Delayed Versus Immediate Surgical Intervention and Prostate Cancer OutcomeJournal of the National Cancer Institute, Vol. 98, No. 5, 355-357, March 1, 2006 For prostate cancer patients with small,
lower-grade tumors, expectant management with delayed surgical
intervention (active surveillance) is a rarely used therapeutic
option because the opportunity for cure may be lost. We
compared outcomes of 38
patients with small, lower-grade prostate cancer in an expectant
management program who underwent delayed surgical intervention
at a median of 26.5 months (95% confidence interval [CI] = 17
to 32 months; range = 12.0–73.0 months) after diagnosis
with 150 similar patients who underwent immediate surgical intervention
at a median of 3.0 months (95% CI = 2 to 4 months; range = 1.0–9.0
months) after diagnosis. Men screened for prostate-specific antigen (PSA) are diagnosed an estimated 10 years earlier in the natural history of prostate cancer than men diagnosed without PSA screening. Although earlier diagnosis may have contributed to a decline in prostate cancer mortality, it has also led to the diagnosis of some cancers that would not have been detected in the absence of screening (i.e., overdiagnosis). Because overdiagnosis can lead to overtreatment, expectant management (or active surveillance) with delayed curative intent (i.e., surgery or radiation therapy) has been proposed as an alternative to immediate surgery for men with newly diagnosed prostate cancer with low-grade, low-stage disease in an effort to reduce unnecessary treatment for prostate cancer. However, this approach is rarely recommended to patients, presumably because of the concern that surveillance will compromise the ability to be cured later if definitive treatment is required. We tested the hypothesis that curability is not lost among patients with small, lower-grade prostate cancers enrolled in an expectant management program by comparing the rates of noncurable cancer among patients undergoing delayed curative surgery with those among patients undergoing immediate curative surgery. At our institution, men suspected of having small, lower-grade prostate cancer have the option of entering an expectant management program that has been approved by the institutional review board. Each year, our program has historically enrolled approximately 1% of the patients with newly diagnosed prostate cancer. Enrollment criteria are based on PSA density and the findings of a biopsy examination. Follow-up involves semiannual measurements of total and free PSA, a semiannual digital rectal examination, and an annual surveillance prostate biopsy examination. Curative surgery is triggered by the finding of adverse pathological features on an annual surveillance biopsy examination (i.e., a Gleason score of 7 or more with a Gleason pattern grade 4 or above, more than two cores that are positive for cancer, or more than 50% of any one core that is involved with cancer) or a patient's request for a change in management. In our program, total PSA changes have not triggered intervention. Between January 1, 1995, and February 1, 2005, 320 men (median age = 65.4 years; range = 48.3–77.1 years) have been enrolled in the expectant management program. Ninety-eight of these 320 men have undergone curative intervention (either radiation or surgery) after an observation period of at least 12 months. Thirty-nine of these 320 men underwent radical prostatectomy; nine of these 39 men requested a change in management without a trigger for intervention. We excluded one patient who received neoadjuvant androgen deprivation therapy before curative intervention. Thus, the final delayed intervention cohort contained 38 men who underwent surgical intervention. The cohort was stratified by quartiles of age at diagnosis and total PSA at diagnosis; the resulting distribution was used for frequency matching to the immediate intervention cohort. From the database of 2266 consecutive prostatectomy patients treated at our institution between January 1, 1975, and December 31, 2004, there were 420 men who underwent immediate surgery and who would have been eligible for expectant management. We randomly selected 150 men from this group who were frequency matched at a 4 : 1 ratio to the distribution of age and PSA in the delayed intervention cohort these 150 men constituted the comparison group in the analysis. Informed consent was not required because we did not use subject identifiers. The primary outcome of this study was the proportion of patients with noncurable disease [i.e., <75% chance of remaining biochemical recurrence-free at 10 years after surgery. We compared outcomes of 38 patients with small, lower-grade prostate cancer in an expectant management program who underwent delayed surgical intervention at a median of 26.5 months (95% confidence interval [CI] = 17 to 32 months; range = 12.0–73.0 months) after diagnosis with 150 similar patients who underwent immediate surgical intervention at a median of 3.0 months (95% CI = 2 to 4 months; range = 1.0–9.0 months) after diagnosis. Nine (23%) of the 38 patients in the delayed intervention group and 24 (16%) of the 150 men in the immediate intervention group had noncurable cancer at the time of surgery. The relative risk (RR) was calculated in a Mantel–Haenszel analysis as the ratio of the proportion of patients with noncurable cancer in the delayed versus immediate intervention groups (nonadjusted RR = 1.48, 95% CI = 0.75 to 2.92; P = .266). After adjustment for age and PSA density at diagnosis, the risk of noncurable prostate cancer was not associated with the type of intervention (adjusted RR = 1.08, 95% CI = 0.55 to 2.12; P = .819). Additional adjustment for other potential confounding factors did not improve this estimate (data not shown). When the analysis was restricted to the 27 patients in the delayed intervention group who met all of the criteria for the expectant management program, the results remained the same (data not shown). All statistical tests were two-sided. Age, PSA, and PSA density were each statistically significantly associated with the presence of noncurable cancer when the median value was used as the cut-point (P = .030, .013, and .008, respectively; two-sided chi-square test) The maximum percentage of the biopsy core involved with cancer, the number of positive cores with cancer, year of surgery, and time between diagnosis and surgery were not associated with the risk of noncurable cancer (data not shown). These results remained the same when the analysis was restricted to those subjects in the delayed intervention group who met all of the criteria for the expectant management program (data not shown). The safety of delayed surgical intervention has been suggested in a small case-control study that used surgical pathology as the end-point and in another study that evaluated freedom from disease for more than 15 months after surgery in 17 men. Our data suggest that the window of opportunity for cure appears to be maintained, despite a delay in surgical intervention averaging 2 years, if men are carefully selected at the time of initial diagnosis for the presence of small-volume, lower-grade cancer. Our findings have two important implications. First, men who are diagnosed with early-stage, lower-grade prostate cancer should not be led to believe that they have an urgent situation that requires immediate treatment. Although they may ultimately decide on treatment, there is no apparent gain to making this management decision quickly with the belief that a delay will compromise cure. Second, when selected carefully by use of criteria that suggest the presence of small-volume, lower-grade cancer and then monitored with a rigorous protocol for disease progression, these patients appear to have the same risk of noncurable prostate cancer for at least 2 years after diagnosis as those patients who received immediate prostate cancer surgery. Our data thus suggest that this expectant management approach should be used more frequently, given that approximately 50% of men today are diagnosed with low-risk prostate cancer. Potential limitations of this study include the small sample of men who underwent delayed surgical intervention and the use of a surrogate end-point for noncurability (i.e., surgical pathology consistent with a <75% chance of remaining biochemical recurrence-free at 10 years after surgery). With longer follow-up, we could find that a delay in surgical intervention compromises disease-free outcomes. However, given the minimal 5% overall improvement in cancer-specific survival at 10 years after diagnosis when comparing surgical treatment to no treatment among men with cancers not detected by screening it seems unlikely that expectant management of low-risk, screen-detected cancers will place patients at undue risk of an adverse outcome. Thus, expectant management with curative intent appears to be a safe alternative to immediate treatment for a carefully selected group of patients with small-volume, lower-grade prostate cancer. |