|Year : 2018 | Volume
| Issue : 3 | Page : 83-88
Retreatment with cabazitaxel in a long-surviving patient with castration-resistant prostate cancer and visceral metastasis
Raquel Luque Caro, Carmen Sánchez Toro, Lucia Ochoa Vallejo
Department of Medical Oncology, Hospital Universitario Virgen De Las Nieves Granada, Granada, Spain
|Date of Submission||16-Apr-2018|
|Date of Acceptance||21-Jun-2018|
|Date of Web Publication||29-Jun-2018|
Dr. Raquel Luque Caro
Department of Medical Oncology, Hospital Universitario Virgen De Las Nieves Granada, Avda De Las Fuerzas Armadas, 18014 Granada
Source of Support: None, Conflict of Interest: None
Prostate tumors are the most frequent malignant cancer among men. In recent years, we have seen a significant progress in the knowledge of the carcinogenesis of prostate cancer, leading to the development of effective drugs in this scenario. Prostate cancer patients had no effective therapeutic alternatives after docetaxel failure, limiting their survival rates. However, new drugs have markedly improved this. Cabazitaxel, a new generation taxane, has shown improved patient survival, despite the disease progression seen after docetaxel treatment. Herein, we present the case of a prostate cancer patient with poor prognosis and lung metastases in < 6 months postdocetaxel treatment. The patient was treated with cabazitaxel, achieving a long and maintained response. Later, on developing a new progressive disease, the patient was retreated with cabazitaxel, achieving a partial response and obtaining a widespread survival and clinical benefit. We currently have no predictive response factors to establish the most appropriate therapeutic sequence. Close monitoring of these patients is of paramount importance to detect early disease progression and try a new line of treatment, while the patient still has the chance to respond.
Keywords: Cabazitaxel rechallenge, castration resistant, prostate cancer
|How to cite this article:|
Luque Caro R, Sánchez Toro C, Ochoa Vallejo L. Retreatment with cabazitaxel in a long-surviving patient with castration-resistant prostate cancer and visceral metastasis. Cancer Transl Med 2018;4:83-8
|How to cite this URL:|
Luque Caro R, Sánchez Toro C, Ochoa Vallejo L. Retreatment with cabazitaxel in a long-surviving patient with castration-resistant prostate cancer and visceral metastasis. Cancer Transl Med [serial online] 2018 [cited 2019 Nov 17];4:83-8. Available from: http://www.cancertm.com/text.asp?2018/4/3/83/235600
| Introduction|| |
Prostate cancer is the most frequent malignant tumor among men in Europe and the USA, being the third leading cause of cancer deaths in Europe and the second in the USA.
Few years ago, castration-resistant prostate cancer (CRPC) was considered as a chemoresistant tumor. In 2004, the results of two Phase III studies (TAX 327 and Southwest Oncology Group [SWOG] 9916) were published,, making a paradigm shift in CRPC therapy. Docetaxel was shown to increase the overall survival (OS) in patients with metastatic CRPC compared to mitoxantrone, standardizing docetaxel plus prednisone as the first-line treatment in this scenario. The TAX 327 study compared two different schedules of docetaxel plus prednisone versus mitoxantrone plus prednisone. The SWOG 9916 study showed that patients who were treated with docetaxel plus estramustine had a significant improvement in survival and biochemical response and decreased prostate-specific antigen (PSA), compared to patients treated with mitoxantrone and prednisone.
