Peter T. Scardino

CANCER CONTROL WITH RADICAL PROSTATECTOMY ALONE IN 1,000 CONSECUTIVE PATIENTS

PURPOSEnWe analyzed the long-term progression-free probability after radical retropubic prostatectomy in a consecutive series of patients with localized prostate cancer.nnnMATERIALS AND METHODSnFrom 1983 to 1998, 1,000 patients (median age 62.9 years, range 37.7 to 81.4) with clinical stage T1 to T2 prostate cancer were treated with radical retropubic prostatectomy and pelvic lymphadenectomy, without other cancer related therapy before recurrence. Mean followup was 53.2 months (median 46.9, range 1 to 170).nnnRESULTSnTen years after radical retropubic prostatectomy the mean probability +/- 2 standard errors that patients remained free of progression and of any further treatment was 75.0% +/- 3.7% and of metastasis 84.2% +/- 4.4%. Mean actuarial cancer specific survival rate +/- 2 standard error was 97.6% +/- 1.7%. In a multivariate analysis pretreatment prostate specific antigen level (p <0.0001), biopsy Gleason sum (p <0.0001) and clinical stage (p=0.0071) were independent prognostic factors for progression. After prostatectomy independent risk factors were Gleason sum in the prostatectomy specimen (p=0.0008), extracapsular extension (p=0.0019), seminal vesical involvement (p <0.0001), lymph node metastasis (p <0.0001) and surgical margin status (p <0.0001). Margins were positive in 12.8% of cases. At 10 years postoperatively radical retropubic prostatectomy was effective for cancer confined to the prostate (92.2% progression-free probability) and also not confined (52.8%), including 71.4% progression-free probability for patients with only extracapsular extension and 37.4% with seminal vesicle invasion without lymph node metastasis.nnnCONCLUSIONSnRadical retropubic prostatectomy provided long-term cancer control in 75% of patients with clinically localized prostate cancer and was effective in the majority of those with high risk cancer, including T2c or biopsy Gleason sum 8 to 10, or PSA greater than 20 ng./ml. Further research should address identifying patients who can safely avoid aggressive therapy.

Prognostic significance of lymph nodal metastases in prostate cancer

Pelvic lymph node metastases indicate a poor prognosis for patients with clinically localized prostate cancer but the significance of minimal nodal metastases still is debated. We determined the progression and cancer specific survival rates based on the extent of nodal metastases in 511 patients followed for a mean of 8.6 years (range 2.5 to 17.5 years) after bilateral pelvic lymph node dissection and irradiation therapy. The patients were divided into 4 groups based on the extent of nodal metastases: NO--negative nodes (359 patients), N1--a single microscopic positive node (37), N2--multiple microscopic positive nodes (86) and N3--grossly positive or juxtaregional nodes (29). The risks of distant metastases and of dying of prostate cancer were much greater in the 152 patients with positive nodes (N+) than in those with negative nodes (p less than 0.00005). The risk of metastatic disease at 10 years was only 31 +/- 7 per cent for the NO patients compared to 83 +/- 7 per cent for the N+ patients, and the risk of dying of prostate cancer was only 17 +/- 6 per cent at 10 years for the NO group and 57 +/- 11 per cent for the N+ patients. Patients with a single microscopic node (N1) had a pattern of progression and cancer specific mortality rate similar to patients with more extensive nodal metastases and markedly worse than patients with negative nodes. The risk of distant metastases was 80 +/- 15 per cent at 10 years for the N1 group, 84 +/- 11 per cent for the N2 group and 88 +/- 13 per cent for the N3 group, while the risk of dying of prostate cancer at 10 years was 40 +/- 19, 66 +/- 15 and 58 +/- 24 per cent, respectively. The finding of a single pelvic lymph node containing microscopic metastatic disease markedly worsened the prognosis of our patients with prostate cancer. Once prostate cancer is found within the pelvic lymph nodes the patient has systemic disease unlikely to be controlled by pelvic lymph node dissection and radiotherapy.

