Journal reading

NCCN, Version 1.2014

Reference

1. Sartor O, Hoskin P, Bruland OS. Targeted radio-nuclide therapy of skeletal metastases. Cancer Treat Rev. 2013;39(1):18-26.
2. Pinto A, Cruz P. Radium-223 chloride: a new treatment option for metastatic castration-resistant prostate carcinoma. Drugs R D. 2012;12(4):227–233.
3. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2013;369(3):213–223.

Bony metastases in prostate cancer

More than 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of bone metastases.

• major cause of death and disbility
• decreased quality of life
• Increased treatment cost

Unlike other cancers, deaths from prostate cancer are often due to bone disease and its complication.

Mechanism of bony metastasis

Seed and soil

Both tumor cells and a variety of stromal cells interact with a number of secreted paracrine factors in a “vicious cycle” that promotes the survival and proliferation of tumor cells.

Micro-environment

In bone, cells such as the osteoblasts, osteoclasts, and hematopoietic cells (and their precursors) also represent components of the tumor micro-environment.

• Osteoclast activating factors are thought to be critical in enabling tumor growth to be established in bone, working in part through RANKL.
• Experiments with fibroblasts derived from bone stroma combined with prostate cancer cell lines display synergistic growth.

Variable bony metastases

• Relative lytic: myeloma and renal cell carcinoma
• Relative osteoblastic: prostate cancer
• Mixed lytic/blastic: breast cancer

It is the tumor associated upregulated osteoblastic activity that promotes new bone formation and incorporation of the ‘bone seeking radioisotopes’ (BSRs) used therapeutically.

Combination of other drugs

The uptake of BSRs is proportional to the osteoblastic nature of the bone metastatic disease.

• Bisphosphonates and RANKL antagonist (eg: denosumab) alter the lytic/blastic ratio in bone lesions after chronic administration.
• Bortezomib treatment in myeloma has also been shown to increase bone scan up take.

Flare up

Another approach to increase BSR uptake is through exploiting the ‘flare’ seen after LHRH agonists or abiraterone used in prostate cancer or after hormonal therapies in breast cancer.

Timing BSR therapy administration to take advantage of this flare is an unexplored but attractive concept.

Mechanism of Denosumab and Biphosphates

http://www.pallimed.org/2011/07/denosumab-palifermin-and-costs-of.html

Bone scans in a breast-cancer patient before/after chronic bisphosphonate therapy

Alteration of Tc-99 MDP bone scan uptake in myeloma after bortezomib treatment

Selected BSRs

Decay chain of Ra-223

http://en.wikipedia.org/wiki/Decay_chain

Phase I trial of Ra-223

Published in 2005, 25 p'ts with bone mets from breast or prostate cancer received single injection of Ra-223 with different dose:
46, 93, 163, 213 or 250 kBq/kg and follow 8 weeks.

• No dose-limiting hematotoxicity.
• Reversible myelosupression in some p'ts with nadirs at 2-4 wks.
• 10 diarrhea, 9 bone pain, 5 nausea, 5 vomiting.

Phase II trial of Ra-223

Published in 2007, only enrolled CRPC p'ts (2004-02 ~ 2005-05). Randomized to received:

• EBRT + placebo
• EBRT + Ra-223 (Four repeated monthly injections, 50 kBq/kg/dose)

Phase II trial of Ra-223 - cont.

Phase II trial of Ra-223 - cont.

Second phase II trial

Published in 2012. Randomized, double-blind.

Aimed to investigate the dose-response relationship and pain-relieving effect in CRPC with bone metastases.

100 p'ts were randomized to received different doses of a single injection (5, 25, 50 or 100 kBq/kg).

Second phase II trial - cont.

Second phase II trial - Side effect

About 97% of patients reported at least one side effect.

Hematologic events were generally not severe, with slightly greater rates in the two highest-dose groups. Most frequent: anemia (11%) and Hb decrease (15%).

Most freq. non-hematologic AEs: nausea, vomiting, diarrhea, constipation, peripheral edema and bone pain. No difference across dose groups.

Second phase II trial - cont.

These two trials suggested efficacy of Ra-223 in p'ts with mCRPC, in both symptomatic improvement and prolongation of survival, and with a favorable safety profile.

Phase III trial - ALSYMPCA trial

Alpharadin in Symptomatic Prostate Cancer Patients study.

Double-blind, RCT, placebo-controlled study.

Primary end point: OS
Secondary end points: time to the first SRE, time to total ALP progression and normalization, total ALP response, time to PSA progression, safety and QoL.

Phase III trial - Patients

A total of 921 p'ts were randomized on a 2:1 basis to receive Ra-223 (2008-06~2011-02).

• CRPC, with two or more bony metastases and no visceral metastasis.
• P'ts had received docetaxel, but not healthy enough or declined to receive it, or it was not available.
• PSA >= 5 ng/mL, with evidence of progression
• ECOG <=2, Life expectary >= 6 months
• Adequate hematologic, renal and liver function

Phase III trial - Exclusion criteria

• C/T within 4 wks or had not recovered from AE due to C/T.
• previous hemibody external R/T
• systemic radiotherapy with radioisotopes within the previous 24 wks
• a blood transfusion or use of EPO within the previous 4 wks
• LN involvement that was more than 3 cm in the short-axis diameter
• visceral metastases
• imminent or established spinal cord compression

Phase III trial - Protocol

50 kBq/kg/dose, 6 injection every 4 wks.

P'ts with CRPC during maintenance treatments were required to continue the treatment throughout the study.

Analgesic medication or EBRT for symptom control.

Phase III trial - Flowchart

Phase III trial - Result

The interim results were analyzed after 314 events and in light of these results the Independent Data monitoring Committee (IDMC) recommened stopping the trial early, because there was evidence of a significant OS benifit favoring Ra-223.

Baseline clinical characteristics was balanced between the study group.

Phase III trial - Result 2

The safety population included 901 pt's (600 in Ra-223 group).

The planned interim analysis was based on data from 809 p'ts (541 in Ra-223 group).

Phase III trial - Efficacy

Phase III trial - Efficacy cont.

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Phase III study - Safety

Adverse events rate was onsistently lower in the Ra-223 group than in the placebo group.

Phase III study - Safety - cont.

• Table 3 shows AEs occurred more at least 5% of p'ts.
• Overall, no clinically meaningful differences in the frequency of grade 3 or 4 adverse events were noted.

Phase III trial - Quality of Life

More rate of patient in Ra-223 group had improvement of quality of life according to FACT-P score.

Increasing >=10 points on a scale of 0 to 156: 25% vs 16%, P=0.02

Mean change in FACT-P score from baseline to 16th wk: -2.7 vs -6.8, P=0.006

Phase III trial - Discussion

• Improving OS
• Prolonged time to first symptomatic SRE
• Improving tumor markers
• Lower incidence of AEs
• No increasing grade 3 or 4 hematologic AEs rate.

Phase III trial - Discussion - conts.

• Liberal definition of best standard of care --> finding of the study may be generalizable to routine practice.
• Liberal definition of CRPC --> high external validity.
• Not suitable or not use Docetaxel is balanced between group and is compatible with routine practice.

Phase III trial - Limitation

• Exclusing patient with visceral metastases (25% of CRPC).

Further studies

New data on use of cabazitaxel, abiraterone and enzalutamide is published as well.

A phase 1-2 trial of Ra-223 combined with docetaxel in patients with CRPC and bone metastases is currently ongoing.