Introduction

Mucositis is a common toxicity following chemotherapy and radiotherapy for cancer [1], often necessitating dose reductions and/or treatment breaks. These patients have twice the infection risk leading to a four-fold higher chance of death and three-fold longer hospital stays. Mucositis also adds substantial health care costs—US data from 2012 estimated a combined cost of $15,500 for each hospitalization due to severe mucositis, adding millions to annual health care expenditure [2]. Patients with mucositis may experience different patterns of toxicities and related consequences including, but not limited to, oral ulceration [3], increased infection rates [4], and diarrhea [5]. Gastrointestinal mucositis (GIM) refers specifically to mucosal injury, and related symptoms, distal to the oropharyngeal cavity. There is currently an unmet need for effective interventions for GIM in patients undergoing cancer therapy [1, 6]. Amifostine has been recommended for prevention of radiation-induced proctitis, and established antidiarrheal medications, loperamide and octreotide, continue to be recommended for treatment of chemotherapy-induced diarrhea [7,8,9]. However, there are limited options for most settings of GIM.

This paper reports the findings from a systematic review of the most recent literature assessing agents for prevention and treatment of GIM. This evaluation has been conducted on the background of previous reviews performed by The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) published in 2004 [7], 2007 [8], and 2014 [9], with the first GIM-specific review published in 2013 [6]. Although much of the underlying pathobiology of mucositis is identical along the alimentary tract [10], beyond the oral cavity there are morphological and microbial differences related to regional specializations [10]. This makes diagnosis, inspection, and treatment of mucositis in these more distal regions all the more clinically challenging [11]. As such, our aim was to comprehensively review available literature and generate new evidence-based clinical practice guidelines for the prevention and/or treatment of GIM.

Methods

The methods related to this guidelines update are described in detail in Ranna et al. [12]. Briefly, a literature search for relevant papers published from 1 January 2011 to 30 June 2016 was conducted using PubMed and Web of Science, with papers selected for review based on defined inclusion and exclusion criteria. The list of keywords used for the literature search of this section is in Table 1.

Table 1 Keywords list
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Papers were reviewed by two independent reviewers, with data extracted using a standard electronic form. Studies were scored for their Level of evidence (LoE) based on Somerfield criteria [13] and flaws were listed according to Hadorn criteria [14]. A well-designed study was defined as a study with no major flaws as per the Hadorn criteria.

Findings from the reviewed studies were integrated into guidelines based on the overall LoE for each intervention. Guidelines were classified into Recommendation, Suggestion, and No Guideline Possible. Guidelines were separated based on the following: (1) the aim of the intervention (prevention or treatment); (2) the treatment modality (radiotherapy, chemotherapy, chemoradiotherapy, or hematopoietic stem cell transplantation); and (3) the route of administration of the intervention. Treatment modalities that included targeted therapies were excluded from this review.

Results

A total of 416 papers were identified in the literature search from PubMed and 535 from Web of Science. Four papers were transferred from other sections of the guidelines update. A further 15 were found by manual searches. After careful assessment of the abstracts, we excluded papers for reasons including: repetition across databases; pre-clinical nature of study; studies assessing mechanisms and not interventions; and systematic reviews. We retrieved 78 papers for final review. After review of these papers, we included 25 in this report, including 18 randomized controlled trials (Fig. 1). Studies were removed at the final review stage due to not investigating GIM directly; no clinical outcome measures presented; and repetitive studies (identical data presented more than once). The following 13 interventions were included in this review: antimicrobials (ciprofloxacine and metronidazole); famotidine; fat-modified diet; fiber; formalin; glutamine; hyperbaric oxygen; octreotide, palifermin; probiotics; sodium butyrate; steroids; and sucralfate (Table 2).

Fig. 1
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Article flowchart

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Table 2 Agents for the prevention and treatment of GI mucositis in this update
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Antimicrobials (ciprofloxacine and metronidazole)

Guideline category: No Guideline Possible

Two papers investigating the combined use of antimicrobials (ciprofloxacin and metronidazole) for the treatment of chronic radiation-induced proctitis were reported since the previous guidelines update [15, 16]. One of these studies was a RCT for treatment of hemorrhagic radiation proctitis [15] that added to an earlier small cohort study by the same group [16]. It compared colonic irrigation and oral antibiotics with 4% formalin rectal administration. Both studies found a positive impact of antibiotics but due to the limited evidence available, no guideline was possible. No other antibiotic combinations or treatment settings have been examined since the previous GIM guidelines were published [6] (Box 1).