The Pathological Features and Prognosis of Prostate Cancer Detectable With Current Diagnostic Tests

The discrepancy between the high prevalence of prostate cancer found at autopsy and the low incidence of clinical cancer prompted a study to determine whether the new diagnostic tests, that is ultrasonography and serum prostatic specific antigen (PSA) levels, detect prostate cancer at an earlier stage than the traditional test, digital rectal examination, without detecting a larger proportion of clinically unimportant cancer. Clinically detected cancer treated by radical prostatectomy (306 cases) and incidental cancer found in cystoprostatectomy specimens (90) were categorized into 3 groups by the volume, grade, extent of the cancer and outcome of treatment: clinically unimportant tumor (0.5 cm.3 or less, Gleason grades 1 to 3 and confined to the prostate), clinically important curable cancer (more than 0.5 cm.3 or grade 4 or 5 and confined, or with microscopic extracapsular extension) or advanced disease (extensive extracapsular extension, seminal vesicle invasion or lymph node metastases). Of 306 clinically detected tumors 9% were unimportant and 29% were advanced. In contrast, incidental cystoprostatectomy disease was either unimportant (78%) or curable (22%) and no tumor was advanced (p < 0.0005). Cancer detectable by digital rectal examination, ultrasonography or PSA was distributed similarly among the 3 groups. Impalpable cancer detected by PSA was less likely to be advanced (11%) than cancer detected by digital rectal examination (34%, p = 0.01) but no more likely to be unimportant (13% versus 8%). Of 29 tumors detected only by systematic biopsies because of an elevated PSA level only 4% were advanced, while 17% were unimportant. Cancer detectable with each of the available diagnostic tests was similar and differed distinctly from that found incidentally in cystoprostatectomy specimens. The detection of impalpable cancer by PSA or ultrasound decreased the proportion of advanced tumor detected without increasing significantly the detection of unimportant disease.

Leptin and prostate cancer

Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition).

The Prognostic Significance of Post-Irradiation Biopsy Results in Patients with Prostatic Cancer

To evaluate the prognostic significance of post-irradiation biopsy results in patients with prostatic cancer, we reviewed the records of 803 patients who had been treated with pelvic lymph node dissection, radioactive gold seed implantation and external beam irradiation. Of the patients 124 had 1 or more biopsies within 6 to 36 months after completion of radiotherapy when there was no evidence of local or distant recurrence of tumor. Patients were followed for a mean of 64 months (range 14 to 175 months) and received no other therapy before relapse. Over-all, 43 of these patients (35 per cent) had a positive biopsy result. The incidence of positive biopsy results correlated directly with the initial stage of the tumor, ranging from 22 per cent of stage B1N to 50 per cent of stage C1 lesions. However, biopsy results did not correlate with the grade of the tumor. Local recurrence and distant metastases were much more common among patients with a positive biopsy result (p equals 0.0006). Local recurrence developed in 58 per cent of the patients with a positive biopsy by 5 years and in 82 per cent by 10 years. Of those in whom all biopsies were negative only 18 per cent had local recurrence by 5 years and 32 per cent by 10 years. Biopsy results retained their prognostic significance even among the more favorable subset of patients whose pelvic lymph nodes were negative initially and those with a normal prostatic examination at biopsy. These results indicate that a post-irradiation prostate biopsy 6 to 36 months after completion of treatment can be used to determine the efficacy of a particular radiotherapeutic regimen as well as the success or failure of radiotherapy in an individual patient.

