Treatment Approaches for High Risk Prostate Cancer

Junzo Chino M.D.

Case

• 55yo AAM presents to Primary Care for initial visit
  
• He has mild HTN on exam
  
• No GU symptoms
  
• Erectile function intact
  
• PSA is sent as a screening test and returns at 325 ng/ml
  
• DRE performed revealing a moderate sized gland, firm nodule in the R apex.
  
• U/S guided Biopsy performed
  
• 7/8 cores reveal prostate cancer 4+4 = 8 GS
  
• Pt is initially seen in Urology Clinic and offered surgery - placed on OR schedule
  

Further Staging

• CT scan reveals moderate sized prostate
  
• 3x4cm R pelvic lymph node just below the bifurcation of the common iliac
  
• No other LAD
  
• No invasion of bladder or rectum
  
• Bone scan negative
  

Case

• We are called by the urology chief resident, to have the patient discuss alternatives to surgery
  

Defining High Risk

D'Amico classification looking at T stage, GS and PSA: any of the below

• T2c or greater
  
• GS 8 or greater
  
• PSA 20 or greater
  

Per Nguyen, IJROBP 2009: Increased # of high risk factors is associated with PCSM. Paper includes PSA velocity as an additional risk factor.

 

Surgery for High Risk Disease

Several Retrospectives series exist comparing results of surgery to radiation (see Zincke Cancer 1981, D'Amico JAMA 1998)

Duke Data (unpublished)

from 1997-2007, 146 patients with clinically high risk disease operated on

• Median PSA 9
  
• 58% had GS 8 or greater
  
• 23% had T-stage T2c or greater
  
• 91% had only one high risk factor
  

Therefore this cohort tended to have a high grade and low-middle disease burden

Pathologic Results

• 76% had at least on indication for adjuvant RT on final path (ECE, SVI, positive margin, or PSA ≥ 0.2ng/ml)
  
• 55% with ECE
  
• 27% with SVI
  
• 54% with positive margins
  
• 20% with PSA ≥ 0.2ng/ml
  
• 28% received early RT (within first 6 months postoperatively)
  

Outcomes at 4 years

• 48% (95% CI 38-57%) had received postoperative radiation therapy
  
• 74% (95% CI 64-83%) remained free of biochemical failure (including those salvaged with RT)
  
• 98% (95% CI 96-100%) alive
  
• 14% (95% CI 8-23%) undergoing indefinite ADT
  

Postoperative Toxicity

• ≥ Grade 2 urinary toxicity in 42 (29%)
  
• ≥ Grade 2 erectile dysfunction in 93 (64%)
  
• ≥ Grade 2 rectal toxicity in 3 (2%).
  

Conclusions -

1. Even in Highly selected patients, ½ of patients undergoing initial surgery had postoperative RT by 4 years.
   
2. With selected adjuvant RT and salvage RT, 4 year biochemical control was reasonable at 74%
   
3. Toxicity rates are not insignificant
   

New directions for Surgery and Radation Therapy

Neoadjuvant RT for high Risk Prostate cancer

• Phase I/II trial is proceeding at Duke with reasonable toxicity to date
  

 

To Compare Approaches (Apples and Oranges)

Merglen Arch Intern Med 2007;167(18):1944

Compared results with 844 consequtive patients treated for ACP in Geneva Switzerland 1989-1998. This demonstrates high survival rates for those treated with RP vs RT, However, there were clearly significant selection biases for surgery have younger age, and a bias against RT + ADT for higher grade disease. When these factors were controlled for with a Cox Regression, the HR of RT + ADT overlapped the Surgery Cohort.

Moreover, there are multiple other factors that go into Surgical selection that are unaccounted for. No details on RT or ADT - given time frame likely these were suboptimal

 

SEER data (Lu-Yao Lancet 1997)

queried the SEER databaes 1983-1992

59,876 pts identified

Cohorts determined by reported Grade (1-3) and Therapy Received

No control for PSA, cT stage or comorbity

RT fared worse with G3-4 disease compared to RP, but again there is no systematic control for other variables.

 

External Beam Radiation Therapy and Hormone Treatment

The majority of randomized data in Prostate cancer treatment lies in this group.

