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Carcinoma prostate stampede trial
This document discusses a trial investigating the role of local radiation therapy for metastatic prostate cancer. The main findings were: 1. No overall survival benefit was seen with radiation therapy, but survival improved in patients with low metastatic burden. 2. Failure-free survival improved with radiation therapy overall and in the low metastatic burden group. 3. Adverse effects from radiation therapy were modest. The trial provides evidence that radiation therapy to the prostate improves outcomes for men with metastatic prostate cancer who have a low metastatic burden and does not negatively impact side effects.
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Introduction to local radiation therapy and its evolving role in treating metastatic prostate cancer.
Explains systemic effects of RT, outlining how it can lead to distant tumor control and its correlation with survival outcomes. Discusses how local treatments can inhibit metastasis, the relationship with systemic treatments, and trial outcomes.Key metrics related to overall survival (OS) and failure-free survival (FFS) in patients treated with RT.
Discussion of survival benefits for patients with low metastatic burden receiving radiotherapy.
Final thoughts on the necessity of RT for specific patient subgroups and future treatment considerations.
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Carcinoma prostate stampede trial
- 1. Locally advanced &Metastatic Prostatic Cancer- Redefining the role of Local RT Dr. Rohit S Kabre. MD, Radiation Oncology
- 3. Local radiation &bystander/ abscopal effect
- 4. • Out-of-field “systemiceffects” of RT exerting tumoricidal control at distant sites- abscopal phenomena- described for decades • Contributed by complex interactions –Involving local tumor ablation, antigen presentation & inflammatory mediators. • Golden et.al (Lancet Oncol, 2016)- Median survival of patients demonstrating an abscopal response (defined as ≥30% size reduction) experienced nearly 3-fold increased survival (21 vs. 8 months) • Radical local treatment of the primary tumour tested in several RCTs in metastatic cancer- clear survival benefit lacking.
- 5. • Metastatic Prostatecancer typically receive systemic treatment, local therapy reserved for symptom palliation. • Primary tumors metastasize by disseminating tumour cells into circulation and by priming the premetastatic niche. • Proliferation of tumor cells at distant sites dependent on compounds secreted by the primary tumor. • local treatment inhibits initiation of distant disease & progression of existing metastases. • Hormone treatment (HT) usually successful at first: prevents growth & shrinks tumor over period leads to resistance. • Newer drugs showing promising activity in prostate cancer i.e ZA, Docetaxel & Celecoxib.
- 6. • Retrospective analysesshowed association between RT to primary tumor and improved OS • HORRAD trial- 432 men with metastatic Ca prostate ADT with or without prostate RT- no overall survival benefit but survival might improve in patients with fewer than five bone metastases. • Hypothesis- Radical radiotherapy to the prostate would improve OS in metastatic prostate cancer and benefit would be greatest in low metastatic burden disease.
- 7. STAMPEDE- RT perspective •If indicated you can also receive radiotherapy (RT) at any time in the trial. For example, if there is no evidence of disease outside the pelvic region. Your doctor may offer you radiotherapy to the prostate gland and nearby lymph nodes according to local practice in your hospital. • Intention to give RT (or not) stated at randomisation- ensuring no bias towards particular combinations of systemic therapy with radiotherapy. • To ensure consistency of timing of administration of radiotherapy in all arms- RT given around 6-9 months after randomisation & after at least 6 months of HT
- 8.
- 9. Metastatic burden • Assessedthrough whole body scintigraphy and CT or MRI staging scans. • Classified according to CHAARTED trial definition • High metastatic burden- four or more bone metastases with one or more outside the vertebral bodies or pelvis, or visceral metastases, or both • All other assessable patients- low meta static burden. Definition used in LATITUDE trial-absence of visceral metastases and fewer than three bone metastases
- 10. • Primary efficacyoutcome OS- time from randomisation to death from any cause. • Failure free survival- outcome measure for interim analyses - time from randomisation to at least one of the following: 1. biochemical failure 2. progression either locally, in lymph nodes, or in distant metastases 3. death from prostate cancer • Biochemical failure- rise above the lowest PSA value reported within 24 weeks after enrolment by 50% and to at least 4 ng/mL • Patients without a fall of 50% - biochemical failure at time zero. • Secondary outcomes were PFS - FFS without biochemical events
- 11. • All patientsreceived lifelong ADT either GnRH agonists/ antagonists or orchidectomy. • RT to the prostate- 1. 36 Gy in six consecutive weekly fractions of 6 Gy 2. 55 Gy in 20 daily fractions of 2·75 Gy over 4 weeks • PTV consisted of the prostate only • Nadir PSA- lowest level of PSA reported within 24 weeks after randomisation.
