Guidelines

Testicular Cancer

7. DISEASE MANAGEMENT

The availability of cis-platin based chemotherapy to which TC is exquisitely sensitive, in combination with surgery and in highly selected cases, radiotherapy, has resulted in the high cure rates seen with this disease [126]. Careful staging at diagnosis, adequate early treatment based on a multidisciplinary approach, rigorous follow-up and adequate initiation of salvage therapies are critical to successful outcomes.

Whilst early stages can be successfully treated in a non-specialist centre, relapse rates are higher than in specialist centres [127,128]. In clinical trials on poor-prognosis patients, OS relates to the number of patients treated at the participating centre (worse if < 5 patients enrolled) [129]. Treatment at high-volume specialist centres is thus strongly encouraged. Establishment of second-opinion clinics for TC patients as well as collaboratively working with specialist centres may also help prevent over- and under-treatment [130]. This will ensure that patients are neither subjected to unnecessary or inappropriate treatment and associated toxicities or denied early management options which may subsequently compromise their long-term quality of life or survival.

Initiation of treatment before histopathological confirmation:

In cases of life-threatening disseminated disease, chemotherapy should commence immediately, particularly when the clinical picture strongly supports TC, and/or tumour markers are increased. Orchidectomy in these circumstances can be delayed until clinical stabilisation occurs or subsequently be performed in combination with resection of residual lesions.

7.1. Stage I germ cell tumours

7.1.1. Germ cell neoplasia “in situ” (GCNIS)

If GCNIS is diagnosed in a patient with a solitary testis, local radiotherapy (18-20 Gy in fractions of 2 Gy) should be considered [107,131-133]. Chemotherapy is significantly less effective, and the cure rates are dose-dependent [131]. Radiotherapy to a solitary testis will result in infertility and increased long-term risk of Leydig cell insufficiency [107]. Fertile patients who wish to father children may delay radiation therapy and be monitored with regular testicular US [76].

If GCNIS is diagnosed and the contralateral testis is normal, management options include orchidectomy or close observation, as the five-year risk of developing TC is 50% [134].

7.1.2. Seminoma germ cell tumour clinical stage I (SGCT CS I)

Approximately 15% of clinical stage I SGCT patients have subclinical metastatic disease, usually in the retroperitoneum, and will relapse after orchidectomy alone [117,120,135,136]. Adjuvant treatment decisions should be based on thorough discussions with the patient, incorporating potential advantages and disadvantages, as well as individual patient circumstances.

7.1.2.1. Surveillance

Several prospective non-randomised surveillance studies have been conducted over the past decade. These have shown an overall risk of relapse in unselected CS I patients of 12-20% at five years with 17% in the largest series of over 1,500 patients [137]. Most occur in the retroperitoneal lymph nodes during the first two years [138-140].

Risk of relapse is 12% with small size (tumours < 3 cm) as a single parameter [119,139]. With both small tumour size (< 4 cm) and absence of stromal rete testis invasion even lower recurrence rates of 6% have been described.

The cancer-specific survival (CSS) rate reported with surveillance for CS I seminoma performed by specialist centres is over 99% [137,138,140,141]. Whilst cost effective compared to other management strategies [142], surveillance can represent a burden to the patient due to the need for repeated imaging of the retroperitoneum and clinic visits. These may impact patient compliance which is crucial to an active surveillance strategy.

7.1.2.2. Adjuvant chemotherapy

A trial compared one cycle of carboplatin reaching area under curve of 7 mg/mL/min (AUC 7) with adjuvant RT. This showed no difference in relapse free rates (95% and 96%), time to recurrence and survival after a median follow-up of four years [143-145]. Non-randomised risk-adapted population-based studies using one cycle of carboplatin reported a lower five-year relapse rate of 3%-4% compared to 14-16% with active surveillance 
[138,140]. Adjuvant carboplatin (AUC 7) is therefore an alternative to RT or surveillance in CS I seminoma 
[138,143,144]. Retrospective data shows a median time to relapse after Carboplatin of nineteen months , with 15% of relapses occurring beyond three years. Time to relapse after after Carboplatin is longer than with active surveillance. Most patients relapsing after adjuvant carboplatin can be successfully treated with a standard cisplatin-based chemotherapy regimen appropriate to their disease stage [146].

7.1.2.3. Adjuvant radiotherapy

Seminomas are extremely radiosensitive tumours. Adjuvant RT to a para-aortic (PA) field or a PA and ipsilateral field (PA and ipsilateral iliac nodes), with a total dose of 20-24 Gy, reduces the relapse rate between 1-3% 
[147-149]. A large MRC RCT of 20 Gy vs. 30 Gy PA radiation in CS I seminoma showed non-inferiority in terms of recurrence rates [148]. A scrotal shield should be considered during adjuvant RT in order to prevent scattered radiation toxicity in the contralateral testis [150]. Adjuvant irradiation of supra-diaphragmatic lymph nodes is not indicated.

Whilst moderate acute gastrointestinal side effects occur in up to 60% of patients, moderate chronic gastrointestinal side-effects are present in about 5% of patients. Severe radiation induced long-term toxicity is seen in less than 2% of patients.

The main concern with adjuvant RT is the long-term risk of radiation-induced non-germ cell malignancies 
[150-153]. This has limited its role in CS I seminoma to elderly patients and those unfit for chemotherapy.

7.1.2.4. Risk-adapted treatment

Tumour size > 4 cm and stromal rete testis invasion may stratify patients into low- and high-risk groups. These risk factors were introduced based on an analysis of retrospective trials [102], and then confirmed in subsequent prospective studies [119,120]. Patients with both risk factors have a 32% of relapse compared to 6% with neither. Prospective trials based on these risk factors have demonstrated the feasibility of a risk-adapted approach to CS I seminoma.

A large study in 744 patients with CS I seminoma managed with a risk-adapted policy (low risk [0-1 factors] receiving active surveillance and high risk [1-2 factors] treated with two adjuvant courses of carboplatin,
AUC 7) with a median follow-up of 67 months showed 12% of low-risk cases relapsed on active surveillance whilst 3% of those with one or both risk factors relapsed with adjuvant chemotherapy. The patterns and outcome of relapse was similar in the two groups [119,154].

A trial of 897 patients offered surveillance to patients with no or one risk factor whilst patients with both risk factors were offered one dose of carboplatin, AUC 7 [120]. The decision regarding adjuvant treatment was made by the individual patient. At a median follow-up of 5.6 years, patients without risk factors had a relapse rate of 4% with surveillance compared to 2% with adjuvant carboplatin. When one or both risk factors were present, 15.5% of surveillance patients relapsed whereas 9% receiving adjuvant carboplatin relapsed. Thirty-three per cent of relapses who received adjuvant carboplatin occurred more than three years after orchidectomy with 3% occurring after five years [120].

7.1.2.5. Guidelines for the treatment of clinical stage I seminoma testis tumours

Summary of evidence

LE

Primary testicular tumour size and stromal rete testis invasion correlate with the risk of relapse. The evidence to guide adjuvant treatment decisions is, however, too limited to justify its routine use in clinical practice.

2a

Active surveillance is a feasible approach with conditional relapse risk in unselected series of between 12% and 20%.

2a

In patients without risk factors the five-year relapse rate under surveillance is 4-6%, whereas in the presence of one or two risk factors, five-year relapse rate in contemporary surveillance series is
15-20%.

2b

In non-randomised prospective series five-year relapse rates with adjuvant carboplatin are 2% in patients without risk factors and 9% in patients with one or both risk factors.

2b

Adjuvant chemotherapy with one course carboplatin AUC 7 is not inferior to adjuvant radiotherapy when pathological risk factors are considered. Relapse rates with both adjuvant treatments are around 5%.

1b

Adjuvant radiotherapy is associated with an increased risk of developing secondary non-germ cell malignancies.