Trials

1. RTOG 8531 (non bulky)
   
2. RTOG 8610 (bulky)
   
3. RTOG 9202 (4 months vs 2 years ADT)
   
4. EORTC 22863 (no ADT vs 3 years ADT)
   
5. EORTC 22961 (6mo ADT vs 3years ADT)
   

RTOG 85-31 "HIgh Risk - NonBulky"

977 patients with cT3 or pT3 ACP, or N+. bulky tumors excluded.

Randomized to

• RT alone (44-46 WPRT + boost to 65-70Gy)
  
• RT + adjuvant goserelin indefinitely
  

10 year results:

• OS 49% ADT vs 39% (SS)
  
• LF 23% ADT vs 38% (SS)
  
• DM 24% vs 39% (SS)
  

RTOG 86-10 "High Risk Bulky"

471 pts with T2-T4 ACP, bulky randomized to

• RT alone (45Gy pelvis, boost to 65-70 Gy)
  
• goserelin + flutamide x 4months (neoadjuvant and concurrent) + RT
  

10 year results:

• OS ADT 43% vs 34% (NS) (primary endpoint)
  
• DSM ADT 23% vs 36% (SS)
  
• DM ADT 35% vs 47% (SS)
  
• BR ADT 65% vs 80% (SS)
  

RTOG 92-02: Short vs Long ADT

1554 pts with T2c-T4 ACP, psa < 150 Randomized to:

• Goserelin + Flutamide x 4 months (neoadjuvant and concurrent) + RT WPRT 45Gy boost to 65-70Gy
  
• Same + 2 years goserelin thereafter
  

10 year results

• OS 52% LTADT vs 54% STADT (NS)
  
• GS 8-10: OS 45% LTADT vs 32% STADT (SS)
  
• DFS 22% LTADT vs 13% STADT (SS)
  

EORTC 22863: Bolla

415 pts with t1-2 G3, or T3-4 any grade (majority T3), randomized to

• RT 50Gy WPRT, boost to 70Gy
  
• Same RT + goserelin x 3 years (start with RT)
  

5 year results

• OS ADT 78% vs 62% (SS)
  
• DSS ADT 94% vs 79% (SS)
  
• DFS ADT 74% vs 40% (SS)
  

D'Amico Study

206 men with Intermediate-High Risk - T1-T2b PSA>= 10, GS >=10, ECE or T3 by MRI

• 70 GY RT (no pelvis)
  
• Same + 6 months leuprolide/goserelin + flutamide (start 2 months prior to RT)
  

8 year results

• OS 74% (ADT) vs 61% (no ADT) SS
  
• Difference seen primarily in men without significant comorbidities
  

What about 6 months vs 3 years? ADT: Bolla EORTC 22961

970 pts with pT2c-T4 or N+ prostate cancer PSA <150, randomized to

• 70Gy + 6 months ADT
  
• 70Gy + 3 years ADT
  

at 5.2 years f/u interim analysis demonstrated futility. 5y OS was 85% LTADT, 81% STADT, failing to prove non-inferiority. 5y bRFS was 78% vs 59%, which was SS for inferiority of STADT

WPRT?

Currently Three Trials exist on +/- WPRT

1. RTOG 77-06
   
2. RTOG 94-13
   
3. GETUG-01
   

None of these trials are perfect

None of these trials demonstrate a benefit to WPRT

However, the EORTC trials and RTOG trials demonstrating benefit of ADT used WPRT

 

ADT summary table

Study		n	stage	ADT		Dose		WPRT	yrs fu	DFS	OS
RTOG 85-31		977	c or p T3, or N+	none ∞ A		65-70Gy		if N+	10		39%* 49%*
RTOG 86-10		471	bulky T2-4	none 4mo NA/C		65- 70Gy		yes	8	10%* 24%* bRFS	44%† 53%†
EORTC 22863		415	T1-2 G3 or T3-4	none 3yr C/A		70Gy		yes	5	40%* 74% *	62%* 78%*
RTOG 92-02		1500	T2c-T4	4mo NA/C 2yr NA/C/A		65-70Gy		yes	5	28%* 46%*	78%‡ 80%‡
D'Amico		206	T1-T2b	none 6mo NA/C/A		70Gy		no	5	57%* 82%*	78%* 88%*

A- Adjuvant, C- Concurrent, NA- Neoadjuvant, * SS, † SS for GS2-6, ‡ SS for GS8-10

 

At this point I ran out of time, but wanted to cover EBRT with brachy boost as another RT based option which has had good preliminary results - Stay tuned!

