Showing posts with label bRFS. Show all posts
Showing posts with label bRFS. Show all posts

Wednesday, October 24, 2018

SBRT has excellent outcomes for intermediate risk patients

Stereotactic Body Radiation Therapy (SBRT, or sometimes SABR or SHARP or CyberKnife) has had excellent 7-year outcomes in an update of the consortium study. Amar Kishan presented the results of his analysis at the ASTRO meeting today.

The consortium consisted of

1 Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA
2 Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA
3 Flushing Radiation Oncology Services, Flushing, NY, USA
4 21st Century Oncology, Fort Myers, FL, USA
5 Department of Radiation Oncology, Georgetown University, Washington, DC., USA
6 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
7 Division of Genesis Healthcare Partners Inc., CyberKnife Centers of San Diego Inc., San Diego, CA, USA
8 Swedish Radiosurgery Center, Seattle, WA, USA.
9 Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON,
10 Section of Radiation Oncology, Virginia Mason Medical Center, Seattle, WA, USA
11 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
12 Department of Radiation Oncology, University of Michigan
13 Scripps Health, 11025 North Torrey Pines Road, La Jolla, CA, USA
14 Virginia Hospital Center, 1701 N. George Mason Dr, Arlington, VA, USA

The meta-analysis covers 2,142 low (n=1,185) and intermediate-risk men treated with SBRT between 2003 and 2012. Intermediate risk men were further subdivided into "favorable intermediate risk" (n=692) and "unfavorable intermediate risk" (n=265) per the NCCN definition.

After a median follow-up of 6.9 years, the 7-year biochemical recurrence-free survival was:

  • low risk: 95.5%
  • favorable intermediate risk: 91.4%
  • unfavorable intermediate risk: 85.1%
  • all intermediate risk: 89.8%

Low risk patients and some of the favorable intermediate risk patients would probably be diverted to active surveillance today. The 7-year intermediate risk biochemical recurrence-free survival compares favorably with (note: this is not a randomized comparison, which is the only valid way of comparing):

  • Surgery: favorable intermediate risk (PSA=6.0, T1c, GS 3+4, 33% cancerous cores): 81% (mean of 5 and 10-yr Progression-free survival) (1)
  • Surgery: unfavorable intermediate risk (PSA=6.0, T1c, GS 4+3, 67% cancerous cores): 53% (mean of 5 and 10-yr Progression-free survival) (1)
  • Hypofractionated IMRT (5 year):  85% (2)
  • Conventional IMRT (5 year): 85% (2)
  • Low dose rate brachytherapy: favorable intermediate risk (avg of 5 and 10-yr): 87% (3)
  • Low dose rate brachytherapy: unfavorable intermediate risk (5-year): 81% (3)
  • Brachy boost therapy: unfavorable intermediate risk (10 year): 92% (4)

7-year metastasis-free survival was:

  • low risk: 99.9%
  • favorable intermediate risk: 98.3%
  • unfavorable intermediate risk: 97.0%
  • all intermediate risk: 98.0%

There were no prostate cancer-related deaths.

Use of ADT and higher doses (doses ranged from 33 Gy to 40 Gy in 4 or 5 treatments) did not affect recurrence.

Acute (within 3 months of treatment) toxicity was low:

  • Urinary toxicity Grade 2: 8.8% Grade 3: 0.6%
  • Rectal toxicity Grade 2: 3.2% Grade 3: 0.1%

Late-term cumulative toxicity was low:

  • Urinary toxicity Grade 2: 9.4% Grade 3+: 2.1%
  • Rectal toxicity Grade 2: 3.9% Grade 3+: 0.4%

Late-term grade 3 or greater urinary toxicity of 2.1% compares favorably to other radiation monotherapies reported in other studies. For example:

  • Low dose rate brachytherapy: 7.6% (5)
  • High dose rate brachytherapy (3 fractions):11% (6)
  • Hypofractionated IMRT (70 Gy/28 fx): 3.5% (7)
  • Conventionally fractionated IMRT: 2.3% (7)
  • Brachy boost therapy: 19% (8)

Late-term grade 3 or greater rectal toxicity of 0.4% compares favorably to other radiation monotherapies reported in other studies. For example:

  • Low dose rate brachytherapy: 0.8% (5)
  • High dose rate brachytherapy (3 fractions):1% (6)
  • Hypofractionated IMRT (70 Gy/28 fx): 4.1% (7)
  • Conventionally IMRT: 2.6% (7)
  • Brachy boost therapy: 9% (8)

This 7-year analysis on a large group of patients from multiple sites, should make intermediate risk patients comfortable in choosing SBRT, especially if they are favorable intermediate risk. For patients who are unfavorable intermediate risk, brachy boost therapy affords incomparable oncological control, but at the risk of much higher late term urinary and rectal toxicity.