2b

Recommendations

Strength rating

Fully inform the patient about all available management options, including surveillance or adjuvant therapy after orchidectomy, as well as treatment-specific recurrence rates and acute and long-term side effects.

Strong

Offer surveillance as the preferred management option if resources are available and the patient is compliant.

Strong

Offer one dose of carboplatin at area under curve (AUC) 7 if adjuvant chemotherapy is considered.

Strong

Do not perform adjuvant treatment in patients at very low-risk of recurrence (no risk factors).

Strong

Do not routinely perform adjuvant radiotherapy.

Strong

Adjuvant radiotherapy should be reserved only for highly selected patients not suitable for surveillance and with contraindication for chemotherapy.

Strong

7.1.3. Non-seminomatous germ cell tumours clinical stage I (CS I-NSGCT)

Management options for CS I-NSGCTs comprise surveillance, adjuvant chemotherapy or retroperitoneal lymph node dissection. Overall, approximately 70% of CS I-NSGCTs are cured with orchiectomy alone. In those with the high-risk feature of LVI, relapse occurs in 50% compared to 15% in those without LVI. A thorough discussion should be undertaken with the patient outlining the potential advantages and disadvantages of treatment options, as well as individual co-morbidities, disease features, risk factors, specific circumstances, and personal preferences, to guide their treatment decision.

7.1.3.1. Surveillance

Surveillance for CS I-NSGCT entails a strict protocol of repeated cross-sectional imaging, monitoring of serum tumour markers and clinical assessment for the early identification of the subset of patients experiencing relapse who must receive salvage treatment.

The largest reports of surveillance indicate a cumulative relapse risk in about 30% of CS I-NSGCT (five-year conditional risk of relapse 42% and 17% for high- and low-risk CS I-NSGCT, respectively) [136,137]. Of these, 92% present within the first two years [136,137].

Serum tumour markers alone are an unreliable indicator of relapse. In a systematic review of CS I-NSGCT patients undergoing surveillance, the rate of marker elevation at time of relapse varied between 28 and 75% [155]. Approximately 60% of relapses occur in the retroperitoneum and 11% have large volume metastatic recurrent disease reinforcing the need for cross-sectional imaging [136,156].

Surveillance studies have reported lower relapse rates compared to some series of patients undergoing primary Retroperitoneal lymph node dissection (RPLND) [157]. This is likely related to both selection bias with both exclusion of high-risk cases and very early marker relapse precipitating treatment prior to surveillance re-imaging. Based on the overall CSS data, surveillance within a rigorous protocol can safely be offered to patients with non-risk stratified CS I-NSGCT who are compliant and informed about the expected recurrence rate and need for salvage treatment [156,158,159].

7.1.3.2. Retroperitoneal lymph node dissection (RPLND)

Prior to the availability of effective systemic therapy for relapsed disease primary RPLND for CS I-NSGCT evolved as a strategy which improved survival following orchidectomy [160]. A large series of 464 unselected cases of CS I-NSGCT commencing within this era reported an overall relapse rate of 14%. Of PS (pathological stage) II cases 36% relapsed. With PS I cases 11% relapsed – which is consistent with more contemporary series reporting approximately 10% of patients with no evidence of nodal involvement at RPLND (i.e., PS I) relapsing at distant sites [123,160,161]. More recent series report lower relapse rates possibly reflecting case selection [162].

Since the introduction of platin based chemotherapy the role of adjuvant primary RPLND in men with stage I GCT has decreased. The few indications in stage I disease include men with Teratoma with somatic malignant transformation, interstitial cell tumours with an increased risk of metastases or patients who are not willing or suitable to undergo chemotherapy in case of a later recurrence.

With RPLND 18-30% of patients have active nodal malignancy (i.e., PS II), [161,163]. Without further treatment approximately 30% of these will recur [161]. The presence of LVI, predominant embryonal carcinoma and pT stage of the primary as well as histologically extranodal tumour extension all appear associated with an increased risk of recurrence. The use of these further parameters has yet to be clearly defined in clinical practice [161,164]. However, following RPLND, presence and extent of lymph-node involvement (specifically lymph-node ratio), may represent stronger predictive factors of recurrence and could be adopted for subsequent decision making [161,162].

Strategies to reduce the morbidity of primary RPLND include nerve-sparing and minimally invasive approaches. In a multicentre setting, higher rates of in-field recurrences and complications have been reported with nerve-sparing RPLND [163,165]. This suggests that primary RPLND, when indicated or chosen, should be performed by an experienced surgeon in a specialist centre. Minimally invasive (laparoscopic or robot-assisted) primary RPLND, appears feasible and safe (e.g., low-complication rate) in experienced hands. However, most of the series have only a short follow-up precluding definitive conclusions regarding oncological outcomes when compared to open primary RPLND. At present, it cannot be recommended outside of a high-volume RPLND centres with appropriate minimally-invasive expertise [166-173].

Follow-up after RPLND is less demanding and costly than other options due to the reduced need for cross-sectional imaging [174]. Nevertheless, in view of the high CSS rates of surveillance with salvage treatment in cases of relapse, the low relapse rates with adjuvant chemotherapy, and the lower reproducibility of primary RPLND on a large scale, its role for CS I-NSGCT has diminished.

7.1.3.3. Adjuvant chemotherapy

Adjuvant chemotherapy has been evaluated with both one and two cycles of BEP in CS I-NSGCT. A prospective trial from 1996, as well as subsequent studies, used two cycles of BEP in high-risk patients (LVI present) [175-177]. In these series, including 200 patients, some with a median follow-up of nearly
7.9 years [175], a relapse rate of only 2.7% was reported, with minimal long-term toxicity. Two cycles of cisplatin-based adjuvant chemotherapy also do not seem to adversely affect fertility or sexual activity [178].

More studies have shown one cycle of adjuvant BEP results in similar very low recurrence rates (2-3%)
[179,180]. Reduction from two to one cycle of BEP improves the risk-benefit ratio of adjuvant chemotherapy considerably. A randomised phase III trial has also compared two-year recurrence free survival with adjuvant BEP x 1 to RPLND. Results favoured chemotherapy with recurrence free survival of 99.5% vs. 91% [165]. The hazard ratio to experience a tumour recurrence with surgery compared to BEP x 1 was 8 [165]. No clinically relevant differences in quality of life (QoL) were detected [181].

A community based prospective study of 490 unselected patients with CS I-NSGCT that received adjuvant single cycle BEP had five-year relapse rates of 3% and 2% for LVI+ and LV- patients, respectively. After a median follow-up of eight years these rates were sustained, no relapses were observed beyond 3.3 years [179,180]. These numbers imply that > 90% of relapses are prevented by single cycle BEP which is now the recommended strategy if adjuvant chemotherapy is considered [179,180]. The very-long term (> 20 years) side effects of adjuvant chemotherapy, particularly cardiovascular, are yet to be fully defined which should be considered with decision-making [182,183].

Limited data are available on outcomes with relapse after adjuvant BEP. A retrospective analysis indicated that about one third of these relapses were late and that the outcome may be slightly worse compared to those presenting with de novo metastatic disease [184].

7.1.3.4. Risk-adapted treatment

A risk-adapted strategy is an alternative to any single approach for patients with CS I-NSGCT. The advantages and disadvantages of treatment options must be discussed with patients in the context of their specific circumstances including disease risk factors, co-morbidities, and personal preference, as well as clinician recommendation in reaching a treatment decision. Lymphovascular invasion appears as the strongest predictive risk factor for relapse and should be carefully outlined to the patient in order to assist in their decision-making.

Patients without LVI should be guided to consider surveillance, although some patients with significant

co-morbidities or concerns regarding salvage chemotherapy with multicycle cisplatin-based chemotherapy may opt for adjuvant therapy. Those with LVI should have their high risk of relapse (up to 50%) highlighted and be guided to consider adjuvant management, and chemotherapy with BEP X 1 as the “preferred” option.

