Significant reduction in burden of metastatic disease by intermittent docetaxel therapy in a patient with castration-resistant prostate cancer

Abstract

Intermittent docetaxel therapy (IDT) is rarely used nowadays as a treatment option for men with metastatic castration-resistant prostate cancer (mCRPC) because of the widespread availability of androgen receptor axis-targeted therapy, which is less toxic. Therefore, there is limited information available on whether IDT has a clinical benefit in the treatment of men with mCRPC. This report describes the case of a 66-year-old man with a diagnosis of cT2N1M0 prostate cancer who underwent neoadjuvant combined androgen blockade and whole-pelvis radiation therapy. However, the tumor had progressed to mCRPC with metastasis to the bladder and a left pelvic lymph node within 2 years. Docetaxel had been administered as first-line chemotherapy, and the patient achieved a complete response in terms of the bladder metastasis. Docetaxel was stopped after 15 cycles. When a durable response had been maintained for more than 2 years, during which only androgen deprivation therapy was administered, the patient was switched to observation only. However, his prostate-specific antigen level gradually increased. Abiraterone was started as second-line therapy, during which there was a rapid increase in the PSA level. Computed tomography revealed further enlargement of the left pelvic lymph node, bladder metastasis, metastasis to the left common iliac lymph nodes, and several disseminated nodules around the bladder. Docetaxel was reintroduced as IDT for third-line therapy, and a complete response was achieved for all metastases, with the exception of the metastasis in the left pelvic lymph node. Thus far, the patient has survived for more than 7 years after starting docetaxel as first-line therapy for mCRPC. IDT is potentially useful in a subgroup of patients with mCRPC and could achieve long-term survival. Comprehensive genomic profiling may help physicians to select patients with mCRPC who are more likely to benefit from docetaxel than other systemic therapy.

Introduction

Docetaxel was approved as a first-line cytotoxic agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in 2004 [1] after demonstrating a survival benefit with reduced pain and improvement in quality of life. However, the advent of androgen receptor axis-targeted therapy (ARAT) in the early 2010s [2, 3] led to agents such as abiraterone and enzalutamide becoming widely used as first-line therapies for mCRPC. These agents can be taken orally, are well tolerated, and have also been approved as second-line treatment for mCRPC. Therefore, opportunities for reintroduction of docetaxel as second-line therapy for mCRPC seem to be limited in clinical practice.

Although the eligibility criteria for intermittent docetaxel therapy (IDT) have not yet been clearly defined, median overall survival from the start of first-line therapy has been shown to be about 20 months after reintroduction of docetaxel [4–6]. In this report, we describe a patient with mCRPC in whom a significant reduction in metastatic disease was achieved by IDT with a particularly favorable long-term survival outcome.

Case report

A 66-year-old man presented with lower abdominal pain and an elevated serum prostate-specific antigen (PSA) level of 107.6 ng/ml. Computed tomography (CT) showed a bulky nodule measuring up to 8.0 cm in the left side of the pelvis (Fig. 1a). A prostate biopsy revealed prostate adenocarcinoma with a Gleason score of 10 (5 + 5). CT-guided biopsy of the left-sided pelvic mass confirmed adenocarcinoma consistent with lymph node metastasis. Diagnostic radiography, including pelvic magnetic resonance imaging, staged the disease clinically as T2aN1M0. Neoadjuvant combined androgen blockade: bicalutamide plus androgen deprivation therapy (ADT) and whole-pelvis radiation therapy (78 Gy) achieved adequate reduction of the lymph node metastasis (Fig. 1b) and a decrease in the PSA level to a nadir value of 0.03 ng/ml. However, during adjuvant combined androgen blockade after radiotherapy, the PSA level gradually increased to 4.7 ng/ml. CT revealed enlargement of the left pelvic lymph node and metastasis to the bladder, consistent with mCRPC (Fig. 1c). The changes in serum PSA and the treatments provided are shown in Fig. 2.

Fig. 1.

Serial abdominal and pelvic computed tomography images. a left pelvic bulky nodule at the initial visit. b reduction of left pelvic lymph node 6 months after the start of combined androgen blockade therapy. c enlargement of the left pelvic lymph node and bladder metastasis at the time diagnosed with CRPC. d, e complete response for bladder matastasis and partial response for left pelvic lymph node after 14 cycles of docetaxel therapy. f, g bladder metastasis again and new metastasis of several disseminated nodules around the bladder (arrow head) and left common iliac lymph nodes (arrow) a month after administration of 2nd-line abiraterone. h, i complete response for bladder metastasis and several disseminated nodules around the bladder, and left common iliac lymph node following docetaxel-rechallenge. j left pelvic lymph node ten months after docetaxel reintroduction. Abbreviation: CRPC, castration-resistant prostate cancer

Fig. 2.

Time-course change of serum PSA levels and therapeutic agents (log 10 scale). ADT androgen deprivation therapy, CAB combined androgen blockade: bicalutamide and ADT, DTX docetaxel, IMRT intensity modulated radiation therapy, PSA prostate specific antigen

Considering that visceral involvement in prostate cancer generally has a poor response to ARAT, we chose docetaxel (75 mg/m² every 3 weeks) with prednisolone in addition to ADT as first-line treatment for mCRPC. The bladder metastasis exhibited a complete response and the volume of the lymph node metastasis reduced markedly to 2 cm (Fig. 1d, e). Adverse events included neutropenia, alopecia, sensory neuropathy, peripheral edema, and nail changes, all of which were grade 1 or 2, with the exception of the neutropenia. The patient developed grade 4 neutropenia during the 12th cycle of chemotherapy, which was managed successfully by pegfilgrastim. After 15 cycles of chemotherapy, the patient’s PSA had decreased to a minimum of 0.009 ng/ml, and docetaxel was stopped. He was then started on ADT as monotherapy, which produced a durable PSA response for more than 2 years. Thereafter, management consisted of observation only.

