Prostate
Cancer: Debates in Staging and Treatment
Prostate
Cancer: Debates in Staging and Treatment
Dr. Albertsen is Associate Professor and Chief of the Division of Urology at the University of Connecticut Health Center in Farmington, Connecticut.
Dr. Hanks is Chairman of the Department of Radiation Oncology at Fox Chase Cancer Center, and Professor of Radiation Oncology at the Temple University School of Medicine in Philadelphia, Pennsylvania.
Dr. Richie is the Elliott C. Cutler Professor of Surgery at Harvard Medical School, Chairman of the Harvard Program in Urology, and Chief of the Division of Urology at Brigham and Women’s Hospital in Boston, Massachusetts.
Dr. Stock is Associate Professor at Mount Sinai Medical School, and Acting Chairman of the Department of Radiology at The Mount Sinai Hospital in New York.
Dr. D’Amico is Associate Professor of Radiation Oncology at Harvard Medical School, and Chief of Genitourinary Radiation Oncology at Brigham and Women’s Hospital/Dana Farber Cancer Insitute Joint Center for Radiation Therapy in Boston, Massachusetts.
In 1999, there will be an estimated 179,300 cases of prostate cancer in the United States, and prostate cancer is currently the second most frequent cause of cancer-related deaths among men.1 Prostate cancer is, however, one of the most slowly progressive malignancies, with low potential for metastasis and excellent survival rates in the early stages. A number of often difficult decisions exist regarding assessment and staging of individual patients with prostate cancer, as well as those that exist regarding appropriate management. It is not always clear when to employ additional assessments such as bone scans, endorectal coil magnetic resonance imaging (MRI), pelvic computed tomography (CT) scanning, seminal vesicle biopsies, or lymph node sampling. Additional decisions must be made regarding treatment, options for which include watchful waiting, external beam radiation, radiation seeds, hormonal therapy, surgery, or some combination of these.
To assist primary care physicians in understanding the considerations that go into these decisions for individual patients with early, intermediate, or advanced-stage prostate cancer, Medical Crossfire recently convened a panel of distinguished experts to review three case studies and debate these complex management issues. This debate was moderated by Anthony V. D’Amico, MD, PhD, Associate Professor of Radiation Oncology at Harvard Medical School and Chief of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana Farber Cancer Institute Joint Center for Radiation Therapy in Boston, Massachusetts.
CASE ONE PRESENTATION A 46-year-old man had a prostate-specific antigen (PSA) level of 1.0 ng/ml in January 1996, 1.6 ng/ml in January 1997, and then 3.6 ng/ml with 10% free PSA in January 1998. Digital rectal examination revealed moderate benign prostatic hypertrophy (45 g gland) and no palpable nodules. A transrectal ultrasound needle-guided biopsy of the prostate was performed and a sextant sampling obtained. One of three cores on the right and zero of three on the left were positive, yielding a Gleason score of 3 + 2 = 5: adenocarcinoma of the prostate. Transrectal ultrasonography demonstrated no hypoechoic regions, and a 45 cm3 prostate gland volume. Other than an appendectomy as a child, the patient’s medical history was insignificant.
Assessment and Staging Issues
Dr. D’Amico asked the panelists whether they would have performed a biopsy upon receiving the results of the January 1998 PSA measurement (i.e., 3.6 ng/ml with 10% free PSA).
Jerome P. Richie, MD, Chairman of the Harvard Program in Urology and Chief of the Division of Urology at Brigham and Women’s Hospital in Boston, Massachusetts, answered: "There is controversy about biopsies when the PSA level is lower than 4 ng/ml," He noted, however, that the patient is quite young and the percentage of free PSA very low. "What we found from a multi-institutional study is that... the lower the free PSA, the higher the likelihood of prostate cancer,2 so this individual could have... almost a 50% likelihood of prostate cancer. As such, I would recommend a biopsy," he said. "Another reason for considering a biopsy is the rate of change or velocity of PSA, which has gone up two points in a year, and based on studies from HB Carter3 and others at [Johns] Hopkins, the PSA should go up no more than about eight tenths of a point per year."