INTERPOSITION OF SURAL NERVE RESTORES FUNCTION OF CAVERNOUS NERVES RESECTED DURING RADICAL PROSTATECTOMY

PURPOSEnThe permanent loss of erectile function when both neurovascular bundles are widely resected at radical prostatectomy as well as the successful use of autologous nerve grafts in reconstructive surgery led us to perform bilateral nerve grafts in an effort to restore erectile function in potent patients treated for prostate cancer who underwent radical retropubic prostatectomy and resection of both neurovascular bundles.nnnMATERIALS AND METHODSnRadical retropubic prostatectomy with deliberate resection of both neurovascular bundles was recommended for high grade, locally extensive prostate cancer in 9 select, sexually active men who reported normal erectile function. After the prostate was removed but before vesicourethral anastomosis an autologous sural nerve graft was interposed between the divided ends of the cavernous nerves bilaterally. Erectile function was monitored by patient interview, questionnaire and nocturnal penile tumescence testing after the operation.nnnRESULTSnFour to 5 months postoperatively patients noticed slowly improving spontaneous erections, as manifested by mild tumescence regularly every several hours. Nocturnal penile tumescence testing with the RigiScan device at 4 to 6 months in 2 cases revealed erections that approached minimal criteria for normalcy. Approximately 14 months after surgery a rigid erection sufficient for penetration and intercourse developed in 1 patient. He described this event as an erection of substance-hard, not just fluffy.nnnCONCLUSIONSnWe have developed a technique using sural nerve grafts to restore continuity of the cavernous nerves, which are resected during radical prostatectomy. The early return of spontaneous partial erections in our patients suggests that interposition nerve grafts may enhance the recovery of erectile function when the neurovascular bundles are resected.

The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer.

Radiotherapy is reported to provide good control of locally advanced prostate cancer. However, few long-term studies have assessed the morbidity related to local tumor recurrence in patients treated with radiotherapy alone (without hormonal manipulation). To determine the frequency and severity of morbidity related to local recurrence we reviewed the course of all patients with clinical stage C prostate cancer treated at our institution between 1966 and 1979 with bilateral pelvic lymph node dissection, radioactive gold seed implantation and external beam irradiation therapy to the prostate. Of the 121 patients 60% died and the 40% still alive at the time of review were followed for a mean of 8.1 years (range 3.3 to 14.8 years). Over-all, 64 patients (53%) had local recurrence, which was defined as a clinical event causing signs or symptoms and was proved by biopsy. On an actuarial basis the risk of local recurrence was 43 +/- 10% (mean +/- 2 standard errors) at 5 years and 74 +/- 11% at 10 years. Any symptomatic episode requiring active intervention or causing morbidity was denoted an adverse event. There were 162 adverse events among the 73 patients (2.2 adverse events per patient): 69% of these were severe (requiring surgical intervention) and 55% were chronic (more than 3 months in duration). The most common cause of an adverse event was bladder outlet obstruction requiring transurethral resection of the prostate (44 patients); 16 patients (13%) became incontinent. Hydronephrosis developed in 24 patients (20%). Local recurrence after definitive radiotherapy for our patients with stage C prostate cancer was common and was associated with serious morbidity, frequently requiring surgical intervention. Radiotherapy alone may not be sufficient to provide long-term local control of stage C prostate cancer.

The Risk of Dying of Prostate Cancer in Patients with Clinically Localized Disease

From 1966 to 1979, 360 patients with clinical stages A2, B and C1 prostate cancer underwent staging pelvic lymphadenectomy, and completed a course of combined interstitial radioactive gold seeds and external beam radiotherapy. All patients had a normal serum prostatic acid phosphatase level and a bone scan negative for metastases. All patients were followed until death or for a mean of 7.3 years (range 1.2 to 18.25 years) for those alive at analysis. To determine the risk of dying of prostate cancer we reviewed the records of the 142 patients (39%) who died. At analysis 21% of the patients had died of prostate cancer and 17% of other known causes. The cause of death could not be determined in 4 patients (1%). Cardiovascular disease accounted for a fifth of all deaths. The actuarial risk of death of prostate cancer for all patients was 8 +/- 3% (+/- 2 standard errors) at 5 years and 30 +/- 7% at 10 years. The risk of death of all causes was 16 +/- 4% at 5 years and 46 +/- 7% at 10 years. An increased risk of cancer death was associated with established risk factors, including advanced local disease, poorly differentiated histology, pelvic nodal metastases and distant recurrence. We also noted a substantial risk of cancer death in patients who had local tumor recurrence. While previous studies have reported a relatively low incidence of cancer deaths (4 to 17%) in patients initially diagnosed with localized disease, our data suggest that prostate cancer is the major cause of mortality in such patients. Aggressive curative therapy, regardless of treatment modality, should be considered for localized prostate cancer in men with a life expectancy of 10 or more years.