Wednesday, September 28, 2016

5-year SBRT trial: high cancer control, low toxicity

Meier et al reported the results of a 5-year multi-institutional trial, (also reported at the 2017 ASTRO meeting), finding that SBRT had high rates cancer control and low toxicity.

This was a prospective clinical trial in which all 21 institutions treated 309 patients according to the same protocol. The institutions were community, regional and academic hospitals across the US. All patients were low (56%) or intermediate risk (44%). Of the 137 intermediate risk patients,  61% were favorable and 39% were unfavorable intermediate risk. The treatment was:
  • 40 Gy in 5 treatments to the prostate
  • 36.25 Gy to the seminal vesicles in intermediate risk patients
  • No concurrent or adjuvant androgen deprivation therapy was allowed.
At five years after SBRT treatment, the following oncological outcomes were reported:
  • 97.1% had no biochemical progression; that is, no increases in PSA to over 2 ng/ml from the lowest value achieved 
      o 97.3% for low risk patients, compared to 92.3% for IMRT historically
      o 97.1% for intermediate risk patients, compared to 91.3% for IMRT historically
           - 100% among favorable intermediate risk
           - 93.1% among unfavorable intermediate risk

By five years after SBRT treatment, the late toxicity outcomes were reported:
  • No grade 3 (serious) rectal side effects
  • Grade 2 rectal side effects in 2%
  • Grade 3 (serious) urinary side effects in 4 of the 309 patients (1.3%)
  • Grade 2 urinary side effects in 12%

These are certainly excellent outcomes, and are in-line with or better than retrospective SBRT studies that have previously been reported. So far, the longest running SBRT single institution study has been reported by Alan Katz (see this link). I’ve heard that a ten-year update is in the works. That will be as long and larger than the longest running IMRT trial.

SBRT is about half the cost of IMRT, and at only 5 treatments, is certainly a lot less bother for the patients. It has excellent outcomes even without adjuvant ADT in unfavorable intermediate risk patients. With large long-term studies now available, it is difficult to understand why some insurance companies still don’t cover it.

Tuesday, August 30, 2016

SBRT Registries

Patient registries are potentially a rich source of information with which to evaluate outcomes. They often include patient characteristics, details of the therapies they received, and outcomes tracked over time. They provide full population data of all patients treated at participating centers, and can provide very large amounts of data over time.

Like a clinical trial, there are specific and uniform definitions used in capturing patient and treatment data, allowing for comparability on a variety of variables. Registries and clinical trials are internal review board (IRB) approved for ethical standards and must comply with HIPAA laws (patients must consent, and patient names are not entered in). In the US, they both have an insurance advantage as well: Medicare, Medicaid and insurance companies may cover the costs of clinical trials and registries for treatments that they would not ordinarily cover. In some situations, they will only provide coverage if the patient is enrolled in a registry or clinical trial.

Unlike a clinical trial, there are usually no detailed patient inclusion and exclusion criteria, and the treatments may vary from center to center and from patient to patient. Because patients are not excluded from the database, registries are capable of providing very large databases for analysis. There is no randomization, so there is selection bias – patients who received different treatments may have been selected for specific reasons. The quality of the data is only as reliable as the clinician entering it, and it is not necessarily subject to peer review as publication of clinical trial results are. As with other large database analyses, it may be possible to find matched cases for control, but that is not the same as randomization. While clinical trials have a hypothesis to be proved or disproved, a registry provides data for quality improvement and for generating hypotheses.

Registries are difficult and expensive to establish and maintain. The American Board of Radiology attempted to create a national brachytherapy registry, but abandoned those efforts in 2015 when issues in its development and implementation “proved to be more daunting and costly than initially anticipated.” In 2012, the American Society of Radiation Oncologists (ASTRO) announced plans to implement a National Radiation Oncology Registry (NROR) with Prostate Cancer as its first focus. A pilot was completed in June 2015, and there are plans for expansion.