Some patients may wish to consider primary RPLND although they need to be aware of the potential additional requirement of adjuvant chemotherapy if nodes contain active disease (pN1), as well as the 10% risk of systemic relapse, even if pN0, requiring subsequent chemotherapy treatment (BEP X 3).

7.1.3.5. Post Pubertal Teratoma with somatic malignant component

According to a multi-institutional study analysing retrospective datasets of CS I patients with post-pubertal teratoma with somatic malignant component (TSMC), these patients had inferior five-year OS of approximately 10% compared to other CS I-GCT patients. Furthermore, CS I TSMC cases undergoing primary RPPLND had a much higher proportion of nodal metastases (PS II) than expected (37.5%). Despite its limitations this study provides the strongest evidence on this issue and supports primary RPLND in CS I-NSGCT with TSMC [185].

For patients presenting with CS I pure post-pubertal teratoma without a somatic malignant component, surveillance provides comparable survival outcomes to primary RPLND [186]. However, subtype discrepancies in primary diagnostic of post-pubertal teratoma are not infrequent. When present they consist in addition of subtype and involve secondary somatic type of malignancy in 83% of cases. As such, central review by expert genitourinary pathologist is recommended when teratoma is diagnosed in the orchidectomy specimen [187].

7.1.3.6. Guidelines for the treatment of clinical stage I non-seminoma testis

Summary of evidence

LE

Lymphovascular invasion increases the risk of relapse.

2a

The relapse rate with active surveillance is up to 50%, depending on LVI status.

2a

The relapse rate in patients who receive adjuvant chemotherapy with BEP (x 1 cycle) is up to 3%.

2a

Adjuvant chemotherapy with BEP is superior to adjuvant RPLND in terms of the risk of relapse.

1b

A risk-adapted approach, based on lymphovascular invasion is feasible.

2b

The acute toxicity of one cycle adjuvant BEP is low.

1b

Recommendations

Strength rating

Inform patients about all management options after orchidectomy: surveillance, adjuvant chemotherapy, and retroperitoneal lymph node dissection, including treatment-specific recurrence rates as well as acute and long-term side effects.

Strong

Offer surveillance or risk-adapted treatment based on lymphovascular invasion (see below).

Strong

Discuss one course of cisplatin, etoposide, bleomycin as an adjuvant treatment alternative in patients with stage I non-seminomatous germ cell tumour if patients are not willing to undergo or comply with surveillance.

Strong

7.1.3.7. Risk-adapted treatment for clinical stage I non-seminomatous germ cell tumour based on vascular invasion

Recommendations

Strength rating

Stage IA (pT1, no vascular invasion): low-risk

Offer surveillance if the patient is willing and able to comply.

Strong

Offer adjuvant chemotherapy with one course of cisplatin, etoposide, bleomycin (BEP) in low-risk patients not willing (or unsuitable) to undergo surveillance.

Strong

Stage IB (pT2-pT4): high-risk

Offer adjuvant chemotherapy with one course of BEP, or surveillance and discuss the advantages and disadvantages.

Strong

Offer surveillance to patients not willing to undergo adjuvant chemotherapy.

Strong

Offer nerve-sparing retroperitoneal lymph node dissection to highly selected patients only; those with contraindication to adjuvant chemotherapy and unwilling to accept surveillance.

Strong

Primary retroperitoneal lymph node dissection should be advised in men with post-pubertal teratoma with somatic malignant component.

Weak

Figure 1: Risk-adapted treatment in patients with clinical stage I non-seminoma NSGCT [188]** Discuss all treatment options with individual patients, to allow them to make an informed decision as to their further care.** In case of PS II, the rate of recurrence is higher and chemotherapy can be administered (max. 2 cycles).# Primary retroperitoneal lymph node dissection should be advised in men with post-pubertal teratoma with somatic malignant component.BEP = cisplatin, etoposide, bleomycin; CS = clinical stage; IGCCCG = International Germ Cell CancerCollaborative Group; NS = nerve-sparing; RLNPD = retroperitoneal lymph node dissection; VIP = etoposide,cisplatin, ifosfamide.

7.2. Metastatic germ cell tumours

The first-line treatment of metastatic GCTs depends on:

  • the histology of the primary tumour;
  • prognostic groups as defined by the IGCCCG (Table 4.3) [61];
  • serum tumour marker decline during the first cycle of chemotherapy in poor-prognosis patients.

In relapsed patients, a prognostic score has been developed including response to first-line therapy which can be used to estimate patient outcome following salvage chemotherapy [189].

7.2.1. Clinical stage I with (persistently) elevated serum tumour markers

If AFP or β-hCG increase or fail to normalise following orchidectomy, US examination of the contralateral testicle must be performed. If a contralateral tumour is excluded, repeat staging four weeks after orchidectomy is required [188].

Some patients may have stable but slightly elevated AFP or β-HCG and can be initially monitored. Treatment should be commenced if markers rise or when follow-up imaging demonstrates metastatic disease [188].

The treatment of true CS IS-NSGT should be the same as other good-prognosis metastatic non-seminoma (stage IIA/B). With this, five- and ten-year disease-free survival of 87% and 85%, respectively, have been recently reported [190].

7.2.2. Metastatic disease (stage IIA/B)

7.2.2.1. Stage IIA/B seminoma

Patients with enlarged retroperitoneal lymph nodes < 2 cm and normal markers may be observed for six to eight weeks with repeat-staging imaging as these may be non-metastatic. Treatment should not be initiated unless metastatic disease is unequivocal based on biopsy, increasing nodal size/number, or subsequent marker rise [188,190]. A special case are those patients who can undergo primary RPLND within a trial or institutional study (see below for further details).

Standard historical treatment of stage II A/B seminoma has been radiotherapy, with reported relapse rates of 9-24% [191,192]. Most reports describe large target fields and high doses. Further studies using more limited fields report similar rates of relapse [193]. The radiation dose recommended in stage IIA and IIB is 30 Gy and 36 Gy, respectively, with the standard field encompassing the PA and ipsilateral iliac nodes. With these, five-year relapse-free survival rates in stage IIA and IIB are 92% and 90%, respectively [191,192]. Further dose reduction in stage IIA to 27 Gy is associated with a higher relapse rate of 11% [140,193].

Accumulating data on long-term morbidity, such as an increased risk of cardiovascular events and second malignancies following radiotherapy has raised concerns. One study with a follow-up of nineteen years reported a sevenfold higher all-cause mortality rate than mortality due to seminoma [194].

Currently, chemotherapy is the preferred alternative to radiotherapy for stage II seminoma. This entails three cycles of BEP as a preferred strategy, or four cycles of etoposide and cisplatin (EP) as an alternative in case of contraindications to bleomycin, or for older patients [195]. There are no randomised studies comparing radiotherapy and chemotherapy. A recent meta-analysis of thirteen high-quality studies, comparing efficacy and toxicity of radiotherapy and chemotherapy in stage IIA/IIB patients [196], showed that radiotherapy and chemotherapy appeared to be similarly effective in both stages, with a non-significant trend towards greater efficacy for chemotherapy (HR: 2.17) in stage IIB seminoma [196]. Acute toxicity was almost exclusively reported following chemotherapy, while long-term toxicity was more frequent following radiotherapy, mainly comprising bowel toxicity and secondary cancers, generally in the irradiated field [196]. Radiation therapy may be considered in highly selected patients who are either elderly or have contraindications or difficulties tolerating systemic chemotherapy.

