div class=”ChapterContextInformation”>
37. Chemotherapeutic Agents for Urologic Oncology: Basic Principles
Keywords
ChemotherapySystemic treatmentCollecting duct tumourRenal medullary carcinomaUrothelial cancerProstate cancerTesticular cancerPenile cancerIntroduction
Key features of commonly use chemotherapeutics in genitourinary cancer
Classification | Mechanism of action | Common Scheduling | Adverse effects of interest | |
|---|---|---|---|---|
Cisplatin | Platinum | DNA damage | 50–100 mg, q3 weeks | Nephrotoxicity Neurotoxicity Otoxicity Nausea and vomiting Electrolyte disturbances Hypersensitivity reaction |
Carboplatin | Platinum | DNA damage | AUC 5–7 (Calvert formula), q3 weeks | Myelosuppression Nephrotoxicity, neurotoxicity, and nausea and vomiting is less frequent or severe than cisplatin |
Docetaxel | Taxane | Anti-microtubule | 75 mg/m2, q3 weeks | Myelosuppression Neuropathy Pneumonitis/pulmonary fibrosis Hypersensitivity reactions Reversible alopecia Nail/skin changes Myalgia, arthralgia Fluid retention |
Gemcitabine | Cytidine analog | Inhibition of DNA synthesis | 1000 mg/m2, q3 weeks | Myelosuppression Fever and flu-like symptoms Deranged liver function tests Pulmonary toxicities Hemolytic uremic syndrome Peripheral edema |
Bleomycin | Antitumor antibiotic | DNA damage | 30 units Day 1, 8, 15, q3 weeks | Pneumonitis/pulmonary fibrosis (oxygen enhances pulmonary toxicity) Desquamation, rash Raynaud’s phenomenon ∗Non-myelosuppressive |
Etoposide | Topoisomerase II inhibitor | Inhibit DNA synthesis and DNA repair | 100 mg/m2, D1–3 or 1–5, q3 weeks | Myelosuppression Secondary malignancies Reversible alopecia |
Mitoxantrone | Anthracenedione/Topoisomerase II inhibitor | Inhibit DNA synthesis and DNA repair | 12 mg/m2, q3 weeks | Cardiotoxicity: congestive heart failure, cardiomyopathy Myelosuppression Blue discolouration to the sclera |
Ifosfamide | Alkylating agent | Inhibit DNA and protein synthesis | 1200 mg/m2, D1–5, q3 weeks | Hemorrhagic cystitis Neurotoxicity Myelosuppression |
Common combination chemotherapy regimens in genitourinary cancer. D day
Dose | Scheduling | Main indications | Adverse events of interest | |
|---|---|---|---|---|
BEP | Bleomycin (B) 30 units, D1, 8, 15; Etoposide (E) 100 mg/m2, D1–5; Cisplatin (P) 20 mg/m2, D1–5 | q3 week for 3 (favourable risk) or 4 (intermediate/poor risk) cycles | Advanced germ cell tumor | Myelosuppression Pulmonary toxicity Neuropathy Nephrotoxicity Ototoxicity Nausea and vomiting Secondary malignancy Reversible alopecia |
VIP | Etoposide (V) 75 mg/m2, D1–5; Ifosfamide (I) 1500 mg/m2, D1–4; Cisplatin (P) 20 mg/m2 D1–5; Mesna 300 mg/m2, D1–5 | q3 weeks for 4 cycles | Advanced germ cell tumor with contraindication to bleomycin or expected lung surgery | Myelosuppression Neuropathy Nephrotoxicity Ototoxicity Nausea and vomiting Secondary malignancy Reversible alopecia Haemorrhagic cystitis |
TIP | Paclitaxel (T) 175 mg/m2, D1; Ifosfamide (I) 1200 mg/m2, D1–5 in germ cell tumour, or D1–3 in penile cancer; Cisplatin (P) 20 mg/m2, D1–5 in germ cell tumour, or 25 mg/m2, D1–3 in penile cancer; Mesna 300 mg/m2, D1–5 | q3 weeks for 4 cycles | Relapsed germ cell tumor, penile cancer | Myelosuppression Neuropathy Nephrotoxicity Ototoxicity Nausea and vomiting Secondary malignancy Reversible alopecia Haemorrhagic cystitis |
MVAC | Classical MVAC: Methotrexate (M) 30 mg/m2 D1, 15, 22; Vinblastine (V) 3 mg/m2 D2, 15, 22; Doxorubicin (A) 30 mg/m2 D2; Cisplatin (C) 70 mg/m2 D2 Dose-dense MVAC: M 30 mg/m2 D1; V 3 mg/m2 D2, A 30 mg/m2 D2; C 70 mg/m2 D2 | Classical MVAC: q3–4 weeks for 3–6 cycles Dose-dense MVAC: q2 weeks for 4 cycles | Urothelial cancer | Myelosuppression Nausea and vomiting Diarrhoea Oral mucositis |
GC | Gemcitabine (G) 1000–1250 mg/m2, D1, 8 Cisplatin (C) 70 mg/m2, D1 | q3 weeks for 4–6 cycles | Urothelial cancer | Myelosuppression Nephrotoxicity Neurotoxicity Otoxicity Nausea and vomiting Electrolyte disturbances Fluid retention |
CaG | Carboplatin AUC 5 (Calvert formula), D1 Gemcitabinej 1000–1250 mg/m2, D1, 8 | q3 weeks for 6 cycles | Urothelial cancer | Myelosuppression Fluid retention |
Cisplatin Etoposide | Cisplatin 75 mg/m2, D1 Etoposide 100 mg/m2, D1–3 | q3 weeks for 4–6 cycles | Small cell carcinoma | Myelosuppression Nephrotoxicity Neurotoxicity Ototoxicity Nausea and vomiting Electrolyte disturbances Secondary malignancies |
Carboplatin Etoposide | Carboplatin AUC 5 (Calvert formula), D1 Etoposide 100 mg/m2, D1–3 | q3 weeks for 4–6 cycles | Small cell carcinoma As part of TI-CE protocol for relapsed germ cell tumor | Myelosuppression Secondary malignancies Reversible alopecia |
The intent of chemotherapeutics can be curative or palliative. Curative intent treatment aims to eradicate all tumour cells to achieve long term survival. It is usually given in the peri-operative setting to eliminate micrometastatic disease either in the adjuvant setting after local therapy (i.e. surgery or radiotherapy), or in the neoadjuvant setting which can also serve to decrease primary tumour bulk to facilitate local therapy. Chemotherapy is also used concurrently as a radiosensitizer to improve efficacy of radiotherapy. Testicular germ cell tumour is the rare example where chemotherapy is given with curative intent even when distant metastases are clinically apparent. Palliative chemotherapy aims to prolong survival as well as improving quality of life by reducing malignancy-related complications.
This chapter outlines major chemotherapeutic agents and regimens used in urological cancers . Although the term “chemotherapy” can be applied to any drug treatment, a traditional classification of non-specific anti-cancer agents is being applied here. Targeted cancer therapies (agents that directed against molecular targets involved in the growth, progression, and spread of cancer) and immunotherapy will be discussed elsewhere in this issue.
Bladder Cancer
The majority of bladder cancer is non-muscle invasive and is treated with local therapy. About 25% of bladder cancer is muscle-invasive, and 4% has metastatic disease on initial presentation [3]. Prognosis for patients with muscle invasive bladder cancer (MIBC) varies with TNM staging. Five-year recurrence-free survival decreases from 80–90% in organ-confined node-negative disease, to 50–60% in patients with extravesical involvement (pT3–4N0), and 35% with nodal metastasis [4]. Urothelial bladder cancer is considered chemosensitive with a response rate of up to 70% in metastatic disease, but duration of response in this setting can be limited. The treatment landscape of MIBC is rapidly changing with the introduction of immunotherapy, but chemotherapy is still the current systemic therapy of choice in both perioperative and first-line palliative settings.