Cabazitaxel is a new taxoid which promotes tubulin assembly and stabilizes microtubules against cold-induced depolymerization in cells, as efficiently as docetaxel. In vitro, cabazitaxel demonstrates cytotoxic activity equivalent to docetaxel, and is also found effective against tumor models that are insensitive to several chemotherapy agents, including docetaxel. Unlike other taxanes, it is a weak substrate of the P-glycoprotein, a plasma membrane protein that functions as an adenosine triphosphate-dependent drug efflux pump and plays an important role in multidrug resistance to antineoplastic agents. Compared to other taxanes, cabazitaxel appears to be less neurotoxic, with only 14% of patients experiencing peripheral neuropathy (1%, Grade 3).,
Cabazitaxel has shown clinical activity in docetaxel refractory patients. So far, the strongest evidence comes from the Phase III, controlled, open-label, randomized clinical study (TROPIC) in 755 patients with metastatic CRPC who had progressed after docetaxel-based regimen. Results of this study showed that cabazitaxel plus prednisone improved survival of this patient population compared to mitoxantrone plus prednisone. Cabazitaxel improved OS up to 2.4 months (hazard ratio [HR] 0.72; P < 0.0001). Febrile neutropenia was a common adverse event in the cabazitaxel arm (7.5% vs. 1.3%). Other adverse events included diarrhea (6%), fatigue (5%), nausea/vomiting (2%), anemia (11%), and thrombocytopenia (4%). Cabazitaxel is approved by both the Food and Drug Administration (FDA) and the European Medicine Agency as second-line treatment, in disease progression postdocetaxel treatment, and NCCN guidelines recommend it to treat prostate cancer patients with or without visceral metastases.
In recent years, a significant improvement in the knowledge of CRPC carcinogenesis has been achieved, leading to the development of effective drugs in this scenario, though the optimal treatment sequence is yet to be established. Further, the cancer treatment has been revolutionized with the advent of immune checkpoint inhibitors, in particular, thanks to agents targeting the programmed cell death-1 (PD-1) receptor and its ligand and the cytotoxic T-lymphocyte-associated protein-4 receptor. However, their role in prostate cancer is yet to be elucidated. Nonetheless, the evidence of survival benefit seen with two cancer vaccines (Sipuleucel-T and PROSTVAC) in advanced prostate cancer patients , provides a strong rationale to support further research with the use of modern immune checkpoint inhibitors in prostate cancer.
We present the case of a CRPC patient with poor prognosis and lung metastases within 6 months of previous docetaxel treatment. The patient was then administered with cabazitaxel, resulting in a long and maintained response. After stopping the treatment, the disease progressed again, and the patient was retreated with cabazitaxel, achieving a partial response and obtaining a survival and clinical benefit. With further progression in the disease, the patient was also treated with abiraterone. In particular, here, we show a consistent example of the impact of the new drugs on survival and how a personalized treatment sequence may dramatically impact the clinical benefit. This case is of great interest due to its long evolution and excellent drug tolerance, along with maintaining a good quality of life.
This case report was reviewed by the local ethics committee and patient consent form was obtained, dated, and signed by the patient.
| Case Report|| |
We report the case of a 63-year-old male patient, with a personal history of high blood pressure, dyslipidemia, and microinvasive pT1 carcinoma of the larynx in 2004 with no evidence of disease.
In June 2000, a total PSA level of 28 ng/mL was detected during routine analysis and a biopsy was performed with a diagnosis of prostatic adenocarcinoma Gleason 2 + 3. Both whole-body computed tomography (CT) scan and the bone scan were negative for metastases. Once classified as high-risk prostate adenocarcinoma, the patient received androgen deprivation therapy (ADT) for 3 months and external beam radiotherapy (66 Gy) and complete androgen blockade (CAB) therapy for 3 years, which was completed in July 2003. By that time, the patient achieved a PSA nadir of 0.01 ng/mL.
However, a year after finishing the adjuvant CAB therapy, biochemical recurrence was detected with no evidence of metastasis, and the patient again received the same hormonal blockage. In November 2009, a body CT scan detected a pulmonary nodule in the left hemithorax, suggestive of metastasis. At that point, the PSA level was 0.81 ng/mL. The case was presented in an uro-oncology committee and the suspicion of having a differentiated neuroendocrine tumor resulted in the decision to perform the biopsy of pulmonary nodule. Resection of two nodules in the left lung was performed by thoracoscopy. The histology report described nonneuroendocrine PSA prostate adenocarcinoma.
