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Taxanes in the management of metastatic castration-resistant prostate cancer: Efficacy and management of toxicity

Critical Reviews in Oncology/Hematology

Abstract

Androgen deprivation is the therapy of choice in the majority of patients with metastatic prostate cancer. However, a state of castration resistance ultimately occurs after hormone therapy, thus defining metastatic castration-resistant prostate cancer (mCRPC). mCRPC has historically been considered a relatively chemoresistant tumor. However, due to its ability to improve survival and the quality of life in comparison with mitoxantrone, docetaxel has been established as the standard chemotherapeutic agent for first-line therapy since 2004. Moreover, recent results have shown that the novel taxane cabazitaxel is able to prolong the overall survival of patients with mCRPC previously treated with docetaxel. Even though these taxanes display a favorable toxicity profile, their routine use in clinical practice requires knowledge about the most frequent and distinct adverse events that may result from their administration.

Keywords: Prostate cancer, Docetaxel, Cabazitaxel, Drug toxicity.

1. Introduction

Prostate cancer is typically diagnosed at early stages, often through transrectal biopsy triggered by elevated levels of prostate specific antigen (PSA) [1] and [2]. In part due to the PSA screening programs, it is now the most common cancer in the male population in the United States, with an estimated 241,740 new cases in 2012 [2] . Despite its indolent course in most cases and the curability of localized disease by prostatectomy and/or radiation therapy in most patients, nearly over 10,000 men in the US alone are newly diagnosed with metastatic disease each year, and many other recur after local therapy, and it was responsible for an estimated 28,170 deaths in 2012 [2], [3], and [4]. For these patients, who typically have involvement of the axial skeleton, treatment is done with a palliative intent and often consists in androgen deprivation through surgical or pharmacological means [5] . Due to the reliance of prostate cancer cells on testosterone, androgen deprivation is initially active in 80–90% of patients and is associated with median progression-free survival (PFS) times that range from 12 to 30 months after treatment initiation [5] and [6]. However, prostate tumor cells eventually acquire the ability to proliferate in a serum androgen-depleted environment [3] and [7], and a median overall survival (OS) of only 8–16 months has been historically observed after the appearance of such androgen independency [5] and [6]. Along the years, the terms ‘androgen-independent’, and ‘hormone-refractory’, were used interchangeably – but today given the demonstrated sensitivity of CRPC to various androgen-targeted therapies, castrate-resistant is the current preferred term [8] – to denote disease that progresses despite castrate levels of testosterone [9] and [10]. Over the past 15 years, substantial progress has been achieved in the treatment of patients with of metastatic castration-resistant prostate cancer (mCRPC) with chemotherapy. In the following review, we will present historical developments and current perspectives on the treatment of these patients with taxanes, the most active class of chemotherapeutic agents in this setting.

2. Historical development of chemotherapy for mCRPC

Historically, prostate cancer has been considered a relatively chemoresistant tumor. Until the early 90s, several authors pointed out that the response rates to the agents that were then available were typically low and varied widely [11], [12], and [13]. Moreover, authors postulated that the documentation of responses in metastatic prostate cancer was complicated by the lack of established criteria, as nearly 80% of patients with this disease have no measurable soft tissue lesions [14] . Thus, objective responses could only be assessed in the minority of patients with measurable disease. In the early 90s, PSA became widely available and was introduced as a measure of response in clinical trials [3] and [15]. In 1999, a broadly cited consensus conference suggested the criterion for partial PSA responses in clinical trials, namely a decline of at least 50% from baseline levels, as long as there was confirmation at least 4 weeks later and no clinical or radiographic evidence of disease progression [16] . These criteria paved the way for a novel generation of trials in mCRPC. It should be noted, however, that PSA responses have not been validated as surrogates for OS in advanced prostate cancer, including both first and second line chemotherapies, with OS remaining the most accepted regulatory endpoint in phase III trials [17], [18], and [19]. In addition, PFS and time to tumor progression (TTP) have been used increasingly in selected clinical trials [9] , and recent data suggest that PSA progression is able to predict OS in mCRPC after some treatments [20] .