Advanced Bladder Cancer
First-Line Chemotherapy
Consensus definition of fitness for cisplatin-based chemotherapy in patients with metastatic urothelial carcinoma
– WHO or ECOG of ≥1, or Karnofsky performance status >70% |
– Creatinine clearance ≥60 mL/min |
– Audiometric hearing loss of ≤25 dB averaged at 2 contiguous test frequencies |
– Peripheral neuropathy not affecting instrumental activities of daily living |
– NYHA class II or less heart failure |
Options for first-line treatment depend on patient’s performance status. For medically fit patients, MVAC (methotrexate, vinblastine, adriamycin, cisplatin) [6], dose-dense MVAC (ddMVAC) [7], or GC (gemcitabine, cisplatin) [8] are commonly used regimens (Table 37.2). MVAC has been a standard first-line regimen for metastatic urothelial cancer since 1990 [6]. The substantial toxicity and poor long-term survival with median survival just over 1 year led to the EORTC 30924 trial testing for dose dense 2-weekly MVAC. Concomitant granulocyte colony-stimulating factor (G-CSF) support was given to mitigate neutropenia and mucositis associated with ddMVAC. Dose-dense MVAC resulted in a higher overall response rate (72% vs. 58%, p = 0.02), complete response (25% vs. 11%, p = 0.006), improved progression-free survival (median 9.5 vs. 8.1 months; HR 0.73, 95% confidence interval (CI) 0.56–0.95, p = 0.017), and 5-year survival (21.8% vs. 13.5%, p = 0.042) compared with the classic four weekly MVAC [7, 9]. However, the difference in primary endpoint of overall survival was not clinically meaningful (median 15.1 vs. 14.9 months; HR 0.76, 95% CI 0.58–0.99, p = 0.04). Dose-dense MVAC was better tolerated than classic MVAC with less febrile neutropenia (10% vs. 26%, p < 0.001) and mucositis (grade ≥ 3, 10 vs. 17%, p = 0.03). Toxic death rate was similar between both groups (3% vs. 4%).
To further improve tolerability of palliative chemotherapy, GC was compared with MVAC in a phase III trial by von der Maase and colleagues. Although overall survival was not different between GC and MVAC (median 14 and 15.2 months respectively; HR 1.09, 95% CI 0.88–1.34, p = 0.66), GC was more tolerable [8, 10]. Compared to MVAC, GC had a lower rate of grade ≥3 neutropenia (82% for MVAC vs. 71% for GC), neutropenic fever (14% vs. 2%), neutropenic sepsis (12% vs. 1%), grade ≥3 mucositis (22% vs. 1%), and treatment-related death (3% vs. 1%) [10].
Two weekly dose dense GC (ddGC) was also evaluated against ddMVAC and resulted in comparable overall survival (median 18 vs. 19 months, respectively) and objective response rates (65.3% vs. 60%), but a safety profile that favoured ddGC (≥G3 neutropenia 13% vs. 19%; febrile neutreopenia 0 vs. 5%; treatment related death from non-neutropenic sepsis 0 vs. 3%) [11].
The addition of paclitaxel to GC (PGC) vs. GC improved response rate (55.5% vs. 43.6%, respectively) but the 3.1 month survival advantage did not reach statistical significance (15.8 vs. 12.7 months, HR 0.85, 95% CI 0.72–1.02, p = 0.075) [12]. PGC was also associated with more toxicity with higher rates of febrile neutropenia (13.2 vs. 4.3%), and toxicity-related death (n = 6 vs. 3). There was no statistically significant difference in all efficacy outcomes between GC and carboplatin gemcitabine (CaG), although 1-year survival rate was 63.6% vs. 37.3% for GC and CaG respectively [13]. Overall toxicity was similar between GC and CaG (grade 3 toxicities 60% vs. 69.1%, respectively), and CaG was associated with less grade ≤ 2 nephrotoxicity (16% vs. 26%) and grade 3–4 nausea and vomiting (3.6% vs. 9.1%). Cisplatin in combination with docetaxel was inferior to MVAC in terms of response rate, time to progression, and median survival [14].
For cisplatin unfit patients with metastatic urothelial carcinoma, EORTC 30986 showed a trend towards higher confirmed response rate (36.1% vs. 21%) and overall survival (median 9.3 vs. 8.1 months) with carboplatin gemcitabine (CaG) versus MCAVI (methotrexate, carboplatin, vinblastine), respectively, but neither reached statistical significance [15]. Severe acute toxicity (9.3% vs. 21.2%) and febrile neutropenia (4.2% vs. 14.4%) were less common with CaG compared to MCAVI, respectively, but CaG caused more grade ≥3 thrombocytopenia (48.3% vs. 19.4%). Two toxic deaths were seen in CaG arm, and four in MCAVI. Other non-cisplatin containing regimens with anti-tumour activity demonstrated in single-arm phase II trials included gemcitabine and paclitaxel [16], gemcitabine docetaxel [17], gemcitabine pemetrexed [18], gemcitabine epirubicin [19], gemcitabine vinorelbine [20], paclitaxel + carboplatin + gemcitabine [21], sequential carboplatin gemcitabine then paclitaxel [22], and dose-dense doxorubicin then carboplatin paclitaxel [23].
Second-Line Chemotherapy
Second-line chemotherapy in patients with advanced urothelial cancer progressed after MVAC or GC has largely been superseded by immunotherapy, but can be considered in patients who are intolerant of immunotherapy or progressed during or after prior immunotherapy.
The optimal second-line chemotherapy is not yet defined. A number of chemotherapeutics including vinflunine [24], docetaxel [25], paclitaxel [26], nab-paclitaxel [27], gemcitabine [28], pemetrexed [29], and ifosfamide [30] showed anti-tumour activity in the second-line setting. However there is no phase III trial data to demonstrate significant survival advantage with second-line chemotherapy. These patients have a poor prognosis with life expectancy between 5 and 10 months [24–26, 28, 29]. A retrospective pooled analysis of eight phase II trials of salvage taxane-based chemotherapy showed combination chemotherapy significantly improved overall survival compared to taxane monotherapy (HR 0.6, 95% CI 0.45–0.82, p = 0.001) [31]. Prospective randomised controlled trials are needed to validate this finding. Combination chemotherapy is often more toxic, and treatment must be tailored to individual patient, and participation in clinical trials should be encouraged.
Muscle Invasive Bladder Cancer
Neoadjuvant Chemotherapy
The tendency for MIBC to metastasize early makes neoadjuvant chemotherapy an ideal treatment option. Neoadjuvant chemotherapy aims to eliminate micrometastatic disease early, offers an opportunity to assess tumour response to therapy, increases rate of pathologic complete response (pT0) and reduces the rate of positive surgical margins [32]. The ABC meta-analysis showed cisplatin-based neoadjuvant chemotherapy is associated with an absolute improvement of 5% in 5-year overall survival (from 45 to 50%; hazard ratio (HR) 0.86, 95% CI 0.77–0.95, p = 0.003) [33]. As in the metastatic setting, commonly employed neoadjuvant regimens include MVAC, ddMVAC, and GC. However, there are no trials directly comparing different neoadjuvant combinations, and the optimal regimen is undefined. Retrospective studies showed similar pathologic complete response rates (pT0pN0) between neoadjuvant MVAC vs. GC [34–36], and MVAC vs. ddMVAC (38% vs. 35%, p = 0.72) [37]. These results are in contrast with two recent multicentre retrospective studies with propensity score analysis of clinical outcomes. Higher complete response rates of 28%–41% vs. 15%–25% between neoadjuvant ddMVAC vs. GC were observed [38, 39]. The study from Zargar and colleagues reported mean Kaplan-Meier estimates of overall survival were significantly higher in ddMVAC compared to GC groups (7 vs. 4.2 years, p = 0.001) [38], while Peyton and colleagues showed survival benefit favoured ddMVAC over GC but did not reach statistical significance in propensity weight modelling (HR 0.44, 95% CI 0.14–1.38, p = 0.16) [39]. These findings must be interpreted with caution due to the limitations inherent in retrospective trial design, including potential selection bias for less well patients to receive GC due to its tolerability, and uncaptured data for patients who did not receive surgery due to intolerance, treatment complications, and disease progression.
