Saturday, February 16, 2019

SBRT has non-inferior acute and late-term toxicity vs IMRT in two randomized clinical trials

In October 2018, the American Society of Radiation Oncologists (ASTRO) strongly endorsed moderately hypofractionated IMRT (20/28 treatments) for primary radiation treatment (see this link). Since then, there has been another publication of a randomized clinical trial with ten years of follow-up (see this link).

The advantages for the patient are large: fewer visits than the conventional 38-44 treatments with a concomitant reduction in costs. Because there is now convincing proof that this can be accomplished without an increase in side effects and without loss of oncological effectiveness, there is no reason why any patient would suffer through the conventional regimen. The remaining question is whether the number of treatments (or fractions) can be reduced even further to only about 4 or 5. This kind of extreme hypofractionation is called stereotactic body radiation therapy or SBRT. This requires proof.

We have seen the results of a Scandinavian randomized clinical trial (RCT) that found that urinary, rectal, and sexual side effects were not inferior with extreme hypofractionation (see this link), and the oncological outcomes were about the same too (see this link).

Now two more RCTs have shown that the toxicity of SBRT is no worse than and possibly better than moderately hypofractionated or conventionally fractionated IMRT.

Van As et al. reported the acute toxicity results of the PACE-B RCT in the UK at the Genitourinary Conference of ASCO. 844 men with favorable risk prostate cancer were randomized to get SBRT (414 men) or conventionally fractionated/moderately hypofractionated  IMRT - "CFMHRT" (430 men). The qualifications were:

  • localized, favorable risk prostate cancer (Gleason score ≤ 3+4, Stage T1 or T2, PSA ≤ 20 ng/ml)
  • unsuitable for surgery or preferring radiation

The two groups were similar. The treatments were:

  • SBRT: 36.25 Gy in 5 fractions over 1-2 weeks
  • CFMHRT: 78 Gy in 39 fractions (conventional) or 62 Gy in 20 fractions (moderately hypofractionated)
  • ADT was not permitted

At 12 weeks post treatment, acute grade 2 or higher toxicity was:

  • rectal: 10% for SBRT vs 12% for CFMHRT - difference was not statistically significant
  • urinary: 23% for SBRT vs 27% for CFMRT - difference was not statistically significant

Poon et al. reported the one year late-term toxicity results of a RCT in Hong Kong. 64 low- and intermediate-risk patients were randomized to get SBRT (31 patients) or conventionally fractionated IMRT - "CFIMRT" (33 patients). The qualifications were: Stage T1 or T2, Gleason score ≤ 7, and PSA < 20 ng/ml.

The treatments were:

  • SBRT: 36.25 Gy in 5 fractions over 2 weeks
  • IMRT: 76 Gy in 38 fractions
  • Intermediate risk patients could optionally have ADT before their radiation.

at 1 year post treatment:

  • one grade 3 (serious) urinary side effect was reported in each arm
  • rectal grade 1 (mild) or higher: 64% for SBRT vs 84% for CFIMRT - significantly different
  • urinary grade 1 (mild) or higher: 93% for SBRT vs 100% for CFIMRT - not significantly different


It is too early to assess if there are any differences in oncological outcomes in these two RCTs.




Sunday, February 3, 2019

Timing is everything with docetaxel (and hormone therapy and probably with immunotherapy and radiopharmaceuticals too)

The conventional wisdom with cancer is that "earlier is better." As cancers progress, they mutate: there are many more genetic errors in older cancers than in younger ones. Because of this, a therapy that may work well against a cancer in one stage of its development, may not work at all in an earlier or a later stage.

Prostate cancer is one of the most slow-growing of cancers in its early stages. This is why we can take so much time to decide on initial treatment, even in high-risk cases (see this link). It is also why low-risk men may safely choose active surveillance over immediate radical therapy. Progression is only weakly correlated with time since diagnosis, even for recurrences (see this link).