Several chemotherapeutic agents that were available before the PSA era, including some anthracyclines, alkylating agents, antimetabolites, platinums, and topoisomerase inhibitors, have been assessed in numerous phase II trials along the years [11] and [12]. In a landmark review of 26 different agents, the average response rate was only 8.7%, but the combination of vinblastine plus estramustine was regarded as promising [12] . The results of randomized trials with this combination at the time did not seem to establish a reference regimen, and the substantial toxicity remained a concern in the setting of palliative therapy [21] and [22]. In parallel, phase II trials of both mitoxantrone and low-dose prednisone had suggested modest single-agent activity and good tolerability profiles for these agents [23] and [24]. In randomized trials, the addition of mitoxantrone to a corticosteroid relieved pain and improved the quality of life more frequently than the same corticosteroid alone [25], [26], and [27], thus establishing mitoxantrone as the reference chemotherapeutic agent for the treatment of patients with mCRPC [28] . Of note, this approach was not associated with improvements in OS, and additional regimens were sought.

During the 90s, the nascent class of taxanes represented a logical next step in the search for novel agents with activity in mCRPC. Agents from this class were noted to bind beta-tubulin and inhibit the intrinsic instability of microtubules, the dynamic structures involved in the development and maintenance of cell shape, intracellular transport, and cell division; as a result, taxanes exert potent antitumor effects in various preclinical models and clinical settings [29] . In prostate cancer, increased expression of class III beta-tubulin may have a role in progression to the castration-resistant state [30] . Paclitaxel, the first taxane to become clinically available, displayed single-agent activity that was described as modest or encouraging in phase II trials [31] and [32]. On the other hand, a plethora of phase II trials assessed paclitaxel in combination with estramustine, another agent that is capable of inhibiting the function of microtubules. However, paclitaxel was not widely used in current clinical practice since there was not any phase III trials of paclitaxel, alone or in combination with estramustine, published so far.

3. Docetaxel in the first line

Docetaxel is a semisynthetic taxane that is able to inhibit the depolymerization of microtubules approximately twice as effectively as paclitaxel in pre-clinical models [33] . After the demonstration of its promising single-agent activity in phase II trials in mCRPC [34] and [35], docetaxel was assessed in two phase III trials with slightly different designs [28] and [36]. In the first trial, named TAX 327, 1006 patients with mCRPC were randomized to receive mitoxantrone (12 mg/m2 every 3 weeks), docetaxel (75 mg/m2 every 3 weeks), or weekly docetaxel (30 mg/m2), all combined with prednisone (5 mg twice daily) [28] . Both docetaxel regimens led to nominal improvements in OS, the primary endpoint of the study, when compared with mitoxantrone; however, the improvement was statistically significant only when docetaxel was administered every 3 weeks (hazard ratio [HR] = 0.76; P = 0.009), whereas weekly docetaxel led to a non-significant improvement (HR = 0.91; P = 0.36). The median OS in an updated analysis of TAX 327 was 19.2 months with docetaxel every 3 weeks, 17.8 months with weekly docetaxel, and 16.3 months with mitoxantrone [37] . Docetaxel was also associated with improvement in several secondary endpoints such as: pain improvement (35% vs 31% vs 22%, respectively for docetaxel every 3 weeks, docetaxel weekly and mitoxantrone), PSA responses (45% vs 48% vs 32%, respectively), and improvements in the quality of life (22% vs 23% vs 13%, respectively), were all significantly superior for both docetaxel schedules ( Table 1 ). An updated analysis of TAX-327 demonstrated that the median time to achieve PSA response or quality of life improvement was about 7 weeks, and there was a close correlation between those endpoints [37] . However, pain palliation usually occurred before, with a median time to pain palliation of about 4 weeks. Therefore, caution should be taken to avoid considering patients resistant to docetaxel too early in the course of first line treatment. The toxicity profile also showed a slightly increase in the adverse events compared to the mitoxantrone regimen [28] . More specific issues about the toxicity of docetaxel will be discussed in Section 5 .

Table 1 Main efficacy results in the phase III trials of docetaxel versus mitoxantrone in metastatic castration-resistant prostate cancer.

