Hypofractionated EBRT with ADT in node positive CA prostate

Hypofractionated EBRT with ADT in node positive CA prostate

1. Presented By : Dr. Paritosh

2. Introduction Prostate cancer is among the most common cancers in males worldwide, with an estimated 1,600,000 cases and 366,000 deaths annually In the United States, 11 percent of males are diagnosed with prostate cancer over their lifetime, with the incidence generally rising with age There are an estimated 268,490 cases and 34,500 deaths annually The overall five-year survival rate is over 98 percent

3. NCCN 2024

4. NCCN 2024

5. Current Treatment Modalities Radical radiotherapy to the prostate is the recommended curative treatment for ‘ high risk’ prostate cancer which is localized to the prostate The standard treatment approach for clinically node-positive prostate cancer typically involves Androgen deprivation therapy (ADT) with Radiation therapy NCCN 2024

6. NCCN 2024

7. For patients without regional pelvic nodal involvement, the benefit of prophylactically treating pelvic lymph nodes with radiotherapy has been debated for decades. The rationale for pelvic radiotherapy is the eradication of nodal micrometastases , providing better regional control and potentially improving survival outcomes. Risk of pelvic nodal involvement is estimated clinically using the Roach formula, based on serum prostate-specific antigen (PSA) levels at diagnosis and tumor Gleason score (GS). Potential clinical gain with prophylactic pelvic irradiation is likely to be relevant in patients with Roach nodal risk of 20%-40%. 

8. Roach Formulas

9. Hypofractionated Radiation Therapy (HFRT) HFRT is an emerging treatment modality that delivers larger doses of radiation per session over a shorter overall treatment duration. It has been gaining attention as a potentially equally effective but more convenient alternative to Conventional RT. NCCN 2024

10. NCCN 2024 RADIATION THERAPY REGIMENS

11. RP + PLND RP + PLND can be considered in patients who are younger and healthier without tumor fixation to the pelvic sidewall. There is limited evidence that RP + PLND is beneficial in the setting of node positive disease. Use of this approach should be limited to patients with >10-year life expectancy and resectable disease NCCN 2024

12. About the Study Sample Size (n) = 60 Retrospective study The medical records of patients with clinically node-positive prostate cancer who underwent definitive RT combined with ADT between January 2008 and November 2018 were reviewed.

13. Inclusion Male patients aged 18 years or older with histologically confirmed prostate cancer. ECOG PS <1 Stage cT3a, cT3b cT4 and N1 Patients who are candidates for both ADT and radiation therapy, with a life expectancy of at least 10 years.

14. Exclusion Patients with evidence of distant metastasis History of prior pelvic radiation therapy, which could increase the risk of severe toxicity. Presence of significant comorbidities, such as severe cardiovascular or pulmonary diseases, which might contraindicate radiation therapy. Patients with prior treatment for prostate cancer, such as surgery, chemotherapy, or other forms of radiation therapy Patients who underwent a follow-up of less than a year and who did not undergo ADT were excluded.

15. Treatment Eligible patients underwent definitive RT with intensity-modulated radiation therapy (IMRT) technique or proton therapy at a total dose of 70 Gy with a fraction size of 2.5 Gy Patients, who were scheduled to undergo definitive RT, started ADT 2–3 months before the initiation of RT. ADT comprised a gonadotropin-releasing hormone agonist (GnRH) and an antiandrogen. It was administered for at least 2 years and could be extended at the discretion of the treating clinicians. Suspected lymph nodes were assessed before initiating RT using MRI and CT to determine their responsiveness at 2–3 months after ADT.

16. RT Planning For RT planning, patients initially underwent simulation CT and MRI scans. A rectal balloon was routinely placed during the simulation CT and MRI scans and the treatment sessions for reproducibility. As stated in the eligibility criteria, IMRT technique or proton therapy was used.

17. RT was delivered to the prostate and regional lymph nodes. High-risk clinical target volumes (HR-CTV) included the prostate, seminal vesicles, and residual metastatic lymph nodes. The seminal vesicles could be partially or completely omitted from the HR-CTV when they showed no evidence of invasion. Low-risk CTV (LR-CTV) included the obturator, external iliac, internal iliac, and presacral lymph nodes

18. The planning target volume (PTV) was constructed by expanding the CTV by 3–10 mm. The prescribed dose was 70 Gy in 28 fractions for the HR-PTV and 50.4 Gy in 28 fractions for the LR-PTV. The plan was optimized to cover 95% of the PTV with 100% of the prescribed dose. A simultaneous integrated boost (SIB) technique was used to differentiate the dose between the HR- and LR-CTV.