Early Use of Docetaxel

We have already seen that docetaxel is of limited (if any) use when combined with radiation therapy and ADT for high risk cancer patients (see this link).

Oudard et al. conducted a randomized clinical trial of docetaxel+ADT vs ADT-alone in non-metastatic men with a recurrence after primary treatment. All 250 patients were "high risk," which was defined as at least one of the following:
  • Gleason score ≥ 8
  • PSA velocity > 0.75 ng/ml/year
  • PSADT ≤ 6 months
  • time to recurrence ≤ 12 months
Previous treatments were:
  • 73% had prior prostatectomy
  • 27% had prior primary radiotherapy ± ADT
  • 60% of men who had a prostatectomy also had salvage EBRT
The outcomes were as follows:
  • Median PSA progression-free survival was no different:19 months if they got docetaxel, 20 months if they didn't
  • Median time to radiographic progression was no different: 9 years in each group
  • There was no difference in 12-year overall survival rates: 60% in the docetaxel group, 55% in the no-docetaxel group. (The docetaxel group was 2 years younger)
  • Adverse hematological events from docetaxel included neutropenia (48%), febrile neutropenia (8%) and thrombocytopenia (3%)
CHAARTED showed that the survival increase attributable to docetaxel in newly-diagnosed, metastatic men was only observed among men with a high volume of metastases, but not among men with a low volume of metastases. "High volume" was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.

One small observational study suggested that docetaxel may benefit men who are castration-resistant but are not yet detectably metastatic.

At the other end of the progression spectrum, in men who are both metastatic and castration-resistant, docetaxel added 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.

Docetaxel remains effective even after second line hormonals (e.g., Zytiga, Xtandi) have stopped working. In fact, there have been cases where use of docetaxel has reversed resistance to them caused by the AR-V7 splice variant.

The "sweet spot" for docetaxel seems to be after there are multiple metastases but before castration resistance is fully established. Used earlier, it seems to have no effect in most men; used later, it is still effective, but less so.


Early Use of Hormone Therapy

It is well established that hormone therapy alone adds nothing to the survival of localized prostate cancer (see this link and this one). We also know that hormone therapy adds nothing to the effectiveness of radiation therapy for favorable risk prostate cancer (see this link and this one and this one). Even with recurrent prostate cancer post-prostatectomy, a major randomized clinical trial (RTOG 9601)  found that adding long-term antiandrogen therapy to radiation did not increase outcomes as much in men who had Gleason score ≤ 7, PSA ≤ 0.7 ng/ml or negative surgical margins.

However, an early analysis of the TOAD randomized clinical trial suggests that using androgen ablation on men who are recurrent after prostatectomy but not yet detectably metastatic may have a net survival benefit over the selective pressure it exerts towards castration resistance. In fact, men who started on ADT earlier developed castration resistance significantly later. This effect was also noted in the TROG 03.04 RADAR trial. The authors wrote, "The cumulative incidence of transition to castration resistance was significantly lower in men receiving [longer term ADT with their EBRT]."


Early Use of Second-line Hormone Therapy

We have learned that the use of abiraterone (Zytiga) in newly-diagnosed metastatic men increases survival markedly over waiting. 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 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 by16.8 months. Abiraterone was equally effective regardless of the number of metastases or whether they were classified as higher or lower risk (see this link).

Enzalutamide (Xtandi) is probably also beneficial if used earlier. A non-randomized clinical trial of early use of Xtandi showed it is very effective if used earlier (see this link), and a Phase 3 trial for its use in hormone-sensitive prostate cancer has had good results, according to a press release.

The FDA has approved apalutamide (Erleada) and enzalutamide (Xtandi) for use in non-metastatic castration-resistant prostate cancer. Darolutamide and abiraterone (Zytiga) will probably also be approved for this indication. Non-metastatic castration-resistant prostate cancer is probably an early version of metastatic castration-resistant prostate cancer, where micrometastases have not yet grown large enough to become detectable on a bone scan/CT.

