CMS Data Demonstrates a Cost and Clinical Advantage for Hyperbaric Oxygen for Radiation Cystitis, A Controlled Study

CMS Data Demonstrates a Cost and Clinical Advantage for Hyperbaric Oxygen for Radiation Cystitis, A Controlled Study

John J. Feldmeier DO ^1, John P. Kirby MD ^2, Helen B. Gelly MD³ Marc Robins DO ^4, John Peters FACHE ⁵ Peter Gruhn, MA⁶, Sarmistha Pal, PhD⁶

1. Professor Emeritus and Past Chairman, Radiation Oncology, University of Toledo Medical Center.

2. Associate Professor of Surgery, Washington University School of Medicine in St Louis, MO

3. President, Regenerative and Hyperbaric Medicine, Marietta, Georgia

4. Marc Robins, DO, MPH, FUHM, FAACP

5. John S. Peters, FACHE, ED UHMS

6. Peter Gruhn, M.A., Dobson DaVanzo and Associates, LLC

6. Sarmistha Pal, Ph.D., Dobson DaVanzo and Associates, LLC

Key Words: controlled study; cost-effectiveness; clinical effectiveness; hyperbaric oxygen; radiation cystitis

Running Title: Hyperbaric Oxygen for Radiation Cystitis

Acknowledgments:

1. The Project was supported by an unrestricted grant from Healogics, LLC

2. The authors also wish to express their thanks to the following individuals for input and editorial review:

a. Joan E. DaVanzo, Ph.D., M.S.W., Chief Executive Officer Dobson DaVanzo and Associates, LLC (deceased)

b. John A. Gelly, MD, Retired Physician, Marietta, GA

c. Costantino Balestra Ph.D., Professor of Physiology, Vrije Universiteit Brussel (V.U.B.)
VP. Research & Education DAN Europe

d. Renee Duncan, BA, UHMS Consulting Copy Editor

CMS Data Demonstrates a Cost and Clinical Advantage for Hyperbaric Oxygen for Radiation Cystitis, A Controlled Study

RUNNING TITLE: HYPERBARIC OXYGEN FOR RADIATION CYSTITIS

ABSTRACT

Introduction:
Increasing cancer survivorship, in part due to new radiation treatments, has created a larger population at risk for delayed complications of treatment. Radiation cystitis continues to occur despite targeted radiation techniques.

Materials and Methods: To investigate value-based care applying hyperbaric oxygen (HBO2) to treat delayed radiation cystitis, we reviewed public-access Medicare data from 3,309 patients from Oct 1, 2014, through Dec 31, 2019. Using novel statistical modeling, we compared cost and clinical effectiveness in a hyperbaric oxygen group to a control group receiving conventional therapies.

Results: Treatment in the hyperbaric group provided a 36% reduction in urinary bleeding, a 78% reduced frequency of blood transfusion for hematuria, a 31% reduction in endoscopic procedures, and fewer hospitalizations when study patients were compared to control. There was a 53% reduction in mortality and reduced unadjusted Medicare costs of $5,059 per patient within the first year after completion of HBO2 treatment per patient. When at least 40 treatments were provided, cost savings per patient increased to $11,548 for the HBO2 study group compared to the control group. This represents a 37% reduction in Medicare spending for the HBO2-treated group. We also validate a dose-response curve effect with a complete course of 40 or more HBO2 treatments having better clinical outcomes than those treated with fewer treatments.

Conclusion: These data support previous studies that demonstrate clinical benefits now with cost-effectiveness when adjunctive HBO2 treatments are added to routine interventions. The

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methodology provides a comparative group selected without bias. It also provides validation of statistical modeling techniques that may be valuable in future analysis, complementary to more traditional methods.

Key Words: contemporaneous cohort controlled; cost savings; hyperbaric oxygen; late radiation effects; Medicare payment; radiation cystitis

Key points:

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INTRODUCTION

Cancer survivorship has increased dramatically over recent decades in part due to the increased application and technological improvements of radiation therapy in treatment protocols, which are often multidisciplinary [1]. The American Cancer Society estimates that about 714,000 cases of pelvic malignancy occur annually in the United States [1]. More than 50% of these are likely to receive radiation as part of their cancer management. Modern radiation techniques and advanced technologies have allowed dose escalation, which has surely contributed to improved tumor control, especially in prostate cancer. Many in the radiation oncology community had predicted superior tumor control and reduced serious toxicity with the newer targeted techniques, prominently including intensity-modulated radiation (IMRT). [2,3]