 

Case Resolution

Pt started on ADT

To be rescanned for potential RT + LTADT in 2 months

 

Adjuvant RT for prostate cancer (SWOG update Journal Club)

AC presents today on the recent SWOG adjuvant RT for prostate cancer update.

Approximately 1/3 of patients undergo prostatectomy for prostate cancer, and of those 1/3 have some form of biochemical recurrence.

There is some debate about the definitions of salvage vs adjuvant RT.  We define adjuvant RT as treatment postoperatively without a detectable PSA, however some institutions will include any treatment within six months of surgery as adjuvant.

30-60% of those undergoing RP have either ECE or Posititive margins.  Additional factors associated with failure include SVI, high GS, and pretreatment PSA.

Randomized Data

EORTC 22911 (Bolla, Lancet 2005) 1005 pts with pT3 or positive margins, randomized to 60Gy vs wait and see.  Results: improved cPFS, LRF, no difference in OS.  See prior post on this trial.  Approximately 2/3 of the wait and see group recieved salvage RT.  Additionally only 10% had detectable PSA.

ARO 96-02 (Wiegel, ASCO 2005) 385 with pT3N0 randomized to 60Gy vs wait and see.  In the randomization, all had an undetectable PSA. 20% had detectable PSA in this trial and were all treated with 66Gy.  in all groups biochemical control improved HR 0.79 p=0.08.  In the adjuvant group only, biochemical control improvement HR 0.49 p=0.001.  See also prior post for link.

SWOG 8794.  pT3 or positive margins, n=425.  Randomized to 60-64Gy vs observation.  Primary endpoint Metastasis Free Survival.  Accrual goal was 558.  Power 0.8, alpha 0.05, HR for MFS would be 0.66.  The accrual goal was revised when a lower event rate was seeing in the control group in 1996.  Longer follow up assumed, and accrual revised to 408.  Also revised to a two-sided test.

10% in intervention arm didn't receive treatment.  ~1/3 of patients in control arm recieved RT.  Also 1/3 had a detectable PSA.

Initial report in JAMA 2006 failed to meet MFS endpoint, though this was borderline p=0.07.  bRFS was improved.

Update with 12.6 years f/u.  DM free survival improved with RT (HR 0.71; 95% CI 0.54, 0.94; p = 0.016), and OS improved with RT (HR 0.72; 95% CI 0.55, 0.96; p = 0.023). NNT was 12 for DM free survival, and for OS NNT was 9.

No subgroup seemed to benefit more from RT.

Moinpour JCO 26:112, 2008: QOL data from this trial.  After year 2 bowel movement QOL was similar between RT vs obs.  In urinary QOL, RT had a consistent reduciton in QOL.  Global QOL seemed to be initially worse in the RT arm, but curves crossed at 2 years, and RT became superior at longer followup.

EORTC & German trial of Postop RT for Prostate Cancer

In response to a question - here are the two other trials of post op RT for Prostate Cancer referred to in the last post

ARO 96-02 (German):
Wiegel ASCO 2005 (abstract only)

•385 s/p RP, pT3N0, undetectable PSA

–60 Gy post op RT to prostate bed

–NFT

•If PSA detectable, 66Gy postop RT (20%of patients entered)

•32 in RT arm did not receive RT (21% of arm)

•39 mo follow up

•Per protocol: bRFS (4) 81% with RT, 60% NFT (p<0.001)

•Intention to treat: bRFS (4) ~75% with RT, 60% NFT (SS)

Grade II rectal toxicity 3%

EORTC 22911: Bolla, 2005

•1,005 Patients underwent RP, node negative with + margins, + ECE, or SVI.

•Randomized to

–50Gy + 10Gy boost to bed

–Close observation (NFT)

•Mean f/u 5 years

•90% had PSA <0.2

•bPFS (5) 74% RT vs 53% NFT (p<0.001)

•Clinical Failure (5) 8.8% RT vs 19.0% NFT (p=0.009)

•No difference in OS or Distant Failures

•Grade 1-2 toxicity 45%NFT vs 60%RT (SS)

•Grade 3 toxicity ~4% for both (NS)

Adjuvant RT for prostate cancer improves Survival

Dr. Lee draws attention to this article in press at J Urol:

The SWOG trial of 431 men with pT3N0M0 prostate cancer, randomized to 60-64 Gy adjuvant radiotherapy or observation. 70 of the observation group recieved salvage RT at failure.   DM free survival improved with RT (HR 0.71; 95% CI 0.54, 0.94; p = 0.016), and OS improved with RT (HR 0.72; 95% CI 0.55, 0.96; p = 0.023).

