What are the treatment options for a patient with locally advanced T4 prostate cancer?

T4 Prostate Cancer: Definition and Treatment

T4 prostate cancer requires multimodal therapy with external beam radiotherapy plus long-term androgen deprivation therapy (ADT) for 24-36 months as the standard approach, with consideration of adding abiraterone and prednisolone for improved outcomes. 1

Definition of T4 Prostate Cancer

T4 prostate cancer represents locally advanced disease with tumor extension beyond the prostate capsule, invading adjacent structures such as the bladder neck, external sphincter, rectum, levator muscles, or pelvic sidewall. 1 This stage is associated with higher PSA levels, higher Gleason scores, and represents a heterogeneous population often presenting with obstructive symptoms causing significant morbidity. 2

Standard Treatment Approach

First-Line Therapy: Radiotherapy Plus ADT

The primary treatment consists of external beam radiotherapy combined with 24-36 months of androgen deprivation therapy, as this combination has demonstrated significant improvements in overall survival and disease-specific mortality compared to single modality treatments. 1

• Radiotherapy dosing: Target dose should be at least 74 Gy when external beam radiotherapy is used as sole modality to increase biochemical control and delay time to salvage hormonal therapy. 3

• ADT timing and duration: Neoadjuvant ADT should be initiated 3-6 months before radiotherapy, continued during treatment, and extended for 2-3 years after radiotherapy completion for high-risk disease. 1

• Enhanced hormonal therapy: Consider adding abiraterone and prednisolone to ADT rather than ADT alone, as this combination demonstrated improved failure-free survival in the STAMPEDE trial. 1

Surgical Considerations

Radical prostatectomy for T4 disease should only be considered after careful staging and multidisciplinary team discussion, and is not a standard first-line approach. 3

• Surgery may be considered for younger patients in good physical condition, particularly after inductive ADT until PSA nadir (typically 6-7 months). 3, 4

• When surgery is performed, extended pelvic lymph node dissection is recommended. 3

• Approximately 20% of patients initially staged as T3-4 are found to have pT2 tumors at pathological examination. 3

• Patients must be informed that postoperative adjuvant radiotherapy or ADT will likely be necessary, with additional side effects beyond those of surgery alone. 3

Special Consideration for Rectal Involvement

For T4 tumors with rectal involvement, radiation therapy fields should be modified to include perirectal and mesorectal lymph nodes, as these patients have a 45% risk of involvement in these nodal stations. 5 These echelons are not typically covered with conventional pelvic external beam radiotherapy and represent a common site of nodal failure. 5

Treatment Selection Algorithm

1. Confirm T4 staging with appropriate imaging (MRI for local staging, bone scan if PSA >10 ng/mL or poorly differentiated tumor). 3

2. Assess patient factors:

   • Age and life expectancy (minimum 5 years for aggressive treatment)
   • Performance status and comorbidities
   • Presence of obstructive symptoms
   • Metastatic status (M0 vs M1) 1

3. Standard approach for most patients:

   • Initiate ADT (LHRH agonist with antiandrogen for first 4 weeks to prevent testosterone flare) 3, 6
   • Add abiraterone and prednisolone if available 1
   • Begin external beam radiotherapy after 3-6 months of neoadjuvant ADT
   • Continue ADT for total duration of 24-36 months 1

4. Consider surgery only if:

   • Patient is young with good performance status
   • Multidisciplinary team consensus after careful staging
   • Patient accepts high likelihood of needing adjuvant therapy 3

5. For rectal involvement: Expand radiation fields to include perirectal/mesorectal nodes 5

Critical Pitfalls and Caveats

• Sexual dysfunction warning: Patients must be informed that ADT combined with radiation significantly increases the likelihood and severity of sexual dysfunction beyond either treatment alone. 1

• Avoid surgery as routine first-line: Despite some single-institution series showing feasibility of surgery after inductive ADT, this approach lacks guideline support and should not be considered standard. 4 The evidence level for surgery in T4 disease is only Level III, Strength C. 3

• Do not use ADT alone: Primary ADT without local therapy (radiotherapy or surgery) is not recommended as standard initial treatment for locally advanced disease when the goal is cure. 7

• Testosterone flare prevention: Always initiate antiandrogen therapy 3-4 weeks before starting LHRH agonist to counteract testosterone flare. 3

• Gynecomastia prevention: Consider breast irradiation (8-15 Gy in 1-3 fractions) 1-2 weeks before initiating antiandrogen therapy. 3

Outcomes with Definitive Local Therapy

Recent evidence demonstrates that definitive local therapy for T4 prostate cancer is associated with improved overall survival (HR 0.3, P<0.001), longer freedom from local recurrence (HR 0.39, P=0.002), fewer obstructive symptoms with progression (HR 0.31, P=0.01), and less death from local disease (HR 0.25, P=0.002), even among men with metastatic disease. 2 This supports aggressive local therapy in select cases despite advanced stage.