"[I]t’s the low percentage of free PSA that really tips the scale in favor of proceeding with a biopsy," agreed Peter C. Albertsen, MD, Associate Professor in and Chief of the Division of Urology at the University of Connecticut Health Center in Farmington, Connecticutt. Dr. Albertsen noted that, in a primary care setting, he would have repeated the PSA measurement after receiving the 3.6 ng/ml result in order to confirm the finding. Upon confirmation, he then would have requested a free PSA measurement. "Typically, the percentage of free PSA is [only tested for] when you’re troubled—[when the patient has a] PSA level between 4 and 10 ng/ml—though I think, in this case, it was appropriate to measure that." Dr. Albertsen added that the free PSA is especially helpful in situations where it is not clear whether an elevated total PSA level is attributable to other causes, such as prostatitis. In such cases, the lower the free PSA value, the more worried you need to be about prostate cancer, he said.
Elaborating on Dr. Albertsen’s comments regarding free PSA, Dr. Richie explained that "If the PSA level is greater than 10, there is enough likelihood of suspicion of prostate cancer that those patients should consider being biopsied, regardless of the free PSA value." If the PSA is between 4 and 10 ng/ml, a free PSA value helps to predict the likelihood of prostate cancer.3,4 However, Dr. Albertsen noted, "It becomes more controversial when you have a PSA level of less than 4. . . . There’s a lot of controversy [regarding biopsies] in the 2.5 to 4 range, especially for younger patients, and that really needs to be individualized," he said. "Whether the free PSA will hold up in that range really awaits further studies, although several studies by Catalona5 and others have suggested that it can be of similar value as it is in the range between 4 and 10." Dr. Richie added, "[T]he free PSA value also gives us some idea of the behavior of the tumor, and we’re finding that, generally, the lower the percentage of free PSA, the more aggressive the tumors."6
"Do you feel that this particular patient is in need of any other staging studies?" asked Dr. D’Amico. For example, he said, is bone scan, CT of the pelvis, or endorectal coil MRI needed?
"I don’t think he needs any of those," said Gerald E. Hanks, MD, Professor of Radiation Oncology at Temple University School of Medicine, and Chairman of the Department of Radiation Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania. "It’s not clear that the frequency of positivity justifies the expense, or that the finding is, in fact, accurate enough to change his treatment, so he doesn’t need further staging studies."
"I know sometimes people have suggested biopsying seminal vesicles for further pathological staging," said Dr. D’Amico.
"We looked at over 300 patients where we performed seminal vesicle biopsies," said Richard G. Stock, MD, Associate Professor at Mount Sinai Medical School and Acting Chairman of the Department of Radiation Oncology at The Mount Sinai Hospital in New York. "We found that a patient like this would not warrant a seminal vesicle biopsy, since his chance of having a positive biopsy would probably be less than 5%, and, currently, we’re only really recommending it for patients who have Gleason scores of 7 or higher, or PSA levels that are over 10." In addition, Dr. Stock said he agreed with Dr. Hanks that no further testing was needed for staging, as the patient has an 80% chance of having organ-confined disease. Thus, he said, "the likelihood of detecting . . . any other valuable prognostic information would be minimal with further testing."
Dr. D’Amico asked whether the fact that the patient has one of three cores positive on the right and none of three positive on the left adds any additional information regarding his likelihood of having disease beyond the confines of the prostate.
"The patients for whom the number of positive biopsies makes a difference . . . are those who have palpable disease," said Dr. Hanks. This patient, who does not have palpable disease, he continued, has the most favorable predicted outcome and is most likely to have organ-confined disease.
Treatment Issues
Dr. Albertsen emphasized that the patient’s young age must be considered in formulating a treatment plan. "The fact is, he has a 30- to 35-year life expectancy, and no one has data that extend out that far," he noted. "He has a Gleason-5 tumor, which is a very favorable prognosis. The volume of tumor present is very small, as suggested by his low PSA level and the fact that only one core is positive. So the main question then becomes, ‘How aggressive is this tumor likely to be?’" Dr. Albertsen decided that "even though his risk of progression is low over maybe five, 10, or even 15 years, [because he has a] 35-year life expectancy, I would probably recommend a more aggressive treatment than conservative management."7 He noted, "Being a surgeon, I’d probably recommend a radical prostatectomy as the most effective way of likely curing him, although I would certainly present all the other options such as radiation and seeds." He added, "I would mention conservative management, but quite frankly, that would be reserved for someone who is 76, not 46."