  Endpoint Docetaxel 75 mg/m2

q3w + prednisone (N = 335)
Mitoxantrone 12 mg/m2

q3w + prednisone (N = 337)
HR P value
TAX-327 Median OS (months) 18.9 16.5 0.76 0.009
Tumor response 12% 7%   0.11
PSA response 45% 32%   <0.001
Pain response 35% 22%   0.01
  Endpoint Docetaxel 60 mg/m2

q3w + estramustine (N = 338)
Mitoxantrone 12 mg/m2

q3w + prednisone (N = 336)
HR P value
SWOG-9916 Median OS (months) 17.5 15.6 0.80 0.02
Median PFS (months) 6.3 3.2   <0.001
Tumor response 17% 11%   0.30
PSA response 50% 27%   <0.001

OS, overall survival; PFS, progression free survival; PSA, prostate specific antigen.

In the second phase III trial (SWOG-9916), 674 patients with mCRPC were randomized to receive docetaxel (60 mg/m2 on day 2) combined with estramustine (280 mg three times daily on days 1 through 5) and dexamethasone (in three divided doses before docetaxel), or mitoxantrone (12 mg/m2) plus prednisone (5 mg twice daily), both regimens given every 3 weeks [36] . The median OS, the primary endpoint, was significantly longer with the docetaxel regimen than with mitoxantrone (17.5 months vs 15.6 months; HR = 0.80; P = 0.02). Likewise, PFS (median of 6.3 months vs 3.2 months), and PSA responses (50% vs 27%), were significantly improved with the docetaxel-containing regimen, which was again slightly more toxic ( Table 1 ). Once again, the role of estramustine remained uncertain after this study since it did not have an arm of docetaxel without estramustine. Nevertheless, there were 2 randomized phase 2 trials comparing docetaxel every 3 weeks with or without estramustine [38] and [39]. These trials have shown an improvement in the PSA response rate with the addition of estramustine (30% vs 68% [39] and 40% vs 75% [38] ). In addition, a meta-analysis has also shown an improvement in survival at the cost of an increased risk of thromboembolic events [40] . Nevertheless, since there was no phase 3 trial evaluating the utility of adding estramustine to docetaxel, and due to the fact of its increased risk for thromboembolic events, estramustine use did not have a widespread acceptance by the medical oncology community overall. In addition, there is no phase III trial in progress pursuing it.

The results of these two phase III trials established docetaxel as the new standard agent for first-line treatment and as a reference for future studies in symptomatic mCRPC. Recently, neither the addition of high-dose calcitriol nor bevacizumab provided benefit, when compared with the standard regimen of docetaxel every 3 weeks and prednisone in patients with mCRPC [41] and [42]. Other agents with potential to improve the activity of single-agent docetaxel are under investigation [43] . In addition, docetaxel is also being evaluated against cabazitaxel, the last generation of taxane, in a phase III randomized trial (FIRSTANA – NCT01308567 ).

4. Cabazitaxel in the second line

Cabazitaxel, a novel taxane identified in a systematic screening for novel compounds in this class, is active in preclinical models that are resistant to paclitaxel and docetaxel [44] and [45]. Cabazitaxel inhibits the depolymerization of microtubules as effectively as docetaxel [46] . Furthermore, pre clinical models show that cabazitaxel is able to cross the blood–brain barrier, a potential advantage in the treatment of some malignancies [44] . Based on the results of phase I and II trials, investigators recommended a dose of cabazitaxel for further studies that ranged from 20 to 25 mg/m2, and activity was seen in docetaxel-refractory prostate cancer as well as in other tumors [45] and [47].

