- Email: [email protected]
Important Considerations in the Clinical Use of Preoperative Prostate Cancer Predictive Nomograms
637
EUROPEAN UROLOGY 58 (2010) 636–638
Table 1 – Recent prospective and retrospective studies conducted on docetaxel retreatment in castration-resistant prostate cancer patients Reference
Type of study, sample size
Main inclusion criteria
Eymard et al. [4]
Retrospective, 148 patients
Loriot et al. [5]
Retrospective, 39 patients
Di Lorenzo et al. [6]
Phase 2 trial, 45 patients
Response to first-line docetaxel; no progression on docetaxel; docetaxel rechallenge Response to or stable disease with first-line docetaxel; progressive disease; docetaxel rechallenge Response to first-line docetaxel; no progression on docetaxel; docetaxel rechallenge
No. of administered cycles at rechallenge, median (range)
50% PSA response rate (95% CI)
Grade 3–4 hematologic toxicity
Overall survival (95% CI)
Not reported
48% (34.1–61.8)
6%
16 mo (13–20)
5 (2–10)
38% (23.3–55.3)
Not reported
16 mo (11.7–20.3)
3 (2–9)
24.5% (12.8–39.5)
Neutropenia: 8% Thrombocytopenia: 4%
13 mo (7–18)
Southwest Oncology Group (SWOG) 9916 trials [2]; however, according to our two-stage study design, it was sufficiently high to consider treatment active and worthy of further investigation. As we have already discussed, cabazitaxel has emerged as a more effective option in comparison to mitoxantrone in docetaxel-pretreated patients. The 17.8% rate of severe neutropenia reported in our study compares extremely favorably to the 81.7% rate of grade 3–4 neutropenia caused by cabazitaxel. Although a more thorough analysis will only be possible when results of the cabazitaxel trial is published in full form, it is our present opinion that in patients who fit the inclusion criteria of our study and who could not tolerate cabazitaxel toxicity, retreatment with docetaxel could be considered by virtue of its minor hematologic toxicity, which should be weighed against the potential greater efficacy of cabazitaxel. The number of docetaxelresponsive patients that could be eligible for docetaxel retreatment is a fundamental question that our study was not designed to answer. In this regard, results from Eymard et al. [4] suggest that such a retreatment could be possible in about 33% of patients who respond to first-line docetaxel, that is to say, a non-negligible proportion of all docetaxeltreated CRPC patients. We believe that in a particular subset of patients, which might represent a sufficiently high proportion of all docetaxel-treated patients, docetaxel rechallenge should be preferred to or should precede novel agents approved as second-line treatment, such as cabazitaxel. It is highly unlikely that a phase 3 trial of docetaxel retreatment versus cabazitaxel will ever be conducted in these patients, so our phase 2 trial appears even more important because it will continue to provide the best available evidence of docetaxel effectiveness in this particular setting.
Conflicts of interest: The authors have nothing to disclose.
Important Considerations in the Clinical Use of Preoperative Prostate Cancer Predictive Nomograms
patients with adenocarcinoma of the prostate remains unclear. Nomograms have been used to predict a wide array of outcomes for nearly every malignancy within the scope of urologic oncology. In prostate cancer, there are nomograms to predict incidence, pathologic stage, lymph node involvement (LNI), biochemical recurrence, development of
The role of pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP) is a subject of significant controversy. Whether PLND offers benefits in terms of biochemical recurrence-free and cancer-specific survival in
References [1] Di Lorenzo G, Buonerba C, Autorino R, De Placido S, Sternberg CN. Castration-resistant prostate cancer: current and emerging treatment strategies. Drugs 2010;70:983–1000. [2] Di Lorenzo G, Autorino R, Figg WD, De Placido S. Hormone-refractory prostate cancer: where are we going? Drugs 2007;67:1109–24. [3] Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 2008;54:1089–96. [4] Eymard JC, Oudard S, Gravis G, et al. Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study. BJU Int. In press. DOI:10.1111/j.1464-410X.2010.09296.x [5] Loriot Y, Massard C, Gross-Goupil M, et al. The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer. Eur J Cancer. In press. [6] Di Lorenzo G, Buonerba C, Faiella A, et al. Phase II study of docetaxel retreatment in docetaxel-pretreated castration-resistant prostate cancer. BJU Int. In press. Carlo Buonerba Giovannella Palmieri Giuseppe Di Lorenzo* Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita` degli Studi Federico II, Napoli, Italy *Corresponding author. Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita` degli Studi Federico II, Naples, Italy. Tel. +39 081 7462053; Fax: +39 081 7463660. E-mail address: [email protected] (G. Di Lorenzo) June 14, 2010 Published online ahead of print on June 23, 2010 doi:10.1016/j.eururo.2010.06.025
638
EUROPEAN UROLOGY 58 (2010) 636–638
metastases, response to salvage radiation therapy, and cancer-specific survival. While all nomograms have limitations, they represent a method to formulate a more individualized outcome prediction than can be obtained by simply grouping patients into risk categories based on a limited number of variables. The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram for prediction of LNI offers one means of determining which patients should have PLND at the time of RP [1]. The diagnostic, staging, and potentially therapeutic benefits of PLND must be weighed against increased operative times, costs, and complications. The most common complication of PLND is lymphocele (2–9%), but other potential complications include vascular injury, obturator nerve injury, and venous thromboembolism [2]. At our institution, we use a cut-off of 2% nomogrampredicted probability of LNI to determine whether PLND should be performed at the time of RP. It was noted that rounding the nomogram-predicted probability of LNI to a whole number (eg, 1%, 2%, or 3%), as is done with many nomograms, can lead to significant variability in the proportion of patients offered PLND. A rounded value of 2% includes all patients with a probability of LNI from 0 to 2.45%, whereas a value of 2.0% includes only those patients with a probability between 0 to 1.95%. While the difference may seem trivial, it is not. The vast majority of patients that undergo RP at our institution have a risk of LNI that clusters around 2%. Based on the application of the nomogram to a cohort of 3721 patients treated at our institution, the use of a >2% cut-off versus a 2.0% cut-off leads to PLND being recommended to 68% versus only 33% of patients. This represents a more than two-fold difference in the number of patients offered PLND at the time of RP.
