Wednesday, June 21, 2017

Eighth randomized clinical trial of hypofractionated radiation therapy

We now have an eighth randomized clinical trial of hypofractionated radiation therapy. There are no surprises: it showed that oncological and toxicity outcomes were not significantly different between the two regimens. We last looked at it here. This trial is unusual because of the length of follow-up.

Arcangeli et al. report the 10-year outcomes of their study covering 168 high risk patients treated using 3D-CRT (not IMRT) at the Regina Elena Cancer Institute in Rome between 2003 and 2007. The details of the treatments were as follows:
  • Half (85 patients) received conventionally fractionated (Conv)  80 Gy in 40 fractions
  • Half (83 patients) received hypofractionated (Hypo) 62 Gy in 20 fractions
After a median of 9 years of follow-up:
  • 10-year freedom from biochemical failure was 72% for the Hypo group vs. 65% for the Conv group.(no statistically significant difference)
  • 10-year prostate cancer -specific survival was 95% for the Hypo group vs. 88% for the Conv group (no statistically significant difference)
  • 10-year overall survival was 75% for the Hypo group vs. 64% for the Conv group (no statistically significant difference)
  • Hypofractionation was a significant variable in determining prostate cancer-specific survival in multivariate analysis
  • There were no differences in late-term grade 2 or higher urinary or rectal toxicity between the 2 groups.

There are a couple of caveats. For those who insist on rigorous analysis, the Hypo group had worse oncological and toxicity outcomes on an intention-to-treat basis. It was only after the patients were analyzed according to the treatment they actually received that the lack of statistically significant difference became apparent. James Yu, in an accompanying editorial, points out that blood in urine was 16.5% for the Hypo group vs. 3.6% for the Conv group. This may be a caution that hypofractionation should not be attempted using 3D-CRT. In the US, where IMRT is widely available, this should not be an issue.

Here's the table summarizing all 8 randomized clinical trials:


Randomized Clinical Trial
Risk Groups
Fractionation
5-yr bPFS
Urinary toxicity
Grade 2+
Rectal toxicity
Grade 2+
Ref.
PROFIT
100% intermediate
60 Gy/20fx
78 Gy/39fx
85%
85%
22%
21%
8%
14%
1
Fox Chase
67% Intermediate, 33% high
70.2 Gy/26fx
76 Gy/38fx
77%
79%
22%
13%
18%
23%
2
CHHiP
73% intermediate, 15% low, 12% high
60 Gy/20fx
74 Gy/37fx
91%
88%
12%
9%
12%
14%
3
MD Anderson
71% intermediate, 28% low, 1% high
72 Gy/30fx
75.6 Gy/42fx
89%†
85%†
16%
17%
10%
5%
4
RTOG 0415
100% low risk
70 Gy/28fx
73.8 Gy/41fx
94%
92%
30%
23%
22%
14%
5
HYPRO
>70% high, <30% intermediate
64.6 Gy/19fx
78 Gy/39fx
81%
77%
41%
39%
22%
18%
6, 7
Cleveland Clinic
49% low, 51% intermediate
70 Gy/28fx
78 Gy/39fx
94%
88%
1%
2%
5%
12%
8
Regina Elena
100% high risk
62 Gy/20 fx
80 Gy/40 fx
72%*
65%*
21%
14%
NA
NA
9
*10-year figures for the Regina Elena trial
† 8-yr failure-free survival update for MD Anderson

Tuesday, June 6, 2017

Newly diagnosed, metastatic (M1), but still hormone sensitive - best options

(Frequently Updated)

In the US, only 3% of new patients are newly diagnosed with metastatic, hormone-sensitive prostate cancer (mHSPC). "Metastatic," for the purposes of this analysis only includes distant metastases (Stage M1), but not pelvic lymph node metastases (Stage N1). This group has been the subject of many major randomized clinical trials over the last few years. CHAARTED, in the US, randomized to early docetaxel + androgen deprivation therapy (ADT) compared to ADT alone. STAMPEDE, in the UK and Switzerland,  has published several studies: one on the use of Zometa and Celebrex, one on docetaxel,  one on abiraterone+prednisolone (I'll refer to this combination as Zytiga), and two on debulking the prostate with radiation (one from STAMPEDE and one from HORRAD). They also included men with locally advanced and recurrent prostate cancer, which we will address at another time (see this link). 