"With the same information presented here, at what age would you recommend watchful waiting versus aggressive local therapy?" asked Dr. D’Amico.
"It depends a little bit on what the comorbidities are, but it would probably be in the early to mid-seventies," particularly if the patient had heart disease, angina, or hypertension," Dr. Albertsen responded. However, he would push that age up if the patient was 75 years of age, in excellent health, and was still "running marathons." "But I think that, for anyone who has a life expectancy of maybe 10 to 12 years and up, no one really knows the answer to this—you could consider conservative management, but the risk is that the tumor progresses and you lose control of it." He noted, "In this particular case, since the PSA level is relatively low, you could argue [in favor of] having the patient come back every six months and tracking the PSA, seeing what the rate of change is, and possibly repeating the biopsy in two years, to see if there’s been any additional tumor load." Dr. Albertsen emphasized that such follow-up is important when choosing conservative management. "You don’t want to just forget about the patient," he said.
Dr. Hanks agreed with Dr. Albertsen that treatment is necessary for this case patient, given the long life expectancy. "He needs to be treated, and his choices are between prostatectomy, conformal radiation treatment, and implants." Outcomes are generally good in patients, such as this one, who have minimal disease. He noted that if the patient "isn’t particularly interested in prostatectomy for whatever reasons—either problems with incontinence or problems of sexual function—he doesn’t have to feel like he’s giving up his chance at living by selecting a less invasive treatment."
Dr. D’Amico asked Dr. Hanks to describe three-dimensional conformal radiation and how it differs from conventional external beam radiation.
"Three-dimensional conformal radiation is a technology that’s been available for about 10 years in the United States, and it enables us to protect the normal tissues better than we used to in the past," said Dr. Hanks. "As a result of protecting the normal tissues better, we have fewer complications. In fact, in cases like this, they would be almost trivial, and we also can give higher doses with safety."
"I would take some issue with Dr. Hanks in that I don’t think that we have the data for 15-year and beyond survival rates to say that three-dimensional conformal radiation is going to be equivalent to surgery," said Dr. Richie. "I would agree with Dr. Albertsen that, based on his young age and his overall good health, presumed sexual activity, etc., that the treatment of choice for this patient would be a nerve-sparing radical prostatectomy." He noted that this patient has a very high likelihood of having organ-confined disease and "with surgery, (a) you get accurate staging, and (b) you have an exact tumor marker to follow, because the PSA should then be zero and should stay zero, which would probably give him, I would say, a 90% to 95% likelihood of cure. With the older series of radiation therapy, it’s not going to be quite that good. With the three-dimensional conformal radiation it may be that good, but we don’t have long- term data."
Dr. Hanks countered, "I don’t think there’s any evidence beyond 10 years with surgery in T1C cancers. . . . I’m not convinced that there’s something magic after 10 years that goes bad with radiation and good with surgery, so I think people ought to still keep an open mind in this issue, which is commonly overwhelmed with our personal biases."
Agreeing with the other panelists that conservative management is not a good option for this particular patient, Dr. Stock noted, "A recent paper from Denmark in the Journal of Urology8 looked at observation and found that young age was associated with the highest risk of death from prostate cancer." He added that the patient’s sexual function is likely to be better if he is treated with either three-dimensional conformal radiation, external beam radiation, or a radioactive seed implant, compared with radical prostatectomy.
Dr. Richie objected, "This is a young man and I think he would have the option of having a bilateral nerve-sparing approach, and in a series where there are experienced surgeons doing this, he would probably have upwards of an 80% likelihood of having a return of potency. I don’t think that’s significantly different from external beam, and may or may not be different from the radioactive implants."
"I would agree with Dr. Richie," said Dr. Albertsen. "The age is a major factor for not only potency but continence." He explained that the younger the patient is, the more likely he is to retain excellent control of continence and to recover potency after surgery. "It’s only when men are moving into their mid-sixties, and especially into their seventies, that I think significant compromise is made in sexual function."
In summary, said Dr. D’Amico, existing controversies in managing patients such as this one stem from the lack of prospective, randomized clinical trials comparing the major treatment modalities (i.e., radical prostatectomy, external beam radiation, and radioactive seed implant). Retrospective studies show that patients with early disease, as in this case study, do equally well regardless of the choice of treatment. The patient’s age is a key consideration in choosing treatment. "And, on the issue of quality of life," he said, "only recently have prospective measures been employed to try to better ascertain the true quality-of-life functions in terms of sexual function, urinary function, and bowel function after these treatment modalities. And clearly age and baseline function plays into that."
