Volume 6 - Issue 1, Jan 2018

Consensus Statements on the Management of Metastatic Prostate Cancer from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology Back

At the 15th Urological Association of Asia Congress held in Hong Kong in August 2017, Dr. Lap-Yin HO and Dr. Darren Ming-Chun POON presented the consensus statements on the management of metastatic prostate cancer (mPC) for Hong Kong, which were recently established by the two main professional organisations of prostate cancer specialists in the city.

Objectives of the consensus
In recent years, with the advent of a number of novel drugs, the management paradigm for mPC has been evolving. To facilitate the management strategies of mPC in Hong Kong, a local expert consensus was organised jointly by the HKUA and the HKSUO to establish a set of consensus statements, which covered six areas that were considered most crucial and relevant regarding the management of mPC.

Process of formulating the statements
With reference to a modified Delphi method,1 a series of panel meetings were held for discussion of local clinical experience and current published evidence on the mPC treatment. At the final meeting, the panel concluded the opinions and each drafted consensus statement was debated again and voted on by every member based on its practicability of recommendation. A consensus statement was accepted only if 80% or above of the panellists chose “accept completely” or “accept with some reservation”. After the panel voting, a total of 45 consensus statements were finally accepted and established.

Part 1 – Management of men with castration-naïve mPC

The first part of the consensus statements was about the management of castration-naïve mPC (Table 1). Dr. Poon highlighted Statement 5 and shared the results of a Hong Kong study, which found that, treated with the combination of androgen-deprivation therapy (ADT) and docetaxel, local patients with castration-naïve mPC had a median time to castration resistance comparable to that of their counterparts in the CHAARTED trial (19.5 months vs. 20.2 months), even though a greater proportion of patients with high-volume disease was included (96.9% in the Hong Kong study vs. 66.2% in the CHAARTED trial).2 This revealed a promising response, at least at an early stage, to the chemo-hormonal therapy among local patients, in particular those with high-volume disease who may not be adequately treated with ADT alone. However, compared with western patients, locals may have a higher risk of chemotherapy-related haematological toxicities, so careful patient selection and consideration of granulocyte colony stimulating factor (GCSF) is warranted.2

Dr. Poon also noted that, based on several clinical trials, when used in combination of ADT for patients with castration-naïve mPC, either docetaxel or abiraterone brought about similar survival benefits,3–6 but a huge cost difference exists between these two agents in the local setting (~HK$40,000 for 6-cycle docetaxel vs. ~HK$800,000 for 24-month abiraterone). In this regard, cost-effectiveness is one of the considerations when deciding on a treatment option. He added that abiraterone is neither reimbursed nor licensed for the treatment of castration-naïve mPC in Hong Kong currently.

Part 2 – Management of men with castration-resistant mPC (mCRPC)

Table 2 lists the consensus statements on the management of mCRPC. Statements 2 and 3 were underscored by Dr. Poon. Among the available treatment options of  mCRPC in Hong Kong, abiraterone, enzalutamide, cabazitaxel, and radium-223 are self-paid items, with the former two having sort of government subsidy programmes under certain conditions, while docetaxel is free-of-charge therapy for mCRPC.

Although abiraterone is a possible treatment choice for mCRPC, a Hong Kong  study showed that it may have inferior efficacy in chemo-naïve mCRPC patients  who had symptomatic disease or short duration of response to prior ADT (i.e. < 10  months).7 The cohort of patients treated with abiraterone had a median overall  survival (OS) substantially shorter than that found in the COU-AA-302 study (18.1 months vs. 34.7 months).7 As proposed by the researchers, the inferior survival  outcome might have been due to the inclusion of patients with higher tumour burden, visceral metastases, or symptomatic disease.7

On the other hand, the study revealed that the clinical efficacy of abiraterone in local post-chemo mCRPC patients was comparable to that of the COU-AA-301 trial  (median OS: 15.5 months vs. 15.8 months; median progression-free survival [PFS]: 6.4 months vs. 5.6 months).7 According to another Hong Kong study, both abiraterone and cabazitaxel were significantly associated with increased OS in post-docetaxel patients with mCRPC.8

Part 3 – Value and use of predictive markers in mCRPC

Dr. Ho noted that, after the review and discussion of the local clinical experience and existing literature, the consensus appraised the relative importance of several  markers and singled out those factors that potentially facilitate the choice of first-line treatment of mCRPC (Table 3).