Data from TAX 327 have suggested that the median OS of patients who cross over from docetaxel to mitoxantrone after disease progression is 10 months [48] , thus signaling the need for further improvements. A phase III trial, named TROPIC, was launched with the aim of comparing cabazitaxel with mitoxantrone in docetaxel-refractory mCRPC. [49] In this study, 775 patients were treated with prednisone (10 mg daily) and were randomized to receive either cabazitaxel (25 mg/m2) or mitoxantrone (12 mg/m2) every 3 weeks, having OS as the primary endpoint in the study. Of note, this trial included a significant number of patients that progressed during or <3 months after last dose of docetaxel (about 75% of patients), meaning a relatively docetaxel-resistant population. Cabazitaxel was associated with a significant improvement in OS, with a median OS of 15.1 months in the cabazitaxel group and 12.7 months in the mitoxantrone group (HR = 0.70; P < 0.0001). These and other efficacy results are depicted in Table 2 . The updated Kaplan–Meier curve of TROPIC trial showed that the probability of surviving ≥2 years almost doubled with cabazitaxel (27% vs 16%), with an OR of 2.11 (95% CI 1.33–3.33) [50] . Additional subgroup analyses have shown that most subgroups of patients have similar benefit favoring cabazitaxel treatment, although not always statistically significant probably due to the smaller number of patients in each subgroup. It is important to note that patients progressing after first line treatment during, <3 months or ≥3 months from docetaxel had similar HR varying from 0.64 to 0.75 [49] . Additionally, subgroup analysis has also shown that treatment with cabazitaxel significantly improved overall survival of patients with poorly differentiated tumor histopathology [51] . Abiraterone and enzalutamide were also recently approved for treatment of patients with mCRPC progressing after docetaxel based on results of phase III trials showing improvement in overall survival [52] and [53]. In both phase III trials there were not reported subgroup analysis regarding the time to progression on or after docetaxel use. However, there are some retrospective studies suggesting that abiraterone may be less effective in patients progressing early on docetaxel [54] . Based on this data, we could speculate that these patients may be better treated with cabazitaxel, although prospective data are lacking.

Table 2 Main efficacy results in the phase III trial of cabazitaxel versus mitoxantrone in metastatic castration-resistant prostate cancer (TROPIC) [46] .

  Endpoint Cabazitaxel + prednisone (N = 378) Mitoxantrone + prednisone (N = 377) HR P value
TROPIC Median OS (months) 15.1 12.7 0.70 <0.001
Median PFS (months) 2.8 1.4 0.74 <0.001
Tumor response 14.4% 4.4%   <0.001
PSA response 39.2% 17.8%   <0.001
Pain response 9.2% 7.7%   0.63

OS, overall survival; PFS, progression free survival; PSA, prostate specific antigen.

Interestingly and compared to the current newer anti-hormonal agents abiraterone and enzalutamide, there are emerging pre-clinical data suggesting that the taxanes may also be involved in the inhibition of androgen receptor (AR) migration to the nucleus, which could be a new mechanism of action partly responsible for the activity against prostate cancer cells. This pre-clinical data shows that mitoxantrone did not inhibit the AR nuclear translocation, while cabazitaxel and docetaxel both partly inhibited, although cabazitaxel was more potent, and abiraterone and enzalutamide were the most potent agents inhibiting the AR nuclear translocation [55] .

The toxicity profile showed that cabazitaxel was associated with a higher incidence of adverse events than mitoxantrone. However, sensory neuropathy was seen in only 14% of patients and was typically mild or moderate in severity [49] . Considering only sensory neuropathy of grade ≥3, the incidence was only 0.8%. Furthermore, few patients with pre-existing grade 1–2 neuropathy reported worsening of symptoms [50] . In addition, it is important to note that subsequent expanded access programs or compassionate use programs with cabazitaxel have shown a clinically lower incidence of adverse events overall [56], [57], and [58]. This could be due to the poor control of these programs with sub-estimated incidences of adverse events. Nevertheless, at the same time we believe that these expanded access programs serve as real world experience with newer drugs. The results of this phase III trial, including the 30% reduction in the risk of death, led to approval of cabazitaxel for the second-line treatment of mCRPC in many countries. Of note, cabazitaxel is the only agent that has been compared with a chemotherapy control in a phase III trial in the second line, as satraplatin [59] , abiraterone [52] and enzalutamide [60] were compared in their respective pivotal studies with placebo with or without prednisone, in the case of enzalutamide, whereas sipuleucel-T was assessed in chemotherapy-naïve patients with asymptomatic or minimally symptomatic disease [61] . Recent phase III trials in second-line therapy are summarized in Table 3 . Furthermore, an exploratory analysis of TROPIC trial have shown some association of improvement in survival with PSA decrease of 30% or more, however this biomarker failed to fulfill the statistical requirement to serve as surrogate marker for overall survival [19] .