The Registry for Prostate Cancer Radiosurgery (RPCR) was established in 2010. There are 45 participating sites in the US, and the database included nearly 2000 men as of 2014. They collect three kinds of data for each patient: screening, treatment, and follow-up.

Screening data include age, performance status, rationale for radiosurgery, initial TNM stage, Gleason score, number of positive biopsy cores, use of hormonal therapy, and several baseline measures, including pre-treatment PSA, IPSS, International Index of Erectile Function (IIEF-5) score, Bowel Health Inventory score, and Visual Analog pain score.

Treatment data include radiation delivery device details, treatment dates, dosimetry (e.g., doses, schedules, targets, margins, including doses to specific organs at risk: rectum, bladder, penile bulb, and testicles), and how image tracking was performed.

Follow-up data include periodic tracking of the baseline data collected at screening, as well as physician-reported toxicity. RPCR encourages sites to record follow-up data every 3months for the first 2years following SBRT treatment and every 6–12months thereafter, for a minimum of 5years.

Some interim findings have been published by Freeman et al. So far, they have only reported 2-year data on 1,743 patients. Oncological control was reported as biochemical disease-feee survival:
·      Low Risk: 99% (n=111)
·      Favorable Intermediate Risk: 97% (n=435)
·      Unfavorable Intermediate Risk: 85% (n=184)
·      High Risk: 87% (n=168)

There was no severe late-term urinary toxicity, and one patient developed severe late-term rectal bleeding. Erectile function was preserved in 80% of men under 70 years of age, and 55% of men over 70.

The other SBRT registry is called the Radiosurgery Society Search Registry (RSSearch Registry) and includes data from 17 community centers treating prostate cancer patients. There were 437 prostate cancer patients enrolled between 2006 and 2015. The data collected is similar to the RPCR Registry. All patients in their first report were treated using the CyberKnife platform (this registry was originated by Accuray, the manufacturer of CyberKnife), although they allowed other platforms in later enrollments.

Davis et al. recently reported their interim findings. Oncological control was reported as 2-year biochemical disease-fee survival:
·      Low Risk: 99.0% (n=189)
·      Intermediate Risk: 94.5% (n=215)
·      High Risk: 89.8% (n=33)

There was no severe (grade 3) acute urinary or rectal toxicity, and very little grade 2. There was no severe (grade 3) late-term urinary or rectal toxicity. The highest incidence of grade 2 late term symptoms was 8% with urinary frequency, They did not collect baseline data on sexual function.

Both of these registries are administered by Advertek. The results of the RSSearch Registry were reported in Cureus, which is their own publication. RPCR results were published in Frontiers in Oncology, which is an independently peer-reviewed journal. It is important to note this because questions about the reliability of the data may arise.

If these data look a little too good to be true… well, let’s dig a little deeper. The biochemical disease-free survival figures only reflect 2 years of follow-up. In that short amount of time, many patients have not yet reached their nadir PSA let alone had time to rise 2 points above that nadir. Most of the low-risk patients and many of the intermediate-risk patients would not have had a rise of 2 points in their PSA even if they’d had no treatment.

The toxicity data are very suspect. Unlike a clinical trial where experienced researchers are carefully evaluating patients on a regular schedule, patient evaluations by community clinicians are haphazard. The clinicians may introduce affirmation bias into their assessments – they have incentive to make their numbers look good. The best way to evaluate toxicity is with patient-reported outcomes on validated, guided-response questionnaires, like EPIC. This was not done in either of these registries. 

I think SBRT is actually quite a good therapy (I chose it for myself!), but we have to look to other sources for more reliable data. With longer term follow-up, the cancer control data from these registries may become more reliable, and may help us generate better hypotheses about which treatment variants work best and on which patient groups.

SBRT Boost Therapy

Recently we have seen evidence of improved cancer control in high-risk patients treated with external beam radiotherapy with a brachytherapy boost to the prostate. This has been demonstrated with both HDR brachytherapy boost and with LDR brachytherapy boost. Can the same cancer control be obtained with IMRT and an SBRT boost to the prostate?

Anwar et al. reported the outcomes of 48 intermediate and high-risk patients treated with SBRT boost therapy between 2006 and 2012 at UCSF. 71% (34 patients) were high risk, 39% (14 patients) were intermediate risk.