LATITUDE was a multinational clinical trial comparing Zytiga+ADT to ADT alone. TITAN was a multinational trial comparing apalutamide (Erleada) +ADT to ADT alone. ENZAMET was a multinational trial comparing enzalutamide (Xtandi) + ADT to early antiandrogens +ADT. ARCHES assessed the effect of enzalutamide on radiographic progression-free survival. TITAN and ENZAMET are discussed in more detail here.

We can look at hazard ratios for overall survival. A hazard ratio (HR) of, say, 0.60 means that the treatment reduced the number of deaths by 40% compared to the standard treatment. Unless it is otherwise noted, the HRs we talk about are all statistically significant with 95% confidence.

Early use of docetaxel

The hazard ratios found for all metastatic men were as follows:
CHAARTED: 0.61
STAMPEDE: 0.81
GETUG-15: 0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
CHAARTED: 0.60
GETUG-15: 0.8 (not statistically significant)
STAMPEDE: 0.81 (not statistically significant)

The hazard ratio for men with low volume mets only were:
CHAARTED: 1.03 (not statistically significant)
STAMPEDE: 0.76 (not statistically significant)

GETUG-15 was a French randomized clinical trial. It has been criticized for including men with more advanced disease than CHAARTED. When STAMPEDE showed similar results to CHAARTED, GETUG-15 was largely ignored, and early use of docetaxel became the new standard of care. Some argued that the  results of STAMPEDE and CHAARTED suggest that docetaxel should be considered for among all metastatic men, but a CHAARTED update suggests a benefit only among those with high volume of metastases. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men. They advocate early use of docetaxel regardless of metastatic burden. (High volume was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.)

One should resist the temptation to compare HRs across studies. Each study had different patient characteristics, and PSA screening policies differ markedly in those countries. In fact, a recent analysis of the STAMPEDE outcomes of men who were randomly assigned to either Zytiga or docetaxel found that there was no difference in survival between the two treatments (see this link).

Early use of Zytiga

The hazard ratios found for all metastatic men were as follows:
LATITUDE: 0.66
STAMPEDE: 0.61

An unplanned secondary analysis presented at ESMO 2018 looked at high volume vs low volume, and found it worked equally well in both situations:

The hazard ratios for men with high volume mets only were:
STAMPEDE: 0.60

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.64

Early use of Erleada

The hazard ratio for metastatic men was 0.67

Early use of Xtandi

The  hazard ratio for all metastatic men was 0.66

The hazard ratio for men with high volume mets only was 0.74 - not statistically significant

The hazard ratio for men with low volume mets only was 0.48 - statistically significant


Early use of Debulking

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.92  (not statistically significant)
HORRAD:  0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
STAMPEDE: 1.07 (not statistically significant)

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.68 (statistically significant)

Early use of Zometa+Celebrex

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.78 (see this link)

Which is best? 

The no-brainer here is Zometa+Celebrex. As long as the patient doesn't have contraindications like heart disease or bad teeth, it is cheap, non-toxic, and reduced risk of death by 22% at the 43 month follow-up. Zometa is usually given along with ADT anyway, so it is hard to argue against including this combination along with Zytiga, Erleada or docetaxel.

The hormonal therapies have differing modes of action, but without a randomized clinical trial, it's impossible to say that one extends life more than the others. Xtandi and Zytiga are being compared in an ongoing arm of STAMPEDE. Zytiga prevents the formation of androgens by the adrenal glands and via intra-tumoral synthesis. A recent study suggests that it stops formation of testosterone by the testicles as well. Xtandi and Erleada block the androgen receptor and prevents its translocation into the nucleus, where it can invigorate the cancer even without outside androgens. Erleada also prevents "upgrading" of the androgen receptor - a mode of castration resistance where multiple copies of the androgen receptor appear on the cancer cell, so it can be activated by even the slightest amount of androgen. However, it is unknown whether it slows down castration resistance in clinical practice - the cancer cell evolves many workarounds. A small trial found that combining Zytiga and Xtandi did not improve survival in the castration-resistant setting. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive setting.