Adjuvant Chemotherapy for MIBC
Adjuvant chemotherapy is an option for patients who did not receive neoadjuvant chemotherapy. Accurate pathological staging post cystectomy allows selection for patients with high risk features for relapse (pT3–4 or node positive disease) who may derive greater benefit with adjuvant treatment. Clinical trials data supporting adjuvant chemotherapy for MIBC is less robust. An individual-patient data meta-analysis by Medical Research Council (MRC) in 2005 reported a hazard ratio for survival of 0.75 (95% CI 0.6–0.96, p = 0.019) in favour of adjuvant chemotherapy over observation post surgery [40]. This translates to an absolute 3-year survival benefit of 9%. The authors however cautioned interpretation of their findings owing to issues in clinical trial design and conduct with four of six trials stopping early, patients not receiving allocated treatments or salvage therapy at relapse. An updated meta-analysis by Leow and colleagues in 2013 found a pooled hazard ratio for survival of 0.77 (95% CI 0.59–0.99, p = 0.049) favouring adjuvant chemotherapy over surgery alone [41]. Limitations of this analysis included that only trial-level data was used, results from unpublished trials were included, trials include had variable inclusion criteria, as well as the limitations associated with the MRC meta-analysis. The most recent EORTC 30994 trial failed to detect a significant improvement in overall survival with adjuvant chemotherapy vs. observation in patients with pT3–4 or node positive MIBC after radical cystectomy (HR 0.78, 95% CI 0.56–1.08, p = 0.13) [42]. Only 284 patients out of the planned 660 patients were enrolled and trial was stopped due to poor accrual, limiting sufficient power for survival analysis. As with neoadjuvant chemotherapy, the choice of adjuvant chemotherapy is a cisplatin-based regimen derived from experience in the metastatic setting. Options for adjuvant therapy may include MVAC, ddMVAC, and GC.
Chemotherapy in Bladder-Sparing Strategies: Trimodality Therapy
Patients with MIBC are often elderly with multiple co-morbidities. For patients who are not surgical candidate or wish to retain their bladder, a bladder-preservation approach with trimodality therapy (TMT) is a potential definitive treatment option. TMT involves maximal transurethral resection of the bladder (TURBT) followed by concurrent chemoradiation. Radiation alone is seldom pursued because of inferior outcomes, although long term survival can be observed in 35% [43]. Five year disease-specific survival is comparable between surgery and TMT in carefully selected patients [44].
Single centre experience has shown favourable oncological outcomes with TMT, with improvement in 5-year disease specific survival from 60 to 84%, and reduction in the rate of salvage cystectomy from 42 to 16%, across the periods 1986–1995 and 2005–2013 [45] This is likely related to improvement in treatment techniques and more stringent patient selection criteria [46]. The landmark trial BC2001 showed a significant decrease in 2-year locoregional disease-free survival from 67 to 54% (HR 0.68, 95% CI 0.48–0.96, p = 0.03) in MIBC patients receiving chemoradiation compared to radiation alone [43]. This locoregional control benefit with chemoradiation persists in an updated analysis with a median follow up of 118 months [47]. There was no difference in overall survival.
Cisplatin alone or in combination with 5FU or paclitaxel [48–50], 5FU plus mitomycin [43], and gemcitabine [51] have been used concurrently with radiation for bladder preservation approach. Direct comparison between different regimens is not available and the optimal radiosensitizer has not been defined.
The role of neoadjuvant chemotherapy prior to definitive bladder chemoradiation is not clear. BC2001 trial allowed but did not require neoadjuvant chemotherapy, and about 33% of the patients received neoadjuvant chemotherapy [43]. The effect of chemoradiotherapy vs. radiotherapy on disease-free survival was similar irrespective of neoadjuvant chemotherapy in subgroup analysis. However BC2001 trial was not designed to address the benefit of neoadjuvant chemotherapy. In the RTOG 89–03 trial, cT2 to cT4aNxM0 bladder cancer patients received two cycles of neoadjuvant cisplatin, methotrexate, and vinblastine prior to concurrent cisplatin radiotherapy were compared to chemoradiotherapy alone [52]. Five-year overall survival rate was 48% and 49% respectively. There is no level 1 data evaluating the benefit of adjuvant chemotherapy following chemoradiothearpy. A systematic review by Ploussard et al. concluded the absence of definitive data to support the benefit of neoadjuvant or adjuvant chemotherapy in bladder cancer patients treated with trimodality therapy [53].
Prostate Cancer
Hormonal manipulation with either surgical or chemical castration has been the cornerstone of treatment for advanced adenocarcinoma of the prostate since 1941 [54]. Hormonal therapy is effective in reducing tumour burden and PSA levels, but treatment resistance is inevitable. Chemotherapy was traditionally considered a palliative treatment of ‘last resort’ in patients with symptomatic prostate cancer. This changed with the demonstration of improved overall survival for patients with metastatic castration resistant prostate cancer (mCRPC) treated with docetaxel chemotherapy [55]. More recently, significant survival benefit has been observed when chemotherapy was added to ADT earlier in the disease for patients with castration sensitive disease.
Metastatic Castration-Resistant Prostate Cancer
The development of rising PSA, progressive symptoms or radiological progression despite castrated levels of testosterone ≤0.5 ng/mL (1.73 nmol/L) heralds the disease state termed castration-resistant prostate cancer. There are two life-prolonging chemotherapeutic agents with docetaxel and cabazitaxel for patients with mCRPC [55, 56]. The prognosis of mCRPC is guarded, with the median overall survival for patients with treatment naïve-mCRPC ranging from 25 to 35 months in contemporary randomised control trials [57–59].
Docetaxel
Docetaxel is an anti-microtubule taxane chemotherapy (Table 37.1). Two parallel phase 3 trials, TAX 327 and SWOG 99–16 independently showed docetaxel extended survival in patients with mCRPC in 2004 [55, 60]. In TAX 327, median overall survival was significantly increased by 2.4 months with docetaxel 75 mg/m2 given once every 3 weeks and prednisone 5 mg twice daily, compared to mitoxantrone and prednisone (median 18.9 and 16.5 months respectively, HR 0.76, 95% CI 0.62–0.94; p = 0.009) [55]. Secondary endpoints including pain response, quality of life score as assessed by the functional assessment of cancer therapy – prostate (FACT-P) questionnaire, and PSA decline ≥50% from baseline (PSA50, 45% vs. 32%) were significantly improved with docetaxel. Bone marrow suppression, gastrointestinal (GI) toxicities, peripheral neuropathy, fatigue, nail changes, and reversible alopecia were adverse effects of interest with docetaxel. The SWOG 99–16 also showed a significant survival benefit of 1.9 months with three weekly docetaxel 60 mg/m2 in combination with estramustine and prednisone against mitoxantrone and prednisone (HR 0.8, 95% CI 0.67–0.97, p = 0.02) [60]. Subsequent study comparing docetaxel with or without estramustine failed to demonstrate survival advantage with the addition of estramustine [61], and docetaxel and prednisone is the established regimen for mCRPC.