At this point, the patient was treated with a luteinizing hormone-releasing hormone analog (LHRHa), and the biochemical analysis showed that the testosterone level was within the castrate range and PSA was 1.21 ng/mL. The patient was diagnosed of metastatic CRPC with biochemical progression and pulmonary metastases. Initiation of docetaxel plus prednisone was decided, and the patient received eight cycles of the same between March and September 2010. After three cycles, the PSA level decreased to 0.15 ng/mL. Although the tolerance to treatment was being acceptable, the patient reported several adverse events, such as Grade-2 fatigue and neurotoxicity. This toxicity was life-limiting and suspension of chemotherapy treatment was decided. By that time, a good PSA response but only a partial pulmonary nodule response, according to the CT scan, was noted [Figure 1].
Following the end of treatment, PSA level started to rise slowly. LHRHa was maintained until a progression in lung metastases was observed during a CT scan in February 2011 [Figure 2]. PSA level was 0.65 ng/mL and the patient was asymptomatic. Since disease progression appeared within 5 months after the initial response to docetaxel, the patient was included in the expanded access study, assessing cabazitaxel plus prednisone. This was a Spanish expanded multicenter access program that provided early access to cabazitaxel to patients with metastatic CRPC before its commercialization. [Table 1] shows a flowchart including all administered treatments and dates of progression.
Nine cycles of cabazitaxel were administered between March and September 2011. Tolerance to the treatment was good and no significant toxicities were presented. Afebrile neutropenia was detected during weekly study tests after first cycle and was treated with 6 mcg of pegfilgrastim. Residual docetaxel-induced neurotoxicity remained stable. Treatment was stopped after nine cycles due to detection of kidney stones and renal failure, unrelated to the treatment, which was further treated with conservative therapy. The patient remained asymptomatic during the treatment. A PSA response of > 50% and a partial response of pulmonary nodules, under lung CT [Figure 3], was achieved. A close monitoring was started. During a medical examination in May 2013, the patient reported lumbar pain associated with general mild discomfort and asthenia. The patient's PSA level was 4.95 ng/mL. Although the CT scan revealed no evidence of progression, a bone scan detected a focus in the 4th lumbar vertebra [Figure 4].
Due to the clinical and biochemical progression as well as the new bone metastatic lesion, cabazitaxel plus prednisone plus zoledronic acid treatment was repeated. This choice was guided by the progression-free interval, both radiological and clinical, of 20 months after the end of the previous treatment.
The patient completed eight full-dose cycles of cabazitaxel without the need for granulocyte colony-stimulating factor support, at the physician's discretion, between June and December 2013. The treatment ended with a clinical response since administration of cycle 1 and a biochemical response (PSA = 3.9 ng/mL) after cycle 8. A new lung CT reported the maintenance of the thoracic response, but a new lesion in the left pedicle of the 1st lumbar vertebra (L1) was observed in the bone scan, with stabilization of the L4 lesion. The patient presented no pain and had an active life. A close monitoring was initiated.
In March 2014, during a follow-up visit, the patient reported lumbar pain, which did not improve after administering nonsteroidal anti-inflammatory drugs (NSAIDs). PSA was 6.21 ng/mL, and the PSA doubling time was above 3.48 months. Analgesic radiotherapy was decided, and the patient received a total dose of 8 Gy.
In July 2014, the patient continued experiencing lumbar pain. Moreover, the patient's PSA level increased to 7.92 ng/mL and a thoracic CT revealed a progression in lung metastases. This led to initiation of abiraterone plus prednisone treatment, suspension of zoledronic acid, and combination with denosumab.