However, late toxicity involving normal tissues still occurs despite new modern targeted techniques. In part, the failure to achieve decreased toxicity may be due to the increased radiation dose that has become the standard of care in many tumors, especially for prostate cancer. Pelvic radiation, in many instances curative, still can cause damage to adjacent normal tissues in some patients. Several reviews do indeed show a reduction in rectal complications when using newer techniques, but for bladder toxicity, the results are not clearly improved. Recent papers report nearly identical incidences of bladder complications with conformal radiation (an older tumor-targeting technique) and IMRT [4]. The reported incidence of bladder late radiation tissue injury (LRTI) in recent studies varies from about 7% to 11 % [5-8] and to perhaps as high as 13%.

A very telling statistic is reported in the Ma paper [5], which prospectively reviewed 1,198 consecutive patients admitted to a tertiary hospital urology service over six months. Twenty-three percent of all emergency urologic admissions in this review were attributable to radiation therapy complications. Radiation cystitis can be a chronic problem that requires multiple hospitalizations, several endoscopic and invasive procedures, multiple transfusions, diminished quality of life, and even death.

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The review of 709 patients by Martin et al. [7]. provides additional perspective here, reporting that radiation cystitis patients require an average of 2.5 admissions and an average hospital stay of 7.6 days (range 1-42 days). Fifty-two percent require a blood transfusion of an average of 4.3 units. These patients underwent procedures including cystoscopy with fulguration +/-clot evacuation in 86% of cases. Four of their 709 subjects died due to radiation cystitis. In another publication, Linder et al. [9] reported a 16% mortality for patients undergoing urinary diversion and cystectomy when the bladder is deemed to be unsalvageable due to the persistence and severity of late effects of radiation injury.

The National Cancer Institute (NCI) has developed a widely employed reporting and grading system for cancer treatment adverse effects and continues to update it to grade the severity of complications. This system is called the Common Terminology Criteria for Adverse Events (CTCAE) [10]. Many publications emphasize Grades 3 and 4 CTCAE damage in their studies of cystitis because, at these levels, the severity of symptoms requires intervention to restore quality of life and/or preserve life.

Our understanding of the pathophysiology of late radiation effects on normal tissue has been historically attributed to vascular injury of the irradiated tissues characterized by endarteritis with resultant tissue hypoxia and attendant tissue damage [11-13]. More recently, some experts have proposed a model known as the Fibroatrophic Effect [14]. In this model, delayed radiation injury evolves due to apoptotic cellular depletion of parenchymal cells and stem cells within tissues and organ systems. Actively functioning cells are replaced by fibrous amorphic, avascular, and acellular tissue fields. The two models are not mutually exclusive. Inadequate vascularity can result from fibrosis replacing normal functional tissues [15], and chronic tissue hypoxia caused by vascular compromise can result in tissue fibrosis [16]. The described mechanisms of both models result in a positive feedback loop that promotes and perpetuates chronic delayed damage. Hyperbaric oxygen has been demonstrated to benefit all three elements of the established pathophysiology of LRTI. It enhances angiogenesis, stimulates stem cell production, and reduces fibrosis [17].

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Pascoe and colleagues [18], after reviewing 23 papers on the topic, published a manuscript providing guidelines and an algorithm for managing radiation cystitis. They discuss cystoscopy with clot extraction, irrigation, chemical, laser, argon coagulation, chemical cautery, and hyperbaric oxygen, although hyperbaric oxygen is not introduced until after more conservative interventions have failed. They also admitted that there is a dearth of Level 1 evidence supporting any of these interventions.

Hyperbaric oxygen has been used to treat radiation cystitis for several decades [19-25]. These publications consist mostly of fairly small clinical series. Results have been consistently positive, but the level of evidence is low. Oscarsson and co-authors have recently [26] reported a multicenter phase 2-3 randomized controlled trial in 2019. The study was conducted employing the Expanded Prostate Index Composite Score (EPIC), a patient self-accomplished quality of life questionnaire. The hyperbaric group improved by 10.1 points on the serial EPIC assessment compared to 7.7 points for the non-hyperbaric group. The comparison of these changes was statistically significant.

The present study utilizes Medicare claims data to compare the clinical outcomes as reconstructed from billing codes and the cost-effectiveness of using hyperbaric oxygen therapy to treat radiation cystitis versus conventional care. Using de-identified billing records and without access to the clinical records, we reconstructed the clinical course and cost to Medicare for treating 3,309 patients between 2014 and 2019. In this fashion, a large experience contrasting treatment with and without hyperbaric oxygen was made available for analysis. Note where billing quotes are presented in this paper, they include both the Medicare payout and the patient co-pays.