After cessation of treatment, the PSA level increased gradually to 1.83 ng/ml. Therefore, combined androgen blockade was restarted. However, the PSA level continued to increase, reaching 6.3 ng/ml, at which point abiraterone acetate was started as second-line therapy for mCRPC. After one month, the PSA had increased further to 10.6 ng/ml. CT at this time revealed metastases in the bladder and left common iliac lymph nodes with several disseminated nodules around the bladder (Fig. 1f, g). No bone metastases were detected on bone scintigraphy. Although cabazitaxel was considered as an alternative third-line therapy, we chose IDT for the following reasons: the patient had responded quite well to first-line docetaxel chemotherapy and was willing to receive docetaxel again; all bioaccumulated adverse events subsided during chemotherapy holidays; and there was a possibility of bone marrow suppression by cabazitaxel, which would necessitate use of granulocyte-colony stimulating factor, as occurred during first-line docetaxel therapy. After reintroduction of docetaxel, his PSA level declined to 0.14 ng/ml after 8 cycles and has remained at this low level. Re-staging CT at 5 months after reintroduction of docetaxel showed a complete response of all metastases except for the lymph node in the left side of the pelvis, which remained at about 2 cm (Fig. 1h, i). The diameter of the left pelvic lymph node remained unchanged even at ten months after reintroduction of docetaxel (Fig. 1j). IDT has been continued, and eleven cycles of docetaxel had been administered at the last follow-up. The patient has maintained a serum PSA level within the normal range without any severe adverse events.

Discussion

There are few reports in the literature on IDT in which patients have achieved a durable disease response and long-term survival while receiving this treatment. In general, the term IDT is based on a limited number of chemotherapy cycles until disease stabilization is seen, with re-administration of treatment upon progression [7, 8]. Notably, our patient has survived for more than 7 years after receiving first-line docetaxel therapy with subsequent reintroduction of docetaxel. Moreover, his response to reintroduction of docetaxel was similar to the previous response to first-line docetaxel therapy despite second-line treatment with abiraterone, and cross-resistance between ARAT and docetaxel has been reported [9, 10]. Therefore, we applied IDT as third-line docetaxel therapy rather than docetaxel re-challenge, which is also used in patients who have become refractory to docetaxel [5]. There are two possible explanations as to why this patient had an excellent response to docetaxel.

First, there are several factors that predict the probability of overall survival in patients with mCRPC. Halabi et al. identified performance status, the sum of the Gleason score at the time of the original prostatectomy and for the prostate biopsy specimen, and lactate dehydrogenase, PSA, alkaline phosphatase, and hemoglobin values to be significant prognostic factors in these patients [11]. Our patient had most of these predictors, including good performance status, lactate dehydrogenase within normal limits, relatively low PSA, and a relatively high hemoglobin concentration, suggesting less advanced disease related to having achieved an excellent response to docetaxel and a higher chance of reintroduction of docetaxel [12].

Second, there was a possibility that heterogeneity of tumor biology rendered this patient more susceptible to the therapeutic effects of docetaxel than those of ARAT. It is now widely recognized that increased intratumoral synthesis of androgen and subsequent partial restoration of the transcriptional activity of the androgen receptor contribute significantly to CRPC [13]. Graf et al. showed that amplification of the androgen receptor, alteration in PTEN, and changes in RB1 are poor prognostic factors in terms of overall survival in patients on ARAT, and the presence of these biomarkers of resistance to ARAT may result in a better response to taxanes [14]. These biomarkers might have been present in our patient and contributed to his excellent response to docetaxel. However, this possibility cannot be confirmed because we did not perform genomic profiling in this case. In the future, with more widespread use of genomic profiling, physicians may be able to decide on optimal treatment by anticipating the relative efficacy of ARAT versus a taxane.

It is possible that reintroduction of docetaxel post-abiraterone could confer an adequate survival benefit in patients with mCRPC. Although there is some debate as to whether the antitumor activity of docetaxel is influenced by the previous response to abiraterone, Azad et al. found no association between the activity of docetaxel and the biochemical response to prior abiraterone therapy [15]. If first-line chemotherapy with docetaxel achieves a reduction in the PSA level of ≥ 50% [5], reintroduction of docetaxel could be one of the therapeutic options even in the post-abiraterone setting.

In conclusion, IDT may be an effective sequencing strategy in patients with mCRPC who have favorable prognostic factors and genomic biomarkers indicating some form of resistance to ARAT and could result in long-term survival. Given that cumulative toxicity is a major concern with docetaxel, the optimal number of treatment cycles should be determined according to the patient’s overall health status on a case-by-case basis.

Abbreviations

ADT

Androgen deprivation therapy

ARAT

Androgen receptor axis-targeted therapy

CT

Computed tomography

IDT

Intermittent docetaxel therapy

mCRPC

Metastatic castration-resistant prostate cancer

PSA

Prostate-specific antigen

Author contributions

All authors read and approved the final manuscript. TK: collection, analysis, and interpretation of data, drafting the article, final approval of the completed article. EN: design of the research, data interpretation and analysis, critical revision, approval of the final version of the article. TO, HH, AM, YS, MK, and HF: interpretation of data, final approval of the completed article. YM: design of the research, data interpretation and analysis, critical revision, approval of the final version of the article.

Funding

None to declare.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Research involving human participants and/or animals

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.