Proton Hypofractionation

We have recently seen Level 1 evidence that IMRT hypofractionation (fewer, more intense treatments) is no worse than conventional fractionation. The same may hold true for proton therapy.

Proton therapy has come under fire because of its high cost and lack of proven benefit compared to photon IMRT. We are, therefore, interested in changes to the treatment protocol that may reduce costs and increase patient convenience, as long as efficacy and safety are not compromised. Vargas et al. reported the interim patient-evaluated quality-of-life scores of a small randomized pilot trial (NCT01230866) to determine whether proton therapy can be completed in just five treatments (similar to SBRT). Low risk patients were randomized to receive either:

• ·      38 RBE in 5 treatments (49 patients), or
• ·      79.2 RBE in 44 treatments (33 patients)

After 18 months median follow up:

• ·      Urinary, rectal, and sexual function scores were not different at 3, 6, 12, 18 or 24 months after treatment.
• ·      At 12 months, American Urological Association (AUA) Symptom Index Score was low, but slightly worse (8/35) for the hypofractionated therapy than for the conventionally fractionated therapy (5/35).
• ·      Scores remained low and equivalent for both groups in all other time periods.
• ·      There was no grade 3 or higher toxicity at any time in either group.

Kim et al. reported on a trial among 83 patients treated with five different fractionation schedules ranging from 60 CGE in 20 fractions to 35 CGE in 5 fractions. There was no significant difference in 4-yr biochemical failure for any of the treatment schedules within any risk group. Toxicity was low in all groups.

The low toxicity is certainly encouraging, and larger scale trials seem warranted based on this. In addition to the ongoing trial of the 5-treatment protocol, prospective patients may want to investigate the following (some include ADT for higher risk patients):

• ·      Loma Linda and Provision Center for Proton Therapy in Tennessee have ongoing clinical trials, (NCT00831623) and (NCT02198222), respectively, of a 20-treatment protocol .
• ·      MD Anderson is testing a 15-treatment protocol (NCT01950351).
• ·      The University of Florida is testing a mild hypofractionation schedule (NCT01368055).

Proton has no toxicity advantage over IMRT in case-matched analysis

Proponents of proton therapy have touted its theoretical healthy tissue-sparing effects.There has never been a randomized clinical trial comparing proton (PBT) to photon (IMRT) treatment that would demonstrate whether such an effect in fact exists in clinical practice. Previous retrospective cohort and database studies have failed to demonstrate significant differences in urinary and rectal toxicity. Fang et al at UOP published a case-matched study of PBT vs IMRT toxicity.

• 91 case-matched pairs were identified from a pool of 394 patients treated from 2010-2012
• They were matched by risk group, age, and prior gastrointestinal and genitourinary disorders.
• Both sets of men received 79.2 Gy of radiation, whether by proton or photon
• Bladder and rectal dosimetry were significantly better for PBT vs IMRT
• Median follow-up was  47 months (range, 5-65 months) for patients who received IMRT and 29 months (range, 5-50 months) for those who received PBT. 

 The results were: no significant differences in: 

• Grade≥2 acute urinary toxicity 
• Grade≥2 acute rectal toxicity 
• Grade≥2 late urinary toxicity 
• Grade≥2 late rectal toxicity 
• They did not measure differences that may have occurred in sexual function.

Proton therapy at University of Florida Jacksonville – 5-year outcomes

We have previously reported on the very good, albeit unremarkable, outcomes of proton therapy as administered at the University of Florida Jacksonville. We now have their 5-year analysis on a much larger dataset, the largest so far in the modern era.

Bryant et al. report on their retrospective analysis of the records of 1,327 men consecutively treated between 2006 and 2010. Almost all of them (98%) were treated with at least 78 GyE and those treated with hypofractionated doses were excluded.  To ensure comparable data, 113 patients were excluded for lack of adequate follow-up and use of adjuvant chemo. Other key patient characteristics included:

• ·      Low Risk: 42%
• ·      Intermediate Risk: 44%
• ·      High Risk: 14%
• ·      15% had concurrent ADT, mostly among high-risk patients
• ·      55% had radiation to seminal vesicles
• ·      3% had IMRT radiation to pelvic lymph nodes (all patients were node negative). These were excluded from the toxicity analysis.