Single agent carboplatin, using three to four cycles at AUC 7 is not an alternative to standard EP or BEP chemotherapy for metastatic disease, due to the risk of failure (19%) or subsequent relapse (13%) at the site of initial nodal disease [197]. The same strategy utilising a higher dose of carboplatin, AUC 10, has also been reported in a trial [198] and a subsequent multi-institutional analysis [199]. The latter study comprised 216 patients and reported three-year PFS of 96.5% and five-year DSS of 98.3% comparable to standard regimens. Myelosuppression was the principal toxicity with 37% and 27% experiencing grade 3 or higher neutropenia and thrombocytopenia, respectively.

Primary RPLND has also been reported for CS II seminoma [200,201]. Data from the National Cancer Data Base identified 155 men who underwent primary RPLND for CS II A/B reporting five-year OS of 92%. Specific trials are addressing the role of primary RPLND compared to standard options.

Figure 2: Treatment options in patients with seminoma clinical stage IIA and B*

*When enlarged retroperitoneal lymph nodes are < 2 cm and with normal markers, treatment should not be initiated unless metastatic disease is unequivocal based on biopsy, increasing nodal size/number, or subsequent marker rise.BEP = cisplatin, etoposide, bleomycin; EP = etoposide, cisplatin.

7.2.2.2. Stage II A/B non-seminoma (NSGCT)

Management of CS II A/B NSGCTs encompasses patients in which retroperitoneal nodal disease is present at diagnosis, or appears with relapse following initial surveillance for stage I disease, or marker negative patients with equivocal radiological findings.

All cases of CS II A/B NSGCT with elevated tumour markers at presentation, as well as those in whom nodal disease evolves with a concomitant increase in the tumour marker AFP or β-hCG, require primary chemotherapy according to the treatment algorithm for patients with metastatic disease and according to IGCCCG risk-group (See section 7.2.3).

In CS IIA NSGCT disease without elevated tumour markers, nerve-sparing RPLND when performed by an experienced surgeon in a specialised centre is the recommended initial treatment [202,203]. Initial surveillance may be considered, in patients with normal markers and lymph nodes < 2 cm of greatest axial diameter, or non-nodular shape with early re-evaluation at six weeks. A shrinking lesion may be observed further. If the lesion progresses further or fails to adequately resolve it should be regarded as CS II and be managed with chemotherapy or primary RPLND based on marker status as outlined in Figure 3.

Patients down-staged to PS I require no further treatment even with LVI in the primary tumour site. With PS II disease RPLND alone may be curative. A recent study from Indiana found that 81% of patients with confirmed PS II disease were cured with RPLND alone without additional adjuvant chemotherapy [204]. A further retrospective report on selected patients with stage II relapse after surveillance for stage I NSGCT confirmed a long-lasting remission in 73% of cases following RPLND alone [156]. Relapse, usually outside the retroperitoneum, occurs in 30% of patients with PS II treated with RPLND alone, requiring systemic treatment according to risk-group.

However, adjuvant chemotherapy to reduce the risk of relapse in PS II may be discussed with the patient. Key issues include the risk of overtreatment in about 70% of cases, the need of adequate follow-up to monitor the usually predictable pattern of relapse with minimal but not absent risk of late relapses, the higher relative risk of more intensive therapy in case of relapse, and the possibility of considering quality of surgery and extent of disease (positive lymph node-ratio) as a predictive factor to orient decision. When the choice is for adjuvant chemotherapy, standard treatment is BEP for a maximum of two cycles, but a recent single-centre study of 150 patients undergoing two cycles EP following RPLND and PS II disease reported excellent outcomes with a ten-year relapse-free survival of 98% [205].

Primary RPLND for CS IIA/B disease with elevated markers is not recommended outside a specific study in a referral centre [202,203].

When a marker negative stage II A/B relapse is diagnosed two or more years after initial diagnosis, a CT- or US-guided biopsy should be advised to confirm the diagnosis of GCT relapse before initiating treatment. A RPLND may be an alternative option and should be performed if biopsy is not feasible or does not provide confirmation of active disease. There is insufficient published data on PET scans in this situation to provide recommendations.

Figure 3: Treatment options in patients with non-seminoma clinical stage IIA* Most of the patients will be good prognostic group (BEP x3 or PE x4).** In case of PS II A/B patient can be followed-up or receive adjuvant chemotherapy (maximum of 2 cycles). BEP = cisplatin, etoposide, bleomycin; NS = nerve-sparing; RPLND = retroperitoneal lymph node dissection; PS = pathological stage; PD = progressive disease; NC = no change.

7.2.3. Metastatic disease (stage II C and III)

7.2.3.1. Primary chemotherapy
7.2.3.1.1. Good-prognosis risk group - seminomatous germ cell tumour

For metastatic seminoma, studies available suggest that a cisplatin-based regimen should be preferred to carboplatin chemotherapy [206].

As data from the GETUG S99 trial indicates that EP x 4 results in cure in almost all cases of good-prognosis SGCTs [207], this regime can also be used; therefore, standard treatment in good-prognosis seminoma should be, BEP x 3 or EP x 4. In the case of contraindications to bleomycin, EP x 4 should be given [208].

Post-chemotherapy masses should be managed as described in Section 7.5.2.

7.2.3.1.2. Intermediate-prognosis risk group - seminomatous germ cell tumour

For patients with intermediate-risk seminoma, BEP x 4 or etoposide, cisplatin, ifosfamide (VIP) when contraindications to bleomycin, are the recommended options, although no RCT has focused specifically on this rare group of patients (see Table 4.3).

7.2.3.1.3. Good-prognosis risk group - non-seminomatous germ cell tumour

For non-seminoma, the primary treatment of choice for metastatic disease in patients with good-prognosis disease, according to the IGCCCG risk classification (Table 4.3.), is BEP x 3 (Table 7.1) [61]. This regimen is superior to cisplatin, vinblastine, and bleomycin (PVB) in patients with advanced disease [208].

The available randomised controlled data support the equivalence of three or four cycles of BEP on a three- or five-day regime for projected two-years PFS. However, the group of patients on the three-days regime experienced increased GI toxicity at three months and increased two-years risk of tinnitus (see section 8.2.6). The difference in toxicity between the three- and five-day regimes reached clinical relevance when BEP x 4 was given [209,210]. Based on these data the BEP x 3 and a five-day regimen is strongly recommended in the good-prognosis risk group.

Table 7.1: Cisplatin, etoposide, bleomycin (BEP) regimen (interval 21 days)

Drug

Dosage

Duration of cycles

Cisplatin

20 mg/m2

Days 1-5*

Etoposide

100 mg/m2

Days 1-5

Bleomycin

30 mg

Days 1, 8, 15

*Plus, hydration.

Patients with a clear contraindication to bleomycin may receive EP x 4 [209]. In all other cases omission of bleomycin is not recommended.

Two RCTs support the superiority of 3 x BEP over other regimes or schedule intensities [195,211]. Additionally, a RCT has suggested that when EP is used the mortality rate is twice that as when BEP is used, although the difference did not reach statistical significance [195]. Furthermore, the incidence of residual active cancer in the post-chemotherapy RPLND group was significantly higher in patients who received EP x 4 compared to
BEP x 3 (32% vs. 8%, p < 0.0.01) [212]. The risk of requiring post-RPLND adjuvant chemotherapy could be higher after EP x 4 which could thereby offset the anticipated advantage of reduced toxicity.

Therapy should be given without reduction of the doses at 21-day intervals. Cytopenias on day fifteen of BEP are common; however, Bleomycin on day fifteen should be given irrespective of neutropenia or thrombocytopenia. Delaying a chemotherapy cycle is justified only in the presence of severe granulocytopenia < 500/mm3 or thrombocytopenia < 50,000/IU. Mild neutropenia without fever alone is not a reason to delay the next cycle. As Granulocyte colony-stimulating factor (GCS-F) lowers the risk of neutropenic sepsis, one may consider up-front administration. Granulocyte colony-stimulating factor must be given if infectious complications have occurred during or after chemotherapy, or when a treatment interval is delayed due to myelotoxicity [213].