This is an extremely important trial, in while adjuvant RT has been demonstrated to improve BRFS in two additional trials (EORTC and a German Trial), this is the first to demonstrate that this translates into a survival benefit.  This is especially relavent when only ~ 15% of patients with pT3 disease are actually referred for RT (unpublished data) nationally.  Duke has done a little better recently with ~35% of patients being referred. 

Pancreatic Cancer - Adjuvant Therapy

JP Presents on adjuvant treatment for pancreatic cancer.

Case presentation is of a 55yo man presenting with obstructive jaundice:  Staging reveals a 2.5cm mass mod diff adenocarcinoma at pancreatic head via diagnosed via biopsy at EUS and ERCP.  Whipple performed with multiple positive margins at neck, with 4/10 lymph nodes positive.  (pT3N1).  PET CT was negative for distant disease.

BC: Whipple in this scenario was probably attempted initially as Pt seemed to be node negative at initial staging.  If nodes were known prior to the patient may have been better served by CTRT upfront, with reevaluation for resection afterwards.

34,000 pancreatic ca per year, with 32,000 deaths per year.  2/3 are found in the head.  80% are unresectable at diagnosis.  Risk factors: Smoking, chronic pancreatitis, obesity, high fat diet.  3y OS with resection 17%, at best 6% unresected.

Whipple classically resected distal stomach, duodenum, pancreatic head, common bile duct above the cystic duct, and the gallbladder.  For tumor in the body or tail, a distal pancreatectomy can be performed, sparing the head.  Spleen may be taken with this procedure.  Recently, pylorus sparing whipples have been gaining popularity at Duke.

T1 <=2cm, T2 >2cm, T3 out of pancreas, T4 celiac axis/sma

N0 no nodes, N1 nodes 

Randomized Trials Examining Adjuvant Treatment.

GITSG 9173 (Kalser, Arch Surg, 1985): n=43 (goal of 100, very poor and slow accrual), resected with negative margins.  XRT (40 gy split course) + 5FU vs. Observation.  2y OS 43% CMT vs 18% obs (p=0.03), Median DFS 11mo vs 9mo (SS).

EORTC 40891 (Ann Surg 1999) ChTRT vs obs.  2 yr OS 51% CMT vs 41% Obs (p=0.208).  Pancreatic head tumors seemed to do slightly better with CMT but not significant.  Again split course RT to 40Gy (split), low 5FU dose.  Poor treatment compliance (>20% in treatment arm did not receive treatment).  Updated in 2007 (link above)

ESPAC-1 (Neoptolemos, Lancet 2001) n=541.  This is a complicated study, which really is three trials, A: 2x2 trial of chemo, and chemort,  B: CMT vs obs, or C: Chemo vs obs.  Investigators could determine which trial patients went on.  RT remains antiquated at 40Gy split course.  No significant difference in CMT vs observation with pooling of the various trials.  Chemotherapy in the pooled arms did have a benefit.  A better analysis was presented of just the 2x2 trial (Neoptolemos, NEJM, 2004) - which demonstrated a benefit to chemotherapy alone, and a detriment to CMT.  The overall results are also poor compared to other trials. 

CONKO-001 (Oettle JAMA 2007). n=386 resected Pancreatic Cancer.  Randomized to Gemcitabine x 6 cycles vs observation.  Primary endpoint was DFS.  5y DFS was 16.5% vs 5.5% (SS).  OS trended toward significance - BC comments that on update, OS has become positive.

RTOG 97-04 (Regine JAMA 2008).  n=451 (388 for head tumors).  After surgery, randomization was to 5FU - ChtRT - 5FU vs Gem - ChtRT - Gem.  Dose was 50.4Gy.  Powered for OS for all comers and for the pancreatic head subset.  3yOS 31% Gem arm vs 22% 5FU in head tumors (p=0.09), HR 0.82 (95% CI 0.65-1.03).

So this leaves us with a mix of less than perfect trials, none of which answer the central question of wether modern RT is beneficial in the setting of adjuvant gemcitabine.  Stay tuned for upcoming randomized trials opening...