MATERIAL AND METHODS

Database construction

This study employed Medicare Part A and Part B fee-for-service (FFS) claims for patients with radiation-induced cystitis. Claims included data for inpatient, outpatient, durable

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medical equipment (DME), home health agency (HHA), hospice, and skilled nursing facility (SNF), as well as carrier administrative data, including Medicare beneficiary demographic and enrollment-related data from the Master Beneficiary Summary File (MBSF) for the period from October 1, 2014, through December 31, 2019. These data were used to construct a study group of beneficiaries who received hyperbaric oxygen treatment (HBO2) and a control group who received only non-hyperbaric care, which included primarily conservative care with irrigation, clot extraction, and cautery for their radiation cystitis. A lack of accurate coding resulted in some cases not being identified, and we felt that it was reasonable to include patients with diagnoses of both chronic cystitis and hematuria, along with a history of pelvic malignancy. All aspects of patient privacy were protected per HIPPA regulations by virtue of the study design, and all information was de-identified without access to clinical records. For inclusion, subjects had to have at least two non-laboratory or non-imaging billings consistent with radiation cystitis. The vast majority of both groups and essentially all of the study group, had been coded with a diagnosis of radiation-induced cystitis. We know that the subjects receiving hyperbaric oxygen were almost certainly coded properly because only those with late effects of radiation would be covered by Medicare.

Beneficiaries were excluded from the analytic file if they had radiation proctitis or had received active cancer treatment less than three months before their enrollment. In instances where a beneficiary had more than one eligible episode of HBO2 over the study period, the longer episode was included in the analysis. In instances where more than one course of hyperbaric oxygen was completed, almost always the second course was the longer of the two, and consistently, the first course was very short, typically consisting of one or two treatments.

The focus was on beneficiaries with chronic delayed radiation cystitis for which standard treatments had not resulted in remission. To be considered in remission after treatment, there needed to be six months or more without cystitis-specific additional therapeutic interventions, including transfusion.

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For both the study group and the control group, the analysis consisted of 3 distinct time periods or phases. Initially, all Medicare records available to us were scanned to identify procedures and tests consistent with radiation cystitis. These included bladder endoscopic procedures or surgical interventions, clot retraction, and bladder irrigation and transfusions. Once the diagnosis of cystitis was made, a one-year pre-treatment review was done to establish baseline Medicare expenditures for all enrolled patients. This pre-treatment phase constituted Phase 1 for both groups. The second phase was the treatment phase, wherein for both the study group and the control group, the costs specifically related to cystitis treatment were identified. Phase 3 was the one-year follow- up for both the study and control groups. In both Phase 1 and 3, total Medicare outlays were reviewed and compared. Figure 1 provides a quick visual depiction of the study design and sequence.

Our inclusion of all Medicare payments in Phase 1 and Phase 3 incorporated the cost of comorbidities and included all therapeutic interventions. For the HBO2 study group, the treatment phase (Phase 2) began on the first day, ended on the last day of hyperbaric treatment, and was 81 days on average. The hyperbaric oxygen phase was considered complete if there was a four or more months break between HBO2 treatments.

For the non-hyperbaric group, Phase 2 began when billings were also consistent with the onset of radiation cystitis. When modeling was done, the length of the treatment group, Phase 2, for the control subjects was initially set at 97 days as an estimate based on preliminary findings. Because of a wide variation in clinical response to treatment, it was decided not to apply this information in calculating differences in the cost of treatment.

Other interventions for radiation cystitis would continue for both groups and be quite variable for each patient until and if there was a remission. Because some patients would continue to have cystitis symptoms beyond the defined and modeled Phase 2 definitions of the treatment period and well into the follow-up period, we decided that the

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most appropriate and relevant financial comparison of treatment expenses would be the cost of the hyperbaric treatments, which was unique to the study group. Certainly, for the study group, these would have the largest impact on the expenditures during that phase. Both groups would continue to have other expenses, including cystoscopies, fulgurations, transfusions, etc. However, since the study group ultimately showed significant clinical improvements comparatively, these interventions and their attendant costs in this group would decrease more on average over time than the costs of those interventions for the control group. A previously cited review paper had recommended 40 hyperbaric treatments routinely for radiation injuries.[17] In order to calculate the Medicare- authorized reimbursement for a typical course of hyperbaric treatment, the number 40 was multiplied by the daily authorized Medicare reimbursement for a single hyperbaric treatment, including the physician’s fee. The total expenditure for 40 hyperbaric treatments would be just about $25,000.