Because neither docetaxel nor Zytiga showed a clear survival advantage when men were randomized to one or the other (Sydes et al.), the decision must be made based on other factors.

Both docetaxel and Zytiga increase toxicity over ADT alone. In the LATITUDE trial, physicians reported grade 3-5 (serious to death) events among 68% taking Zytiga vs 52% on ADT only. Higher rates of grade 3 hypertension and hyperkalemia were observed. In the STAMPEDE trial, physicians reported grade 3-5 events among 47% of those taking Zytiga vs. 33% of those taking ADT only. Higher rates of hypertension and liver enzyme elevation were observed. In the TITAN trial (Erleada), where almost two-thirds had high-volume metastases, Grade 3 (serious) and Grade 4 (life-threatening) toxicities were similar (41-42%) for those who got apalutamide or placebo. In the ENZAMET trial, serious side effects were experienced by 42% of those taking Xtandi vs 34% of those taking an early antiandrogen. The rate of serious side effects is remarkably similar.

In the docetaxel trials, STAMPEDE reported grade 3-5 events among 52% taking docetaxel vs 32% taking ADT only. Neutropenia, lethargy and GI disorders were especially elevated. CHAARTED reported grade 3-5 events among 30% taking docetaxel. Neutropenia, fatigue, gastrointestinal and allergic reactions were elevated.

One might expect that the increase in toxic events would have been worse with docetaxel, but while they were different in kind, the incidence of all events requiring medical attention was similar for both treatments. All medicines seem to have lower incidence of side effects when they are used earlier, while patients are healthier.

One downside for Zytiga is cost. Zytiga costs about $9,000 per month and patients stayed on it for about 2 years so far (drug resistance is low when patients are ADT-naive). This use of Zytiga is now FDA-approved, so Medicare and most insurance should cover such early use. Lower cost generics have become available.

Docetaxel is available as a generic for a cost of about $9,000 for six 3-week cycles. Not only is it less expensive, it is covered by Medicare and all insurance. On a cost/benefit basis, it is preferable.

High volume/low volume of metastases

Planned subgroup analyses of both CHAARTED and STAMPEDE showed that certain different therapies may improve survival depending on the number of distant metastases found using a bone scan/CT. Remember that high volume was arbitrarily defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae; low volume is anything less than that (often referred to as oligometastatic).

For men who are diagnosed with a low volume of metastases (oligometastatic), debulking can add to survival. STAMPEDE recruited participants before the benefit of early Zytiga was known, so it is unknown how the two therapies might interact. It is reasonable to speculate that early Zytiga may be used to radio-sensitize the cancer to debulking with radiation. The role of metastasis-directed SBRT has yet to be proven, but may be considered when safe to do so.

In a post-hoc analysis of LATITUDE data, men with high volume disease benefited from early use of Zytiga, but men with low volume disease did not. In STAMPEDE, there was no difference - Zytiga was equally effective in both groups. Erleada also seems to be equally effective in both groups. However, LATITUDE had mostly high-volume disease men in its sample. For men with a high volume of metastases, docetaxel or Zytiga (but not debulking) may confer a survival benefit). Xtandi seems to benefit most those with low volume of metastases.


Can they be combined or sequenced?

There is a hint that docetaxel may have some efficacy in keeping Zytiga working longer. The androgen receptor always eventually becomes resistant to the effect of Zytiga. Sometimes resistance is attributable to a change in the androgen receptor called "the AR-V7 splice variant." There was a very small (n=14) trial at JH where they were looking at the role of the AR-V7 splice variant in resistance to second-line hormonals (Zytiga or Xtandi). In a few guys (6 out of 14) who were AR-V7 positive after that hormone therapy, they became AR-V7 negative after docetaxel treatment. This is also an effect that they were hoping that supraphysiological doses of testosterone might sometimes create (see this link).