Clinical trials suggest or are in process to determine if there is a role for advanced hormonal agents even earlier; for example in any of the following early settings:

• as part of an active surveillance protocol for men with favorable risk prostate cancer (see this link)
• adjuvant to radiation in high-risk localized prostate cancer (see this link)
• when it as advanced to only as far as pelvic lymph nodes (Stage N1 M0) (see this link)
• when it is recurrent but not yet detectably metastatic (see this link)

Early Use of Immunotherapy

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 in one small study (see this link). There are several clinical trials to help determine whether immunotherapy can play a role in extending the time that a man can stay on active surveillance (see this link and this one and this one).

In the "CHECKMATE 650" clinical trial of a combination of the two checkpoint inhibitor-type immunotherapies, nivolumab (Opdivo) and ipilimumab (Yervoy), there was some response (in 25% of pre-chemo men and 10% of post chemo men) from the combination, but no response from either drug alone in earlier trials. However, all of the responders  (60% of the pre-chemo group and 40% of the post-chemo group) had a high mutational burden and/or showed the presence of PD-L1 in the tumors (33% of the pre-chemo group and 19% of the post chemo group). Conversely, none of the men who had low mutational burden or PD-L1 had any response to the combination therapy. Toxicity was unacceptably high. This indicates that the cancer must evolve to a high degree of genetic breakdown before such therapies become effective. Early use causes unacceptable toxicity without any survival benefit.

At some point, cancer cells start displaying antigens that can be recognized by the immune system as "non-self," but it is not clear when that occurs in prostate cancer progression. Perhaps the fragments generated by chemo or radiation may make the cancer more susceptible to immune attack (see this link). It is also unclear when immune infiltration into tumors can occur, when checkpoint inhibitors (like PD-L1) begin to appear, and when regulatory T cells are overwhelmed by killer T-cells. Pro- and anti-inflammatory cytokines undoubtedly play a role in immune signaling and may occur at different stages.

Early Use of Radiopharmaceuticals

The ideal candidate for Xofigo will get all 6 treatments, preferably earlier, while bone health is still good (see this link). It has been found to work better on smaller tumors, so it is best used earlier rather than later (see this link). Because the combination of Xofigo and Zytiga caused excessive fractures and deaths (see this link), they can't be given simultaneously, at least not without a bone-preserving agent (like Zometa or Xgeva). Since a full cycle is completed in 24 weeks, taking Xofigo before Zytiga allows one to get the benefit of both in less time.

We do not know enough about the natural history of PSMA yet. We don't know when the PSMA protein first appears on the tumor surface. It has been detected in "high risk" patients, and is more often associated with higher grade cancer and in men with higher PSAs (see this link and this one). It as been detected in up to 95% of metastases. PSMA-based PET scans (Ga-68-PSMA-11 or DCFPyL) are used to check for PSMA-avidity before treatment. Without significant PSMA, the radiopharmaceutical would have nothing to latch onto, and might cause toxicity with no cancer-killing benefit.

A pilot test in South Africa suggests that Ac-225-PSMA-617 had good efficacy in patients who were not heavily pretreated, but their cancer was more progressed when treated. A trial with Lu-177-PSMA found that overall survival was 11 months in patients who had already had chemo (and were more progressed) and was 27 months in chemo-naive patients (who were also less progressed). Earlier seems to be better.


Although it is generally true that earlier treatment is better, we have learned that there are exceptions. There is tremendous individual variation, and it is likely that the window of opportunity varies.

Monday, January 7, 2019

SBRT: Optimal Dose

While excellent outcomes of stereotactic body radiation therapy (SBRT) have been reported since it was first used for prostate cancer in 2003, the delivered doses have ranged from 35 Gy in 5 treatments to 40 Gy in 5 treatments. We saw in a University of Texas Southwest (UTSW) study (see this link) that toxicity escalates when doses are greater than 45 Gy.