7.2.3.1.4. Intermediate-prognosis risk group - non-seminomatous germ cell tumour

With this group the available data support BEP x 4 as standard treatment [214].

7.2.3.1.5. Poor-prognosis risk group - non-seminomatous germ cell tumour

For patients with a poor-prognosis non-seminoma as defined by the IGCCCG, one standard treatment consists of BEP x 4. Four cycles of cisplatin, etoposide and ifosfamide (PEI) has similar efficacy, but is more myelotoxic [215]. Several RCTs have shown no advantage in OS for upfront high-dose chemotherapy (HDCT) in the overall poor-prognosis patient group [216,217].

Patients with a slow tumour marker decline after the first or second cycle represent a prognostically inferior subgroup [217,218]. There are several ways to calculate slow tumour marker decline with an example available at: https://www.gustaveroussy.fr/calculation-tumor/NSGCT.html.

A trial in poor prognosis NSGCT demonstrated that intensifying treatment with dose-dense chemotherapy improves PFS in patients with an early unfavourable tumour marker decline [219]. The trial was not powered to estimate overall survival. Based on the results from this trial, patients with an unfavourable tumour marker decline after BEP x 1 can be switched to a more intensive (dose-dense) chemotherapy regimen [219]. Further prospective trials/registries are planned to validate this approach. Additional patient groups with an unfavourable prognosis on standard treatment are mediastinal primary non-seminoma and patients with brain metastases at initial diagnosis [220,221]. These may also be candidates for upfront intensified treatment, preferably in a prospective study.

As a matched-pair analysis comparing high-dose to conventional treatment resulted in a better survival rate [222], poor-prognosis patients should still be treated in ongoing prospective trials or registries, whenever possible. Patients meeting poor-prognosis criteria should be transferred to a specialist centre, as better outcomes are reported for intermediate and poor-prognosis patients treated within a clinical trial at high-volume centres [129,223]. There are no general recommendations for treatment modifications for patients with poor performance status (Karnofsky < 50%) or extended liver infiltration (> 50%), although two small reports indicate that an initial cycle of dose-reduced therapy may reduce acute mortality without compromising long-term outcome. The number of subsequent cycles of full-dose therapy should, however, not be reduced after an initial low-dose induction cycle [223,224].

Patients with extended pulmonary infiltration are at risk for acute respiratory distress syndrome (ARDS). They should receive only two to three days of EP, followed by standard chemotherapy when the risk of ARDS has passed (typically after ten days). Management of patients with advanced disease in high-volume centres is associated with improved survival and is consequently recommended [225].

Table 7.2: Level of evidence for prognostic group and treatment

Prognostic group IGCCCG

Treatment

LE

Good (SGCT and NSGCT)

BEP x 3 or PE x 4

1b

Intermediate (SGCT and NSGCT)

BEP x 4 or PEI x 4

1b


Poor (NSGCT)

BEP x 4 or PEI x 4 if favorable marker decline

1b

Dose escalation in selected cases with slow marker decline

1b

7.2.3.1.6. Prevention of thromboembolism events during chemotherapy

Thromboembolic events (TEE) occur more frequently in patients with GCT receiving chemotherapy than in young males under chemotherapy for other cancers [226]. In Denmark, comparison of TEE incidence between 5,185 GCT patients and 51,850 men without GCT revealed that GCT patients undergoing BEP chemotherapy had significantly more TEE within the first year: with hazard ratios (HRs) of 6.3, 6.0, and 24.7 for myocardial infarction, cerebrovascular accident, and venous thromboembolism, respectively [227]. Indwelling venous access devices (VADs) have been identified as TEE risk factors [228].

Recent RCTs have assessed the risks and benefits of thromboprophylaxis in ambulatory cancer patients receiving chemotherapy and report a relative risk reduction of 30-60% in venous thromboembolic events (VTE) but a doubling of bleeding risk [229-232]. Based on these results, the most recent ASCO Clinical Practice Guideline Update recommends thromboprophylaxis with apixaban, rivaroxaban, or low molecular weight heparin (LMWH) to cancer patients with a high risk of VTE and low risk of bleeding [233]. Metastatic germ cell tumour (mGCT) patients were under-represented in all trials and; thus, it is not clear whether this recommendation applies to this group although retrospective data suggests a similar efficacy of VTE prophylaxis [234].

Several retrospective cohort studies published mGCT specific VTE and bleeding risks as well as potential VTE risk factors. In the largest multi-centre cohort study, men with mGCT showed a cumulative VTE incidence of 11% and < 1% were fatal [235]. Nearly all VTEs occurred shortly prior to or during the first 90 days of commencing chemotherapy [235]. Bleeding was observed in 0.5% (95% CI: 0.02–1%) of men not on thromboprophylaxis, 2.5% (95% CI: 0.3–8.8%) of men on thromboprophylaxis and 3.6% (95% CI: 1.2–8.3%) of patients fully anticoagulated because of VTE [235]. A cumulative VTE incidence of 5% during or after chemotherapy occurred in men without any risk factors for VTE. This would translate to a number needed to treat of 32-55 depending on the assumed efficacy of thromboprophylaxis [228]. If thromboprophylaxis resulted in a similar VTE risk reduction and bleeding risk increase observed in other cancers [229-232], VTE may decrease by a relative risk of 30-60%. This would translate to an absolute risk reduction from 5-10% to 2-5% with the absolute risk of bleeding increasing from <1% to approximately 2-3% [228].

Critics of thromboprophylaxis in mGCT argue that the interobserver reliability of detecting incidental asymptomatic VTEs on staging scans is poor and some asymptomatic VTEs may only represent artifact. Nevertheless only <1% mGCT have asymptomatic VTEs detected on staging scans [228]. Furthermore, incidental VTEs may not truly be asymptomatic as affected patients may have mild symptoms such as cough and fatigue which may be misinterpreted because of the underlying cancer or its associated treatment.

Advocates of thromboprophylaxis contend that reduction of VTE risk may improve outcomes as VTE can be fatal directly or indirectly in <1% of cases. An immediate initial consequence of VTE is the need for therapeutic anticoagulation which is associated with a higher risk of clinically significant bleeding [228,236] including critical areas particularly intracerebral and complicate post chemotherapy surgery. Venous thromboembolic events may also result in long term complications including post-thrombotic syndromes leading to venous leg ulceration and chronic pain. Similarly, pulmonary embolism can impair right ventricular function and pulmonary arterial pressure that does not resolve in 10-30% of patients, with up to 4% ultimately developing chronic symptomatic pulmonary hypertension [237]. These complications all reduce QoL and increase lifetime healthcare costs.

Based on disease specific VTE risk assessments in numerous retrospective cohort studies and the long life-expectancy of mGCT patients, the European Association of Urology Testis Cancer Guideline panel has discussed a recommendation regarding thromboprophylaxis. All members agreed that men with mGCTs undergoing chemotherapy are at high-risk for VTE and low-risk of bleeding. Although several mGCT specific VTE risk factors have been described in the literature [238] only data from retrospective cohorts is available, VTE outcome definitions are heterogeneous and, in most of the studies, only univariable analyses without external validation were performed. Given the apparent high VTE incidence and only non-validated VTE risk factors, the panel preferences were divided between those panel members that favoured thromboprophylaxis in all men and those panel members that restricted thromboprophylaxis to men with certain risk factors. For the final guideline recommendation, the panel agreed that based on the current literature only a generic statement about the use of thromboprophylaxis should be given until stronger evidence is available. Therefore, RCTs or well conducted prospective cohort studies with an adequate sample size allowing adjusting for potential confounders and numerous risk factors are needed to clarify the indication for thromboprophylaxis.

However, no randomised trials are underway to answer those questions and the only two retrospective studies analysed the risk benefits of thromboprophylaxis reported contradictory results [234,239]. Both studies only had a limited number of men with VTE limiting the ability to account for known confounders which limits the conclusion from both studies.