Some small prostate cancers are nondiploid by nuclear image analysis: Correlation of deoxyribonucleic acid ploidy status and pathological features

The biological behavior of a prostate cancer can be predicted to some degree by the volume and extent (stage) of the tumor, and its histological grade. The deoxyribonucleic acid (DNA) ploidy status has been reported by some to be another independent prognostic factor for localized prostate cancer. We determined the DNA ploidy value of each individual focus of cancer in radical prostatectomy specimens using nuclear image analysis (CAS 200 system). Ploidy results were correlated with the volume, Gleason grade and zone of origin (transition zone or peripheral zone) of each tumor, and with the presence of extracapsular extension or seminal vesicle invasion. There were 141 separate cancers in 68 patients (mean 2.1 per prostate): 9 clinical stage A1, 22 stage A2, 23 stage B1 and 14 stage B2. DNA ploidy correlated significantly (p < 0.0001) with volume, grade, extraprostatic spread and zone of origin. Remarkably, some small cancers (1 cc or less) were nondiploid (3 as small as 0.03 cc). Overall, 15% of cancers 0.01 to 0.1 cc and 31% of those 0.11 to 1.0 cc in volume were nondiploid. Of 101 cancers confined to the prostate 76% were diploid, compared to only 13% of those with extraprostatic spread. Most cancers of transition zone origin (86%) were diploid, compared to only 49% of peripheral zone cancers, and ploidy and volume relationships were significantly different for peripheral zone cancers compared to transition zone cancers. All small nondiploid cancers arose in the peripheral zone, while in the transition zone the smallest nondiploid cancer was 1.17 cc. We conclude that prostate cancers that are nondiploid are highly likely to have adverse pathological features. Some small prostate cancers contain a nondiploid cell population and these cancers arise predominantly within the peripheral zone of the prostate. Ploidy and volume relationships provide further support for the hypothesis that there is a difference in malignant potential between cancers of peripheral zone and transition zone origin.

The risk of distant metastases after transurethral resection of the prostate versus needle biopsy in patients with localized prostate cancer.

Although transurethral resection of the prostate provides an effective treatment for obstructive voiding symptoms associated with prostate cancer, there is growing concern about the possible role of transurethral resection in the dissemination of this malignancy. To determine the effect of transurethral resection on the rate of development of distant metastasis, we analyzed a large series of patients (379) treated at our institution with definitive radiotherapy for localized prostate cancer that was diagnosed by either needle biopsy or transurethral prostatic resection. In our series the presence of lymph node metastasis was documented by pelvic lymph node dissection in all patients. An initial univariate analysis suggested that patients diagnosed by transurethral resection had distant metastases significantly more rapidly than patients diagnosed by needle biopsy. However, transurethral resection usually was performed because of the presence of obstructive voiding symptoms and such patients were much more likely to have positive lymph node dissections than patients without obstructive voiding symptoms. A proportional hazards regression analysis showed that nodal status and the degree of obstructive voiding symptoms at diagnosis were independent and powerful predictors of the interval to distant metastases, along with stage and grade. The type of initial biopsy (transurethral prostatic resection versus needle biopsy) had no independent prognostic significance in this analysis. Among patients who had substantial obstructive voiding symptoms there was no significant difference in interval to distant metastases between the transurethral prostatic resection and needle biopsy groups. We conclude that the apparent adverse effect of transurethral prostatic resection results from the poor prognosis of tumors causing obstructive voiding symptoms rather than as a direct result of the resection itself.