Alternative scheduling with weekly docetaxel was also explored in TAX 327 trial, but overall survival was not significantly different compared to mitoxantrone [55]. In another phase 3 trial comparing two and three-weekly docetaxel schedules, the primary endpoint of time to treatment failure (TTTF) was significantly longer in the two weekly group (5.6 months vs. 4.9 months, respectively, HR 1.3, 95% CI 1.1–1.6, p = 0.014), although the absolute difference was only 0.7 months [62]. Two-weekly schedule was well tolerated with less myelosuppression (grade ≥ 3 neutropenia (36% vs. 53%) and febrile neutropenia (4% vs. 14%) in the two and three-weekly groups, respectively), and two-weekly schedule can be considered in patients where there are concerns about myelosuppression with the every 3 week regimen.
Cabazitaxel
Cabazitaxel is another taxane chemotherapy (Table 37.1). It has less affinity for drug efflux pump P-glycoprotein than docetaxel, and has shown anti-tumour activity in docetaxel-refractory pre-clinical models [63]. In mCRPC patients who had progressed during or after docetaxel-based therapy, the TROPIC trial showed an overall survival benefit of 2.4 months comparing three weekly cabazitaxel 25 mg/m2 and prednisone to mitoxantrone and prednisone (median 15.1 vs. 12.7 months, respectively, HR 0.7, 95% CI 0.59–0.83, p < 0.0001) [56]. Objective response rate (14.4% vs. 4.4%, p = 0.0005) and PSA50 (39.2% vs. 17.8%, p = 0.0002) were all significantly in favour of cabazitaxel. Cabazitaxel also has anti-tumour activity in the first line setting. FIRSTANA showed comparable overall survival with a median of 25.2, 24.5, and 24.3 months, in patients with chemotherapy-naïve mCRPC randomised 1:1:1 to receive cabazitaxel 25 mg/m2, 20 mg/m2, and docetaxel 75 mg/m2, respectively [59].
Compared to three weekly schedule, weekly cabazitaxel (weekly for 5 out of 6 weeks) resulted in comparable median doses, PSA50, and median PFS (6 vs. 6.4 months, respectively; HR 0.73, 95% CI 0.47–1.13, p = 0.156) [64] in a small phase II Scandinavian trial. Febrile neutropenia was more common with the three-weekly schedule (10 vs. 1 events), while weekly scheduling had more haematuria (20 vs. 6 events, p = 0.001). Three cases of painful ureteric inflammation were described with weekly cabazitaxel.
Cabazitaxel has a different toxicity profile from docetaxel, with adverse effects of interest including myelosuppression (8% febrile neutropenia), diarrhoea and haematuria. Alopecia and peripheral neuropathy are uncommon with cabazitaxel. Cabazitaxel-related toxicities including myelosuppression can be partially mitigated by prophylactic G-CSF or reducing cabazitaxel dose to 20 mg/m2, which has been shown to be non-inferior to the 25 mg/m2 dosing in terms of overall survival in the PROSELICA trial [65].
Mitoxantrone
Mitoxantrone is an anthracenedione (Table 37.1). It inhibits type II topoisomerase and is structurally similar to doxorubicin and daunorubicin. Mitoxantrone and prednisone were shown to be superior to prednisone alone using palliative response as the primary endpoint in patients with metastatic CRPC in 1996 [66]. Palliative response, as defined by a 2 point decrease in pain in a 6-point pain scale completed by patients, was 29% in the mitoxantrone group and 12% in the prednisone alone arm (p = 0.01). The duration of symptom control was 43 and 18 weeks, respectively (p < 0.001). There was no difference in overall survival between the two groups. The absence of survival advantage with mitoxantrone and corticosteroid combination was confirmed by Kantoff and colleagues comparing mitoxantrone plus hydrocortisone against hydrocortisone [67].
Platinum-Based Chemotherapy
Platinum-based chemotherapy (including cisplatin, carboplatin, oxaliplatin, satraplatin) exerts its cytotoxic effects by covalently binding to purine DNA bases, forming DNA intrastrand and interstand cross-links. This disrupts the normal functions of cellular DNA, causing DNA double-strand breaks and cell death. Platinum has shown anti-tumour activity in mCRPC either as monotherapy or in combination, but this enthusiasm has dampened since the phase III SPARC trial failed to demonstrate an overall survival benefit with oral satraplatin in unselected mCRPC patients [68].
The phase II RECARDO trial evaluated the benefit of adding carboplatin AUC4 to docetaxel 60 mg/m2 compared to docetaxel 75 mg/m2 in previously docetaxel-treated mCRPC patients with a progression-free interval of ≥3 months [69]. The primary endpoint of progression-free survival was 11.7 and 12.7 months in the combination and docetaxel arm, respectively (p = 0.98).
There is renewed interest in platinum-based chemotherapy with the increased understanding of the genomic landscape of mCRPC, particularly the high prevalence of germline and somatic alterations in homologous recombination repair genes especially BRCA1 and BRCA2 [70–73]. Although predictive of response to PARP inhibitors [74], tumour with a homologous recombination deficiency (HRD) have exhibited a high response rate to platinum-based therapy in retrospective studies [75–77].
Small Cell Carcinoma of the Prostate
Platinum-etoposide is the treatment of choice for patients with small cell carcinoma of the prostate, as extrapolated from the management of small cell lung cancer and supported by the NCCN clinical practice guidelines [78]. Although de novo small cell carcinoma of the prostate is rare [79], incidence of treatment-emergent neuroendocrine prostatic cancer (t-NEPC), or small cell carcinoma, increases with treatment and advanced disease, and was observed in 17% (27 of 160) of mCRPC patients [80].
As with small cell lung cancer, treatment response of t-NEPC to platinum chemotherapy is high but often short-lived, and new treatment strategies are needed. In an attempt to improve oncological outcomes, Aparicio and colleagues select 120 patients based on seven aggressive clinical features suggestive of small-cell carcinoma in a single arm phase II trial [81]. The seven inclusion criteria include small cell histology (pure or mixed), visceral metastases, predominant lytic bone metastases, bulky (≥5 cm) lymphadenopathy or bulky (≥5 cm) Gleason ≥8 prostate/pelvic mass, low PSA (≤10 ng/mL) plus high volume (≥20) bone metastases, presence of neuroendocrine markers on histology or in serum plus either one of elevated LDH (≥2 x institutional upper limit of normal, IULN), malignant hypercalcaemia, or elevated serum CEA (≥2 x IULN), and short interval (≤6 months) to androgen-independent progression. Histologic confirmation of small cell carcinoma was not required. Patients were treated with docetaxel 75 mg/m2 and carboplatin AUC 5, then cisplatin and etoposide upon progression, and achieved an overall survival of 16 months.
A retrospective study identified 29% (5/17) of patients with small cell prostatic carcinoma also harboured biallelic loss of DNA repair genes [79]. The median overall survival of these subsets of patients with or without DNA repair defects was 40.7 months and 20.1 months (p = 0.088), respectively. One patient with homozygous BRCA2 deletion had an exceptional durable response first to platinum-based chemotherapy and CNS radiation, and subsequently to olaparib which continued for at least 16 months was reported. This suggested novel therapeutic opportunities in a population traditionally with very poor outcomes.
Metastatic Castration-Sensitive Prostate Cancer (mCSPC)
Surgical or chemical castration with androgen deprivation therapy (ADT) alone has been the standard of care for patients with mCSPC for over 70 years when first described by Hugginsand Hodges [54]. The treatment landscape for mCSPC was transformed by the publications of CHAARTED and STAMPEDE trials in 2015 and 2016, respectively, to incorporate docetaxel with ADT in patients with mCSPC.