Memorial Sloan Kettering designed a clinical trial (described here) among low and intermediate-risk men. They started with about 35 men treated at 32.5 Gy and checked for dose-limiting toxicity. When most reached 6 months of follow-up, and fewer than 10% had dose-limiting toxicity, they increased the dose to the next group of 35 men by 2.5 Gy in 5 treatments. In all, they had 136 patients who were followed up for 5.9 yrs, 5.4 yrs, 4.1 yrs and 3.5 yrs with doses of 32.5 Gy, 35 Gy, and 37.5 Gy and 40 Gy, respectively.

Their toxicity and oncological outcomes are reported here and shown in the table below:



Dose delivered in 5 treatments

32.5 Gy
35.0 Gy
37.5 Gy
40.0 Gy
Acute toxicity




Urinary – grade 2
16.7%
22.9%
8.3%
17.1%
Rectal – grade 2
0%
2.9%
2.8%
11.4%
Late-term toxicity




Urinary – grade 2
23.3%
25.7%
27.8%
31.4% (1 grade 3 stricture)
Rectal – grade 2
0%
0%
0%
0%
Oncological outcomes




5-year PSA failure
15%
6%
0%
0%
2-year positive biopsy
47.6%
19.2%
16.7%
7.7%

Other than the one urinary stricture, there were no acute or late-term grade 3 (serious) toxicities.

Because follow-up decreased with increasing dose, it is unclear whether the zero biochemical failure rates for doses of 37.5 Gy and 40 Gy will be sustained, but in other studies, almost all SBRT failures had occurred within 5 years. The positive biopsy rates will probably continue to decline with longer follow-up because the non-viable cancer cells can take up to 5 years to clear out. Clearly, 32.5 Gy is too low because of its unacceptable oncological results.

A dose of 40 Gy in 5 treatments has very acceptable toxicity and excellent cancer control. It would be reasonable to use doses as low as 37.5 Gy in patients with insignificant amounts of low grade cancer (who would usually be excellent candidates for active surveillance). Based on the UTSW study, it would be reasonable to escalate the dose as high as 45 Gy in patients judged to have radioresistant cancers.


Monday, November 26, 2018

Can surgery+radiation+ADT provide equal outcomes to brachy boost therapy +ADT in high risk men?

As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10 year metastasis-free survival and 10 year prostate cancer specific survival (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

  • 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
    • 88 received adjuvant EBRT
    • 49 received adjuvant ADT
    • 50 received both (called MaxRP)
    • Median ADT duration - 8.6 months in 49 men with negative lymph nodes
    • Median ADT duration - 14.5 months in 39 men with positive lymph nodes
  • 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
    • Median ADT duration - 6 months
After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:
  • 2.8 times greater for any RP (statistically significant)
  • 0.5 times less for RP+adjuvant EBRT (not statistically significant)
  • 3.2 times greater for RP+adjuvant ADT (statistically significant)
  • 1.3 times greater for MaxRP (not statistically significant)
The 5-year PCSM was:
  • 2% for MaxRT
  • 22% for any RP (significantly higher than MaxRT)
  • 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
  • 27% for RP+adjuvant ADT (significantly higher than MaxRT)
  • 10% for MaxRP (not significantly different from MaxRT)
They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study
Tilki
Kishan
Sample size
BBT: 80
RP+EBRT: 88
RP+ADT: 49
RP+EBRT+ADT: 50
BBT: 436
RP+EBRT: 272
RP+ADT: 175
ADT duration (median)
BBT: 6 months
RP (N1): 14.5 mos.
RP (N0): 8.6 mos.
BBT: 12 months
RP (% N1)
44%
17%
5-year % PCSM
RP (any): 22%
BBT: 2%
RP (any): 12%
BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:
RP+ADT: 3.2
RP+EBRT: 0.5 (not sig.)
RP+ADT: 3.2
RP+EBRT: 2.0


We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.