Cancer Control

After median follow-up of 5.3 years, the 5-yr freedom from biochemical failure by risk group was:

• ·      Low Risk: 99%
• ·      Intermediate Risk: 96%

o   95% if there was only one intermediate risk factor

o   90% if there were two or more intermediate risk factors

• ·      High Risk: 74%

o   80% if there was only one high risk factor

o   32% if there were two or more high risk factors

o   87.5% who were high risk only based on Gleason 8

• ·      Among those who did not receive adjuvant ADT, the median nadir and time to nadir were:

o   Low Risk: 0.3 ng/ml and 4.2 years

o   Intermediate Risk: 0.2 ng/ml and 3.6 years

o   High Risk: 0.3 ng/ml and 2.2 years

• ·      Of the 94 patients who had biochemical failure:

o   42 had biochemical failure only

o   6 had local (biopsy-proven) failure only

o   10 had pelvic lymph node failure only

o   24 had distant metastases only

o   12 had failure in a combination of sites

• ·      Survival and freedom from metastases were 95+percent in all risk groups.

Toxicity

• ·      Acute genitourinary (GU) toxicity≥ grade 3: 1% (12 patients)
• ·      Late genitourinary (GU) toxicity≥ grade 3: 5% (61 patients)
• ·      Interventions for Grade 3 GU toxicity included catheterization, hyperbaric oxygen therapy, blood transfusion, TURP, and cauterization for symptoms including urinary obstruction, bladder irritation, hematuria, irritative symptoms, incontinence, and pain.
• ·      Larger prostates, ADT use, pre-treatment urinary therapy, diabetes, and higher doses to the bladder were associated with greater urinary toxicity.
• ·      Late gastrointestinal (GI) toxicity≥ grade 3: 1% (9 patients)
• ·      Interventions for Grade 3 GI toxicity included transfusion and colostomy for diarrhea, rectal bleeding, and ulceration.
• ·      Long-term patient-reported urinary and bowel status were unchanged from baseline.
• ·      Sexual quality of life scores declined by 22 points (29%) by 4 years post treatment (excluding those who used ADT).

Comparison to other radiation therapies

The following table shows some oncological and toxicity outcomes at 5 years for various radiation therapies as practiced at single institutions in the last several years. While differences in patient selection confound our ability to rigorously compare the therapies, they do show a general range of best-expected outcomes. Until we see the results of large-scale prospective randomized comparative trials, this is about as good as we can do in comparing them.

	Proton	IMRT	SBRT	LDR-BT	HDR-BT
5-yr bRFS
Low risk	99%	97%	97%	95%	99%
Intermediate risk	94%	94%	91%	89%	95%
High Risk	74%	87%	74%	68%	77-93%*
Late toxicity
GI grade≥3	0.6%	2%	0%	0.8%	0%
GU grade≥3	2.9%	2%	1.6%	7.6%	4.9%

bRFS= biochemical recurrence-free survival

References:

Proton: Bryant et al. http://www.redjournal.org/article/S0360-3016(16)00158-9/pdf: 78 GyE median dose, 15% received ADT

IMRT: Liauw et al. http://tct.sagepub.com/content/8/3/201 :76 Gy median dose, 50% received ADT, 4-year data

SBRT: Katz et al. http://ro-journal.biomedcentral.com/articles/10.1186/1748-717X-8-118: 35 Gy/5fx, 18% received ADT

LDR-BT (low dose rate brachytherapy – monotherapy): Kittel et al. http://www.redjournal.org/article/S0360-3016%2815%2900253-9/abstract: 18% received ADT

HDR-BT (high dose rate brachytherapy – monotherapy): Hauswald et al. http://www.redjournal.org/article/S0360-3016(15)03101-6/abstract: 43.5 Gy /6fx, 9% received ADT, 10-year data.