Box 1. Interventions for which no new evidence was added since the previous MASCC/ISOO systematic review [6, 9]

Prevention

  5-ASA*

PO

RT, pelvic ca

  Activated charcoal

PO

CT, solid ca

  Amifostine*

Enema, IV, SC

CT, CT-RT, RT, solid ca, pelvic ca

  Antidiarrheal program

PO

CT, lung ca

  Balsalazide

PO

RT, pelvic ca

  Budesonide

PO

CT, colorectal ca

  Celecoxib

PO

CT, solid ca

  Cholestyramine

PO

CT, RT, solid ca

  Chrysin

PO

CT, solid ca

  Circadian rhythm

n/a

RT, pelvic ca

  Glutamine

IV

CT, hematological

  Misoprostol*

Enema

RT, pelvic ca

  Neomycin

PO

CT, solid ca

  Physical activity

n/a

CT, RT, solid ca

  Sucralfate*

PO, enema

RT, pelvic ca

  Sulfasalazine*

PO

RT, pelvic ca

Treatment

  Cefixime

PO

CT, solid ca

  Heater probes

Rectal

RT, pelvic ca

  Leucovorin

IV

RT, bone ca

  Metronidazole

Enema

RT, pelvic ca

  Octreotide*

IM, IV, SC

CT, CT-RT, solid ca, hematological

  Probiotics*

PO

RT, solid ca

  Sodium butyrate

Enema

RT, pelvic ca

  Sucralfate*

Enema

RT, pelvic ca

  1. ca, cancer; CT, chemotherapy, CT-RT, chemoradiotherapy,  IM: intramuscular; IV, intravenous; n/a, not applicable; PO, oral; RT, radiotherapy, SC, subcutaneous; *existing guidelines available [6, 9]

Famotidine (oral)

Guideline category: No Guideline Possible

A single RCT investigating famotidine, a histamine H2 receptor antagonist, for the prevention of acute radiation-induced GIM in 36 patients with prostate cancer was successful [17]; however, due to a lack of supporting evidence, no guideline is possible.

Fat-modified diet

Guideline category: No Guideline Possible

The use of low fat or fat-modified diet to prevent radiotherapy-induced GIM was investigated in a multi-site RCT [18]. Patients with cancers of the pelvic region consumed the diets throughout radiotherapy; however, neither arm showed a significant improvement in GI symptoms. The compliance to the required fat intake for the control group was noted as a possible cause for a lack of effect seen in the study.

Fiber (with combinations of prebiotics, nutritional supplements, and probiotics)

Guideline category: No Guideline Possible

Studies have combined fiber (including using inulin and oligosaccharides often referred to as prebiotics) with additional interventions that we have grouped together due to this overarching dietary modification. Prebiotics are defined as “selectively fermented ingredients in the colon that produce specific changes in the composition and/or activity of gastrointestinal microbiota and have beneficial effects for host health” [40].

One paper examined fiber combined with a nutritional supplement, including vitamins, minerals, and probiotics, named Dixentil, for prevention of chemoradiotherapy-induced gastrointestinal toxicity [19]. This was a phase II study of 40 consecutive patients whom received a daily 10-ml vial of Dixentil (Gamfarma srl, Milano Italy) starting from 1st day of radiotherapy until the end of the scheduled treatment. Each vial contained 500 mg of galacto-oligosaccharides, 10 mg of L. casei, 10 mg of Lactobacillus acidophilus, 10 mg of zinc, 1 mg vitamin B1, 1 mg vitamin B2, 1 mg vitamin B6, and 10 mg nicotinamide. This study primarily focused on the safety and tolerance of Dixentil, being the first study to evaluate a nutritional supplement based on zinc, prebiotics, tyndalized probiotics, and vitamins for reducing the duration and frequency of severe and or persistent diarrhea. There was some indication of activity relative to historical control levels.

Hydrolyzed rice bran for prevention of GIM [20] was investigated in a small RCT (n = 20) of cervical cancer with limited evidence of effectiveness for diarrhea improvement. The main ingredient was water soluble fiber which is believed to carry anti-inflammatory properties, although the authors found no impact of fiber on immune cell activity in the study.

One RCT examined the capacity of prebiotics to prevent radiation-induced diarrhea [21]. Briefly, 38 women with gynecological cancer receiving radiotherapy were randomized to receive either prebiotics (6 g twice daily of an equal mix of inulin and fructo-oligosaccharide) or 6 g twice daily of matching placebo (maltodextrin). The main outcome measure was stool consistency as measured by the Bristol stool score, with no significant improvement in the prebiotic group for days with watery diarrhea. A previous paper in the same population confirmed that prebiotics modulated the levels of Lactobacillus and Bifidobacterium [41].

Finally, a small RCT investigated fiber (inulin plus partially hydrolyzed guar gum mixture) with Lactobacillus reuteri for prevention of radiotherapy-related proctitis in patients with prostate cancer [22]. Although effective, the small size of the study (n = 20) meant there was limited evidence to support a guideline. Overall, the use of fiber/prebiotics in studies for prevention of GIM had conflicting results regarding effectiveness and as such, no guideline is possible.

Formalin (rectal)

Guideline category: No Guideline Possible

One RCT investigated formalin rectal dab compared with sucralfate-prednisolone enema for treatment of hemorrhagic proctitis [23]. The study included 102 patients that had previously received radiotherapy for management of cervical carcinoma and found that formalin was superior to sucralfate. This supports the findings of Tsujinaka et al. 2005, which when reviewed in the previous update [6], showed that formalin was effective at treating hemorrhagic proctitis in patients treated with radiotherapy for pelvic cancers. However, due to the lack of studies in this area, no guideline is possible.