In conclusion, it is important to consider the effects of rounding and patient clustering when applying nomogrampredicted probabilities to decision making, not only in the context of PLND at the time of RP but also for all potential applications of nomograms within the field of urologic oncology. The MSKCC Web site nomograms have now been modified to round to the nearest tenth of a percentage point to provide more precise predictions [1]. Conflicts of interest: The authors have nothing to disclose.
References [1] Prostate cancer nomograms: a tool for doctors and patients. Memorial
Sloan-Kettering
Cancer
Center
Web
site.
http://www.
mskcc.org/mskcc/html/10088.cfm. Accessed July 12, 2010. [2] Naselli A, Andreatta R, Introini C, et al. Predictors of symptomatic lymphocele after lymph node excision and radical prostatectomy. Urology 2010;75:630–5. Geoffrey T. Gotto Angel M. Cronin Vincent P. Laudone* Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Corresponding author. Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Tel. +1 917 940 7774 E-mail address: [email protected] (V.P. Laudone) July 20, 2010 Published online ahead of print on August 4, 2010 doi:10.1016/j.eururo.2010.07.029
EUROPEAN UROLOGY 58 (2010) 636–638
Table 1 – Recent prospective and retrospective studies conducted on docetaxel retreatment in castration-resistant prostate cancer patients Reference
Type of study, sample size
Main inclusion criteria
Eymard et al. [4]
Retrospective, 148 patients
Loriot et al. [5]
Retrospective, 39 patients
Di Lorenzo et al. [6]
Phase 2 trial, 45 patients
Response to first-line docetaxel; no progression on docetaxel; docetaxel rechallenge Response to or stable disease with first-line docetaxel; progressive disease; docetaxel rechallenge Response to first-line docetaxel; no progression on docetaxel; docetaxel rechallenge
No. of administered cycles at rechallenge, median (range)
50% PSA response rate (95% CI)
Grade 3–4 hematologic toxicity
Overall survival (95% CI)
Not reported
48% (34.1–61.8)
6%
16 mo (13–20)
5 (2–10)
38% (23.3–55.3)
Not reported
16 mo (11.7–20.3)
3 (2–9)
24.5% (12.8–39.5)
Neutropenia: 8% Thrombocytopenia: 4%
13 mo (7–18)
Southwest Oncology Group (SWOG) 9916 trials [2]; however, according to our two-stage study design, it was sufficiently high to consider treatment active and worthy of further investigation. As we have already discussed, cabazitaxel has emerged as a more effective option in comparison to mitoxantrone in docetaxel-pretreated patients. The 17.8% rate of severe neutropenia reported in our study compares extremely favorably to the 81.7% rate of grade 3–4 neutropenia caused by cabazitaxel. Although a more thorough analysis will only be possible when results of the cabazitaxel trial is published in full form, it is our present opinion that in patients who fit the inclusion criteria of our study and who could not tolerate cabazitaxel toxicity, retreatment with docetaxel could be considered by virtue of its minor hematologic toxicity, which should be weighed against the potential greater efficacy of cabazitaxel. The number of docetaxelresponsive patients that could be eligible for docetaxel retreatment is a fundamental question that our study was not designed to answer. In this regard, results from Eymard et al. [4] suggest that such a retreatment could be possible in about 33% of patients who respond to first-line docetaxel, that is to say, a non-negligible proportion of all docetaxeltreated CRPC patients. We believe that in a particular subset of patients, which might represent a sufficiently high proportion of all docetaxel-treated patients, docetaxel rechallenge should be preferred to or should precede novel agents approved as second-line treatment, such as cabazitaxel. It is highly unlikely that a phase 3 trial of docetaxel retreatment versus cabazitaxel will ever be conducted in these patients, so our phase 2 trial appears even more important because it will continue to provide the best available evidence of docetaxel effectiveness in this particular setting.