CASE TWO PRESENTATION
An asymptomatic 68-year-old man underwent a first PSA measurement, which was elevated at 22.0 ng/ml. Digital rectal examination revealed a 4.5-cm nodule encompassing the right gland, with palpable evidence of unilateral right-side extracapsular extension. A transrectal ultrasound needle-guided biopsy of the prostate is performed and a sextant sampling obtained. Three of three cores on the right and two of three on the left were positive, yielding a Gleason score 4 + 5 = 9: adenocarcinoma of the prostate. Transrectal ultrasonography demonstrated bilateral hypoechoic regions in the right base, midzone, and apex, and in the left midzone and apex, corresponding to the areas of the positive biopsy results. The prostate gland was 30 cm3 in volume. The patient had no significant medical history, but his father presented with metastatic prostate cancer at age 52 years and died of the disease at age 55 years, despite bilateral orchiectomy performed at presentation.
Assessment and Staging Issues
"Are there any other staging studies that you would perform in this patient, including possibly a seminal vesicle biopsy?" Dr. D’Amico asked.
"Well, certainly with a Gleason score of 9 and a PSA level of 22, I would absolutely get a bone scan," responded Dr. Stock. "CT scan of the pelvis... is questionable, even though this patient is at high risk for having lymph node metastases. If he does have lymph node metastases, it’s more likely to be of the microscopic variety, which probably would not be detected on a CT scan." Dr. Stock added that he absolutely would recommend a seminal vesicle biopsy for this patient. "It can give you an idea of the extent of disease, and we’ve shown that seminal vesicle disease has been associated with extracapsular expansion, and more importantly, with a much higher risk of having lymph node metastases. In the setting of a positive seminal vesicle biopsy, there’s no question that I would recommend some type of lymph node dissection prior to doing any type of definitive therapy."
Dr. Riche said that he would get a CT scan of the pelvis in this case "because you may see some positive nodes; you could do a guided needle biopsy and avoid a surgical procedure."
"The main driver here is the high Gleason score," noted Dr. Albertsen. "Also, the PSA being above 20 puts him at a higher likelihood of having a yield on the bone scan of at least 10%, maybe as high as 20%, and I think those yields are high enough to certainly warrant doing the study." He added that he agrees with Dr. Stock that CT scan is likely to be negative, "only in the sense that the limit of resolution on many of these exams is only about 2 cm, and that’s not sufficient to pick up the microscopic disease." Furthermore, he said that Dr. Stock’s recommendation regarding seminal vesicle biopsy "makes a lot of sense, and I think this patient is at very high risk of having extracapsular disease. Therefore, if aggressive therapy is being planned, I would absolutely agree that a lymph node dissection, either laparoscopic or open, should be performed."
"When I see these patients, I can’t find a urologist who will do the node dissections!" explained Dr. Hanks. "In practice, what we have all said here is great, but the reality of life is it’s really hard to get the node dissection done." Having said that, Dr. Hanks supported the use of lymph node dissection, saying that it was helpful because it triages patients into two separate treatment groups. He explained, "I think the best treatment of node-positive intact prostate disease is radiation treatment and . . . life-long androgen deprivation. For a patient who has negative nodes and these other bad pathological features, there isn’t good evidence for the long-term hormone component of that treatment plan, so you might consider treating those patients with regional radiation only."
"I would agree with the bone scan, [but] I’m not a big fan of seminal vesicle biopsies," said Dr. Richie. Rather, he said, he would probably recommend an endorectal coil MRI to determine seminal vesicle involvement, but acknowledged that he has access to an excellent radiologist with extensive MRI experience. He added, "I think this man makes a perfect case for the issue of early detection. His father died of prostate cancer and he waited until he was 68 to get a PSA, which is clearly too late." This also raises the issue, he said, of "[I]f you do screening or early detection, when do you stop doing it? And, generally, if somebody has less than a 10-year life expectancy, I don’t think they should be screened for prostate cancer."