19. Adverse Effects Patients were evaluated for acute toxicity at the outpatient clinic one month after RT completion. Subsequently, they were monitored using prostate-specific antigen (PSA) tests every 3–6 months

20. Outcomes The oncological outcomes analyzed in this study were Biochemical failure rate (BFR) Clinical failure rate (CFR) Overall survival (OS) Prostate cancer-specific survival (PCSS)

21. DEFINITIONS Biochemical failure was defined as a rise in the PSA level by at least 2.0 ng/mL from the PSA nadir after undergoing RT, or administration of salvage ADT Clinical failure was defined as an evidence of disease progression on physical or radiological examination. An event for OS was defined as a patient’s death from any cause An event for PCSS was defined as a prostate cancer-related death , evaluated by a board-certified radiation oncologist.

22. RESULTS

23. Results The 3-, 5-, and 7-year BFR rates were 5.2%, 19.1%, and 35.6% The 3-, 5-, and 7-year CFR rates were 3.2%, 11.3%, and 23.1% The 3-, 5-, and 7-year OS rates were 96.6%, 89.0%, and 83.4% The 3-, 5-, and 7 year PCSS rates were 100%, 98.2%, and 95.3% Significantly lower PCSS was associated with non-regional lymph node metastasis

24. Limitations Retrospective Nature: The study's retrospective design was a limitation. Small Cohort Size: The small cohort size and few events may have reduced the study's statistical power. Potential Under-reporting: Oncological outcomes and adverse events, particularly prostate cancer-specific survival (PCSS), might be under-reported due to premature discontinuation of follow-up and unclear causes of death. Nodal Staging Accuracy: The diagnosis of clinically node-positive prostate cancer may have been inaccurate, as the nodal staging only included MRI and CT, without PET/CT or pathological confirmation.

25. Definitive radiotherapy (RT) combined with androgen deprivation therapy (ADT) was shown to be a viable treatment option for clinically node-positive prostate cancer. The study reported a 7-year prostate cancer-specific survival (PCSS) rate of 95.3%. Most biochemical failures occurred after the cessation of ADT. Prolonging ADT may decrease the failure rate, though its impact on PCSS remains unclear.

26. The results of the COHORT trial, a prospective study on the role of definitive RT combined with ADT for clinically node-positive prostate cancer, are eagerly awaited. More studies are needed to clarify the clinical efficacy of prolonged ADT beyond 2–3 years.

27. Toxicities Grade 2 and beyond late genitourinary toxicities: 5.0%. Grade 2 and beyond late gastrointestinal toxicities: 13.3%. Only two grade 3 events were recorded, and all adverse events were manageable. No grade 4–5 adverse events were reported.

28. Discussion Biochemical and Clinical Failures: Kaplan–Meier curves indicated that most biochemical (BFR) and clinical failures (CFR) occurred 3 years after treatment initiation. 78.6% of biochemical failures occurred after the cessation of ADT. Long-term ADT for at least 2 years was recommended in the study, with the possibility of extending its use. Extended or lifelong ADT might reduce recurrences in node-positive prostate cancer. However, a clear association between extended ADT and improved prostate cancer-specific survival (PCSS) could not be established from the study data.

29. Previous randomized trials, like DART01/05, showed that 2-year adjuvant ADT had better overall survival (OS) than 4 months of ADT in high-risk localized prostate cancer. The 5-year benefit in OS was not sustained at 10 years, but a clinically relevant benefit was noted in a high-risk subgroup.

30. POP RT Trial Randomized trial of Prostate Only or Pelvic Radiotherapy in high risk prostate cancer (POP-RT) from Tata Memorial Centre is comparing the benefit of radiotherapy to pelvic nodes in addition to prostate, using modern conformal technique of image guided intensity modulated radiotherapy (IG-IMRT).

31. Key Outcomes: 5-Year Biochemical Progression-Free Survival ( bPFS ): WPRT: 95% PORT: 81.2% 5-Year Metastasis-Free Survival (MFS): WPRT: 96.9% PORT: 89.5% 5-Year Overall Survival (OS): WPRT: 96.4% PORT: 93.4% (not statistically significant)

32. Acute Gastrointestinal (GI) Toxicity (Grade 2+): WPRT: 20% PORT: 7%   Conclusion: Prophylactic WPRT using a contemporary dose and technique along with long-term ADT for high-risk and very high-risk prostate cancer resulted in a large and significantly improved BFFS and DFS as compared with PORT, but did not impact OS .

33. WPRT is associated with a higher incidence of acute gastrointestinal toxicity. Overall survival did not differ significantly between the groups at the 5-year follow-up. The trial suggests that WPRT offers better disease control but with an increased risk of side effects.