Finding Value for Protons: The Case of Prostate Cancer?☆,☆☆,
Introduction
For men in the United States, prostate cancer is the most common malignancy.1 When the disease is localized, it can be cured by radiotherapy.2, 3 This treatment is typically intensity-modulated radiotherapy (IMRT)4—an external beam of photons sculpted to closely fit the target. These photons are massless, uncharged quanta of electromagnetic radiation. They pass completely through the patient and deliver dose along their entire path.
An alternative treatment is proton beam therapy (PBT). Unlike photons, protons are heavy, charged particles. PBT stops within the body and delivers virtually no dose past the target, thus reducing radiation exposure to normal tissues (Fig).5 PBT is a safe and effective treatment for prostate cancer6, 7, 8—but does it add value over IMRT? In the article that follows, we explore this controversial question.9, 10
Section snippets
Value: A Two-Part Equation
First, we must define value. A common formulation is health care outcomes divided by cost.11 This equation’s denominator poses a challenge for expensive technologies. For example, prostate PBT costs ~$13,000-14,000 more than IMRT,12, 13 although this gap may shrink with cheaper PBT equipment14 and shorter-course treatment.15
To provide value, PBT must therefore improve health outcomes relative to IMRT. This could mean either better cancer control or fewer side effects. It seems unlikely that PBT
Radiotherapy Side Effects: Scope of the Problem
The principal potential side effects from prostate radiotherapy are bladder, bowel, and erectile dysfunction. The precise frequency and magnitude of these toxicities is challenging to pinpoint,21 but we can reach some general conclusions: in the short term, radiotherapy causes moderate rates of transient urinary and rectal irritation; in the long run, it causes moderate rates of erectile dysfunction and a smaller risk of rectal complications.22, 23, 24, 25
One source of high-quality toxicity
Dosimetric Evidence
New radiotherapy technologies are often initially evaluated in silico. There are many of these dosimetric studies comparing PBT and IMRT for prostate cancer.34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 The analyses are heterogeneous; they vary with respect to target volumes (prostate alone, prostate plus seminal vesicles, and prostate plus pelvic lymph nodes), planning uncertainty margins, delivered dose, beam arrangements, photon/proton delivery technique, and planning optimization strategy.
Claims-based Evidence: Pros and Cons
Claims-based analyses draw “information from a diverse array of patients, providers, and treatment facilities in real-world practice.”61 These studies can leverage the power of large numbers to detect even modest differences between IMRT and PBT. Yet, claims-based datasets also have notable weaknesses. For example, exposure misclassification (incorrectly identifying the type of radiotherapy a patient received) and outcome misclassification (incorrectly assuming that billing codes accurately
Patient-level Evidence: Pros and Cons
Patient-level analyses bring a wealth of granular data that are often missing from claims-based studies. For example, baseline comorbidities and details of treatment can help ensure that IMRT and PBT cohorts are reasonably similar. Toxicity can be directly measured by physician or patient report, rather than relying on surrogate billing claims. However, patient-level analyses also have limitations. They often examine fewer subjects, and therefore may fail to detect modest differences between
Summary and a Way Forward
Can PBT provide value in the case of prostate cancer? In our view, this question hinges on whether PBT can meaningfully reduce side effects compared to IMRT. To date, the available evidence leaves us in the state of equipoise.
Dosimetric studies suggest that the potential benefit of PBT depends on whether side effects are caused by low-to-intermediate doses (where PBT is better than IMRT) or by higher doses (where PBT might be the same, better, or worse than IMRT).
Clinical studies largely
References (72)
- et al.
Ten- and 15-yr prostate cancer-specific mortality in patients with nonmetastatic locally advanced or aggressive intermediate prostate cancer, randomized to lifelong endocrine treatment alone or combined with radiotherapy: final results of the scandinavian prostate cancer group-7
Eur Urol
(2016) - et al.
Proton therapy for prostate cancer: the initial Loma Linda University experience
Int J Radiat Oncol Biol Phys
(2004) - et al.
Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities
Int J Radiat Oncol Biol Phys
(2011) - et al.
Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer
Int J Radiat Oncol Biol Phys
(2014) - et al.
The world′s first single-room proton therapy facility: Two-year experience
Pract Radiat Oncol
(2017) Hypofractionation for prostate cancer: tested and proven
Lancet Oncol
(2016)- et al.
Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03-12
Int J Radiat Oncol Biol Phys
(2011) - et al.
Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial
Int J Radiat Oncol Biol Phys
(2013) - et al.