Treatment Issues
Assuming that a seminal vesicle biopsy was performed and was positive, and that pathological assessment of lymph node involvement was negative, said Dr. D’Amico, is this patient curable?
"I suspect he is not," answered Dr. Albertsen. "That doesn’t mean that it’s 0%, but if you performed aggressive therapy, either by surgery or by radiation, I think he has a high probability of having a rising serum PSA within two years of that treatment." Dr. Albertsen explained that he would certainly treat the patient with hormonal therapy at some time. "The big research question becomes: ‘What is the relative value added by either surgery or by radiation?’" He said, "I would not perform a radical prostatectomy on this patient because I don’t think it will alter his course." Rather, he said he would consider the relative value added by radiation and the associated morbidity in making a treatment decision. "But quite frankly," he said, "I don’t think he’s curable, and the question becomes now how to best palliate [his disease]. Since he has no symptoms at the present time, the question is: ‘Do you delay hormonal therapy or do you start immediately?’ and that leads into the controversy: ‘Is there any additional life expectancy added from immediate versus delayed hormonal therapy?’" He noted, "There isn’t good literature on that."
"I believe ‘curable’ depends on of how long you can follow this patient," said Dr. Hanks. However, he believed that only a small fraction of such cases are "ultimately curable." Dr. Hanks then questioned whether seminal vesicle involvement means inevitable metastasis? "I don’t know the answer to that," he said, although he acknowledged that there are some data indicating that many such patients will have metastases.9,10 He added that prospective randomized trials show a survival advantage to treating patients with advanced disease (T3 or poorly differentiated disease) with three years of androgen deprivation plus radiation therapy versus radiation therapy alone. This strategy, he said, would be his recommendation for treatment.11
Dr. Richie also supported use of long-term androgen deprivation coupled with radiation therapy. "I think this man is probably not curable, but he only has evidence of local disease, even though he’s at very high risk for occult metastatic disease. . . . He would be a good candidate for external beam radiation plus hormones, and then, at some point, stopping the hormones and following his PSA."
"I think the reason many of the panel [members] feel that these patients are incurable is that standard therapies have been suboptimal. These patients have extremely high-volume local disease and are being treated with inadequate local therapies," noted Dr. Stock. He explained that with non–organ-confined disease, prostatectomy would be unable to remove all of the disease. Moreover, he said, "[S]tandard external beam radiation therapy . . . we now know, delivered to standard doses, is really incapable of curing large-volume disease." Therefore, he said, "I agree with Dr. Hanks that hormone therapy needs to play a key role in the treatment of this patient, but I would also opt for dose escalation in the form of a seed implant combined with external beam radiation therapy."
"Exactly what would you implant in this particular case?" Dr. D’Amico asked him. "And do you have any data on the toxicity of such an approach?"
"We have been implanting these types of patients by putting seeds both in the prostate and in the more proximal aspects of the seminal vesicles, and following this with radiation in both the seminal vesicles and prostate," Dr. Stock explained. In terms of toxicity, he noted that "the published data on the combination of implants and external beam has shown a higher rate of grade-2 radiation proctitis, and probably a higher incidence of impotency, than would be seen with either therapy alone."12
Dr. Hanks cautioned that such an approach is investigational and has not been compared with the "current best treatment" based on class-1 data. Furthermore, he pointed out that it is also possible to increase the dose of radiation by using three-dimensional conformal radiation therapy.13
Dr. Richie then asked Dr. Stock whether he truly would be comfortable implanting seeds into such a large, palpable nodule, and not be concerned about increased toxicity.
"I’m assuming that the nodule is within the gland, and, having done many implants . . . if it’s not something that’s 4.5 cm outside of the prostate—which I have yet to see—yes, I would feel very comfortable implanting what I would see as the prostate," Dr. Stock responded.
"The trial I’d love to see done would be hormone therapy alone versus the hormone-plus-radiation therapy, because you’re balancing here the question of toxicity versus potential improvement in quality of life," said Dr. Albertsen. "At this point . . . the rationale for giving either seeds or radiation is the hope of controlling local disease, but, for most of these men, that’s not usually where they get into trouble—usually they get into trouble with disseminated disease."
Dr. Hanks objected, "But if you look at node-positive patients treated with hormones plus or minus a local treatment, in the form of either prostatectomy14 or radiation treatment,15,16 in these retrospective studies . . . treating the primary [disease] with more than the hormones clearly produces a better result."
