the adjuvant setting in some jurisdictions.

To note, though, more contemporary data from SWENOTECA suggests that single-dose carboplatin, only reduces the risk of relapse to 9.3%,[38] and many centres now utilize two cycles of adjuvant carboplatin. Data on the late toxicities of carboplatin have been limited. Recent reports have raised concerns of rates of secondary malignancy, as well as carboplatin-induced cisplatin resistance.[39,40] It is important to note, though, that event rates and follow-up time in these studies were limited, and therefore results are more speculative. Given our increasing understanding of the risk of second malignancy with cisplatin, it is justifiable to raise such concerns with the use of adjuvant carboplatin; however, longer follow-up studies are required to fully determine this.

As an additional note, in both the MRC TE19 and SWENOTECA clinical trials, the retroperitoneum was the predominant site of relapse following use of adjuvant chemotherapy. Therefore, patients receiving adjuvant carboplatin require an active surveillance strategy following treatment with regular abdominal imaging. This is obviated with radiotherapy, making it a more appealing approach where adjuvant treatment is indicated.

Nonseminomatous Germ Cell Tumours

Adjuvant Chemotherapy. The role of active surveillance in stage I NSGCT is more debated. Approximately 20–30% of patients presenting with CSI disease relapse,[41] and this increases to 50% in those deemed high-risk with features of lymphovascular invasion and/or pure embryonal carcinoma.[42–44] Guidelines suggest that a risk-adapted approach be considered in discussion with the patient,[6–9] and many institutions offer two cycles bleomycin, etoposide, cisplatin (BEP) chemotherapy for high-risk patients. The recently published '1 : 1 : 1' study explored de-escalation of therapy in this patient group, utilizing single cycle BEP chemotherapy in the adjuvant setting.[45] In this single-arm study, the reported recurrence rates were 2.6% at 2 years and 3.1% at 4 years which were comparable with historical reports on the use of two cycles BEP; suggesting that equal efficacy could be gained with less toxicity.

Active Surveillance. Proponents for active surveillance in high-risk CSI NSGCT highlight key points to support this approach. The main rationale being that half of patients avoid further treatment after orchiectomy alone when employing a nonrisk adapted approach with 5-year survival estimates at 99%, as previously demonstrated in a Princess Margaret series.[46] It has also been suggested that relapses after adjuvant BEP may have worse biological disease.[47] To highlight this, in a recent report by Fischer et al.,[48] of the 51 patients assessed who relapsed following adjuvant BEP, almost 30% experienced a subsequent relapse and half of these patients died as a result of disease progression. In contrast, more favourable results were found in a much larger cohort of 580 patients treated for relapse following active surveillance, as recently reported by Hamilton et al..[49] Here, second relapses were seen in only 5% of the entire cohort, with 0.7% of patients dying due to progressive disease. An argument against an active surveillance approach, is that the total chemotherapy burden may greater when used in the salvage setting. However, with the selective use of RPLND monotherapy in the relapse setting, the overall chemotherapy burden in the entire population would be comparable with one cycle adjuvant BEP, as was previously modelled by Hamilton et al..[49] At Princess Margaret Hospital a nonrisk adapted approach is generally applied, taking into consideration patient preference.

Active Surveillance Protocol. Table 2 presents the active surveillance protocol at Princess Margaret Hospital. In CSI NSGCT, given the higher recurrence rates and earlier recurrences, the recommendations are for more frequent clinical assessments and tumour markers in years 1–2. Five low-dose CTs are undertaken during the 5-year surveillance program, avoiding radiation exposure.

Relapsed Stage I Nonseminomatous Germ Cell Tumours. The majority of NSGCT patients who relapse on active surveillance are treated with salvage chemotherapy. Notably, though, many of these patients have disease confined to the retroperitoneum; and therefore, RPLND presents as an alternative to chemotherapy. While recognizing potential toxicities of this approach, including antegrade ejaculation, postoperative ileus, ventral hernia; the overall toxicity burden compared with chemotherapy is much less. This is particularly so, when acknowledging chemotherapy toxicities such as bleomycin-related pneumonitis, secondary malignancy, metabolic syndrome, neurotoxicity, amongst others. Hamilton et al.[49] recently presented the local experience at Princess Margaret Cancer Centre. To note, 157 patients who relapsed on active surveillance were treated with either chemotherapy (95) or RPLND (62), and of these, 65.6% underwent single modality treatment. In those who were treated with RPLND, 45/62 (73%) did not require further treatment. Most patients treated with RPLND had N1 disease, with a lesser proportion with N2 disease. In addition, all RPLND patients were deemed good risk by IGCCCG classification. Elevated tumour markers at relapse was the only factor found to be associated with requirement for further treatment post RPLND. Therefore, with appropriate patient selection, RPLND presents as an alternative treatment option in relapsed stage IIA/B NSGCT, thereby avoiding potentially significant toxicities of chemotherapy.

Regionalization of Care. Given the rarity of testicular cancer, there has been growing interest in regionalization of care, to optimize management. This has been introduced at the National Health Service in the United Kingdom and recognized in Germany.[50] The Kaiser Permanente Northern California group initiated this approach in 2016. In a recent review of their undertaking, it was found to be well received by physicians, and more so, there were notable clinical benefits.[51] In particular, the rates of active surveillance in CSI seminoma patients increased from 48 to 87%, in accordance with recommendations. In addition, pathology and radiology review altered treatment decisions in 14.5% of cases. Similar findings were reported at Princess Margaret Cancer Centre.[52]

At Princess Margaret Cancer Centre, we acknowledge that this approach would allow for better adherence to guidelines and potentially improved patient outcomes, and measures are being undertaken to move towards this model of care provision in testicular cancer patients.

processing....