Scoring the short form ICSmaleSF questionnaire. International Continence Society
J Urol
(2000) - et al.
Angiosarcoma of the bladder following prostate radiotherapy
Am J Med
(2015)
Second primary cancers after radiation for prostate cancer: a systematic review of the clinical data and impact of treatment technique
Radiother Oncol
Intensity modulated radiation therapy after radical prostatectomy: Early results show no decline in urinary continence, gastrointestinal, or sexual quality of life
Pract Radiat Oncol
Potential role of intensity modulated proton beams in prostate cancer radiotherapy
Int J Radiat Oncol Biol Phys
Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison
Int J Radiat Oncol Biol Phys
Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer
Int J Radiat Oncol Biol Phys
Dosimetric study of pelvic proton radiotherapy for high-risk prostate cancer
Int J Radiat Oncol Biol Phys
Helical tomotherapy and intensity modulated proton therapy in the treatment of early stage prostate cancer: a treatment planning comparison
Radiother Oncol
Dosimetric considerations to determine the optimal technique for localized prostate cancer among external photon, proton, or carbon-ion therapy and high-dose-rate or low-dose-rate brachytherapy
Int J Radiat Oncol Biol Phys
Incidence of secondary cancer development after high-dose intensity-modulated radiotherapy and image-guided brachytherapy for the treatment of localized prostate cancer
Int J Radiat Oncol Biol Phys
Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions
Radiother Oncol
Rectal toxicity after intensity modulated radiotherapy for prostate cancer: Which rectal dose volume constraints should we use?
Radiother Oncol
Statistical analysis of dose-volume profiles and its implication for radiation therapy planning in prostate carcinoma
Int J Radiat Oncol Biol Phys
Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms
Int J Radiat Oncol Biol Phys
Radiation dose-volume effects in radiation-induced rectal injury
Int J Radiat Oncol Biol Phys
Rectal toxicity after proton therapy for prostate cancer: an analysis of outcomes of prospective studies conducted at the university of Florida Proton Therapy Institute
Int J Radiat Oncol Biol Phys
Multi-institutional prospective evaluation of bowel quality of life after prostate external beam radiation therapy identifies patient and treatment factors associated with patient-reported outcomes: the PROSTQA experience
Int J Radiat Oncol Biol Phys
Do intermediate radiation doses contribute to late rectal toxicity? An analysis of data from radiation therapy oncology group protocol 94-06
Int J Radiat Oncol Biol Phys
Dose-volume effects for normal tissues in external radiotherapy: pelvis
Radiother Oncol
Radiation dose-volume effects of the urinary bladder
Int J Radiat Oncol Biol Phys
The relationship between external beam radiotherapy dose and chronic urinary dysfunction—a methodological critique
Radiother Oncol
Considerations for observational research using large data sets in radiation oncology
Int J Radiat Oncol Biol Phys
Late gastrointestinal toxicities following radiation therapy for prostate cancer
Eur Urol
Continued benefit to rectal separation for prostate radiation therapy: Final results of a phase III trial
Int J Radiat Oncol Biol Phys
Establishing evidence-based indications for proton therapy: An overview of current clinical trials
Int J Radiat Oncol Biol Phys
Promoting the appropriate use of advanced radiation technologies in oncology: Summary of a national cancer policy forum workshop
Int J Radiat Oncol Biol Phys
Cancer statistics, 2017
CA Cancer J Clin
Cited by (3)
Proton therapy for prostate cancer: A review of the rationale, evidence, and current state
2019, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Essential to understanding the controversy of PBT for prostate cancer, one must also appreciate the economics and practice patterns of these competing modalities. The value (healthcare outcomes divided by cost [62]) of PBT for prostate cancer has been questioned [63–67]. The adoption of expensive technologies with unproven benefit in radiation oncology has invited scrutiny to the specialty, and prostate cancer epitomizes this [68,69].
Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy
2022, British Journal of RadiologyProton versus photon-based radiation therapy for prostate cancer: emerging evidence and considerations in the era of value-based cancer care
2019, Prostate Cancer and Prostatic Diseases
- ☆
Disclosures: Dr. Bekelman received support from grant K07-CA163616 from the National Cancer Institute and the Young Friends of the Abramson Cancer Center Fund. The contents of this paper do not represent the views of the United States Department of Veterans Affairs or the United States Government.
- ☆☆
Conflicts of interest: none.
Acknowledgements: We thank Maura Kirk, MS, from the Department of Radiation Oncology at the University of Pennsylvania, for assistance with the manuscript figure. Ms. Kirk was not compensated for her efforts.