Statistical design and analysis

For analysis, we used Difference-in-Differences (DiD) modeling to evaluate the effect of HBO2 on Medicare spending as well as for other outcome measures, including the incidence of bleeding, the need for transfusion, the number of transfusions, and the record of urologic endoscopic procedures. For other metrics, the DiD model was applied separately. Finally, using a linear probability model, we examined whether there was any difference in mortality rate between the study and control groups.

The main statistical challenge arises from the fact that patient assignment to treatment or control group is not random. Self-selection could be expected to increase entry into the HBO2 study group. Other factors, observed (e.g., health status or comorbidities) and unobserved (e.g., mental stress or family background), could have also affected the number of patients seeking hyperbaric treatment.

There may also be a physician bias in referring only more severely affected patients for hyperbaric oxygen due to the perceived increase in expense when HBO2 is

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employed. Several review articles, including clinical practice guidelines, do not include consideration of hyperbaric oxygen until most or all other common interventions have failed. We used an inverse probability of treatment weighting (IPTW) propensity score model to address the non-randomness issue. [27].

The IPTW method has several advantages [27-30]. The over-expressed weight of the control group is weighted down [28]. The IPTW approach uses the entire cohort and can address a very large number of confounding variables, and in doing so, it provides increased precision and representativeness [28,29]. Additionally, IPTW requires fewer distributional assumptions about the underlying data and avoids the potential residual confounding that arises from stratification on a fixed number of strata [30].

To address the potential self-selection issues, we estimated the Propensity Score model to assign appropriate weights to each of the comparison group and treatment group beneficiaries. [31-33] This method allows observational studies to be designed similarly to randomized experiments. We have also performed the Balanced Diagnostic Test to ensure that the observed baseline covariates are similar between the treatment and comparison groups. [34] We used the Standardized Mean Difference statistic to confirm that the covariates are balanced between these two groups at the baseline period. The balanced diagnostic test result suggests that all the covariates satisfy this diagnostic test in the base year since the absolute value of the standardized mean difference of all the explanatory variables is less than 0.25. Please reference Table 1.

RESULTS

Results are included below in two major categories and summarized in Tables 2 and 5. The first is a cost comparison of Medicare payments in the three phases. In Phases 1 and 3, both one-year periods, the comparison was made for average total Medicare outlays for both groups. See Table 2. For Phase 2, it was felt that the most pronounced difference in billings was the cost of the hyperbaric treatments and that the other cystitis-specific

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interventions would be comparable or reduced in the study group as more hyperbaric treatments were completed. Such a reduction would offset some of the expenses incurred by the hyperbaric treatments. A more specific comparison of these relative outlays is not possible due to the ongoing interventions for radiation cystitis in those who were not brought into remission in either group. Our modeling was not designed to provide this information. We note that the costs of continued specific interventions for unresolved cystitis are included in the total expenditures incurred during the one-year follow-up period. As noted earlier, these payments would include cystitis-specific interventions.

We found that the hyperbaric group was more likely to carry a diagnosis of hematuria and more likely to require transfusion in Phase 1. These findings suggest that the hyperbaric group included patients with more severe radiation cystitis. See Tables 3 and 4. Notably, the HBO2 group also had higher billings than the control during Phase 1 (pre-treatment). These higher payments for the hyperbaric group during Phase 1 also suggest that the study group started with more serious radiation complications on average at entry.

Table 5 shows several important comparisons. Control patients are compared to hyperbaric patients treated at four increasing hyperbaric dose points: one or more treatments, more than or equal to 20 treatments, more than or equal to 30 treatments, and more than or equal to 40 treatments. Analyses at these dose points show better results as the number of treatments is increased sequentially to 40 or more. The figures in the parentheses indicate the percent change relative to the mean value of the respective dependent variables in the pre-treatment period (except for mortality). The mortality analysis was based on a linear probability model, so the figures reflect the percent change relative to the mean value of the comparison group in the post-treatment period.

As shown in Table 5, total Medicare spending in the post-treatment period relative to the mean value in Phase 1 (pre-period) among patients in the HBO2 study group who received at least 40 treatments was $11,548 lower than the change in spending

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• • •

for the control group patients during the same period, a reduction in spending of about 37%. This finding was significant at the 1% level. The spending reduction was primarily driven by lower inpatient hospital spending of $9,222 and lower physician services- related spending of about $1,149, a reduction of 60% and 15%, respectively. These reductions in spending were also significant at the 1% level. As shown in the analyses of the subgroups divided according to the number of hyperbaric oxygen treatments, the savings to Medicare increased as the number of treatments increased in almost all clinical outcomes.