The treatment consisted of:
  • ·      IMRT: 45-50 Gy in 25 fractions to the entire pelvis if the risk of lymph node involvement was > 15%, otherwise with a 1 cm margin.
  • ·      SBRT boost: 9.5 or 10.5 Gy in 2 fractions to the prostate, seminal vesicles + a 2 mm margin, 0 mm on the rectal side.
  • ·      Heterogeneous planning was used to mimic HDR brachytherapy dosimetry.
  • ·      Gold fiducials were used for daily (IMRT) and intra-fractional (SBRT) image tracking.
  • ·      Intermediate risk patients had 4-6 months of adjuvant hormone therapy.
  • ·      High-risk patients had up to 2 years of adjuvant hormone therapy
After a median of follow-up of 42.7 months, they reported the following results:
  • ·      5-yr  biochemical no evidence of disease: 90%
  • ·      PSA nadir (median): 0.05 ng/ml
  • ·      2 patients had a PSA bounce over 2 ng/ml, which declined with longer followup
  • ·      4 patients had a clinical recurrence outside of the radiation field
  • ·      Local control (within the radiation field) was 100%.
  • ·      Acute toxicity:
o   Urinary, grade 2: 17%
o   Rectal, grade 2: 10%
  • ·      Late toxicity:
o   Urinary, grade 2: 25%; grade 3: 1 patient
o   Rectal, grade 2 or higher: none

Clearly, these are excellent results for cancer control.  The table below shows outcomes in similar trials of SBRT boost treatments and of SBRT monotherapy.

SBRT boost
SBRT boost
SBRT monotherapy
SBRT boost
Risk levels treated (# of patients)
Intermediate (14)
High (34)
High (45)
High (52)
High (41)
Relative BED*
ADT used
Biochemical Disease-free survival
90% at 5 years
70% at 5 years
68% at 5 years
92% at 4 years
Late-term urinary toxicity

* Biologically Effective Dose for cancer control relative to 80 Gy in 40 fractions

Compared to these other small trials, Anwar et al. used significantly higher effective radiation doses and got perhaps better control (remembering that almost a third were intermediate risk), but late-term urinary toxicity was high. Lin et al. used lower doses, had similar control in their all high-risk group trial at 3 years, and none suffered from late-term urinary toxicity. Katz treated consecutive high-risk patients with SBRT boost and with monotherapy, respectively, but had the same cancer control in both groups, and the late-term urinary toxicity was not significantly different. Katz concluded that the SBRT boost accomplished nothing compared to the monotherapy, and also found that ADT use did not contribute to cancer control in his patients. He treated all subsequent high-risk patients with SBRT monotherapy only and without ADT.

We can also look at the Anwar outcomes next to those of a recent LDR brachy boost therapy trial and an HDR monotherapy trial in the table below.

SBRT boost
LDRBT boost
HDR-BT monotherapy
Risk levels treated (# of patients)
Intermediate (14)
High (34)
Intermediate (122)
High (276)
Intermediate (103)
High (86)
Relative BED*
ADT used
Biochemical Disease-free survival
at 5 years
High Risk-83%
at 7 years
High Risk-87%
at 4 years
Late-term urinary toxicity
25% Grade 2
2% Grade 3
NA Grade 2
18% Grade 3
19% Grade 2
10% Grade 3

SBRT boost therapy seems to provide similar rates of cancer control, but with less late term urinary toxicity compared to brachy boost therapy or HDR-BT monotherapy.

In an interesting twist, Memorial Sloan Kettering Cancer Center is running a clinical trial of SBRT supplemented with an LDR-BT boost to the prostate in intermediate-risk men (NCT02280356). I would guess that this would have considerable toxicity, but the clinical trial will prove or disprove that hypothesis.

So far, trials of SBRT boost therapy are too small to draw anything but provisional conclusions. There is a larger trial nearing completion at Georgetown University Hospital next month. Based on these pilot studies, SBRT boost therapy seems to be capable of providing good cancer control in high-risk patients and may be able to accomplish that with less toxicity than brachytherapy-based treatments. As we’ve seen, SBRT monotherapy and HDR brachy monotherapy are emerging therapies for high-risk patients as well. It would certainly be a lot more convenient to accomplish the same cancer control, at lower cost, and with perhaps less toxicity using just 5 SBRT monotherapy treatments instead of 27 treatments with SBRT boost. Only a randomized comparison clinical trial can tell us whether one therapy is better than another. The most appropriate radiation dose level, dose constraints, the size of margins, lymph node treatment, and whether adjuvant ADT provides any benefit are variables yet to be determined.