CHAARTED randomised 790 patients with metastatic castration-sensitive prostate cancer to ADT and six cycles of docetaxel 75 mg/m2 or ADT alone [82]. Concomitant prednisone was not a requirement. The addition of docetaxel significantly improved median overall survival by 13.6 months (57.6 vs. 44 months for chemohormonal combination vs. ADT alone, respectively; HR 0.61, 95% CI 0.47–0.8, p < 0.001). Time to CRPC was delayed by 8.5 months (median 20.2 vs. 11.7 months, respectively; HR 0.61, 95% CI 0.51–0.72, p < 0.001). With a longer median follow-up of 53.7 months, an a priori subgroup analysis revealed a median overall survival benefit of 17 months in patients with high-volume disease (defined as the presence of visceral metastases or ≥ 4 bone lesions with ≥1 beyond the vertebral bodies and pelvis) treated with chemohormonal therapy vs. ADT (median 51.2 vs. 34.4 months, respectively; HR 0.63, 95% CI 0.5–0.79, p < 0.001) [83]. No overall survival advantage was observed in patients with low-volume disease (HR 1.04, 95% CI 0.7–1.55, p = 0.86). There were no new safety concerns with docetaxel use in the castration-sensitive setting.
The survival benefit with chemo-hormonal treatment vs. ADT alone in mCSPC was confirmed in the multi-arm, multi-stage STAMPEDE trial. In the standard of care (SOC) + docetaxel arm, median overall survival was 81 months compared to 71 months in the SOC arm (HR 0.78, 0.66–0.93, p = 0.006) [84]. Failure free survival was also significantly improved with combination therapy over ADT alone (median 37 vs. 20 months, respectively; HR 0.61, 95% CI 0.53–0.7, p = 0.413 x 10−13). Unlike the CHAARTED trial, outcomes analysis according to tumour burden was not possible as this was not prospectively predefined in STAMPEDE. About 40% of patients had high-risk localised prostate cancer. Although failure-free survival was improved by the addition of docetaxel to ADT (HR 0.6, 95% CI 0.45–0.8; p = 0.28 x 10−3), overall survival data was immature in the subset of non-metastatic patients. The febrile neutropenia rate was high at 15% compared to 6.1% [82] in CHAARTED, otherwise the toxicity profile of docetaxel was in accordance with previous experience.
The above findings were in contrast with GETUG-AFU 15 [85]. Overall survival was not significantly different between mCSPC patients receiving docetaxel plus ADT vs. ADT alone (median 58.9 vs. 54.2 months; HR 1.01; 95% CI 0.75–1.36, p = 0.955). A post hoc retrospective analysis of the survival data according to volume of disease showed a nonsignificant trend towards improved overall survival in high-volume disease (39.8 vs. 35.1 months; HR 0.78, 95% CI 0.56–1.09, p = 0.14), and no overall survival difference in low volume disease [86].
The results of these three trials (CHAARTED, GETUG-15, STAMPEDE) were analysed by the Systemic Treatment Options for Prostate Cancer (STOpCaP) meta-analysis. It confirmed a significant survival benefit with the addition of docetaxel to standard of care in patients with mCSPC (HR 0.77, 95% CI 0.68–0.87, p < 0.0001), which translated to an absolute improvement in 4-year survival of 9% (95% CI 5–14) [87].
Taken together, these data confirm the benefit of docetaxel + ADT in metastatic CSPC patients. Subgroup analysis from CHAARTED indicated that the benefit is restricted to high volume disease, and the benefits and risks of adding docetaxel to SOC to patients with non-high volume disease must be carefully considered. Recently, abiraterone + ADT has been shown to improve overall survival (LATITUDE and STAMPEDE) and a further option for patients with mCSPC [88, 89]. An opportunistic analysis of the STAMPEDE trial comparing ADT + docetaxel vs. ADT + abiraterone suggested similar overall survival outcomes, although there are obvious difference in schedule and toxicity associated with each regimen [90]. ADT plus docetaxel plus next generation androgen receptor inhibitor will be evaluated directly and indirectly in several trials including PEACE1 (NCT01957436), TITAN (NCT02489318), ENZAMET (NCT02446405), and ARASENS (NCT02799602).
Localised Prostate Cancer
The practise-changing data from CHAARTED and STAMPEDE suggested earlier use of chemotherapy provided the greatest benefits for patients with metastatic disease. However, results from perioperative chemotherapy in localised prostate cancer have not been as promising, with no evidence of overall survival benefit identified as yet.
GETUG-12 compared four cycles of three-weekly docetaxel 70 mg/m2 + estramustine + 3 year of ADT vs. ADT alone in patients with high risk localised prostate cancer [91]. Local therapy was given after 3 months of systemic therapy, and could have been either radiotherapy (87%) or prostatectomy. The updated survival outcomes were recently presented in ESMO 2018. With a median follow-up of 12 years, clinical relapse-free survival was improved in the combination arm compared to ADT alone (adjusted HR 0.75, 95% CI 0.56–1, p = 0.049). Median metastases free survival (MFS) rates at 12 year were 62.2% vs. 55.8% (adjusted HR 0.81, 95% CI 0.6–1.09) [92].
RTOG 0521 randomised high-risk localised prostate cancer patients to docetaxel + ADT vs. ADT alone after definitive radiotherapy [93]. Preliminary results after a median follow-up of 5.5 years showed an improvement in 4-year overall survival (93% vs. 89%, docetaxel + ADT vs. ADT, respectively; HR 0.68, 95% CI 0.44–1.03, 1-sided p = 0.03). However, one must interpret these results with caution as non-prostate cancer death due to other primary tumour was disproportionately higher in the ADT arm than the combination arm.
The STOpCaP meta-analysis showed an absolute reduction of 8% in 4-year failure-free survival rates from 30 to 22% with docetaxel (HR 0.7, 95% CI 0.61–0.81, p < 0.0001) [87]. There was no statistically significant difference in 4-year overall survival between docetaxel and ADT (HR 0.87, 95% CI 0.69–1.09, p = 0.218). Since the report of the STOpCaP meta-analysis, SPCG12 trial reported no difference in the primary endpoint of PSA progression between adjuvant docetaxel without ADT or corticosteroids vs. surveillance in patients after prostatectomy. Note that 20% had detectable PSA at trial entry, one third of patients had no pelvic lymph node dissection, and this trial included patients without high-risk features e.g. pT2, Gleason 7.
SWOG S9921 trial with adjuvant mitoxantrone + prednisone + ADT (MP) vs. ADT post prostatectomy was a negative trial with comparable 10-year overall survival (86% vs. 87% respectively) [94]. More patients in the MP than ADT arm died of other cancers (36% vs. 18%, respectively).
At present, there was no evidence of either metastases-free survival, a potential surrogate for overall survival [95], or overall survival advantage of neoadjuvant or adjuvant docetaxel in localised prostate cancer. Results from two ongoing trials CALGB 90203 (NCT00430183) and PEACE-2 (NCT01952223) evaluating perioperative chemotherapy in localised prostate cancer will be reported in 2019.
Germ Cell Tumours
Testicular germ cell tumours (GCT) , even in patients with widely disseminated disease, are highly curable neoplasms with chemotherapy. Treatment strategy varies with staging. Management of early stage disease focuses on minimising exposure to treatment-related toxicity, while high dose myeloablative chemotherapy followed by autologous peripheral blood stem cell transplant (PBSCT) is used to overcome treatment resistance in relapsed disease.