By the first year post-HBO2, the unadjusted Medicare payments for Phase 3 (follow-up) were $5,059 lower across the board for any patient receiving any number of hyperbaric treatments. The Difference in Differences regression modeling compares the pre-and-post-treatment financial outlays in both the study and control groups internally. When patients received the recommended 40 or more hyperbaric treatments, the total Medicare payments decreased by more than $11,548 per patient compared to the control group. [17] Interestingly, the majority of our patients received fewer than 40 treatments. Phase 3 costs for the control group were higher than Phase 1 in the control group, suggesting little response or even worsening cystitis with standard treatment. See both Table 2 and Figure 2 and their legends.

In addition to Medicare spending, we also examined and compared a number of key clinical outcomes. As shown in Table 5., patients in the HBO2 study group had consistently better outcomes relative to the pre-treatment period. For example, patients in the HBO2 study group at one-year follow-up (phase 1) relative to the same group in Phase 1 (Pre-treatment) had:

a 53% reduction in mortality, significant at the 1% level;
a 78% reduction in the probability of receiving a blood transfusion, significant at 5%; a 39% reduction in the number of endoscopic procedures, significant at 1%;

• a 31% reduction in patients receiving any endoscopic procedure, significant at the 1% level;

• a 5% reduction in the probability of having a urinary bleeding diagnosis, with an average 36% reduction in urinary bleeding among patients with a coded diagnosis of radiation cystitis with bleeding. This finding was significant at the 1% level.

  Although this study shows more overall Medicare savings in Phase 3 when the number of HBO2 treatments equals or exceeds the standard of care of 40 or more, even with fewer treatments, patients who receive HBO2 have better outcomes than those who do not receive any number of HBO2 treatments.

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REFERENCES

1. American Cancer Society. Cancer Facts & Figures 2023. Atlanta: American Cancer Society; 2023.

2. Mangar SA, Huddart RA, Parker CC, Dearnaley DP, Khoo VS, Horwich A. Technological advances in radiotherapy for the treatment of localised prostate cancer. Eur J Cancer. 2005 Apr;41(6):908-21. doi: 10.1016/j.ejca.2004.12.028. PMID: 15808957.

3. Lemanska A, Byford RC, Correa A, Cruickshank C, Dearnaley DP, Griffin C, Hall E, de Lusignan S, Faithfull S. Linking CHHiP prostate cancer RCT with GP records: A study proposal to investigate the effect of co-morbidities and medications on long-term symptoms

16

and radiotherapy-related toxicity. Tech Innov Patient Support Radiat Oncol. 2017 Jun 27;2:5-

12. doi: 10.1016/j.tipsro.2017.06.001. PMID: 32095558; PMCID: PMC7033766.

4. Bekelman JE, Mitra N, Efstathiou J, Liao K, Sunderland R, Yeboa DN, Armstrong K. Outcomes after intensity-modulated versus conformal radiotherapy in older men with nonmetastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e325-334. doi: 10.1016/j.ijrobp.2011.02.006. Epub 2011 Apr 16. PMID: 21498008; PMCID: PMC4265571.

5. Ma JL, Hennessey DB, Newell BP, Bolton DM, Lawrentschuk N. Radiotherapy-related complications presenting to a urology department: a more common problem than previously thought? BJU Int. 2018 May;121 Suppl 3:28-32. doi: 10.1111/bju.14145. Epub 2018 Feb 27. PMID: 29360286.

6. Mohammed N, Kestin L, Ghilezan M, et al. Comparison of acute and late toxicities for three modern high-dose radiation treatment techniques for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):204-12. doi: 10.1016/j.ijrobp.2010.10.009. Epub 2010 Dec 16. PMID: 21167653.

7. Martin SE, Begun EM, Samir E, Azaiza MT, Allegro S, Abdelhady M. Incidence and morbidity of radiation-induced hemorrhagic cystitis in prostate cancer. Urology. 2019 Sep;131:190-195. doi: 10.1016/j.urology.2019.05.034. Epub 2019 Jun 12. PMID: 31201826.

8. Zelefsky MJCH, Hunt M, Yamanda Y, Shippy A, Amold H. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localised prostate cancer. J Urol 2006; 176: 1415-1419.