A generic statement in the TC Guideline should remind clinicians about the high VTE incidence and to prescribe thromboprophylaxis after balancing the risk and benefits. Additionally, the majority of the panel agreed that a central venous-access device should be avoided whenever possible as this represents the only modifiable risk factor which remained significantly associated with VTE in a multivariable risk-prediction model [228].

Thromboprophylaxis includes either LMWH or oral thromboprophylaxis (apixaban 2.5 mg bid or rivaroxaban 10 mg qd) starting before chemotherapy and continued for at least 90 days. Thromboprophylaxis should only be prescribed if no drug interactions or significant risk factors for bleeding are present. Although GCT patients specific risk factors for bleeding are ill-defined the personal experience of panel members and case reports suggest that men with organ infiltration, cerebral metastases and/or significantly elevated β-hCG levels suggestive of choriocarcinoma are at a higher risk of bleeding.

Summary of evidence

LE

Thromboembolic events occur more frequently in male patients with GCTs receiving chemotherapy than in young males under chemotherapy for other cancers.

2b

Retrospective studies have identified multiple risk factors for the development of thromboembolic events including increasing stage, size of retroperitoneal lymph nodes at different cut-offs, Khorana score > 3 and indwelling vascular access device (only modifiable risk factor).

2b

Recommendations

Strength rating

Balance the individual patients’ potential benefits and risks of thromboprophylaxis during first-line chemotherapy in men with metastatic germ cell tumours.

Weak

Avoid use of central venous-access devices during first-line chemotherapy whenever possible.

Weak

7.3. Treatment evaluation and further treatment

7.3.1. Treatment evaluation

Response to treatment should be assessed after the initial induction cycle by repeat imagining and/or re-evaluation of tumour markers. With marker decline and/or radiologically regressing or stable tumour features, the planned chemotherapy, based on prognostic group, should be completed [240,241]. If markers decline, but metastases progress on imaging, induction therapy must be completed followed by early resection [242].

With initial disease progression following induction (primary cisplatin refractory), patients should be switched to experimental drug trials [243]. Slow marker decline with the initial one to two cycles of chemotherapy warrants consideration for dose intensification (see section 7.2.3.1.5).

Following completion of treatment, cases with a low-level β-hCG plateau should be observed to determine whether complete normalisation subsequently occurs. In patients with a low plateau serum AFP level after chemotherapy, removal of residual masses should be undertaken, with subsequent AFP monitoring. Salvage chemotherapy is only indicated for documented marker progression [244,245].

7.3.2. Residual tumour resection

7.3.2.1. Seminoma

A residual mass of seminoma should be monitored with imaging and tumour markers and not primarily resected, irrespective of size [246-249]. Those with AFP elevation should be regarded as mixed GCTs, be managed as NSGCTs and considered for surgical resection. False-positive AFP elevation (e.g., due to liver toxicity after chemotherapy) has to be excluded.

Fluorodeoxyglucose-positron emission tomography has a high NPV in patients with residual masses after treatment of seminoma. False positive results are less frequent when scans are scheduled more than two months after chemotherapy. In patients with residual masses > 3 cm, FDG-PET should be performed in order to provide more information on disease viability. In patients with residual masses < 3 cm, the use of FDG-PET may be useful, but it is optional [55,56].

When a post-chemotherapy mass remains positive at reclassification with FDG-PET with no volume increase, repeat FDG-PET should be performed six weeks later. A recent publication shows a low PPV for vital tumours in residual lesions (generally > 3 cm) after chemotherapy in metastatic seminoma (11% to 38% depending on sub-group). Therefore, caution is recommended with FDG-PET as a single parameter to drive clinical decisions in a persistent mass [57]. In patients with progressive disease on radiological criteria (i.e., a growing mass which enhances with CECT or is FDG-PET avid), salvage therapy is indicated (usually chemotherapy or radiotherapy) [250-252]. Surgery may be an option in patients with a residual nodular mass and contraindications to further chemotherapy or irradiation.

Patients with persistently high and/or progressing β-hCG elevation after first-line chemotherapy should proceed to salvage chemotherapy. Progressing patients without β-hCG progression should undergo histological verification (e.g., by percutaneous or surgical biopsy) before salvage chemotherapy is given. When RPLND is indicated, this should be performed in referral centres, as residual seminoma masses may be extremely difficult to remove due to intense fibrosis [251]. Ejaculation may be preserved in some of these cases [253].

7.3.2.2. Non-seminoma

Following first-line BEP chemotherapy, only 6-10% of residual masses contain active cancer, 50% have post-pubertal teratoma, and 40% comprise of necrotic-fibrotic tissue only [254]. Fluorodeoxyglucose-positron emission tomography is not indicated to re-stage patients following chemotherapy [50,52,53]. With complete radiological remission, RPLND is not indicated [255,256].

Usual timing for restaging is three to four weeks after the beginning of the last cycle. No diagnostic or risk calculator can accurately predict histology of the residual masses. Thus, resection is mandatory in all patients with a residual mass > 1 cm in greatest axial diameter at cross-sectional CECT imaging until novel predictive models are externally validated [257-260]. Surgery when indicated should be performed within six to eight weeks after the last chemotherapy cycle.

There is uncertainty regarding the role of surgery with residual retroperitoneal lesions < 1 cm. It is difficult to distinguish between a true residual node below 10 mm and a complete remission, and many authors consider these situations as equivalent. Residuals containing cancer or teratoma are possible, but the vast majority of patients have fibro-necrotic tissue only [261]. So far, post-chemotherapy RPLND in case of residuals < 10 mm or complete remission is an option [262], but the alternative option is an observation protocol with recurrence risk of 6-9% depending on the follow-up duration [255,256]. In the series with the longest follow-up of 15.5 years, twelve (9%) of 141 patients relapsed despite a complete response following primary treatment [256]. Eight of the twelve relapsing patients were cured with subsequent treatment. These cases should be discussed on individual basis taking into account the orientation and expectations of the patient.

Patients after salvage chemotherapy or HDCT in first or subsequent salvage situations harbour vital tumour at a much higher rate [263]. Surgery is therefore indicated in salvage patients even with residual masses < 1 cm [255,256].

When resection is indicated bilateral nerve-sparing RPLND is the standard option. Ipsilateral template resection avoids contralateral nerve dissection and leads to improved functional results together with favourable clinical results although mapping studies describe the risk of missed contralateral disease [264].

In men with post-chemotherapy residuals with a residual diameter < 5 cm [265], as well as unilateral lymph node metastases on pre- and post-chemotherapy CT scans, left-sided tumours only require para-aortic resection whereas right-side tumours need paracaval and interaortocaval resection down to the iliac arteries [266,267].

Indications for ipsilateral template resection after first-line chemotherapy represent men with a residual tumour volume < 5 cm and ipsilateral metastatic disease on pre- and post-chemotherapy scans. The mere resection of the residual tumour (so called lumpectomy) should not be performed [256,260,261,263,265,267,268].

Laparoscopic or robotic RPLND may yield comparable outcomes to open procedures in selected cases with low-volume residual disease and when undertaken by very-experienced surgeons. This should only be considered in specialist TC centres with expertise in open RPLND and minimally invasive surgery to ensure appropriate case selection. In this setting, up to 30% of post-Chemotherapy RPLND have been reported via a laparoscopic approach [269-271]. Experience with robot-assisted laparoscopic RPLND remains limited [272] and atypical recurrences have been reported, and occur more often, with this approach [167].

