New video - panel discussion: "Prostate Cancer: Combination Therapy with Radium-223" [1].
From left to right:
Chris Parker (Royal Marsden)
Joe OSullivan (Northern Ireland Cancer Centre, Belfast)
Johann de Bono ((Royal Marsden) ... silent during this topic
Bertrand Tombal (Cliniques Universitaires Saint-Luc)
Interesting discussion of timing.
CP thought there would be benefit in starting at the same time as Abiraterone, rather than later, when "Abi" had shrunk bone mets. BT warned of waiting for bone pain. Made reference to the ALSYMPCA trial, where "42% of patients on the radium 223 arm had not received all 6 doses" [2], suggesting that Xofigo should have started earlier in those men.
There was an ASCO presentation in 2015 [2] that considered timing:
"TIMING OF RADIUM 223 VERSUS CHEMOTHERAPY OR OTHER TREATMENT OPTIONS
"The treatment landscape for patients with symptomatic CRPC is complex and manifested by the availability of a wide array of therapeutic modalities ranging from oral androgen inhibitors, cytotoxic chemotherapy, and external beam radiotherapy as well as radium 223. Although radium 223 may have a place in treatment for many patients with symptomatic CRPC, timing its use in a treatment sequence for any specific patient presents a challenging decision for a treating physician. Given the potential for additive and long-term myelosuppression associated with bone-target radiopharmaceuticals and cytotoxic chemotherapy, most of the available analyses focus on the timing of radium 223 before or after docetaxel-based chemotherapy.
"Tolerability of radium 223 was similar in men who had received chemotherapy first and in those who declined or were not felt to be eligible for chemotherapy. A retrospective analysis from ALSYMPCA identified modestly higher rates of hematologic toxicity in docetaxel-pretreated patients receiving radium 223 compared with those not previously treated with docetaxel (Table 2). There was also a higher rate of packed red blood cell transfusion, which persisted during the 13-week time period after completion of the sixth cycle of radium 223 therapy.4 Nonhematologic toxicities were similar in the two groups, although there was more nausea (40% vs. 30%) and vomiting (24% vs. 11%) for docetaxel-pretreated compared with nonpretreated patients.
"Efficacy of radium 223 was seen in both docetaxel-pretreated and docetaxel-naive patients in ALSYMPCA. However, subgroup analysis did identify that symptomatic skeletal events were not substantially delayed in the docetaxel-naive group.5 Specifically, the median time to sSRE was 17 months for patients treated with radium 223 and 19.5 months for placebo in docetaxel-naive patients (p = 0.12), whereas the median time to sSRE was 13.5 months in the radium 223 group compared with 7.8 months for placebo in docetaxel-pretreated patients (p = 0.00087). Although this is a subgroup analysis, and this finding warrants caution in interpretation, it may be that patients pretreated with docetaxel with bone pain represent an enriched, more aggressive subgroup in which bone targeting therapy may yield a greater effect.
"In terms of the tolerability of chemotherapy after radium 223, no published data exist regarding how many men treated with radium 223 went on to receive docetaxel (or other chemotherapy) and how they tolerated therapy in terms of myelosuppression. This may be because of the fact that enrollment in ALSYMPCA was restricted to men who had either received docetaxel or were not eligible for or declined docetaxel therapy such that there may be limited numbers of patients from this trial who subsequently received docetaxel. As noted above, the increased need for blood transfusions persisted in the 13 weeks following completion of radium 223 therapy, which suggests that tolerance of chemotherapy may be affected, at least in the short term. Thus the potential for higher rate of hematologic toxicity during radium 223 treatment when docetaxel has been administered first must be considered against the possibility that radium 223 may confer fewer benefits when administered first, before docetaxel as well as against the theoretical concern for compromised marrow reserve affecting future docetaxel therapy. Data are still awaited to answer these questions with greater certainty. However, given the relatively mild myelosuppression and previous experience with samarium in combination with docetaxel, combination therapy is undergoing study (NCT01106352). In the phase I experience of radium 223 and docetaxel, substantial hematologic toxicity limited administration of full doses and thus further combination studies will utilize a reduced dose of docetaxel 60 mg/m2.6
"Another significant concern when the potential for earlier administration is considered is the risk of secondary myelodysplasia. Very limited long-term data are currently available. The long-term report presented at 2014 American Society of Clinical Oncology Genitourinary Cancers Symposium consisted of median follow-up of 10.4 months.7 At that time point, no myelodysplastic syndrome or acute myeloid leukemia had been reported, and secondary solid tumors were similar in the radium 223 and placebo arms. However, longer follow-up will be critical to address this concern.
"Much less is known about the timing and interaction between radium 223 and the newer antiandrogen agents (abiraterone or enzalutamide). Both agents have demonstrated noteworthy clinical activity defined by increases in overall survival in patient subsets defined by the presence of cancer-related bone pain. Further, both agents have shown important benefits in quality-of-life measures including palliation in bone pain or delay to skeletal-related events in certain patient subpopulations.8,9 ALSYMPCA allowed standard care, including ketoconazole and older androgen receptor antagonists, but this cannot be extrapolated to assume that newer agents such as abiraterone and enzalutamide can be safely combined with radium 223. No data exist to suggest that combination use is superior to single sequential therapy. The open-access protocol did allow abiraterone, and the safety and efficacy of these combinations will be formally evaluated in an ongoing clinical trial (NCT02034552).