This is an area of active investigation. If readers are interested in participating in a clinical trial of SBRT boost therapy, below is a list of open trials and their locations:

Fountain Valley, CA (NCT02016248)
Sacramento, CA (NCT02064036)
San Francisco, CA (NCT02546427)
Miami, FL (NCT02307058)
Park Ridge, IL (NCT01985828)
Boston, MA (NCT01508390)
Madison, WI (NCT02470897)
21st Century Oncology- Scottsdale, AZ, Ft. Myers and Plantation, FL, Farmington Hills, MI, Myrtle Beach, SC (NCT02339948)
Sydney, Australia (NCT02004223)
Gliwice, Poland (NCT01839994)

Poznan, Poland (NCT02300389)

9-year SBRT outcomes

Katz and Kang have posted their 9-year SBRT outcomes on 515 patients. This represents the longest tracking of SBRT outcomes -- just one year short of the IMRT tracking reported by Alicikus et al. on a starting cohort of 170 patients treated at Memorial Sloan Kettering Cancer Center.

The patients were treated between 2006-2010 using the CyberKnife platform.
  • ·      324 were low risk, 139 intermediate risk, and 52 were high risk according to NCCN definitions.
  • ·      70 patients received adjuvant ADT for up to one year.
  • ·      158, all with Gleason score<4+3, received 35 Gy in 5 fractions.
  • ·      357 received 36.25 Gy in 5 fractions
  • ·      Median age was 69
  • ·      Median PSA was 6.5 ng/ml

After a median followup of 84 months:
  • ·      Oncological Control:

o   9-yr freedom from biochemical failure was:
§  95% for low-risk men
§  89% for intermediate risk men
§  66% for high-risk men
o   Median PSA nadir was .1 ng/ml
o   No difference in biochemical control for the lower vs. the higher radiation dose.
o   99.6% prostate cancer survival
o   86% overall survival
  • ·      Toxicity:

o   Late rectal toxicity:
§  Grade 2: 4%
o   Late urinary toxicity:,
§  Grade 2: 9.5%
§  Grade 3: 1.9%
§  Grade 2 or 3: 6.9% for the lower radiation dose vs. 13.2% for the higher dose.
o   Patient-reported bowel and urinary quality-of-life (EPIC questionnaire) declined at one month then returned to baseline by 2 years. Sexual quality-of-life declined by 29% at last followup.

These are clearly excellent results for any kind of radical therapy. The authors conclude:
These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy.”

While it’s tempting to conclude that neither the higher dose of radiation, with its greater toxicity, nor the addition of ADT conferred any incremental benefit, that can only be proved with a randomized clinical trial. Until so proven, it must be understood as only a good hypothesis to be discussed by patients with their radiation oncologists. It is also worth noting that these reflect the outcomes of one very expert practitioner. There is an SBRT registry currently collecting data across many treatment centers.

The reported outcomes are nearly identical to those reported at 7 years (see this link and this link and this link), indicating very stable control and no additional late term toxicity with longer followup. In light of that, its low cost, convenience, and the fact that the standard of care, IMRT, has only one more year of follow-up on a much smaller sample size, it’s difficult to understand why some insurance companies still balk at covering SBRT for low and intermediate risk patients. Medicare does cover it.

Friday, August 26, 2016

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.

  • ·      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.

5-yr bRFS

Low risk
Intermediate risk
High Risk
Late toxicity

GI grade≥3
GU grade≥3
bRFS= biochemical recurrence-free survival

Proton: Bryant et al. 78 GyE median dose, 15% received ADT
IMRT: Liauw et al. :76 Gy median dose, 50% received ADT, 4-year data
SBRT: Katz et al. 35 Gy/5fx, 18% received ADT
LDR-BT (low dose rate brachytherapy – monotherapy): Kittel et al. 18% received ADT
HDR-BT (high dose rate brachytherapy – monotherapy): Hauswald et al. 43.5 Gy /6fx, 9% received ADT, 10-year data.

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.