*For high-risk HDR-BT patients, see: HDR Brachy Boost and Monotherapy for High-Risk Prostate Cancer

Proton therapy afforded rates of cancer control comparable to the other monotherapies. Urinary and rectal toxicity were similar as well. Sexual quality of life deterioration was also similar to what we have seen for IMRT and LDR-BT (see this link). HDR-BT and SBRT seem to be superior in preserving erectile function.

If they can bring down the cost of proton therapy, it can be competitive with IMRT. As with IMRT, hypofractionation (fewer treatments) of proton therapy may deliver equivalent results at lower cost. Pencil-beam proton therapy may be able to improve toxicity still further.

Trends in the use of radiation for primary therapy

Two separate database analyses have now reported an increasing trend in adoption of SBRT, while brachytherapy use has been declining.

In an analysis of the National Cancer Data Base, Baker et al. reported that use of SBRT increased from <1% in 2004 (it was first used for prostate cancer in 2003) to 8.8% of low-risk patients treated at academic centers in 2012. Similarly, Halpern et al., in an analysis of the SEER/Medicare database,  found that SBRT was the fastest-growing of all radiation therapies between 2004 and 2011, but it only accounted for 1.6% of all men treated with radiation in that database. They also found that adoption was highest among low-risk patients: 54% of those using it had a Gleason score of 6. The median cost was $27,145.

Proton beam therapy use also increased. It accounted for 2.3% of all radiation therapy utilization. Half of those using it had a Gleason score of 6. It had the highest cost of all radiation therapies at $54,706.

Brachytherapy use, on the other hand, is on the decline. It accounted for 28% of all primary radiation therapies. Compared to other radiation therapies, a higher proportion of those utilizing it had a low Gleason score: 64.2% of those utilizing it had a Gleason score of 6. It was the lowest cost of all radiation therapies at a median cost of $17,183.

It is unclear how combination therapies of EBRT with a brachytherapy boost were counted in The SEER/Medicare database analysis. Orio et al. reported that in their analysis of the National Cancer Data Base, use of such combination therapy in intermediate and high-risk patients declined markedly between 2004 and 2012. They found that among intermediate and high-risk patients, 66% were treated with EBRT alone, 20% were treated with brachytherapy alone, and only 14% were treated with the combination. Use of combination therapy declined from 15% to 8% in academic centers, and from 19% to 11% in non-academic centers. We will have to see if the results of the ASCENDE-RT randomized clinical trial last year (discussed here) reverses this trend.

IMRT took the lion’s share of all radiation therapies at 68.1%. Relative to the other radiation therapies, it was most likely to be used by patients with higher Gleason scores: almost two-thirds of patients using it had Gleason scores of 7 or greater. I suspect that it continues to be the treatment of choice in older patients, who tend to have more progressed prostate cancer at the time of diagnosis. Next to proton therapy, it was most expensive, costing a median of $37,090. Hypofractionation may be able to cut the cost if it is widely adopted.

It should be noted that the high rate of utilization of brachytherapy, SBRT and proton therapy among low risk patients has historical roots. Those therapies were originally tried in low risk patients before we had results from Active Surveillance trials. While proton therapy and brachytherapy are given as boosts to IMRT, their use as monotherapies has not been established in intermediate and high-risk patients. SBRT, as both a boost and a monotherapy, is in trials for the higher risk categories, but many institutions still do not offer it for that purpose, and insurance may be reluctant to cover it.

It is sad to witness the decline in brachytherapy utilization, especially considering it is the lowest cost alternative. But that works to its detriment as well: new practitioners are not attracted to its relatively low profit potential. With the passing of Peter Grimm this year, it has lost one of its greatest proponents. The generation of brachytherapists who developed its modern techniques at the University of Washington Seattle have mostly dispersed and some have retired. It is a very specialized therapy, requiring years of practice to get superlative results. I expect we will continue to lose our best practitioners, and patients will find it increasingly difficult to find.