9. Linder BJ, Tarrell RF, Boorjian SA. Cystectomy for refractory hemorrhagic cystitis: contemporary etiology, presentation and outcomes. J Urol. 2014 Dec;192(6):1687-1692. doi: 10.1016/j.juro.2014.06.030. Epub 2014 Jun 14. PMID: 24936722.

10. National Institutes of Health. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). v5.0. 2017 [cited 2017 Nov 27]. Report no. 2. Available online: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm

11. Rubin P, Casarrett GW. Clinical Radiation Pathology, Vol I, 38-62, Philadelphia Pa: WB Saunders, 1968.

17

12. Stone HB, Coleman CN, Anscher MS, McBride WH. Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol. 2003 Sep;4(9):529-36. doi: 10.1016/s1470- 2045(03)01191-4. PMID: 12965273.

13. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41:283-288.

14. Delanian S, Lefaix JL. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol. 2004 Nov;73(2):119-131. doi: 10.1016/j.radonc.2004.08.021. PMID: 15542158.

15. O'Sullivan B, Levin W. Late radiation-related fibrosis: pathogenesis, manifestations, and current management. Semin Radiat Oncol. 2003 Jul;13(3):274-289. doi: 10.1016/S1053- 4296(03)00037-7. PMID: 12903016.

16. Darby IA, Hewitson TD. Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 2016 Sep;365(3):553-562. doi: 10.1007/s00441-016-2461-3. Epub 2016 Jul 16. PMID: 27423661.

17. Feldmeier JJ. Hyperbaric oxygen therapy and delayed radiation injuries (soft tissue and bony

    necrosis): 2012 update. Undersea Hyperb Med. 2012 Nov-Dec;39(6):1121-1139. PMID:

    23342770.

18. Pascoe C, Duncan C, Lamb BW, et al. Current management of radiation cystitis: a review

    and practical guide to clinical management. BJU Int. 2019 Apr;123(4):585-594. doi:

    10.1111/bju.14516. Epub 2018 Nov 28. PMID: 30113758.

19. Bevers RF, Bakker DJ, Kurth KH. Hyperbaric oxygen treatment for haemorrhagic radiation cystitis. Lancet:1995;346:803-805.

20. Neheman A, Nativ O, Moskovitz B, Melamed Y, Stein A. hyperbaric oxygen therapy for radiation-induced haemorrhagic cystitis. BJU Int. 2005;96:107-109.

21. Corman JM, McClure D, Pritchett R, Kozlowski P, Hampson NB. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen. J Urol. 2003;160:2200-2202.

22. Norkool DM, Hampson NB, Gibbons RP, Weissman RM. Hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis. J Urol. 1993 Aug;150(2 Pt 1):332-334. doi: 10.1016/s0022-5347(17)35476-9. PMID: 8326555.

23. Cardinal J, Slade A, McFarland M et al. Scoping review and meta-analysis of hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis. Current Urology Reports. 2018.;19:38 published on line.

18

24. Hampson NB, Holm JR, Wreford-Brown CE, Feldmeier J. Prospective assessment of outcomes in 411 patients treated with hyperbaric oxygen for chronic radiation tissue injury. Cancer. 2012 Aug 1;118(15):3860-3868. doi: 10.1002/cncr.26637. Epub 2011 Dec 2. PMID: 22139864

25. Villeirs L, Tailly T, Ost P, et al. Hyperbaric oxygen therapy for radiation cystitis after pelvic radiotherapy: Systematic review of the recent literature. Int J Urol. 2020 Feb;27(2):98-107. doi: 10.1111/iju.14130. Epub 2019 Oct 15. PMID: 31617263.

26. Oscarsson N, Müller B, Rosén A, et al. Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial. Lancet Oncol. 2019 Nov;20(11):1602-1614. doi: 10.1016/S1470-2045(19)30494-2. Epub 2019 Sep 16. Erratum in: Lancet Oncol. 2019 Sep 23; PMID: 31537473.

27. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70.1:41-55.

28. Raad H, Cornelius V, Chan S, Williamson E, Cro S. An evaluation of inverse probability weighting using the propensity score for baseline covariate adjustment in smaller population randomised controlled trials with a continuous outcome. BMC Med Res Methodol. 2020 Mar 23;20(1):70. doi: 10.1186/s12874-020-00947-7. PMID: 32293286; PMCID: PMC7092449.

29. Brookhart MA, Schneeweiss S. Preference-based instrumental variable methods for the estimation of treatment effects: assessing validity and interpreting results. Int J Biostat. 2007;3(1): Article 14. doi: 10.2202/1557-4679.1072. PMID: 19655038; PMCID: PMC2719903.