Table 3 Summary of completed phase III trials in the second-line treatment of metastatic castration-resistant prostate cancer (mCRPC).

Study Experimental agent N Interventions Primary endpoint Main results
SPARC [47] Satraplatin 950 Satraplatin + prednisone

Placebo + prednisone
PFS HR for PFS: 0.67 (P < 0.001);

HR for OS: 0.98 (P = 0.80)
TROPIC [46] Cabazitaxel 755 Cabazitaxel + prednisone

Mitoxantrone + prednisone
OS HR for PFS: 0.74 (P < 0.001);

HR for OS: 0.70 (P < 0.001)
COU-AA-301 [48] Abiraterone 1195 Abiraterone + prednisone

Placebo + prednisone
OS HR for PFS: 0.67 (P < 0.001);

HR for OS: 0.65 (P < 0.001)
AFFIRM [49] MDV3100 1199 MDV3100 ± corticosteroids a

Placebo ± corticosteroids a
OS HR for OS: 0.63 (P < 0.001)

a Corticosteroids were allowed but not required.

HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

5. Incidence and management of taxane-associated toxicity

Despite their activity, all taxanes are associated with adverse events that may compromise patient quality of life and that may lead to dose reduction or discontinuation of treatment, potentially compromising its efficacy. In some circumstances, inadequately managed toxicity may outweigh the potential benefits of treatment with these agents. Thus, knowledge about the most frequent and the most distinct adverse events that may result from their administration is one of the keys to the successful use of docetaxel and cabazitaxel in clinical practice.

5.1. Hematological toxicity

Overall, myelosuppression is the most frequent adverse event category associated with the use of taxanes. Table 4 displays the rates of neutropenia, thrombocytopenia and anemia with single-agent docetaxel and cabazitaxel, always in combination with a corticosteroid, in the phase III trials among patients with prostate cancer. It should be noted that the incidence of grade 3 or 4 neutropenia in the control group of these two trials, both treated with mitoxantrone and prednisone, was markedly different (22% vs 58%, respectively), likely as a reflection of more advanced disease and extent of prior therapy in the first line. It is also noteworthy that monitoring of neutropenia was distinct between the first line and second line trials. Therefore, the numerical differences in rates of the adverse events shown in Table 4 should not be taken to indicate quantitative differences between the toxicity of docetaxel and cabazitaxel. Only randomized head to head comparisons can truly compare neutropenia rates, and this is currently being evaluated in the randomized first-line treatment of mCRPC (FIRSTANA trial – NCT01308567 ).

Table 4 Rates of grade 3 or more hematological adverse events with 3-weekly docetaxel and cabazitaxel in the phase III trials among patients with prostate cancer.

Adverse event Docetaxel (N = 332) [27] Cabazitaxel (N = 371) [46]
Neutropenia (%) 32 82
Febrile neutropenia (%) 3 8
Thrombocytopenia (%) 1 4
Anemia (%) 5 11

NR, not reported.

Although neutropenia is frequent with both agents, febrile neutropenia is the most relevant hematological adverse event, as this is a life-threatening complication that may also require dose reductions or delays [62] . Febrile neutropenia was seen in 3% of patients treated with 3-weekly docetaxel in the TAX 327 trial and in 8% of those treated with cabazitaxel in the TROPIC trial [28] and [49]. In the latter trial, primary prophylaxis with granulocyte-colony-stimulating factor (G-CSF) was not allowed in the first cycle, but G-CSF use was permitted after a first occurrence of neutropenia with protocol-defined complications. Thus, 72% of treatment cycles were administered without, and 28% with, G-CSF. In a retrospective analysis, the authors found that G-CSF use reduced the incidence and severity of cabazitaxel-associated neutropenia, especially when done as prophylaxis [63] . Randomized study is under way to assess whether the use of lower initial dose of cabazitaxel is non-inferior to the standard 25 mg/m2 comparing the efficacy and overall safety. It will help to determine if a lower dose could reduce the incidence of adverse effects without compromising efficacy.