7.3.3. Sequencing of surgery in the case of multiple sites

In general, surgery should commence at the site with the highest volume of residual disease. The histology of the mass diverges in different organ sites [257]. In cases of residual retroperitoneal and lung masses, the presence of fibro-necrotic tissue in the retroperitoneum is associated with a probability as high as 90% that lung masses contain the same histology [273]. Resection of contralateral pulmonary lesions is not mandatory when pathologic examination of the lesions from the initial side show complete necrosis. Discordant histology between lung sites, however, may occur in up to 20% of cases [274,275].

7.3.3.1. Quality and intensity of surgery

Post-chemotherapy surgery is always demanding. Whilst most post-chemotherapy RPLNDs do not require resection of major vessels or organs, a proportion of patients may require an intervention in which organs affected by the disease are removed in order to achieve radical resection (e.g., kidney, psoas muscle or gross vessels), and may potentially also require ad hoc reconstructive surgery (e.g., vascular interventions such as vena cava or aortic prostheses). Patients undergoing adjunctive complex surgery benefit from disease control but have a greater risk of complications [276,277]. In patients with intermediate- or poor-risk and residual disease > 5 cm, the probability of vascular procedures is as high as 20% [278]. This “maximal” surgery must therefore be referred to specialised centres capable of interdisciplinary surgery (hepatic resections, vessel replacement, spinal neurosurgery, thoracic surgery). Even with centralisation of treatment, the median number of RPLNDs performed per surgeon/year in the U.K. is six [279]. Nevertheless, patients treated within such centres benefit from a significant reduction in peri-operative mortality from 6-0.8% [280]. In addition, specialised urologic surgeons are capable of reducing the local recurrence rate from 16-3% with a higher rate of complete resections [281].

7.3.3.2. Salvage and desperation surgery

Surgery of resectable disease after salvage treatment remains a potentially curative option in patients with any residual mass following salvage chemotherapy. Survival after surgery and first salvage chemotherapy improved by 70% at ten years, following taxane-containing regimens [282]. Also, even with extensive salvage chemotherapy, surgery remains a fundamental tool to achieve durable complete remissions in up to 20% of patients [283,284].

Desperation surgery refers to resection of non-responsive or progressive (e.g., rising markers) disease following salvage chemotherapy. When the disease is resectable, a significant proportion of these patients can be rendered disease-free in the long term [285].

7.3.3.3. Consolidation chemotherapy after secondary surgery

After resection of necrosis or post-pubertal teratoma, no further treatment is required. In cases of incomplete resection of viable cancer, two adjuvant cycles of conventionally dosed cisplatin-based chemotherapy may be given in certain subgroups (e.g., poor-prognosis patients) [268]. However, caution is required with cumulative doses of bleomycin. After complete resection of ‘vital’ tumour < 10% of the total volume, particularly in patients who initially had a good-prognosis based on IGCCCG criteria, the relapse rate is very low and adjuvant chemotherapy is not beneficial in preventing further relapse [286]. The prognosis is worse if malignant disease is present in masses resected after second- and third-line chemotherapy. In this latter situation, post-operative chemotherapy is not indicated [287].

7.3.4. Systemic salvage treatment for relapse or refractory disease

Cisplatin-based combination salvage chemotherapy will result in long-term remissions in approximately 50% of patients who relapse after first-line chemotherapy. These results are highly dependent on several prognostic factors [288]. The regimens of choice are four cycles of a three-agent regimen including cisplatin and ifosfamide plus a third drug: etoposide (PEI/VIP), paclitaxel (TIP), or potentially gemcitabine (GIP) (Table 7.3) [289,290]. No RCT has compared these regimens. Due to their potential risk of lethal haematological toxicity, these regimens should be used with G-CSF support and by well-trained oncologists.

The only available RCT comparing standard-dose and HDCT plus transplantation in the salvage setting showed no benefit in OS in patients treated with three cycles of vinblastine, ifosfamide, and cisplatin (VeIP) plus one cycle of consolidation HDCT, compared with VeIP x 4 [291]. For methodological reasons, this trial design can no longer be considered state of the art.

Table 7.3: Standard PEI/VIP, TIP and GIP salvage chemotherapy (interval 21 days)

Regimen

Chemotherapy agents

Dosage

Duration of cycles

PEI/VIP

Cisplatin*

Etoposide

Ifosfamide

20 mg/m2

75-100 mg/m2

1.2 g/m2

Days 1-5

Days 1-5

Days 1-5

TIP

Paclitaxel

Ifosfamide

Cisplatin*

250 mg/m2 xx

1.5 g/ m2

25 mg/m2

24 hour continuous infusion day 1

Days 2-5

Days 2-5

Alternative schedule

Paclitaxel

Ifosfamide

Cisplatin*

175 mg/m2

1.2 g/m2

20 mg/m2

Day 1, 3 hour infusion

Days 1-5

Days 1-5

GIP

Gemcitabine

Ifosfamide

Cisplatin

1000 mg/m2

1200 mg/m2

20 mg/m2

Day 1 + 5

Days 1-5

Days 1-5

* Plus, hydration.

Plus, mesna protection.

xx An MRC schedule uses paclitaxel at 175 mg/m2 in a 3 hour infusion [290].

A retrospective analysis by the International Prognostic Factors Study Group (IPFSG) evaluated the risk of relapse in patients in whom this occurred after at least three cisplatin-based cycles and subsequent cisplatin-based conventional-dose or carboplatin-based high-dose salvage chemotherapy [189]. Seven variables - histology, primary tumour location, response, progression-free interval after first-line treatment and level of AFP, hCG and the presence of liver, bone or brain metastasis at salvage treatment were identified as independent prognostic variables of relapse after initial cisplatinum-based chemotherapy [189]. Using these factors, five risk-groups: very low-risk = -1 points; low-risk = 0 points; intermediate-risk = 1-2 points; high-risk = 3-4 points; and very high-risk > 5 points; were identified with significant differences in PFS and OS. Table 7.4 illustrates these five risk groups and the corresponding two-year PFS and three-year OS rates [189]. Several recent trials have validated this scoring system [292-295]. As in first-line therapy, the prognostic impact of tumour marker decline applies in the salvage setting [296]. While progression to induction chemotherapy was negative for OS, prior use of paclitaxel was not significantly associated with a negative outcome [297].

A secondary analysis of the IPFSG cohort (n = 1,600 patients) showed an improvement of about 10-15% in OS in all prognostic subgroups when treated with high-dose salvage therapy compared to standard dose therapy. To prospectively confirm this finding, an RCT of high-dose vs. conventional dose chemotherapy in patients with first-line relapse is underway (Tiger trial). When HDCT is used as a salvage treatment, sequential treatment cycles of high-dose carboplatin and etoposide (HD-CE) should be preferred to a single high-dose regimen as the former is associated with less toxicity-related deaths [292]. A recent systematic review confirmed the superiority of using at least two high-dose cycles in the salvage setting over a single high-dose cycle [298]. It is clearly of the utmost importance that these rare patients with relapse are treated within clinical trials and at specialised centres.

Table 7.4: The International Prognostic Factors Study Group Score for seminoma and non-seminoma that relapse after cisplatin-based first-line chemotherapy [189]

Points

-1

0

1

2

3

Variable

Histology

Seminoma

Non-seminoma




Primary site


Gonadal

Retroperitoneal


Mediastinal

Response


CR/PRm-

PRm+/SD

PD


PFI


> 3 months

< 3 months



AFP salvage


Normal

< 1000

1000


hCG salvage


< 1000

1000



LBB


No

Yes



AFP = alpha-fetoprotein; CR = complete remission; PRm- = partial remission, negative markers;

PRm+ = partial remission, positive markers; hCG = human chorionic gonadotrophin; LBB = liver, bone,
brain metastases; PD = progressive disease; PFI = progression-free interval; SD = stable disease.