30. Curtis LH, Hammill BG, Eisenstein EL, Kramer JM, Anstrom KJ. Using inverse probability- weighted estimators in comparative effectiveness analyses with observational databases. Med Care. 2007 Oct;45(10 Supl 2):S103-107. doi: 10.1097/MLR.0b013e31806518ac. PMID: 17909367.

19

35.

36. Löndahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care. 2010 May;33(5):998- 1003. doi: 10.2337/dc09-1754. PMID: 20427683; PMCID: PMC2858204.

37. Tai CJ, Lu CK, Lee CY, Lee SS, Yang YH. Real-world evidence of hyperbaric oxygen therapy on cardiovascular outcomes in patients with chronic osteomyelitis. J Infect Public Health. 2023 May;16(5):705-712. doi: 10.1016/j.jiph.2023.03.006. Epub 2023 Mar 7. PMID: 36940497.

38. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987 40(5): 373-383. doi:10.1016/0021-9681(87)90171-8. PMID 3558716.

39. Mendenhall WM, Henderson RH, Costa JA, et al. Hemorrhagic radiation cystitis. Am J Clin Oncol. 2015 Jun;38(3):331-336. doi: 10.1097/COC.0000000000000016. PMID: 24322335.

40. 27. D'Amico MJ, Foss H, Uhr A, Rudnick B, Kloniecke E, Gomella LG. Hemorrhagic cystitis: a review of the literature and treatment options. Can J Urol. 2022 Oct;29(5):11276- 11283. PMID: 36245196.

41. Goucher G, Saad F, Lukka H, Kapoor A. Canadian Urological Association Best Practice Report: Diagnosis and management of radiation-induced hemorrhagic cystitis. Can Urol Assoc J. 2019 Feb;13(2): 15-23.

hyperbaric oxygen therapy. Diving Hyperb Med. 2012 Jun;42(2):92-7. PMID: 22828818.

20

44. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=12 accessed 11/26/2023

45. Chong KT, Hampson NB, Corman JM. Early hyperbaric oxygen therapy improves outcome for radiation-induced hemorrhagic cystitis. Urology. 2005 Apr;65(4):649-653. doi: 10.1016/j.urology.2004.10.050. PMID: 15833500.

46. Crall TS, Bishop JA, Guttman D, Kocher M, Bozic K, Lubowitz JH. Cost-effectiveness analysis of primary arthroscopic stabilization versus nonoperative treatment for first-time anterior glenohumeral dislocations. Arthroscopy. 2012 Dec;28(12):1755-1765. doi: 10.1016/j.arthro.2012.05.885. Epub 2012 Oct 5. PMID: 23040837.

47. Cohen JR, Bradley AT, Lieberman JR. Preoperative interventions charges before knee arthroplasty. J Arthroplasty2016 Dec;31(12):2730-2735.e7.doi: 10.1016/j.arth.2016.05.048. Epub 2016 May 31.

48. Jones PE, Kissenberth MJ, Brooks JM, Thigpen CA, Shanley E, Pill SG. Unanticipated costs associated with interscalene nerve catheters for shoulder surgery. J Shoulder Elbow Surg. 2023 Jun;32(6S):S118-S122. doi: 10.1016/j.jse.2023.02.010. Epub 2023 Feb 23.

49. Zpancic JA, Richardson DK, O'Brien BJ, Eichenwald EC, Weinstein MC. Cost-effectiveness analysis of predischarge monitoring for apnea of prematurity. Pediatrics. 2003 Jan;111(1):146-152. doi: 10.1542/peds.111.1.146. PMID: 12509568.

50. Mark DB, Nelson CL, Anstrom KJ, et al. Cost-effectiveness of defibrillator therapy or amiodarone in chronic stable heart failure: results from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation. 2006 Jul 11;114(2):135-142. doi: 10.1161/CIRCULATIONAHA.105.581884. Epub 2006 Jul 3. PMID: 16818817.

51. Mills MD, Spanos WJ, Jose BO, Kelly BA, Brill JP. Preparing a cost analysis for the section of medical physics-guidelines and methods. J Appl Clin Med Phys. 2000 Spring;1(2):76-85. doi: 10.1120/jacmp.v1i2.2648. PMID: 11674821; PMCID: PMC5726149.

52. Mesel E, Wirtschafter DD, Ramsey-Klee DM. Economic analysis of an automated billing system for physicians' services. Med Care. 1976 Dec;14(12):1037-1051. doi: 10.1097/00005650-197612000-00007. PMID: 794599.