Stage I Seminoma
Orchiectomy alone cures over 80% of patients with stage I seminoma [96–98]. The risk of relapse can be reduced to <5% with adjuvant radiotherapy or one cycle of carboplatin. However, active surveillance is often adopted to avoid late toxicities associated with adjuvant therapy, and effective salvage therapy exists such that long term overall survival and cause-specific survival are comparable and approach 100% regardless of the strategy used [98–100].
Traditionally, adjuvant radiotherapy has been the standard of care prior to the availability of effective chemotherapy for testicular GCT. The emerging knowledge of late toxicities including secondary malignancies and increased cardiovascular risks associated with radiotherapy has resulted in decline of adjuvant radiotherapy use in stage I seminoma [101, 102]. The finding of similar 5-year relapse-free rate of 94.7% for carboplatin and 96% for radiotherapy, the reduction in the rate of contralateral GCT with carboplatin versus radiotherapy (HR 0.22, 95% CI 0.05–0.95, p = 0.03), and the potential cumulative toxicities of salvage chemotherapy after adjuvant radiotherapy has made carboplatin the ideal choice should adjuvant therapy be considered [99]. It is important to dose carboplatin to AUC 7 as a lower dose is associated with a trend toward an inferior 5-year relapse-free rate [99].
A single course of carboplatin is usually well-tolerated. A prospective UK study evaluated 199 patients with a median follow-up of 9 years failed to show an excess mortality from secondary malignancies for adjuvant carboplatin [103]. A high standardized mortality ratio of 4.59 (95% CI 0.56–16.6) was observed for cerebrovascular disease but this was not statistically significant. Longer follow up measuring in decades is needed to establish the presence (or absence) of late toxicity for adjuvant carboplatin as testicular GCT patients are usually young men.
In practice, most men undergo active surveillance after orchiectomy unless compliance to regular follow-up is a concern. Giving adjuvant therapy to patients with high risk of relapse in a risk-adapted strategy has been proposed. Primary tumour size >4 cm and rete testis invasion were identified as independent predictors for relapse [96, 97]. Five-year relapse-free rates were 87.8%, 84.1%, and 68.5% for 0, 1, and 2 risk factors, respectively [97]. However effort to validate these risk factors in a prognostic model for risk of relapse in patients with stage I seminoma undergoing active surveillance has not been successful [104, 105]. Furthermore, in patients with equivocal retroperitoneal nodes, active surveillance would be the preferred option as carboplatin may be an insufficient treatment if stage II disease emerges with time.
Stage I Nonseminoma
Patients with clinical stage I nonseminomatous germ cell tumour (NSGCT) whose tumours exhibited lymphovascular invasion (LVI) and/or embryonal carcinoma predominant histology are at higher risk for relapse [106–108]. The risk of relapse was 10–15% in patients without LVI, compared with 40–50% in patients with LVI positive tumour [109, 110]. The majority (90%) of relapsed patients developed International Germ Cell Cancer Consensus Group (IGCCCG) good-risk disease [109]. Most relapses (>90%) occurred within 2 years, and all late recurrences were cured with standard of care. Importantly five-year disease specific survival was 99.7%.
Management options for stage I NSGCT post orchiectomy include active surveillance, nerve-sparing retroperitoneal lymph node dissection (RPLND), or adjuvant chemotherapy. Adjuvant RPLND was the standard of care prior to the advent of effective chemotherapy. The relapse rate after RPLND varies between 5 and 15%, and higher at 32% in patients with pathological stage II disease [111–113]. By excluding patients with persistently elevated serum tumour markers post RPLND or stage IIB disease, the 4-year progression-free probability improved from 83 to 96% [112]. Adjuvant chemotherapy with one cycle of bleomycin, etoposide and cisplatin (BEP, Table 37.2) reduced the relapse rate of LVI-positive and LVI-negative stage 1 nonseminoma to 3.2% and 1.3%, respectively, in the SWENOTECA trial [110]. An excellent long term outcome was achieved with 100% 5-year relapse free survival [114]. In a phase 3 trial comparing one cycle of adjuvant BEP versus RPLND, the 2-year recurrence-free survival rates were 99.5% and 91.9%, respectively, with a hazard ratio for recurrence of 7.9 for surgery versus chemotherapy (95% CI 1.8 to 34.5) [113].
Most oncologists recommend active surveillance for stage I nonseminoma patients with no risk factors for relapse and can adhere to regular follow up. There is still much debate over the optimal management of high risk stage I nonseminoma patients [115, 116]. NCCN guidelines recommended either active surveillance, RPLND, or adjuvant chemotherapy, and many large specialised centres advocate active surveillance regardless of risks [117–119]. RPLND is still an option for patients who would like to minimise their risks of relapse and avoid adjuvant chemotherapy, but it should be performed in high volume centres by an experienced surgeon to optimise clinical outcomes [113]. BEP-related toxicities is expected to be lower with only one cycle, as the risks of acute leukaemia, cardiovascular disease, pulmonary toxicity, nephrotoxicity, peripheral neuropathy, and ototoxicity increase with higher cumulative dose of BEP [120–124]. The extent of risk in particular late-toxicity remains unknown but is unlikely to be negligible. Ideally, adjuvant therapy should be given only to patients who will relapse to avoid unnecessary intervention for 85% of the low risk and 50% of high risk stage I nonseminoma patients who otherwise would have been cured with orchiectomy alone.
Stage II Seminoma
For patients with stage IIA disease, radiotherapy to the paraaortic and ipsilateral iliac lymph nodes, or chemotherapy with either three cycles of BEP or four cycles of etoposide cisplatin (EP) is indicated. Carboplatin AUC 7 alone is not recommended for clinical stage IIA seminoma as viable residual disease is unacceptably high and found in 19% of cases, including one patient (0.9%) with progressive disease [125].
The SWENOTECA study found 10.9% (3/29) of clinical stage IIA patients relapsed after radiotherapy, compared with no relapses (0/73) in clinical stage IIA/B patients who received chemotherapy [105]. The lower total radiotherapy dose of 27 Gy used in the SWENOTECA study compared to the conventional dose of 30–36 Gy may contribute to a higher reported relapse rate [126]. The efficacy of BEP x3 or EP x4 was again demonstrated in a study by the Spanish Germ Cell Cancer Group, which showed no relapses (0/18) in stage IIA patients treated with chemotherapy [127].
Chemotherapy with three cycles of BEP or four cycles of EP is the standard of care for patients with bulky (>3 cm) stage II disease. Five year cancer-specific and overall survival rates were 97.6% and 95.1%, respectively, in patients with stage IIC seminoma treated with chemotherapy [105].
Stage II Nonseminoma
Patients with clinical stage II nonseminoma with elevated serum tumour markers are treated as advanced disease according to IGCCCG risk groups with chemotherapy (see ‘Advanced Testicular Germ Cell Tumours below). RPLND may be an option for stage II nonseminoma with normal serum tumour markers and slowly growing tumours suspicious of teratoma or undifferentiated malignancy.
Advanced Germ Cell Tumours
The discovery of cisplatin’s efficacy in germ cell tumours has revolutionised the management of germ cell tumour [1]. The addition of vinblastine and bleomycin to cisplatin (PVB) in 1977 [2], and the substitution of vinblastine to etoposide in 1987 [128] improved the long term outcomes and tolerability of chemotherapeutics, and formed the basis of contemporary treatment for patients with advanced germ cell tumours.
Prognosis of advanced germ cell tumour is stratified into three risk groups by IGCCCG based on serum tumour marker levels, location of the primary tumour and metastases [129]. Five-year survival rates were 94%, 83%, and 71% for low, intermediate, poor risk groups, respectively [130]. Seminoma is only classified as low and intermediate risk as it is a more chemosensitive tumour and thus has a more favourable prognosis than nonseminoma.