It is also important to point out that the incidence of neutropenia in several expanded access and compassionate use programs have shown a clinically significant lower incidence of neutropenia. These trials usually reflect a less selected patient population and they usually do not have a very strict control of adverse events. The incidence if high-grade neutropenia varied from 7.2 to 35.2% in these trials, while the incidence of febrile neutropenia was 1.8 to 4.2% (REF) [56], [57], and [58]. These variations are probably explained by the differences in the use of prophylactic granulocyte colony stimulating factor. Nevertheless, they seem to be much lower than the ones observed in the phase III TROPIC trial. Due to the nature of these compassionate and expanded access programs, these clinically significant lower incidences may indicate that the true incidence in the real world may not be as high as shown in the phase III TROPIC trial. In addition, a phase III trial comparing a lower cabazitaxel dose of 20 mg/m2 to the standard dose of 25 mg/m2 is being conducted in order to evaluate the efficacy and the toxicity profile (PROSELICA – NCT01308580 ).

Unfortunately, prostate-cancer specific validated models that are able to predict the risk of febrile neutropenia in individual patients are not currently available. When general models are considered, risk factors for febrile neutropenia that are commonly present in patients with prostate cancer include age of 65 years or older, history of prior neutropenia, advanced stage and the presence of comorbidities [62] . In the TROPIC trial, an association was confirmed between the incidence of neutropenia and age, with patients older than 65 years displaying a significantly higher risk than the younger patients [49] . Prevention and management of febrile neutropenia among patients treated with docetaxel and cabazitaxel should therefore follow one of the published guidelines on this subject [64] and [65]. The US FDA have suggested in the label: “Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age >65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications.” Moreover, recommendations for dose modification are available from the manufacturer and are shown in Table 5 [66] and [67].

Table 5 Manufacturer's recommendations for dose reduction of docetaxel and cabazitaxel in patients with selected adverse events [55] and [56].

Agent Toxicity Recommended action
Docetaxel Febrile neutropenia, neutrophil count <500/mm3 for more than 1 week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms. Reduce dose from 75 mg/m2 to 60 mg/m2.
Continued adverse events at the dose of 60 mg/m2. Discontinue.
 
Cabazitaxel Grade ≥3 neutropenia for more than 1 week despite appropriate medication, including G-CSF. Delay treatment until neutrophil count is >1500/mm3, then reduce dose from 25 mg/m2 to 20 mg/m2. Use G-CSF for secondary prophylaxis.
Febrile neutropenia. Delay treatment until improvement or resolution, and until neutrophil count is >1500/mm3, then reduce dose from 25 mg/m2 to 20 mg/m2. Use G-CSF for secondary prophylaxis.
Grade ≥3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement. Delay treatment until resolution, then reduce dose from 25 mg/m2 to 20 mg/m2.
Continued adverse events at the dose of 20 mg/m2. Discontinue.

G-CSF, granulocyte-colony-stimulating factor.

5.2. Non-hematological toxicity

Although nausea and vomiting are relatively frequent after the administration of docetaxel, the incidence of these adverse events was not significantly different from the one associated with mitoxantrone in prostate cancer [28] . In comparison with mitoxantrone, however, cabazitaxel is associated with a significantly higher incidence of nausea and vomiting, but most cases were graded as mild or moderate in severity [49] . On the other hand, diarrhea is significantly more frequent with these two taxanes than with mitoxantrone, although most cases are graded as mild or moderate [28] and [49]. For cabazitaxel, there are dose-reduction recommendations from the manufacturer in cases of persistent or severe diarrhea ( Table 5 ) [67] . In the TROPIC trial, in which diarrhea was managed expectantly, this adverse event was significantly more frequent among patients aged 75 years or older, as well as in those with prior radiotherapy, in comparison with their respective counterparts [49] . Therefore, it is usually recommended that patients presenting with diarrhea after treatment with docetaxel or cabazitaxel, not resolved by oral antidiarrheal medicines and fluids, should receive aggressive intravenous hydration in order to avoid further deterioration.