53. Enestvedt CK, Mayo SC, Diggs BS, et al. Diagnostic laparoscopy for patients with potentially resectable pancreatic adenocarcinoma: is it cost-effective in the current era? J

21

Gastrointest Surg. 2008 Jul;12(7):1177-84. doi: 10.1007/s11605-008-0514-y. Epub 2008 May

10. PMID: 18470572.

54. Marchioni M, DE Francesco P, Campi R, et al. Current management of radiation cystitis after

    pelvic radiotherapy: a systematic review. Minerva Urol Nephrol. 2022 Jun;74(3):281-291.

    doi: 10.23736/S2724-6051.21.04539-0. Epub 2021 Oct 29. PMID: 34714035.

55. Saturni S, Bellini F, Braido F, et al. Randomized controlled trials and real life studies.

    Approaches and methodologies: a clinical point of view. Pulm Pharmacol Ther. 2014

    Apr;27(2):129-138. doi: 10.1016/j.pupt.2014.01.005. Epub 2014 Jan 24. PMID: 24468677.

56. Moore TJ, Zhang H, Anderson G, Alexander GC. Estimated costs of pivotal trials for novel

    therapeutic agents approved by the US Food and Drug Administration, 2015-2016. JAMA Intern Med. 2018 Nov 1;178(11):1451-1457. doi: 10.1001/jamainternmed.2018.3931. PMID: 30264133; PMCID: PMC6248200.

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Table 1. Summary of Covariates and Diagnostic Test in Pre-Period for HBOT and Comparison Group

Without Weight

With IPTW Weighting

Hyperbaric Group (1,030)

Control Group (2,279)

Hyperbaric Group (1,030)

Control Group (2,279)

Age

Female

Dual

White Black Asian Hispanic North American Native Others

CCI

76.59

8.06%

5.15%

85.92% 9.51% 0.78% 0.97%

0.19% 2.62%

0.46

Age

Female

Dual

White Black Asian Hispanic North American Native Others

CCI

76.90

25.81%

13.08%

89.30% 6.54% 1.00% 0.82%

0.17% 2.17%

0.47

Age

Female

Dual

White Black Asian Hispanic North American Native Others

CCI

76.76

21.33%

12.98%

88.08% 7.27% 0.86% 1.05%

0.31% 2.42%

0.45

Age

Female

Dual

White Black Asian Hispanic North American Native Others

CCI

76.92 31.41% 15.50%

89.98% 5.91% 1.06% 0.80%

0.18% 2.07%

0.48

-0.02 -0.23 -0.07

-0.06 0.05 -0.02 0.03

0.02 0.02

-0.06

Legend for Table 1:

Table 1 compares pre-treatment demographics and the Charlson Co-morbidity Index for both unweighted and weighted study and control groups. Both groups are well-matched in each category, as demonstrated by the Balanced Diagnostic Test, which reflects the validity of the weighting and subsequent statistical determinations.

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Table 2. Average Total Annual Patient Medicare Authorized Payments

Study (HBO2)

Control
Difference (HBO2 minus control)

Legend for Table 2:

$31,293 $26,234 $29,130 $31,496 $2163 -$5261

-$5,059 (any hyperbaric treatment)

+$2,366 -$7425

This table presents total Medicare-authorized payments for both groups, comparing post- treatment to pre-treatment (Phase 3-Phase 1) The entries suggest a more severe initial
level of disease in the Study vs Control Group with $2163 additional charges. At the one-year
r follow-up, the average savings for the Study Group at all hyperbaric dose levels equals $5059. Note in the Table a minus sign indicates a savings and a + sign represents an increased Medicare-authorized payment.

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Table 3. Incidence of radiation cystitis with bleeding for each group during Phase 1

Radiation cystitis with urinary bleeding Study Group

Control Group
Difference (study-comparison)

Legend for Table 3:

Phase 1. Pre- treatment 63.6%

14.9% 48.7%

Table 3 shows that the occurrence of hemorrhagic cystitis is more than four times more likely to occur in the study group than in the control group
during the pretreatment phase strongly suggesting more severe disease.

Table 4. Percent of patients receiving blood transfusion during Phase 1 (Pre-treatment)

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Study group 10.4%

Control 5.1% Difference (study-comparison) 5.3%

Legend for Table 4:

Table 4 demonstrates that transfusion during Phase 1 is twice as likely in the hyperbaric group compared to control suggesting more severe disease.

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