See full text: [2].
...
In a new paper from Taiwan [3]:
"To optimize treatment outcomes, selection of appropriate patients is important. As well as osteoblastic bone metastases, mCRPC patients should be well enough to receive six doses of radium-223 as this treatment duration has been shown to greatly improve OS outcomes compared with administration of four or fewer doses. Additionally, alkaline phosphatase and lactate dehydrogenase are emerging as important biomarkers during radium-223 treatment. Optimal concomitant standard-of-care therapies (such as abiraterone or enzalutamide) to be administered with radium-223 have yet to be defined as does the most efficacious dose and duration of radium-223 treatment."
...
Chris Parker was author of a recent international safety study [4]:
"Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns."
"Consistent with previous analyses, this updated final long-term safety follow-up analysis from ALSYMPCA trial in CRPC patients with symptomatic bone metastases showed that radium-223 continued to be well tolerated, with a low incidence of myelosuppression, long-term preservation of hematopoietic function, and no new safety signals.
"Radium-223 compares well in safety with the hormonal therapies abiraterone and enzalutamide, but is unlike the cytotoxic chemotherapies, in which myelosuppression is the most frequent AE. In the phase 3 TROPIC study, treatment with cabazitaxel was associated with significant myelosuppression (all grades neutropenia [94%], leukopenia [96%], anemia [97%], and thrombocytopenia [47%]) with relatively high rates of febrile neutropenia (8%). Furthermore, neutropenia frequently occurs in docetaxel-treated patients. Radium-223 is also distinct from the beta-emitting radiopharmaceuticals, which are associated with significant hematologic AEs (mainly leukopenia and thrombocytopenia).
"In this 3-yr long-term safety analysis, secondary malignancies occurred in four radium-223 patients and three placebo patients. The percentages of radium-223 and placebo patients who received anticancer medications and radiotherapies during follow-up were generally similar. A study limitation is that assessment of long-term radium-223 safety may be difficult given that many participants were treated with other anticancer therapies in combination with radium-223 during the follow-up period. Secondary malignancies induced by cancer therapies are of clinical interest, as they are a cause of morbidity and mortality in long-term cancer patients. Although secondary malignancies are uncommon, they can be a serious consequence of radiotherapy for cancer treatment. None of the secondary malignancies were considered related to radium-223, and no new primary bone cancer was reported; however, another study limitation was that the follow-up was limited to 3 yr, which is a relatively short time to assess the number of treatment-induced cancers, including hematologic malignancies. Additional studies with longer follow-up times are necessary to more accurately assess the long-term safety of radium-223. Another study limitation was that AEs were reported during follow-up only if considered by the investigator to be treatment related and may therefore be under-reported. Enrollment is currently ongoing in an international, prospective, observational, single-arm study (Radium-223 Alpha Emitter Agent in Safety Study in mCRPC Population for Long-Term Evaluation) aiming to assess the incidence of second primary malignancies in CRPC patients with bone metastases who are receiving radium-223 in routine clinical practice. Patients will be followed until 7 yr after the last radium-223 dose (NCT02141438).
"Of the patients who entered long-term safety follow-up, a higher percentage of radium-223 patients compared with placebo patients were alive at the end of the 3-yr period (14% vs 7%). These results, together with the unique mechanism of action and favorable safety profile during treatment and follow-up periods, make radium-223 an important treatment option, with potential for sequencing and combination with other agents for CRPC patients.
"The current safety profile of radium-223 is based on a treatment course of six injections (50 kBq/kg [55 kBq/kg following the NIST update]) given at 4-wk intervals. Studies are ongoing with higher-dose or extended-dose radium-223 regimens (NCT02023697) and combination with other agents (NCT02034552 [radium-223 + abiraterone or enzalutamide], NCT02043678 [radium-223 + abiraterone + prednisone/prednisolone], NCT01106353 [radium-223 + docetaxel]). Results from a phase 1/2 international, multicenter, prospective study in a highly selected population of patients with CRPC and bone metastases who were retreated with six additional radium-223 doses (NCT01934790) showed that retreatment with radium-223 was well tolerated, with minimal hematologic toxicity. Results from these studies will further contribute to our understanding of the overall safety and efficacy of radium-223."
...
Radium-223 is a calcium mimetic that targets osteoblastic metastatic lesions. As such, is vitamin K status important? K is essential for calcium transport to bone.
-Patrick
[1] onclive.com/peer-exchange/p...
[2] meetinglibrary.asco.org/rec...
Gratitude & Radiation & Xofigo
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New developments, Xofigo, Xgeva
Xofigo Radium 223 Dichloride 
Starting Xofigo RA 223