Dr. D’Amico summarized: "The major pattern of failure in these patients—that ultimately causes the patient’s death—is systemic disease. And, really, it’s no fault of the radiation oncologist or urologist that that occurs. . . . We look to our medical oncology colleagues to hopefully provide us with something more than androgen deprivation therapy as a systemic treatment down the road. With the lack of more effective systemic therapy, one wonders: Will we ever do better with these patients than we’re currently doing, and can the increased local control provided by dose-escalation techniques, such as external beam and implant boosts, provide any better long-term outcome?"
Dr. D’Amico emphasized that one of the "take-home messages" of this case is that when a patient has a family history of prostate cancer, "likely there will be value in earlier detection and PSA screening so we don’t face this terrible situation." He added, "But if this situation presents . . . [at the current time] efforts are being based at maximal local control in addition to systemic therapy, which, for the most part, is androgen-suppression therapy."
CASE THREE PRESENTATION
A 59-year-old man had a PSA measurement performed as part of an annual physical; results were 12.0 ng/ml. No prior PSA results were available. Digital rectal examination revealed a 1.5 cm nodule encompassing the right base and right midgland. A transrectal ultrasound needle-guided biopsy of the prostate was performed and a sextant sampling obtained. Three of three cores on the right (base, mid, apex) and one of three on the left (base) were positive, yielding a Gleason score 4 + 3 = 7: adenocarcinoma of the prostate, and perineural invasion was identified in the core obtained from the right apex. Transrectal ultrasonography demonstrated bilateral hypoechoic regions in the areas of the positive biopsy results and a 15 cm3 prostate gland volume. The patient had hypertension and type 2 diabetes mellitus controlled with Vasotec (enalapril, Merck & Co., Inc.) and diet, respectively.
Assessment and Staging Issues
Dr. D’Amico asked the panel whether they would order any additional staging studies for this patient.
"I would get a bone scan," said Dr. Hanks. "[H]e has an intermediate histology and he has an intermediate PSA, and there is some chance the scan would be positive." He indicated that he would also get a CT scan, although he admitted that it is rarely clinically useful. "I would not use endorectal coil MRI because I don’t believe it has a great deal of value," he noted.
"We’ve said we would get bone scans in cases 2 and 3, but not in case 1," noted Dr. D’Amico. He asked Dr. Richie to give some general guidelines for when a bone scan is indicated.
"We used to perform bone scans for everybody, and some still do [in order to have] a baseline," Dr. Richie explained, "but I think the yield of a bone scan, if the PSA level is less than 8 ng/ml and there’s no Gleason 8, 9, or 10 component, is so minuscule that most oncologists—radiation oncologists, urological oncologists, and medical oncologists—have ceased obtaining bone scans in that situation." He added, "[G]enerally, aggressive-type tumors, you want to know whether there’s bony metastases and that’s when I would obtain a bone scan."
Dr. Hanks said that he reserves bone scans for patients who have Gleason scores of 8 to 10 or a PSA level of greater than 20 ng/ml. "So, on this particular case, I probably would not have gotten a bone scan, though I would have been on the fence on this one because of the number of other parameters such as the hypoechoic lesions and the Gleason score readout."
Dr. D’Amico then asked about the general utility of pelvic CT scans.
"Dr. Hanks recommended a CT of the pelvis in case 3," Dr. Richie pointed out, and Dr. Richie himself had recommended one in case 2. "I would not get a CT scan of the pelvis or of the abdomen [in this case]," Dr. Richie said. "I really find they haven’t been very helpful, except to pick up the occasional patient who has an undisclosed renal mass or something else."
Rather, for this particular patient, Dr. Richie recommended an endorectal coil MRI. "I don’t routinely do endorectal coil MRIs . . . but if I’m on the fence regarding whether there’s seminal vesicle involvement or extracapsular extension, which would make a difference in my recommendation for treatment options, then I obtain an MRI." He continued, "This man has enough risk for that. I assume that you feel a nodule but it doesn’t feel like it’s outside the prostate. He has three cores positive on the right, which increases his risk of extracapsular extension, and most importantly, he has a Gleason 4 component as the primary component of his Gleason score, and that’s different from a 3 + 4—that’s why we separate the two numbers. The Gleason 4 has an increased risk of extracapsular extension. So, for all of those reasons, I would obtain an MRI, and, if it’s positive, that would change my [recommendation to] radiation rather than surgery."
Dr. Stock agreed that if radical prostatectomy is a treatment consideration, given that this patient has a 50% chance of capsular penetration based on the Partin tables endorectal coil MRI should be performed for this patient.17,18 "Similarly, if you’re going to treat a patient with an implant alone—although many would not recommend this type of treatment for patients with high-grade cancers—you might add the endorectal coil to assess for capsular penetration." He added, "We would also do a seminal vesicle biopsy on this patient because he has a reasonable risk of having disease in the seminal vesicles."
"I think they’ve oversold the MRI a little bit, because several of you work at places where you have great faith in your MRI reader," cautioned Dr. Hanks. "It’s really important to say that the randomized studies have not shown it’s very accurate" in prostate cancer.19
Dr. D’Amico noted, "I would support that standard MRI (certainly pelvic coil MRI) has been shown to be no better than CT in prospective trials, and the use of endorectal coil MRI, is currently limited to the subgroup of case 3—moreover, only in the hands of experienced radiologists."
Dr. Richie pointed out that the Partin tables,17,18 mentioned earlier by Dr. Stock, "really are old data." He explained that "70% of the patients we’re seeing now [have] T1C [tumors], and the Partin tables really tend to overestimate extent of disease outside the prostate. I think we’ve seen a stage migration or a shift to where many more patients have organ-confined disease and we need to have updated tables to use."
Dr. D’Amico responded, "The only comment I would add is that the Partin tables’ end point is looking at the pathological parameters found in prostatectomy—that is, whether the disease is inside or outside the capsule, and inside the seminal vesicles or lymph nodes. And, ultimately, what we really want to have one day are tables that tell us, given a certain treatment, what is the outcome for the patient in terms of life or death from the disease? And we’re still several years from that."
Returning to the case study, Dr. D’Amico asked Dr. Richie to explain perineural invasion and describe its potential significance in terms of treatment.
"Perineural invasion means that there’s tumor . . . inside the nerve sheath of some twigs of nerves that are inside the prostate," explained Dr. Richie. "These are not necessarily the same nerves that are outside the prostate, but the implication is, once it’s in that channel, this may be a path of egress from the prostate to the outside." He acknowledged, however, that there are conflicting studies on whether perineural invasion increases the likelihood of disease outside of the prostate.20,21 "I view it as a factor, but a minor factor," he said. "In this man, there are so many other factors that make it likely that he has disease outside the prostate."
Dr. Stock added that perineural invasion is also a predictor of lymph node metastases in the setting of a negative seminal vesicle biopsy.8
Treatment Issues
"What would you recommend or discuss with this patient as treatment options?" asked Dr. D’Amico.
Dr. Albertsen responded, "I think, with a radical prostatectomy, there’s a high probability that he’ll have margin-positive disease, so I’d be somewhat leery about offering him a radical prostatectomy." In addition, he said, "I think if you do nothing—in other words, watchful waiting—this patient is clearly likely to die from his disease." Furthermore, according to Dr. Albertsen, the patient is likely to die from prostate cancer within five to seven years if he is treated with hormone therapy alone. Therefore, Dr. Albertsen concluded, the patient’s best option would be some type of combination therapy that includes radiation.
Dr. Stock answered that he would consider this patient to be high risk and would treat him in a manner similar to the patient in case 2, "which would be a combination of hormone therapy, external beam [radiation], and radioactive seed implant as a boost." He acknowledged, "I guess my inherent bias is to favor this approach, since the kinds of doses that you can deliver with a seed implant as a boost are really greater than anything we’re capable of delivering with three-dimensional conformal or intensity-modulated radiation therapy alone. The external beam doses that have been used in combination with seed implantation have ranged from 40 to 60 Gy." He compared this with external beam radiation therapy doses given without a seed implant, which, he said, range from 75 to 80 Gy with three-dimensional conformal radiation therapy.