Conflicts of interest: The authors have nothing to disclose.
Important Considerations in the Clinical Use of Preoperative Prostate Cancer Predictive Nomograms
patients with adenocarcinoma of the prostate remains unclear. Nomograms have been used to predict a wide array of outcomes for nearly every malignancy within the scope of urologic oncology. In prostate cancer, there are nomograms to predict incidence, pathologic stage, lymph node involvement (LNI), biochemical recurrence, development of
The role of pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP) is a subject of significant controversy. Whether PLND offers benefits in terms of biochemical recurrence-free and cancer-specific survival in
References [1] Di Lorenzo G, Buonerba C, Autorino R, De Placido S, Sternberg CN. Castration-resistant prostate cancer: current and emerging treatment strategies. Drugs 2010;70:983–1000. [2] Di Lorenzo G, Autorino R, Figg WD, De Placido S. Hormone-refractory prostate cancer: where are we going? Drugs 2007;67:1109–24. [3] Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 2008;54:1089–96. [4] Eymard JC, Oudard S, Gravis G, et al. Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study. BJU Int. In press. DOI:10.1111/j.1464-410X.2010.09296.x [5] Loriot Y, Massard C, Gross-Goupil M, et al. The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer. Eur J Cancer. In press. [6] Di Lorenzo G, Buonerba C, Faiella A, et al. Phase II study of docetaxel retreatment in docetaxel-pretreated castration-resistant prostate cancer. BJU Int. In press. Carlo Buonerba Giovannella Palmieri Giuseppe Di Lorenzo* Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita` degli Studi Federico II, Napoli, Italy *Corresponding author. Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita` degli Studi Federico II, Naples, Italy. Tel. +39 081 7462053; Fax: +39 081 7463660. E-mail address: [email protected] (G. Di Lorenzo) June 14, 2010 Published online ahead of print on June 23, 2010 doi:10.1016/j.eururo.2010.06.025
638
EUROPEAN UROLOGY 58 (2010) 636–638
metastases, response to salvage radiation therapy, and cancer-specific survival. While all nomograms have limitations, they represent a method to formulate a more individualized outcome prediction than can be obtained by simply grouping patients into risk categories based on a limited number of variables. The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram for prediction of LNI offers one means of determining which patients should have PLND at the time of RP [1]. The diagnostic, staging, and potentially therapeutic benefits of PLND must be weighed against increased operative times, costs, and complications. The most common complication of PLND is lymphocele (2–9%), but other potential complications include vascular injury, obturator nerve injury, and venous thromboembolism [2]. At our institution, we use a cut-off of 2% nomogrampredicted probability of LNI to determine whether PLND should be performed at the time of RP. It was noted that rounding the nomogram-predicted probability of LNI to a whole number (eg, 1%, 2%, or 3%), as is done with many nomograms, can lead to significant variability in the proportion of patients offered PLND. A rounded value of 2% includes all patients with a probability of LNI from 0 to 2.45%, whereas a value of 2.0% includes only those patients with a probability between 0 to 1.95%. While the difference may seem trivial, it is not. The vast majority of patients that undergo RP at our institution have a risk of LNI that clusters around 2%. Based on the application of the nomogram to a cohort of 3721 patients treated at our institution, the use of a >2% cut-off versus a 2.0% cut-off leads to PLND being recommended to 68% versus only 33% of patients. This represents a more than two-fold difference in the number of patients offered PLND at the time of RP.
In conclusion, it is important to consider the effects of rounding and patient clustering when applying nomogrampredicted probabilities to decision making, not only in the context of PLND at the time of RP but also for all potential applications of nomograms within the field of urologic oncology. The MSKCC Web site nomograms have now been modified to round to the nearest tenth of a percentage point to provide more precise predictions [1]. Conflicts of interest: The authors have nothing to disclose.
References [1] Prostate cancer nomograms: a tool for doctors and patients. Memorial
Sloan-Kettering
Cancer
Center
Web
site.
http://www.
mskcc.org/mskcc/html/10088.cfm. Accessed July 12, 2010. [2] Naselli A, Andreatta R, Introini C, et al. Predictors of symptomatic lymphocele after lymph node excision and radical prostatectomy. Urology 2010;75:630–5. Geoffrey T. Gotto Angel M. Cronin Vincent P. Laudone* Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Corresponding author. Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Tel. +1 917 940 7774 E-mail address: [email protected] (V.P. Laudone) July 20, 2010 Published online ahead of print on August 4, 2010 doi:10.1016/j.eururo.2010.07.029