Good-Risk Advanced Germ Cell Tumours
Three cycles of BEP or four cycles of EP is the standard of care for patients with good-risk advanced GCT. Substituting cisplatin with carboplatin is associated with inferior outcomes and is not recommended [131, 132].
To minimise chemotherapy-related toxicities in this patient group with generally favourable prognosis, three cycles of BEP was compared to four cycles of BEP and showed no significant difference in survival [133, 134]. EORTC compared four cycles of EP vs. four cycles of BEP, although in this study the etoposide dose utilized was lower at 360 mg/m2/cycle than the conventional dosing of 500 mg/m2/cycle [135]. The inclusion of bleomycin was associated with higher complete response (95% vs. 87%), fewer deaths (3% vs. 6%), at the expense of greater rates of pulmonary toxicity, neurotoxicity, and Raynaud-like phenomenon. Using the conventional etoposide dosing of 500 mg/m2/cycle, GETUG designed an equivalence trial which aimed to detect no more than 10% difference in favourable responses (clinical, biochemical and pathological complete responses or partial responses with normal serum tumour markers and subcentimeter residual masses) between three cycles of BEP and four cycles of EP [136]. No significant differences in 4-year event-free survival (91% vs. 86%, respectively; HR 0.58, 95% CI 0.29–1.19, p = 0.135) or 4-year overall survival (5 vs. 12 deaths, respectively, p = 0.096) were observed, but BEP x3 had significantly more all grade neurotoxicity (16% vs. 5%), dermatological toxicity including Raynaud phenomenon (29% vs. 8%), without significant difference in pulmonary toxicity (9% vs. 6%).
The importance of maintaining treatment dose-intensity was shown in the Australian and New Zealand Germ Cell Trial Group. The standard BEP was compared with an alternative regimen consisted of four cycles of three weekly 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide and days 1–3, and 30 kU bleomycin on day 1 [137]. The trial was stopped at the second planned interim analysis due to a substantially better overall survival with the standard BEP (HR 0.22, 95% CI 0.06–0.77, p = 0.008), with 1 and 9 disease-related death seen in the standard and alternate BEP respectively.
Intermediate/Poor Risk
Four cycles of BEP is the standard of care for intermediate and poor-risk patients. Other strategies including doubling cisplatin dose, alternating or sequential chemotherapy regimens, and high dose chemotherapy with stem cell rescue all failed to improve clinical outcomes over the standard BEP and are often associated with more toxicity [138–141].
Treatment intensification with the addition of paclitaxel to BEP in intermediate-risk patients was not associated with a significant difference in 3-year progression-free survival, although this EORTC 30983 trial was underpowered and included non-eligible patients with good and poor prognosis patients [142]. Serum tumour marker directed treatment intensification was explored in poor risk patients. After one cycle of BEP, patients with favourable tumour marker decline had ongoing BEP, while the rest were randomised to BEP or an intensified regimen with the addition of paclitaxel, oxaliplatin, and ifosfamide to BEP. This GETUG 13 trial showed patients with an unfavourable tumour marker decline treated with an intensified regimen had a superior 5-year progression-free survival compared to standard BEP (60% vs. 47%, respectively; HR 0.69, 95% CI 0.43–0.97, p = 0.04), but the difference in 5-year overall survival was not significantly different [143, 144]. The intensified regimen is also more toxic.
Although ifosfamide in combination with etoposide and cisplatin (VIP) was not superior to BEP and was more toxic [145, 146], it is an option for patients with underlying lung disease, high volume of pulmonary metastases or mediastinal NSGCTs in anticipation of upcoming thoracic surgery who would like to avoid bleomycin-related pulmonary toxicity.
A modified treatment in the first cycle with cisplatin 20 mg/m2 and etoposide 100 mg/m2 on days 1–3, followed by bleomycin 30 IU and 2 days of cisplatin etoposide between day 10 and 15, is recommended in patients with choriocarcinoma syndrome at risk of acute respiratory distress syndrome (ARDS) from induction chemotherapy [147].
Relapsed Disease
Patients with relapsed germ cell tumour after cisplatin-based therapy can be managed with either conventional-dose chemotherapy (CDCT) or high-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplant (PBSCT).
Common CDCT salvage regimens include VeIP (vinblastine, ifosfamide, ciplastin), TIP (paclitaxel, ifosfamide, cisplatin), and VIP (Table 37.2) [148–150]. As chemotherapy is often selected on the basis of absence of prior exposure in salvage therapy, TIP is commonly used as second-line therapy after standard first-line BEP. However, there is no direct comparison between different CDCT salvage regimens. For HDCT, two cycles of tandem carboplatin 2100 mg/m2 + etoposide 2250 mg/m2 over 3 days followed by PBSCT, and the TI-CE protocol (two cycles of paclitaxel + ifosfamide, followed by three cycles of high-dose carboplatin etoposide and PBSCT) is advocated by Indiana University and Memorial Sloan Kettering Cancer Center, respectively [151, 152]. More than one cycle of HDCT is preferred. A phase III trial showed 5-year overall survival was superior in the group receiving one cycle of VIP followed by three cycles of HDCT with carboplatin and etoposide, than three cycles of VIP followed by one cycle of HDC (49% vs. 39%, respectively, HR 1.42; 95% CI 0.99–2.05; p = 0.57) [153].
It is unclear whether patient with relapsed germ cell tumour should be treated with CDCT or HDCT as initial salvage therapy, and the optimal regimen for HDCT is undefined. Multicentre retrospective study showed 5-year overall survival was improved with HDCT compared with CDCT (53.2% vs. 40.8%, respectively; HR 0.65, 95% CI 0.56–0.75, p < 0.001) [154]. Apart from low risk group, this survival benefit was seen across all prognostic groups, and 27% of very high-risk patients who had HDCT were alive at 5 years compared to 3% for those with CDCT. Multivariable analysis of 364 patients from Indiana University identified HDCT as third-line or later therapy, platinum-refractory disease, mediastinal primary, nonseminoma histology, intermediate- or poor-risk disease at diagnosis, hCG ≥1000 U/L at initiation of HDCT as factors associated with disease progression [155]. Toxic death was reported in 2.5% (n = 9) of patients, and secondary leukaemia in 5 patients. The results of the TIGER study (NCT02375204) comparing CDCT using four cycles of TIP with HDCT using the TI-CE protocol as initial salvage treatment in patients with relapsed or refractory germ cell tumours are awaited.
Penile Cancer
Patients with locally advanced squamous cell carcinoma of the penis require multi-modality treatment including chemotherapy to improve long term outcomes. Palliative chemotherapy is the mainstay of treatment for patients with unresectable or metastatic disease. Due to the rarity of penile cancer it is difficult to validate standard of care in large prospective phase III trials, and only retrospective studies and small phase II trials are available to guide management.
