|INDICATION: CLINICAL STUDY - ORIGINAL ARTICLE
|Year : 2014 | Volume
| Issue : 3 | Page : 363-365
Beyond ten cycles of cabazitaxel for castrate-resistant prostate cancer
V Noronha, A Joshi, K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||10-Dec-2014|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: There are limited data regarding cabazitaxel use beyond 10 cycles. Patients and Methods: Retrospective analysis of prospectively collected data of patients with metastatic castrate-resistant prostate cancer who received over 10 cycles of cabazitaxel after docetaxel failure. Results: Four patients received between 14 and 27 cycles. Reasons for stopping cabazitaxel were toxicity (2), progression (1) and logistics (1). Two of the three patients with measurable disease attained a partial remission (PR). Three patients continued to have a PSA response after 10 cycles; PSA nadir occurred between 17 and 23 cycles. Other than peripheral neuropathy (PN), all the cabazitaxel-related toxicities occurred after the initial cycles and did not increase cumulatively. Clinically significant neuropathy occurred after 15-17 cycles. The cabazitaxel-induced PN was partially reversible, with improvement from grade 3 to grade 2 after a 3-5-month long drug holiday. Conclusion: Cautiously continuing cabazitaxel until progression or intolerable toxicity may maximize efficacy.
Keywords: Cabazitaxel, carcinoma, cycle number, extended, neuropathy, peripheral nerve disease, prolonged chemotherapy, prostate
|How to cite this article:|
Noronha V, Joshi A, Prabhash K. Beyond ten cycles of cabazitaxel for castrate-resistant prostate cancer. Indian J Cancer 2014;51:363-5
| » Introduction|| |
Cabazitaxel is approved as second-line chemotherapy in castrate-resistant prostate cancer (CRPC). The pivotal TROPIC trial demonstrated a survival advantage for cabazitaxel over mitoxantrone in combination with prednisone in CRPC patients who had failed first-line docetaxel-based therapy.  The maximum number of cabazitaxel cycles was limited to 10 to minimize cardiac toxicity from mitoxantrone and to allow a comparable exposure to chemotherapy in both arms. There are limited data for the safety and efficacy of administering over 10 cycles of cabazitaxel. Thus, treating oncologists face the dilemma of whether to continue cabazitaxel beyond 10 cycles in patients who are responding without major toxicity.
| » Patients and Methods|| |
Before January 2012, cabazitaxel was not commercially available in India and was provided on a compassionate basis by Sanofi Aventis. All the patients had CRPC, had failed docetaxel chemotherapy, had no uncontrolled comorbidities and normal liver and renal functions. Cabazitaxel was administered at 25 mg/m 2 intravenously over 1 h weekly with standard pre-medications. All details were prospectively entered into a Microsoft excel database. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Response was assessed according to the response evaluation criteria in solid tumors (RECIST), version 1.1. PSA response was defined as PSA decrease of ≥50%. Progression was defined as PSA progression (standard definition),  symptom deterioration, objective progressive disease (PD) on scan or death from any cause. Progression-free survival (PFS) and overall survival (OS) were calculated as the time interval between the date of first cabazitaxel cycle to the date of progression or death from any cause for PFS and death for OS. We present a retrospective analysis of the prospectively entered data of the patients who received over 10 cycles of cabazitaxel. Analysis of toxicity and response was by simple percentages. Survival was analyzed using SPSS version 17.
| » Results|| |
Between April 2011 and February 2013, we treated 14 patients with cabazitaxel, four of whom received over 10 cycles [Table 1].
|Table 1: Details of patients who received over 10 cycles of cabazitaxel |
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PSA response was noted in all patients [Figure 1]. In three of the four patients, the PSA continued to decrease after 10 cycles, with the PSA nadir attained after 17-23 cycles. Patient 1 had progressive decrease in the sum of maximal tumor diameters on serial scans and attained maximal response radiologically after 10 cycles; this PR was maintained on subsequent scans. His PSA continued to decrease from his pre-cabazitaxel baseline of 89 ng/mL to a nadir of 0.25 ng/mL after cycle 15. His PSA continued to remain low, measuring 0.26 ng/mL after cycle 17. Cabazitaxel was then held due to peripheral neuropathy (PN). Patient 4 achieved a PR after four cycles; reimaging after 10 cycles revealed PD; however, his PSA decreased from 130 ng/mL pre-cycle 1 to a nadir of 5 ng/mL after cycle 6. His PSA then started to rise, but he continued to experience symptom relief; hence, cabazitaxel was continued until 14 cycles. Patient 3 had PD as best response even on initial imaging after three cycles; however, cabazitaxel was continued as he had significant subjective improvement (60% decrease in bone pains, reduction in analgesic usage, decreased weakness and improvement in general well-being); his baseline PSA was 555 ng/mL, which increased after the first two cycles to 610 ng/mL (PSA-flare phenomenon), then progressively decreased to 113 ng/mL after 10 cycles to a nadir of 8.17 ng/mL after cycle 23.
|Figure 1: Graph of PSA value (logarithmic value of actual PSA value in ng/mL on the y-axis) measured prior to each cycle of cabazitaxel (the cabazitaxel cycle number is plotted on the x-axis). This figure shows that the PSA value continues to decrease after 10 cycles in three of four patients on cabazitaxel|
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Patient 2 had bone-only metastases, with no measurable lesion. Radiologic assessment in this patient consisted of serial bone scans. His baseline scan was a superscan, indicative of extensive bony metastases; he had marked symptom relief from chemotherapy with complete resolution of bone pains by cycle 13; however, all follow-up bone scans were unchanged and were read as superscans. His PSA decreased from a baseline of 4229 ng/mL pre-cabazitaxel to a nadir of 11.5 ng/mL after 22 cycles; his PSA then remained relatively stable and, at pre-cycle 26, his PSA was 11.74 ng/mL.