Table 7.5: PFS and OS estimates for all patients according to IGCCCG prognostic score for seminoma and non-seminoma that relapse after cisplatin-based first-line chemotherapy [190]

Score (n = 1,435)

N

%

HR

2-years PFS (%)

3-year OS (%)

Very Low

76

5.30

1

75.1

77.0

Low

257

17.9

2.07

52.6

69.0

Intermediate

646

45.0

2.88

42.8

57.3

High

351

24.5

4.81

26.4

31.7

Very High

105

7.3

8.95

11.5

14.7

Missing

159

-

-

-

-

HR = hazard ratio; PFS – progression-free survival; n = number of patients; OS = overall survival.

7.3.5. Second relapse

No RCTs have been reported for patients with second relapse and overall conventional therapy does not appear effective. For patients who have received two series of conventionally dosed therapy (first-line and first-salvage), high-dose chemotherapy with autologous stem cell support should be used [293]. With this the prospect of cure is only 20% to 25%.

Patients relapsing within four to eight weeks after platinum-based therapy, or who are progressing despite platinum-based therapy, as well as those relapsing shortly after high-dose chemotherapy, are considered as cisplatin refractory. Combinations of gemcitabine and oxaliplatin or the triple combination of gemcitabine, oxaliplatin and paclitaxel have resulted in response rates of 25-45% in this setting. Cisplatin re-challenge in association with gemcitabine and paclitaxel may be considered in patients with adequate renal function [299]. For patients with a second relapse not responding to the combination of oxaliplatin and gemcitabine or the triple combination, inclusion in clinical trials is encouraged.

Patients with a good response undergoing subsequent resection of residual tumour lesions may still have a 15-20% chance of long-term cure [283,300].

Various targeted agents have generally failed in refractory disease, including immune checkpoint inhibitors [292-298,301]. Trials combining PD1/PDL-1 and CTLA4 inhibitors are ongoing; however, even for those combinations early results are not encouraging.

7.3.5.1. Late relapse (more than two years after end of first-line treatment)

Late relapse is defined as recurrence more than two years after completion of successful primary treatment of metastatic TC [54]. According to a pooled analysis, this occurs in 1.4% and 3.2% of seminoma and non-seminoma patients, respectively [302]. Interestingly, in a population-based study all late-relapsing seminoma patients had viable GCT [303]. These can be treated with chemotherapy and radiotherapy.

In contrast, patients with late-relapsing NSGCT should undergo surgical resection when feasible, alone or in combination with chemotherapy. Some patients, including those with rapidly rising β-hCG, may benefit from induction salvage chemotherapy with subsequent reconsideration of surgery for resection of persisting residual masses [202]. In general, however, surgery represents the mainstay of treatment, and it should be performed in most patients when feasible irrespective of the level of their tumour markers in order to completely resect all viable GCT post-pubertal teratoma or TSTC [202,304]. Survival strongly relates to the histology of the recurrent lesions rather than that of the initial disease. If not completely resectable, biopsies should be obtained for histological evaluation to direct salvage chemotherapy based on the tumour phenotype. Review by an experienced pathologist is critical to avoid misinterpretation of the therapeutic morphological changes that occur with the treatment of GCT [305]. If the patient responds to salvage chemotherapy, secondary surgery should then be undertaken if feasible. With unresectable, but localised refractory disease, stereotactic or conventional radiotherapy may be considered. To avoid excess mortality, late relapses should be treated only at centres experienced in managing such patients [306].

7.3.6. Treatment of brain metastases

Brain metastases occur in the context of initial metastatic disease, systemic relapse and rarely as an isolated site of relapse. Long-term survival of patients presenting with brain metastases at diagnosis is poor
(30-50%) and even poorer when a site of recurrent disease (five-year survival-rate is 2-5%) [307,308]. A large international database comprising 523 patients reported 48% three-year OS rates in patients with brain metastases at initial diagnosis and 27% three-year OS rates for patients with brain metastases at relapse [45].

Chemotherapy as initial treatment proved effective in a first-line setting (potentially even as dose-intensified therapy upfront) with data also supporting the use of multimodal treatment particularly in relapsed disease [45]. Consolidation RT, even with total response after chemotherapy, should therefore be used in patients with brain metastases at relapse, but must be carefully discussed in a first-line setting [309]. Surgery may be considered in cases with a persistent solitary metastasis, depending on the systemic disease status, histology of the primary tumour and the location of the metastasis.

7.3.6.1. Guidelines for the treatment of metastatic testicular germ cell tumours

Summary of evidence

LE

In the NSGCT good-prognosis-risk group (IGCCG), BEP x 3 is superior to other chemotherapy regimens. Toxicity is lower when treatment is delivered in five-day regimes rather than three-day regimes.

1b

In NSGCT intermediate-prognosis-risk group (IGCCCG) BEP x 4 is the standard treatment of choice with a five-year survival of 89% in contemporary series.

1b

In pathological stage II NSGCT disease, RPLND performed in specialised centres without adjuvant chemotherapy results in 73-81% of long-lasting remissions.

2b

In patients with a poor-prognosis metastatic NSGCT (defined by IGCCCG), treatment with BEP x 4, results in a five-year PFS of 67%. There is no advantage in OS for high-dose chemotherapy.

1b

Patients with a poor-prognosis metastatic NSGCT and early unfavourable tumour marker decline may benefit from intensification of treatment with dose-dense chemotherapy, with improvement of PFS despite no benefit being observed for OS.

1b

Following first-line BEP chemotherapy, 6-10% of NSGCT residual masses contain active cancer,
50% have post-pubertal teratoma, and 40% comprise of necrotic-fibrotic tissue only. Figures regarding persistence of residual active are slightly lower in post chemotherapy residual masses
< 1 cm. Currently there is no accurate prognostication method of histology.

2b

In CS IIA/B seminoma radiotherapy and chemotherapy treatment show similar effectiveness, with a non-significant trend towards greater efficacy of chemotherapy in CS IIB. However, risk of second malignancies and cardiovascular events is higher after radiotherapy.

2a

In metastatic seminoma stage > IIC, primary chemotherapy with BEP, tailored to the IGCCCG risk group, has proven superior to Carboplatin based chemotherapy.

1b

Fluorodeoxyglucose-positron emission tomography has a high NPV in patients with post-chemotherapy seminoma residual masses (> 3 cm) when performed more than two months after chemotherapy.

2b

Recommendations

Strength rating

Treat low-volume non-seminomatous germ cell tumour (NSGCT) stage IIA/B with elevated markers like metastatic good- or intermediate-prognosis risk group IGCCCG with three or four cycles of cisplatin, etoposide, bleomycin (BEP).

Strong

Nerve-sparing retroperitoneal lymph node dissection when performed by an experienced surgeon in a specialised centre is the recommended initial treatment in clinical stage (CS) IIA NSGCT disease without elevated tumour markers.

Weak

Repeat staging after six weeks before making a final decision on further management should be considered in patients with small volume (CS IIA < 2 cm) marker-negative NSGCT.

Weak

Treat metastatic NSGCT (stage > IIC) with an intermediate prognosis with four cycles of standard BEP

Strong

In metastatic NSGCT with a poor-prognosis, treat with one cycle of BEP, (or cisplatin, etoposide and ifosfamide [PEI], in cases with pulmonary dysfunction), followed by tumour marker assessment after three weeks. Continue the same schedule up to a total of four cycles with favourable marker decline. With unfavourable decline, initiate chemotherapy intensification.

Weak

Perform surgical resection of visible (> 1 cm) residual masses after chemotherapy for NSGCT when serum levels of tumour markers are normal or normalising.

Strong

Initially offer cisplatin-based chemotherapy according to IGCCCG prognosis groups, or alternatively radiotherapy to seminoma patients with stage II A/B and, inform the patient of potential long-term side effects of both treatment options.

Weak

Treat seminoma stage IIC and higher, with primary chemotherapy according to IGCCCG classification (BEP x 3 in good-prognosis and BEP x 4 in intermediate prognosis).

Strong