After receiving this treatment, the patient became asymptomatic with no need of NSAIDs, as well as an improvement in biochemical response (PSA of 5.18 ng/mL) and a relatively good tolerance to the treatment was observed. By July 2015, the patient's back pain reappeared with a raise in PSA and a minimal progression of bone metastasis, detected by the bone scan, which led to the abiraterone treatment discontinuation.
Subsequently, the patient received oral metronomic cyclophosphamide and vinorelbine with poor clinical benefit and the disease progression (both biochemical and bone metastases) [Figure 5]. Because of that, it was considered that the patient could benefit from radium-223 treatment. Two doses of radium-223 were administered between August and September 2016, resulting in stable bone lesions but with the appearance of liver metastasis [Figure 6]. The patient received local radiotherapy on skull base bone injury that ended with loss of vision. Thus, active cancer treatment was discontinued. Last, in May 2017, the clinical condition of the patient quickly deteriorated and died.
| Discussion|| |
There has been a large progress in the field of metastatic CRPC treatment, with EMA approval of new drugs after disease progression postdocetaxel treatment. In June 2010, cabazitaxel was approved by the FDA, after TROPIC study showed positive results. Thus, the administration of cabazitaxel plus prednisone was shown to be superior to mitoxantrone plus prednisone, in patients with metastatic CRPC whose disease condition has progressed postdocetaxel treatment, in terms of OS and PFS. Importantly, around 75% of the patients included in the TROPIC study had a poor prognosis, since they progressed during treatment or within the 1st 3 months after finishing treatment.
Two other Phase III studies, with the same therapeutic scenario and similar inclusion criteria, were conducted with positive results for the experimental arm. Abiraterone acetate is a steroidal CYP17 inhibitor and by extension androgen synthesis inhibitor. The COU-AA-301 Phase III study showed positive survival results in abiraterone-administered metastatic CRPC patients, who had developed progressive disease after docetaxel treatment. Enzalutamide is a competitive androgen receptor inhibitor, which also inhibits androgen receptor nuclear translocation and DNA binding. The AFFIRM study randomized patients with metastatic CRPC to receive enzalutamide or placebo, showing a survival benefit by a median of 4.8 months. This survival benefit was met by all subgroups.
Radium-223 dichloride (radium-223) is a targeted alpha emitter that became the first radionuclide to improve survival in CRPC patients. The ALSYMPCA study randomized 921 patients, who were not fit for docetaxel treatment, to receive Ra-223 or placebo. The trial was stopped due to early evidence of benefit in terms of survival (P< 0.001; HR = 0.70; 95% confidential interval, 0.58–0.83; median OS 14.9 months vs. 11.3 months, respectively) that was better in all subgroups except for patients with ECOG-PS ≥ 2.
We currently have no predictive response factors to establish the most appropriate therapeutic sequence. This problem is well illustrated in the postdocetaxel castration-resistant setting, for which, as seen above, there are indications to use all other approved agents.
For this reason, close monitoring of these patients is highly needed to detect early disease progression to treatment. The new Prostate Cancer Working Group 3 criteria (PCWG3) are stricter and recommend a closer follow-up in clinical trials, with clinical and analytical evaluation every 3–4 weeks and imaging every 8–9 weeks within the first 24 weeks. It is intended to individualize each case, considering to “stop and change” the treatment when the patient does not benefit any longer, as revealed by biochemical progression, image, or any other parameter.
Prognostic factors include the duration of response to ADT, Gleason score, androgen levels, and the presence of visceral metastases. All these factors have been identified as possible predictive response factors, but to date, no prospective study data are available.