Locally Advanced Penile Cancer
Patients with multiple, fixed, or bulky inguinal lymph node >4 cm, or evidence of pelvic lymphadenopathy i.e. ≥N2 disease can be considered for neoadjuvant chemotherapy followed by complete inguinal and pelvic lymph node dissection. Bleomycin-based and cisplatin-based regimens are both active in penile cancer, but bleomycin containing chemotherapy is poorly tolerated and associated with significant pulmonary toxicity [156, 157]. Taxane was later integrated into neoadjuvant chemotherapy to mirror its adoption in head and neck squamous cell carcinoma. A prospective, phase II, single arm trial evaluated the safety and efficacy of paclitaxel, ifosfamide and cisplatin (TIP) in patients with stage TxN2-3 M0 penile cancer (Table 37.2) [158]. Thirty men were recruited by MD Anderson Cancer Centre, of which 23 (77%) completed the scheduled four cycles of chemotherapy. Objective response rate (ORR) was 50%, including 3 (10%) complete response. Twenty-two (73.3%) patients proceeded to subsequent surgery. With a median follow up of 34 months, median time to progression (TTP) and overall survival were 8.1 months (95% CI 5.4–50+) and 17.1 months (95% CI 10.3–60+), respectively. Objective response to chemotherapy resulted in statistically significant improvement in TTP and overall survival. Univariate analysis showed absence of bilateral residual tumour, extranodal extension, or skin involvement were also associated with longer TTP and overall survival. A follow-up study increased the cohort size to 53 patients who had received neoadjuvant TIP. The updated ORR and CR were 65% and 19% respectively [159].
A similar regimen containing docetaxel, cisplatin, and 5-fluorouracil (TPF) was evaluated in two phase II studies [160, 161]. ORR ranged from 38.5 to 60%, with complete response seen in 4–8% (15/25). Median PFS and OS were 7 months and 10 to 14 months, respectively. About one quarter of patients failed to complete the planned cycles, and the regimen was poorly tolerated with 66% patients reported to have grade ≥3 toxicity. Due to substantial toxicity TIP is favoured over TFP. Other active neoadjuvant regimens include cisplatin + irinotecan and cisplatin +5-fluorouracil [156, 162] .
Standard adjuvant chemotherapy following surgery for locally advanced penile cancer has yet to be defined due to paucity of data. A retrospective multicentre study showed adjuvant chemotherapy (n = 36) was associated with improved overall survival (HR 0.4, 95% CI 0.19–0.87, p = 0.021) compared to expectant management (n = 48) in patients with positive pelvic lymph nodes following lymph node dissection from 1978 to 2013 [163]. A median OS of 22.7 months was achieved in another retrospective study in 21 patients who received adjuvant TPF [164].
NCCN guidelines recommend neoadjuvant TIP, and by extrapolation from the neoadjuvant data, adjuvant TIP in patients with penile cancer and ≥ N2 disease [165] . EAU guidelines also recommend neoadjuvant cisplatin and taxane based triplet in patients with fixed, unresectable lymphadnoeapthy [166]. Despite the curative intent of perioperative chemotherapy, prognosis is poor in patients with locally advanced penile cancer. In a multicentre analysis of individual patient-level data involving 201 patients who underwent perioperative chemotherapy and surgery from 1990 onward, 2-year survival in the neoadjuvant and adjuvant arms were only 36% and 57% respectively [167]. There was no statistically significant difference in overall survival between the two groups. The inherent limitations associated with small retrospective studies preclude accurate comparison of benefit derived from neoadjuvant versus adjuvant therapy. Objective response to neoadjuvant chemotherapy is an important prognostic factor. Patients who had an objective response following neoadjuvant chemotherapy achieved a 5-year survival rate of 50% in a series involving 61 patients [159].
Unresectable or Recurrent, or Metastatic Penile Cancer
Chemotherapy is the mainstay of treatment for patients with unresectable, recurrent, or metastatic penile cancer. First-line chemotherapy varies, and depends on prior treatment, patient’s co-morbidities and performance status. Similar to neoadjuvant chemotherapy, cisplatin-based therapy is preferred over bleomycin-containing regimen as it has a more favourable toxicity profile.
First-line cisplatin monotherapy resulted in a response rate of 15.4% [168]. To improve clinical outcomes, cisplatin was combined with 5-fluorouracil [169] or irinotecan [162]. These combinations were well-tolerated and improved response rate to >30%. Triplet combination with cisplatin, 5-fluorouracil, and docetaxel yielded a response rate of 38% and was tolerable in a Chinese study [170]. Bleomycin-based regimen with cisplatin and methotrexate provided similar response rate of 32.5%, but the treatment was toxic with five (11%) treatment related deaths out of 45 patients [171]. Other active regimens include cisplatin + gemcitabine [172], and carboplatin + paclitaxel [173]. MD Anderson study described above reported recurrence in 19 (63.3%) of 30 TxN2-3 M0 patients who had received neoadjuvant TIP for penile cancer [174]. Two of five evaluable patients responded with second-line bleomycin, methotrexate, and cisplatin, but one developed fatal pneumonitis. Prognosis is poor in patients with disseminated disease, with median PFS reported as 20 weeks in patients treated with first-line cisplatin and 5-fluorouracil [169].
The role of second-line chemotherapy remains undetermined. A phase 2 multicentre study evaluated paclitaxel in patients with disseminated penile cancer who had prior cisplatin-based chemotherapy in the neoadjuvant, adjuvant, or advanced setting found a response rate of 20% [175]. Median PFS was only 11 weeks, and median survival in responders was 32 weeks.
In patients with metastatic or recurrent penile cancer, NCCN guidelines recommend cisplatin-based chemotherapy [165], and EAU guidelines suggest chemotherapy with a grade C recommendation [166]. Epidermal growth factor receptor (EGFR) targeted therapies e.g. cetuximab, erlotinib, gefitinib, and panitumumab have shown promising activity and tolerability in patients with unresectable or metastatic penile cancer [176, 177]. The efficacy of checkpoint inhibitor (NCT02837042, NCT02721732, NCT03333616) and its combination with tyrosine kinase inhibitor cabozantinib (NCT02496208) are being evaluated in clinical trials. Integrating these therapies into current clinical practice, either alone or in combination with chemotherapy, may improve clinical outcomes. Identification of a predictive biomarker is critical to enrich patients who will benefit from treatment, and to avoid futile treatment in this cohort of patients with otherwise very poor prognosis.
Kidney Cancer
Clear cell renal cell carcinoma originates from the renal cortex and represents up to 85% of primary kidney neoplasms [178]. Targeted therapy such as anti-vascular endothelial growth factor (anti-VEGF) and immunotherapy with checkpoint inhibitor are the mainstay of treatment for advanced clear cell renal cell carcinoma. Chemotherapeutics have limited role in the management of renal cell carcinoma. The exceptions are collecting duct carcinoma and renal medullary carcinoma. Objective response rate to platinum-based regimens was 26% and 29%, respectively, in retrospective studies [179–181]. Prognosis was poor for these patients. The median overall survival was 10.5 months for patients with metastatic collecting duct carcinoma [179], and 2 year survival was only 13% in patients with renal medullary cancer [181].
Conclusion
Systemic therapy with chemotherapy plays an increasing role in the management of urological malignancies over the last 50 years. It contributes to incremental gain in survival in bladder, prostate, and penile cancer, and revolutionised treatment of testicular cancer offering cure to those even with advanced disease.
The optimal strategy to integrate chemotherapy with local therapies, as well as with other modalities of systemic therapies in the era of targeted therapy and immunotherapy requires multi-disciplinary approach and will be the focus of future research. This is particularly relevant for urothelial and kidney cancer where the potential of immunotherapy is being realised. The absence of significant recent advances in the management of testicular and penile cancer, especially for patients with relapsed germ cell tumour and advanced penile cancer where prognosis remains dismal warrant novel therapeutic approaches. Understanding the tumour genomic profile can refine patient selection to optimise treatment response and reduce exposure to futile therapy, as observed in exceptional responders to platinum in mCRPC patients with HRD tumours. This is critical as chemotherapy is often toxic and patients with urological cancer are often elderly and multi-comorbid. Even with quality data from well-designed RCTs, the treatment strategy must be tailored to individual patients based on their unique clinical attributes. The goal of care will always aim to maximise clinical benefit while minimising therapy-related toxicity.