This may work both ways. Hormonal agents may even re-sensitize the cancer to docetaxel after it has become docetaxel-resistant (see this link). It may turn out that alternating the use of chemo and advanced hormonals (and testosterone!) is a good strategy.

For logistical reasons, it may be useful to start with six cycles of docetaxel, which would take 15 weeks. In this way, Zytiga, Erleada or Xtandi can begin 15 weeks later. If one starts with Zytiga, it may take three or more years before it stops working and docetaxel can be tried (Among metastatic men, failure-free survival was about 4 years in STAMPEDE, radiographic progression-free survival was 33 months in LATITUDE). It seems that one can receive more therapies in less time if a patient begins with docetaxel.

It is possible that concomitant early use of Zytiga and docetaxel may have a synergistic effect on the cancer, and in preventing the onset of Zytiga resistance. This is pure conjecture and would have to be proved in a clinical trial. The downside is the cumulative side effects.

The other possibility is starting with docetaxel only and following up with the combination of Zytiga +ADT. By holding off on ADT use, it might delay some of the selective evolutionary pressure that leads to early Zytiga resistance. It is unknown whether early docetaxel without ADT has similar efficacy to the combination. Again, this is a good hypothesis to be tested in a clinical trial.


Will Provenge, Xofigo and Jevtana also be more beneficial if used earlier?

Isn't earlier always better? Not necessarily (see this link). Cancer is a moving target, continually altering its genetic make-up. What works when cancer is in one state may not necessarily work when cancer is in another state. There can be unpredictable interactions. Early and prolonged use of bicalutamide, for example, may actually eventually increase the cancer growth rate; yet, with cancers that have become castration-resistant, adding bicalutamide may sometimes slow it down.

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC (see this link). Xofigo is in a clinical trial for mHSPC, and Jevtana is in trials for use before docetaxel.

What about nuclear medicines?

An exciting new field is the use of nuclear medicines (alpha-emitters like Xofigo, and beta-emitters like Lu-177-PSMA). Their use has historically been restricted to men with mCRPC. There is a clinical trial of Lu-177-PSMA for men who are castration-resistant but are not yet detectably metastatic (see this link). The hope is that they can seek out and destroy micrometastases that may be in systemic circulation.

What happens if they are used later?

Most of the advanced prostate cancer medicines were approved for men who were metastatic and castration-resistant (mCRPC). In that setting, docetaxel adds a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival has not been reached with the limited follow-up of the STAMPEDE trial, but we can look at 60% survival and  note that the curves are diverging, so the median survival improvement is at least this large. In STAMPEDE, early Zytiga increased median survival by at least 18 months; In LATITUDE, early Zytiga increased median survival by 16.8 months.

We might surmise that if used after metastatic diagnosis but before castration-resistance sets in, the survival improvement might be somewhere in between. However, long-term use of ADT drives changes in the androgen receptor that might shorten the time during which Zytiga is effective. Docetaxel, on the other hand, remains effective even after advanced hormonal agents have been utilized.

What are the other alternatives for metastatic hormone-sensitive prostate cancer (mHSPC)?

Supraphysiological doses of testosterone alternating with ADT (called Bipolar Androgen Therapy or BAT) has shown efficacy in some men (see this link). Expanded trials will tell us which men are most likely to benefit from it.

Treatment of the prostate even after metastases have been discovered  (called "debulking") is an intriguing prospect. However, the most recent reported arm of the STAMPEDE trial showed that prostate-only radiation only provided a survival benefit in oligometastatic men (see this link). There are clinical trials at MD Anderson and Rutgers (not recruiting), and registries at UT Southwestern and MSKCC and the Los Angeles VA that will further explore this opportunity. Princess Margaret Hospital in Toronto is using SBRT for this purpose (see this link). Other trials are ongoing in Europe (this one includes docetaxel and Zytiga): Ghent, and Hamburg.

Other early-use therapies are combined with ADT in clinical trials. These are no longer recruiting:
These are still recruiting:
This will be recruiting soon: