Three randomized clinical trials (Sathya et al., 2005; Hoskin et al., 2012; and Guix et al., 2013) established the combination of external beam radiation therapy (EBRT) with a high dose rate brachytherapy (HDRBT) boost as a standard of care in the treatment of high-risk prostate cancer. In all three of those trials, the outcomes exceeded those from EBRT alone, but at a cost of higher toxicity.
In previous studies of this combination therapy for high-risk patients, rates of freedom from biochemical relapse have ranged from 67 to 97 percent at 5 years, and from 62 to 74 percent at 10 years. Late term genitourinary (GU) grade 3 toxicity ranged from 0 to 14.4 percent (median, 4.5 percent); gastrointestinal (GI) grade 3 toxicity ranged from 0 to 4.1 percent (median, 0.5 percent); chronic incontinence ranged from < 1 to 3.8 percent; urethral strictures ranged from 0.9 to 7.4 percent (median, 4.5 percent); and erectile dysfunction ranged from 10 to 51 percent (median, 31.5 percent).
It may be helpful to understand how large the effective doses of radiation were that were used in all of the aforementioned studies. The term “biologically effective dose” (BED) enables us to compare the cancer-killing power of the absorbed radiation across different radiation modalities. To provide a point of comparison, I show the BED as a percent of the BED of a typical modern IMRT schedule, 80 Gy in 40 fractions (fx), which has a BED of 187 Gy.
Could equal oncological outcomes be accomplished but with less toxicity by using high dose rate brachytherapy as a monotherapy? The maturing of data from a clinical trial in Japan suggests it can be.
Yoshioka et al. (2015) have used HDRBT monotherapy on 111 high-risk patients treated between 1995 and 2012. Almost all of them (94 percent) received ADT as well. They evaluated three dosing schedules: 48 Gy in eight fractions, 54 Gy in nine fractions, or 45.5 Gy in seven fractions inserted over 4 to 5 days.
With a median of 8 years of follow up, the authors report:
- Biochemical no evidence of disease, 77 percent
- Metastasis-free survival, 73 percent
- Overall survival, 81 percent
- Cause-specific survival, 93 percent
- Late GU grade 3 toxicity, 1 percent
- Late GI grade 3 toxicity, 2 percent
Unfortunately, they haven’t reported rates of erectile dysfunction. Other monotherapy series report ED rates of about 25 percent, and there’s no reason to suppose it would be particularly different for high-risk patients. They report no significant differences in oncological control or toxicity according to total dose or dose schedule used.
The biochemical control rates are well within the range seen for combination therapy at 5 to 10 years after treatment. At the same time, the rates of serious late term GU and GI side effects seem to be improved by the monotherapy.
Other recent studies have reported excellent results for HDRBT monotherapy for high-risk patients. Zamboglou et al. (2012) reported the monotherapy outcomes of 146 high-risk patients treated between 2002 and 2009. Sixty percent received ADT as well. They evaluated three dosing schedules: 38 Gy in four fractions in one implant, 38 Gy in four fractions in two implants, and 34.5 Gy in three fractions in three implants. After 5 years, biochemical control was 93 percent, late grade 3 GU toxicity was 3.5 percent, and late grade 3 GI toxicity was 1.6 percent. The differences in toxicity among the dosing schedules were not statistically significant. Among previously potent men, only 11 percent lost potency sufficient for intercourse. The highest dose schedule did not have better oncological control or worse toxicity than the lower dose schedules.
Hoskin et al. (2012) reported the monotherapy outcomes of 86 high-risk patients treated between 2003 and 2009. Almost all of them (92 percent) received ADT as well. They evaluated four dosing schedules: 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, and 26 Gy in two fractions. After 4 years, biochemical control was 87 percent, late grade 3 GU toxicity was 12 percent, and late grade 3 GI toxicity was 1 percent. It is not clear why GU toxicity was higher than in the other two studies. They did not report erectile dysfunction. Although higher rates of strictures (ranging from 3 to 7 percent), and urinary toxicity occurred on the most aggressive dosing schedules, the differences were not statistically significant on this sample size. Similarly, the difference in recurrence-free survival at the lowest dose was not statistically significant.
Within all three published studies, there were no statistically significant dose-response relationships in terms of either oncological control or toxicity. However, looking across the three, it may be that the higher doses provided better control at the cost of some higher toxicity. I hope someone will do a meta-analysis on the full data sets to confirm that. Larger studies will be needed to determine whether toxicity increases with the more aggressive dosing schedules. All the control rates were within the range of the combination therapies, and all of the toxicities were acceptable. Evidently, all of the studies applied enough radiation to effectively kill the high-risk cancer. Nor did the dosing schedule used have an impact on results. HDRBT monotherapy as currently practiced uses anywhere from a single fraction to nine fractions, and anywhere from a single implant to three implants.
It is difficult to draw conclusions about the use of ADT. All three studies utilized high rates of adjuvant ADT — over 90 percent in two of the studies. The study with the lowest rate of ADT utilization (Zamboglou et al., at 60 percent) also used the highest radiation doses. Although Demanes et al. found that ADT had no incremental benefit when used with combination therapy, that study was in the early years (1991 to 1998) when relatively low radiation doses were used. Until there is a randomized clinical trial of its use with HDRBT monotherapy, it will be hard to walk away from using ADT.
Unlike low dose rate brachytherapy (seeds), HDRBT can treat areas outside of the prostate, including the prostate bed and the seminal vesicles. However, to my knowledge, it has not been used to treat pelvic lymph nodes, which would be impossible to find using current imaging technology. In all three studies, patients were screened for evidence of lymph node involvement. Clearly, HDRBT monotherapy is not a good choice if lymph node involvement is suspected. There are calculators for predicting such risk based on Gleason score, PSA, and cancer volume. High-risk patients may have a statistically high risk for lymph node involvement without showing evidence, but even the “high risk” levels are not very high, so treatment remains controversial. One clinical trial (Lawton et al.) demonstrated a benefit to full-pelvic IMRT coupled with neoadjuvant ADT, and there is a current clinical trial that allows for a brachytherapy boost (RTOG 0924) that may confirm that finding.
SBRT is radiologically identical to HDRBT, and as discussed in a recent article, its use for high-risk patients is also being explored. Both of these treatments have the potential to provide excellent cancer control while minimizing the side effects of treatment, and with a considerable time and cost advantage over IMRT + combination treatments. I encourage high-risk patients to enroll in clinical trials for both alternatives. HDRBT monotherapy for high-risk disease is part of a clinical trial at Stanford University (NCT02346253).
Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.
Filed under: Diagnosis, Management, Risk, Treatment, Uncategorized | Tagged: "high risk", brachytherapy, HDRBT, high-dose-rate, monotherapy, outcome, side effects |
THE "NEW" PROSTATE CANCER INFOLINK 
Dear Sitemaster,
Thank you for posting this. I had trimodal treatment, with the highest dose escalation used anywhere at that time (Feb – June 2009). It was fascinating. I have all toxicity types except stricture. These are of moderate level. So far the PSA density value is undetectable.
As to lymph node involvement, a laparoscopic investigation revealed no detectable involvement. I learned the Linear Quadratic Model to understand the boost effect of HDRBT. As I had studied a lot of maths at college and university, it was indeed rocket science. Since the model’s mathematical formula for effectivity has a simple additive term in its exponent, and is derived from a simple molecular biological mechanistic hypothesis, I feel that the boost should be explained to as many patients as possible. Patients must often choose a treatment modality, so where trimodal is one option, explanation of its special character would be helpful.
George Berger,
I’m glad to hear the triple modality worked so well for you, albeit with high toxicity. In general, I avoid writing that involves math. It is also beyond the scope of a single commentary like this to give the readers a course in radiobiology. I’ve found that many patients, unlike yourself, are math-averse. Part of my job as a communicator is to present the findings in a very broadly comprehensible manner, and I hope I have done so. Rest assured that I did use the LQ model and alpha/beta ratios in computing BEDs. (I used an alpha/beta of 1.5.) I do applaud you for teaching yourself about it — you sound like quite an empowered patient.
Dear Allen,
I was referring to information given to patients a bit before they must choose a treatment option. You need not explain the LQ Model to patients then and there. Its statistical predictions and working can be explained with two simple diagrams and one + sign. I am a retired teacher of philosophy and mathematical logic and have explained more complicated notions whilst using no maths.
There is a more personal reason for this. Suppose I had to choose between bimodal therapy with EBRT and ADT, and my trimodal. I’d be lost and angry if I were not told a lot about trimodal. How could I choose properly whilst lacking information? Indeed, I might well not know I lacked data and might choose a statistically less effective bimodal treatment. This article is the latest in a series of three or four comparative articles I have looked at, so by ‘statistically’ I refer to it.
Now, something close to this happened to me in December 2008, when I lived in Amsterdam. I am high risk: T2cN0M0, Gleason 4 + 4, cPSA = 31. I was ordered to choose between EBRT and RP, but given no information at all, after two visits. I was rejected for any type of brachytherapy, as “[your] prostate is too large,” quoting a head urologist. This seemed incomplete, as the role of volume was not explained. I flew to Sweden 2 days later, to formally discuss this. That is how I learned about trimodal, but not yet about LQ. It was described informally. Although the diagnosis at home was incomplete I had enough info to choose trimodal over the Dutch options. Nine days later I left the Netherlands for good. Yet before I left, the Dutch doctor inadvertently told me about his guideline, insisting that he was following it. (I confronted him.) I found it and noticed that trimodal was never a possible option and that the guideline concerned only men of 65 or older. I was 66. This doctor was the final editor. This gave me yet more reason to leave.
Without the informal Swedish explanations of boost effects I could not have acted properly, i.e. by using all the international information I could get. This article is the latest one I have read about trimodal vs monomodal (with or without ADT). In our EU and globalised world, it is simply ethically wrong and dangerous for doctors to tell patients only about treatments available in their countries. I can go on about these issues, as I was one of the first non-medical persons to have studied the privatisation of Dutch care on January 2006 and its consequences through 2008. But that is enough for now.
Several problems here:
First, none of the three randomized trials showed a survival benefit, it was primarily biochemical failure but other outcomes were included.
Second, hormone therapy was not part of the routine and we know that this group of patients clearly benefits so it is difficult to know whether the high dose brathytherapy was really necessary or beneficial.
Third, at least in the first of the three studies, the dose of IMRT was only 66 Gy, which we know is inferior to higher doses.
The bottom line is we still do not know if high dose brachytherapy is a real advantage for patients or whether it is better than high dose IMRT plus ADT or even high dose IMRT, plus ADT, plus permanent brachytherapy. High dose therapy is really an inconvenient treatment modality for patients and before recommending it, better data are needed to prove it is worth the hassle.
Dr. Chodak-
You are quite right that survival benefit must be proved in a randomized clinical trial, but in the real world, we seldom get to that. Since these are high-risk patients, the surrogate measure of biochemical failure provides at least some decision-making support for the patient. My attitude is that for the patient faced with a difficult treatment decision, he is better off having the best data available, while acknowledging the deficiencies in it.
Hormone therapy was absolutely part of it, used by 94%, 60% and 92% in the three monotherapy studies, We do not know that hormone therapy is of any benefit with HDR. Dr. Demanes’ early study showed no benefit.
I agree that the Sathya study used sub-optimal doses, as can be clearly seen in Table 1, although the other studies were in line with contemporary best practice. There is clearly a dose/response relationship. The problem is that IMRT hits a toxicity wall at about 80 Gy. We have to look to other modalities to exceed that barrier.
I differ with you that HDR monotherapy is inconvenient. Some are doing it now in a single hospital visit. Patients I’ve met who have done the combo therapy were more inconvenienced by the IMRT part of it — they would have been thrilled to undergo only HDR monotherapy. But that is a patient preference. Sadly, HDR is a dying art. It is not well reimbursed and few radiation oncologists want to invest in the technology and learning curve to do it.
I sympathize with you in wanting more randomized comparative clinical trials. As you know, in the real world, that seldom happens. Even the Stanford clinical trial I recommended is not comparative. The patient, especially the high-risk patient, does not have the luxury of delaying his decision. As of now, this data is about as much as he can hope for.
Allen.
I am curious about the lack of ADT in the top combo study. The article is from 2005, so perhaps the benefit of ADT to high-risk persons was not established then. I really do not know. I got neoadjuvant ADT with 3 months of Casodex, and adjuvant ADT with 3 years of Zoladex. Can I assume that I benefited with respect to the Sathya study? With benefit expressed either informally or in terms of some statistical notions?
As to convenience, I was not inconvenienced at all. HDR in two fractions was an interesting experience and a welcome break from monotonous EBRT.
George,
You are right that the Sathya trial was the first in the early days of combo therapy. While it was published in 2005, patients were treated 1992-1997, using the best equipment (they did not have 3D-CRT or IMRT) available and best practices (the value of dose escalation was not yet established) at the time. Here’s what the article says about the use of ADT:
“The optimal treatment approach for intermediate- and high-risk patients is evolving. Short-term neoadjuvant hormone therapy combined with standard-dose EBRT is now commonly used to treat intermediate-risk patients. Long-term adjuvant hormonal therapy combined with EBRT is emerging as standard therapy for high-risk patients. However, hormonal therapy is associated with risk of osteoporosis, sexual dysfunction, anemia, and unfavorable body composition, which adversely affect quality of life. To avoid the use of hormonal therapy, optimization of modern radiotherapy techniques and dose escalation to achieve better local and biochemical control are being explored.”
The benefit of ADT with dose-escalated EBRT in high-risk patients was only established last year by the DART 01/05 randomized clinical trial. There are many open questions about its optimum sequencing, duration, and use with hypofractionated radiation. Until there are more data, there is no one optimal protocol, and in my opinion, the approach should be designed through a process of shared decision-making by the doctor and patient.
Dear Allen:
Thanks for the information and reference. Yes, the doctors did discuss me extensively early in 2009 and maybe when I started the adjuvant ADT. Three years of ADT was chosen when or a bit before doctors elsewhere and maybe here — Uppsala, Sweden — started recommending 18 months. I decided that the Uppsala doctors were playing maximally safe and that more toxicities were accepted over greater probability of biochemical failure. For this is no choice. After all, I have all high-risk indications for T2N0M0 cPSA = 31 and would most likely have died from the cancer within 10 years without maximally aggressive treatment. This justifies the choice of 3 years instead of 18 months, assuming the choice was ever considered. (Some papers called 3 years the “gold standard.)
A final remark. Before I left Amsterdam I met a Dutch radiologist at the same hospital and asked him why they did not use trimodal. He replied that the risk of high-stage toxicity was too great. (He did not know that I had found the guideline, with an age number that struck me as an insurer-mandated upper age limit.) Now, this reply was not ethical: I should have been asked about my preferences and desires. I said nothing but realised that I had indeed better leave the country. I later learned that my suspicions re age were correct and that I could have gotten trimodal at another Dutch hospital. The key here is, I think, that the guideline was not legally binding. I should have been told about the other hospital(s). I acted rationally given my evidence, desires, and medical-ethical principles. I shall remain here.
In the first phase of this study design, patients who received neoadjuvant HT for more than 4 months or for whom adjuvant or salvage HT was started within 1 year after treatment were excluded from this study because of the significant influence of how the HT therapy would obscure the subject patients’ evaluations of their primary therapies. Two low-risk patients who selected active surveillance were also excluded from this study because of the very small population that they represented.
In one of his most recent video blogs on the Medscape web site, we note that Dr. Gerald Chodak has commented on this issue for fellow clinicians — referring specifically to Allen Edel’s article here. See also Dr. Chodak’s comment above.