- 12. RESULTS • Median age68 years (IQR 63–73) • Median PSA before ADT - 97 ng/mL (33–315) • 1630 (79%) patients had a Gleason score of 8–10 • Groups balanced with respect to baseline characteristics • Median time to starting radiotherapy- 35 days (IQR 28–60) after randomisation, and 95 days (74–120) from starting HT • Median follow up was 37 months (IQR 24–48)
- 14. • Overall Nosurvival advantage was noted with radiotherapy (stratified log-rank test p=0・451; HR 0・92, 95% CI 0・80–1・06; p=0・266) • OS improved in low metastatic burden disease with radiotherapy (HR 0・68, 95% CI 0・52–0・90; p=0・007; 3-year survival 73% with control vs 81% with radiotherapy) • Overall, FFS improved with radiotherapy (HR 0・76, 95% CI 0・68–0・84; p<0・ 0001 • FFS improved in low metastatic burden WITH radiotherapy (HR 0・59, 95% CI 0・ 49–0・72; p<0・0001 • prostate cancer-specific survival (Fine and Gray method)- no evidence of an overall treatment effect (sub-HR 0・94, 95% CI 0・81–1・10; robust p=0・431 • There was evidence of an effect in patients with low metastatic burden • A significant interaction was seen between treatment effect and metastatic burden (robustly estimated interaction p=0・007
- 17. • 1082 patientsof daily RT schedule- strong evidence of FFS advantage with RT (HR 0・69, 95% CI 0・59–0・80; p<0・0001). • 212 deaths were reported in the control group and 188 in the radiotherapy group (stratified log rank p=0・123; HR 0・86, 95% CI 0・71–1・05; p=0・128) • insufficient evidence of a difference for FFS in weekly RT schedule ( HR 0・85, 95% CI 0・73–0・99; p=0・033) to report on survival
- 18. • Adverse effectson RTOG scale during RT- modest over 3 years of follow up.
- 19. Discussion • RT tothe prostate no improvement in OS in unselected patients. • RT did improve overall survival & FFS in those with a low metastatic burden without compromising on side effect profile. • Can be a standard treatment in this subgroup. • Extrapolating results from these findings- 1. RT may improve survival in pelvic node-positive disease 2. for prevention of symptomatic local events
- 20. Probable limitations • Determinationof metastatic burden retrospectively • Low metastatic burden status determined from scans taken before randomization. • Uncertainty regarding the optimum definition of low metastatic burden (oligometastatic) prostate cancer. • Definitions based on CT and bone scans- extrapolation to patients imaged with more sensitive techniques needs caution • Compliance with allocation to prostate radiotherapy was not complete (94%)- underestimate the true effect size for radiotherapy. • Median follow-up (37 months) shorter than median survival (46 months) particularly relevant to the analysis of symptomatic local events- occur late and after disease progression • Most patients in this comparison received androgen deprivation alone • Up-front systemic treatment of metastatic prostate cancer has evolved.
- 21. • If thebenefit of radiotherapy is mediated by local tumour eradication- feasibility of radical prostatectomy ? 1. gRAMMP trial (NCT02454543) 2. TROMBONE feasibility study • Value of prostate RT in men receiving abiraterone tested in 1. PEACE1 trial (NCT01957436) 2. prospectively planned STOPCAP M1 metaanalysis • Prostate RT does not require regulatory approval and is readily available at modest cost in most parts of the world.
- 22. • Prostate RTshould be a standard treatment option for men with a low metastatic burden. • Local treatment to the primary tumour should be explored for patients with small volume metastatic disease from other malignant diseases.
Editor's Notes
- #2 Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE)
- #4 These cells can generate additional cytokines that act locally and circulate systemically or propagate either hematogenously or lymphatically to act on normal tissues and tumor cells located at distant sites apart from the irradiated primary tumor.
- #6 Primary Aim was to investigate whether combining newer drugs with HT can lengthen the time before the cancer starts to grow Hormone Treatment and Zoledronic Acid and Docetaxel Hormone Treatment and Zoledronic Acid and Celecoxib
- #16 Solid lines show the Kaplan-Meier analysis and dotted lines show the flexible parametric model.
- #19 The incidence of acute bladder and bowel effects (grade 1–4) lower for weekly radiotherapy schedule than for those who nominated the daily schedule Patients in both control and radiotherapy groups reported a low incidence of grade 3 and 4 RTOG late effects (one [1%] control vs 37 [4%]