"I have treated 60 patients like this man—the patient I’ve treated longest is a man I’ve treated for seven years, and he’s 80% biochemically free of disease at seven years," countered Dr. Hanks. He said he delivers doses of greater than 76 Gy, adding, "It’s clear that, with conformal therapy, and with high doses that can be given safely, . . . you can achieve a pretty satisfactory outcome." Dr. Hanks agreed that patients with intermediate disease who have poor prognostic indicators "really need a higher dose than is commonly given," but said that, with doses higher than 76 Gy, he was comfortable with the level of control achieved.
According to Dr. Hanks, the American Society for Therapeutic Radiation and Oncology (ASTRO) will begin a program to offer instruction at various sites around the country on how to safely deliver high doses of radiation to locally difficult-to-control cancers. He added, "[T]here are maybe 50 or 100 centers that can do this safely now, and there are 1,500 facilities in the United States, and we need to get further up the ladder than a hundred or two. I think that might have a real impact on the outcome of patients."
Dr. D’Amico cautioned that "only a randomized trial and time will really be able to discern whether the potential for dose escalation via the technique of external beam irradiation and seeds—as compared with dose escalation using three-dimensional conformal—really will confer an advantage or not, and we don’t have that trial yet."
Dr.Richie wondered about the difference in cost associated with adding radiation seeds to external beam radiation.
"Well, it depends on what type of external beam therapy is being employed," replied Dr. Stock. He suggested that intensity-modulated and three-dimensional radiation therapy alone is expensive, but acknowledged that, with the addition of seed implants, "you’re talking about a more expensive treatment—probably the most expensive prostate cancer treatment available, since the cost of seeds—which can range from $4,000 to $7,000—must be factored into the total cost."
Posing this hypothetical scenario to Dr. Richie, Dr. D’Amico said,"Let’s say you got the endorectal coil MRI at a good institution and it shows organ confined disease, negative bone scan. What are your treatment recommendations?"
"I would tell this patient that he has a substantial likelihood of extracapsular disease, and as such, radiation therapy would be the standard treatment," responded Dr. Richie. However, he said, "I wouldn’t absolutely rule out surgery as an option with a negative MRI showing there’s no seminal vesicle involvement, although, in my heart, I think he probably has a substantial likelihood of pathologic seminal vesicle involvement, which may be slightly different from clinical seminal vesicle involvement. If he did have surgery, he may end up with a positive margin and may end up needing additional radiation therapy as well. Would that give him any better survival? The data really aren’t out there."
Dr. D’Amico asked Dr. Richie whether nerve-sparing surgery would be an option for this patient, if he was insistent on surgery.
"No, I would absolutely not consider nerve-sparing surgery on the right side, and with a Gleason 4 component on the left, I would probably be leery of considering it on that side, either," he answered. "Nerve-sparing can be used as an adjunct to radical prostatectomy, if it can be done without compromising the cancer aspects, and here, where there is a Gleason 4 component, I’m a little concerned about that."
"There are some people who suggest that the lymph node sampling could be eliminated in some patients prior to the radical prostatectomy. Would this be one such patient . . . ?" asked Dr. D’Amico.
Dr. Richie responded that the incidence of positive lymph nodes has decreased dramatically. "It used to be 25% to 50%, and that’s when we were doing all the lymph node dissections. The incidence now is much less than 2% overall." He noted, however, that this particular patient is at increased risk of lymph node involvement, as suggested by the PSA level of 12 ng/ml, the Gleason 4 component, and the palpable nodule, and, therefore, he would not eliminate lymph node sampling in this patient. "I think that sampling the lymph nodes gives you more accurate staging, adds maybe half an hour to the procedure, and the morbidity is fairly low, so we still do it." On the other hand, he said, "[in] patients who have very low PSAs, low Gleason grade, and no palpable nodule, you probably could skip doing the lymph node dissections."
Dr. D’Amico concluded that the management of prostate cancer is evolving. In summarizing this third case, he emphasized that "it points out the importance of prognostic factors in selecting treatment and the need for long-term follow-up to evaluate the outcome of treatment for prostate cancer. We are moving towards an era in medicine where the molecular signatures of cancer are being discovered, providing the ability to utilize therapies targeted at the genetic aberrations responsible for the development of diseases such as prostate cancer. With such knowledge, cancer prevention should become a reality. For today, however, the best weapon against prostate cancer is early detection through the use of annual PSA screening for men age 40 or older who have a familly history of prostate cancer, and for men age 50 or older who are without such a history."
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