Docetaxel displays some distinct adverse events that have not occurred with cabazitaxel (i.e., have not been seen in grade 3 or higher in more than 1% of patients with prostate cancer): sensory neuropathy, nail changes, and tearing. These adverse events were seen in 30%, 30%, and 10%, respectively, of patients treated with 3-weekly docetaxel in TAX 327 [28] . Of note, it is important to point out that only 1% of patients with prostate cancer treated with cabazitaxel in the second line had sensory neuropathy of grade 3 [49] . This may be very important since several patients treated with docetaxel may have residual neuropathy before cabazitaxel treatment. Onycholysis during treatment with docetaxel typically resolve after discontinuation; during chemotherapy, patients may be advised to protect their nails from dirt and trauma, to wear comfortable shoes, and to use bath oil [62] . Epiphora, or excessive tearing, is caused by canalicular stenosis and nasolacrimal duct obstruction induced by docetaxel [68] . Although often unrecognized, it appears to be common when a standardized ophthalmologic assessment is undertaken, especially with weekly docetaxel [69] . Epiphora that does not improve with topical antibiotics and dexamethasone should be managed aggressively through catheterization or surgical procedures performed by ophthalmologists, in order to prevent further complications.

Fluid retention, another frequent adverse event associated with docetaxel despite the preventive use of corticosteroids, was seen in 19% of patients treated with this agent and in only 1% of those treated with mitoxantrone in TAX 327 [28] . In the TROPIC trial, peripheral edema was seen in 9% of patients in each group, which suggests that fluid retention is not a distinct adverse event associated with cabazitaxel [49] . Fluid retention that results from the use of taxanes should be managed with diuretics without delay [62] .

6. Conclusions

The introduction of docetaxel started a new era for patients with mCRPC, whose median OS was extended for the first time in randomized trials [28] and [36]. Over the past 5 years, additional progress has resulted from the introduction of novel agents, including cabazitaxel, abiraterone, ezalutamide and radium-223, with activity in docetaxel-refractory disease and with the potential to improve OS also in the second line [49], [52], [53], and [70]. As a result, a median OS approaching 30 months can now be expected in properly selected patients with mCRPC who are able to receive both first-line docetaxel and second-line cabazitaxel [71] . Due to the recent development and approval of all these new drugs almost concomitantly, it is not well understood how to sequence them. Several retrospective series have shown that there is some cross-resistance among them. It is expected that further results of studies on these and other novel agents will expand the therapeutic arsenal against mCRPC over the next few years. Meanwhile, judicious use of docetaxel and cabazitaxel, with proactive management of the adverse events associated with these agents in their respective treatment lines, is the surest way to translate clinical trial results into practice and to provide patients with a longer and better survival.

Conflict of interest

FAS: None to declare.

ACB: Member of the advisory board of Sanofi-Aventis.

OS: Investigator and consultant, Sanofi.

Role of the funding source

Editorial support was provided by Dr. Everardo D. Saad from Dendrix Ltd. and supported by Sanofi. Neither Dendrix Ltd. nor Sanofi had any role in the final content of this manuscript. The authors had the final responsibility for the decision to submit the manuscript for publication.

Reviewers

Joaquim Bellmunt, MD, PhD, Section Chief, Solid Tumor Oncology (GU & GI), Hospital del Mar, Medical Oncology Service, Passeig Marítimo 25-29, E-08003 Barcelona, Spain.

Prof. Cora Sternberg, San Camillo and Forlanini Hospitals, Department of Medical Oncology, Nuovi Padiglioni, Circonvallazione Gianicolense 87, I-00152 Rome, Italy.

Dr. Dominik R. Berthold, Medical Oncology, Rue Bugnon 46, CH-1011 Lausanne, Switzerland.

Acknowledgement

We would like to thank Dr. Everardo D. Saad for the editorial support in this manuscript.

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Dr. Fabio A.B. Schutz is a former Research Associate at Dana Farber Cancer Institute/Harvard Medical School, Lank Center for Genitourinary Oncology department. Currently, Dr. Schutz is a staff medical oncologist of Hospital Sao Jose and the clinical coordinator of Medical Oncology of the Hospital Sao Joaquim from the Beneficencia Portuguesa de Sao Paulo. Dr. Schutz authored and co-authored several manuscripts in genitourinary oncology.

Footnotes

a Hospital Sao Jose – Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil

b Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, United States

lowast Corresponding author at: Rua Martiniano de Carvalho 965, Sao Paulo 01321-001, Brazil. Tel.: +55 11 3505 6615; fax: +55 11 3505 6615.


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