With respect to the aggressive variant criteria, our patient was considered under high-risk category since diagnosis. These criteria include small-cell prostate carcinoma, visceral metastases only, lytic bone metastases, bulky node or prostate mass, low PSA relative to volume, elevated neuroendocrine markers, carcinoembryonic antigen or lactate dehydrogenase, and early castration resistance. They allow the detection of patients with a more aggressive course and who are likely to benefit from chemotherapy rather than new hormonal agents. In our case, the biopsy denied neuroendocrine differentiation and certainly has had a much easygoing course than expected. Despite a poor response to docetaxel, due to the short duration of the treatment, the patient presented a very long period of partial radiological response with cabazitaxel treatment (approximately 20 months after the end of treatment). Furthermore, tolerance was satisfactory, with no reports of Grade 3–4 toxicities and without worsening of the residual docetaxel-induced neurotoxicity. This confirms the fact that cabazitaxel has a toxicity profile somewhat different to docetaxel, with limited neurotoxicity, tearing, and nail toxicity.
After disease progression postcabazitaxel treatment, we considered the possibility to rechallenge due to the previously achieved response and excellent tolerance. The patient experienced an undeniable clinical benefit and initial biochemical response. No radiological progression was confirmed according to the PCWG3 criteria until 6 months after the end of the retreatment.
The patient survived for over 7 years since the onset of docetaxel. In line with the search for the optimal treatment sequence, our patient received docetaxel followed by cabazitaxel followed by abiraterone. A large number of retrospective studies have demonstrated that this strategy is more effective than docetaxel followed by abiraterone and then cabazitaxel in terms of OS, more likely due to the window of therapeutic opportunity. Contrary, the lower survival rates were found in the sequences where two new hormonal treatments (abiraterone and enzalutamide) were set up after docetaxel, without using cabazitaxel. Although these data come from retrospective studies, they show the key role of choosing the optimal sequence for metastatic CRPC treatment, suggesting an impact of the sequence on the OS.,
There are no clinical case series or clinical trials answering exactly how a cabazitaxel rechallenge may impact the patient survival, but there is an interesting expanded access study with cabazitaxel in 125 patients that also showed positive results. Docetaxel was received as first-line treatment in 72 patients. Progressive disease occurred at a median time of 6.5 months from the last docetaxel dose. A PSA response to cabazitaxel was achieved in 47.7% of patients. Median progression-free survival was 4.4 months (range: 2.7–6.1). In 11.4% of patients, the treatment was discontinued because the best clinical benefit was achieved or because they had completed 10 cycles of cabazitaxel treatment.
There are no data to clarify the optimal sequence that should be followed, which is more necessary with the recent approval of new drugs and immunotherapy clinical development. Interestingly, three clinical studies were very recently presented showing promising results with PD-1/PD-L1 inhibitors in metastatic CRPC patients. The first study, a Phase-II clinical trial (Keynote-028), treated twenty chemotherapy-naive progressive metastatic CRPC patients on the androgen receptor antagonist enzalutamide, with four doses of pembrolizumab with continued enzalutamide. Interestingly, 20% of patients achieved a confirmed PSA reduction ≥ 50%. The second study was a Phase Ib study evaluating the safety and efficacy of pembrolizumab in 23 metastatic CRPC patients progressing to standard therapy and with PD-L1 expression in ≥ 1%. Importantly, pembrolizumab produced reliable response among heavily pretreated patients with an objective response rate of 13% and median response duration of 59 weeks (range, 28–62 weeks). The third study was a Phase I trial which evaluated avelumab in an expansion cohort of patients with progressive metastatic CRPC posttreatment with approved therapies. Eighteen patients were enrolled in this cohort. Treatment was well tolerated and promising efficacy results were seen. Seven patients had stable disease longer than 24 weeks, while six patients showed progressive disease.
In conclusion, we report a case of a patient treated with cabazitaxel rechallenge after receiving docetaxel, showing that this strategy is an effective and well-tolerated treatment sequence which allows the patient to take advantage of the window of therapeutic opportunity and still benefit from abiraterone acetate beyond taxane progression. A clinical benefit was achieved along with minimal toxicity. Although there are no predictive factors of response to new therapies, choosing the correct sequence of treatment offers the patients the possibility to achieve prolonged survival, with controlled symptoms and a good quality of life, all of which were unthinkable just a few years ago.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]