Regarding OS, the patient who stopped cabazitaxel due to PD died 12 months after starting cabazitaxel, while two other patients died at 29 and 30 months from the date of the first cycle of cabazitaxel, while the patient who had PD as the best response to cabazitaxel but went on to receive 23 cycles is still alive 32 months after the first cycle of cabazitaxel.
The toxicities that occurred after cycle 10 are listed in [Table 1]. Most of the toxicities, other than PN, occurred after the first cycle of chemotherapy, and did not appear to cumulatively increase with increasing number of cycles.
PN occurred in three of the four patients. The first patient developed grade 1 PN after cycle 13, which increased to grade 3 after cycle 17. Cabazitaxel was held and electromyography and nerve conduction studies (EMG/NCV) revealed axonal type of sensorimotor PN in the lower extremities. After stopping cabazitaxel, his PN gradually decreased within the next 5 months to grade 2. The second patient developed tingling and weakness of the lower extremities (grade 1) after the first cycle of cabazitaxel, which remained stable for the first 11 cycles, increased to grade 2 following cycle 16, then remained stable until cycle 27, when it was noted to be grade 3; hence, chemotherapy was held for 2 months, during which time his neuropathy symptoms again decreased and so cycle 27 was administered. Neuropathy again increased to grade 3; hence, further chemotherapy was abandoned. His neuropathy symptoms gradually improved and, 3 months later, he was fully functional with grade 2 PN. The third patient developed grade 2 lower extremity weakness after cycle 15, and EMG/NCV studies revealed generalized distal > proximal sensorimotor polyneuropathy, more in the lower extremities than in the upper extremities with additional evidence of right proximal neurogenic lesion at the L4-S1 level mostly involving the roots (he had extensive bone metastases in the vertebrae and had initially presented with paraplegia that was treated with surgical decompression, fixation and palliative radiotherapy). Cycle 16 was delayed by 3 weeks, during which time his leg weakness improved to grade 2; hence, chemotherapy was resumed. His PN symptoms remained stable at grade 2 until cycle 23, after which chemotherapy was stopped due to logistics.
| » Discussion|| |
Four of our patients received over 10 cycles of cabazitaxel. All the patients reported subjective improvement, which continued and further improved with additional chemotherapy beyond 10 cycles. Radiologically, the maximal benefit was attained by 10 cycles in all patients. Measuring serial PSA levels is a reliable surrogate of tumor response in prostate cancer. In three of our four patients, the PSA continued to decrease with increasing number of cycles, with the PSA nadir occurring as late as 23 cycles. Thus, administering additional cycles of cabazitaxel beyond the traditional 10 cycles may help maximize efficacy in patients who appear to be clinically responding in terms of symptom improvement and decreasing PSA values.
All the four patients continued on cabazitaxel beyond the event that defined "progression" (either PSA progression or evidence of increasing tumor on restaging scans), because the treating physician felt that they were continuing to benefit from the chemotherapy. Thus, there was discordance between symptomatic relief, PSA response and objective response on scans. The concept of continuing chemotherapy beyond traditionally defined disease progression until maximum clinical benefit should be tested in the setting of a clinical trial to assess whether survival may be further prolonged. This issue is getting more attention with newer and effective treatments available, e.g., gefitinib in lung cancer.
A concern with administering additional chemotherapy cycles is cumulative toxicity. Cabazitaxel results in less PN than the other taxanes; paclitaxel at the dose of 175 mg/m 2 every 3 weeks causes neuropathic symptoms in 79% of patients, which is dose limiting in 21% patients.  Docetaxel leads to sensorineural side-effects in 49% of patients, which is severe in 4% of the patients.  In the TROPIC trial, PN of any degree occurred in 14% of the patients; however, grade 3 PN occurred in only 1% of the patients.  The median number of cabazitaxel cycles delivered in the TROPIC trial was 6. From our limited experience using an extended number of cabazitaxel cycles, it appears that the dose-limiting toxicity of cabazitaxel is PN, and this PN is cumulative. It manifests as tingling, numbness and weakness, usually in the lower extremities. On EMG/NCV, it is seen as axonal or generalized sensorimotor PN, more in the lower extremities. Three of the four patients developed clinically significant neuropathy symptoms between cycles 15 and 17, which increased to dose-limiting neuropathy in one patient by cycle 17 and in the other by cycle 27. However, the PN was at least partially reversible and, after stopping cabazitaxel, symptoms decreased to grade 2 by 3-5 months.
Thus, in patients who are continuing to respond to cabazitaxel without intolerable toxicity, cabazitaxel may be cautiously continued beyond 10 cycles, with careful attention toward the development of PN. If severe neuropathy develops, stopping cabazitaxel results in gradual improvement in neuropathy. Continuing cabazitaxel until progression or intolerable toxicity may help to maximize the efficacy obtainable from chemotherapy.
| » Acknowledgment|| |
The authors thank Sanofi Aventis for providing cabazitaxel to patients free of cost as part of the named patient program.
| » References|| |
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al
.; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010;376:1147-54.
Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM, Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol1995;6:489-94.
Docetaxel prescribing information (2010).Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020449s059lbl.pdf. [Last accessed on 2014 Mar 24].
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