Part 4 – Sequencing treatment in mCRPC

According to Dr. Ho, in view of the lack of strong evidence, the consensus panel was difficult to formulate a clearcut guidance on sequencing treatment in mCRPC. However, some important conclusions were still reached. He underscored that the time to disease progression after initial chemotherapy / AR pathway inhibitor is a crucial factor when deciding on a second-line treatment for mCRPC patients who fail firstline docetaxel / AR pathway inhibitor (Table 4, Statement 1c). He also highlighted Statement 4, pointing out no evidence available from the literature to show a major cross-resistance between radium-223 and other systemic agents.

Part 5 – Management of men with oligometastasis 

In general, oligometastasis in prostate cancer is defined as having five or fewer metastases (Table 5, Statement 1). There is emerging evidence supporting that patients with oligometastasis may have a more favourable prognosis compared with those with extensive metastases. As highlighted by Dr. Poon, metastasis-directed therapy (MDT) is getting more popular in Hong Kong for the treatment of oligometastasis in prostate cancer, with two major advantages: (1) provide good local control at the sites of oligometastasis; (2) spare or delay the toxicity related to the use of systemic therapies.

Dr. Poon shared a real-life case to illustrate the use of MDT. He had a 70-year-old male patient with history of localised prostate cancer (T1c, Gleason Score 3+4, PSA = 7.8) who had been treated with brachytherapy in the U.K. in 2013. Since August 2016, the patient had disease progression (PSA = 7.42) with L3 and T9 bone metastases shown by a dual-tracer PET/MRI scan, but there was no local recurrence. After the initiation of ADT, despite a normalised PSA level, the MRI scan still found active spine metastases. In December 2016, stereotactic body radiotherapy (SBRT) with 16 Gy in single fraction was done to the L3 and T9 bone metastases. Neither acute nor late complications were observed, and the post-SBRT dual-tracer PET/MRI scan found no residual uptake.

Part 6 – Staging and monitoring of mCRPC treatment

The last part of the consensus statements was about the staging and monitoring of mCRPC treatment (Table 6). Dr. Poon underscored the conditions for probable termination of mCRPC therapy (Statement 4) and the PSA flare phenomenon (Statement 6). A PSA flare can be defined as an initial serum PSA rise under therapy, followed by a drop to values below the baseline.9 However, it does not necessarily cause clinically relevant issues.9,10 In a Hong Kong study, among mCRPC patients on abiraterone with an initial PSA flare, above half of them had ultimate responses to the agent.7 In addition, there was no substantial difference in clinical outcomes in patients with or without a PSA flare.7 As a result, as long as patients are not clinically deteriorating, a temporary PSA increase during initial systemic treatment should be monitored for a sufficient period (i.e. 3 months) to avoid early withdrawal from treatment in the absence of genuine disease progression.

Conclusions

The consensus statements were derived from the recent clinical evidence and major overseas guidelines, with the consideration of clinical experience and practicability in Hong Kong. In the next step, the consensus panel would establish consensus statements on the management of localised prostate cancer for Hong Kong, with results expected in March 2018.

Note: To formulate the consensus statements, the panel reviewed the literature published from Jan 2005 to Aug 2016. The statements and their details were accepted by BJU International on 6 Dec 2017 for online publication (DOI: 10.1111/bju.14091).

References

  1. Linstone HA, et al. The Delphi method: techniques and applications.
    Boston, MA: Addison-Wesley Publishing Co. Inc.; 2002.
  2. Poon DM. Key Opinions in Medicine (Conference News). 2017; 5: 1–4.
  3. Sweeney CJ, et al. N Engl J Med. 2015; 373: 737-46.
  4. James ND, et al. Lancet. 2016; 387: 1163-77.
  5. Fizazi K, et al. N Engl J Med. 2017; 377: 352-60
  6. James ND, et al. N Engl J Med. 2017; 377: 338-51.
  7. Poon DM, et al. BMC Urol. 2016; 16: 12.
  8. Poon DM, et al. Prostate Int. 2015; 3: 51-5.
  9. Olbert PJ, et al. Anticancer Drugs. 2006; 17: 993-6.
  10. Burgio SL, et al. Clin Genitourin Cancer. 2015; 13: 39-43.