Glutamine (oral)

Guideline category: No Guideline Possible

There has been no previous guideline possible for oral glutamine to prevent or treat GIM in either hematological or solid cancers treated with chemotherapy despite 6 studies published over a decade ago (reviewed in [6]).

In the HSCT setting, this current guideline update found one new study [24], which was a historical case control study investigating oral glutamine for prevention of GIM in 22 patients receiving allogeneic HSCT. The oral supplement was referred to as GFO (15 g) and contained 3 g glutamine, 5 g dietary fiber, 1.5 g oligosaccharide, and 1.2 mg sodium. Two packages of GFO dissolved in 200 mL of water were administered to patients orally 3 times per day beginning 7 days prior to the start of conditioning and continued until 28 days after transplantation. This regimen was associated with decreased days of severe diarrhea compared with 22 matched historical controls; however, due to the limited evidence, there was no change to the former guideline.

With regard to lung cancer treated with chemoradiotherapy, a single historical case control study examining the role of oral glutamine in prevention of acute radiation-induced esophagitis was identified [25]. This study compared 56 patients that received 10 g of glutamine three times daily starting 1 week prior to first day of radiation and finishing 2 weeks after completion of radiotherapy to 48 patients that did not receive glutamine. Glutamine supplementation was associated with significantly decreased incidence of grade III esophagitis in patients receiving radiation with concurrent chemotherapy. Of note, another study that utilized the same database and patient files was subsequently published, albeit with fewer included patients, and found a consistent beneficial effect for glutamine [42]. This work adds to the studies previously included in the 2013 guidelines [43, 44]; however, due to the lack of randomized clinical trials for this indication and inconsistent results, no guideline is possible.

In regard to solid tumors in the pelvis (including genitourinary, gynecological and rectal) treated with concurrent chemotherapy and radiotherapy, there has been 2 RCTs [26, 27] and 1 non-RCT [28] since the last guidelines [6]. In patients with rectal cancer [27], oral glutamine was not effective at reducing severity of diarrhea, although the study was terminated prior to reaching the recruitment target. In patients with mixed pelvic cancers, oral glutamine caused significantly more acute radiation enteritis than placebo [26]. In contrast, in the non-RCT, patients with mixed pelvic tumors treated with glutamine had significant protection against severe diarrhea [28]. Due to the inconsistences seen in these studies, no guideline is possible.

No papers that have investigated IV glutamine have been published since the last update [6] (Box 1).

Hyperbaric oxygen therapy

Guideline category: Suggestion for treatment of RT-induced proctitis (LoE II)

There have been two recent studies investigating hyperbaric oxygen for treatment of pelvic radiotherapy-related proctitis [29, 30]. A cohort study found that daily hyperbaric oxygen was effective at reducing proctitis severity when started at the onset of chronic symptoms [30]. The majority of patients received radiotherapy in combination with hormone therapy for prostate cancer, and less than a quarter received chemotherapy. In contrast, a RCT of patients with over 12 months of gastrointestinal symptoms that had failed to respond to 3 months of optimal medical therapy, hyperbaric oxygen delivered 5 days a week was ineffective at resolving rectal bleeding or bowel symptoms at 12 months [29]. This RCT is the first to oppose the existing evidence supporting hyperbaric oxygen therapy (reviewed in [6]), and as such the panel continues to suggest hyperbaric oxygen therapy for treatment of radiation-induced proctitis in pelvic cancers. However, additional RCTs are urgently required given the now conflicting results.

Octreotide (intramuscular)

Guideline category: No Guideline Possible

A single RCT investigating the effectiveness of long-acting intramuscular octreotide for prevention of chemotherapy-induced-diarrhea in patients with colorectal cancer found no improvement compared with standard of care [31]. This is consistent with 2 previous RCTs; first, for prevention of chemoradiation-induced diarrhea in patients with anorectal cancer when compared with placebo [45], and second, in pelvic radiation-induced diarrhea when compared with placebo [46], which found no benefit for long-acting octreotide. Each study has been in a different population with different treatments and as such, no guideline was possible. The existing guideline that recommends the use of octreotide for treatment of chemotherapy-induced diarrhea is unchanged [6].

Palifermin

Guideline category: No Guideline Possible

As part of a larger RCT to investigate efficacy of different dose schedules of idarubicin for AML, Bradstock and colleagues recruited 155 patients from 23 centers to assess palifermin efficacy in preventing chemotherapy-related adverse events [32]. Incidence of severe GI toxicity was significantly different (p = 0.002) between placebo and palifermin, contributed mostly by decreased incidence of severe diarrhea in the palifermin group.

Two studies investigated the effectiveness of palifermin for prevention of GIM related to HSCT. A control-matched cohort study found that palifermin did not prevent clinically meaningful GIM in patients undergoing HSCT for non-Hodgkin and Hodgkin lymphoma [33]. In contrast, a retrospective case control study in the same setting found that palifermin was effective at reducing the number of days with moderate diarrhea [34]. Given the inconsistencies in findings across studies, no guideline is possible.

Probiotics

Guidelines category: No Guideline Possible for prevention of diarrhea due to chemotherapy alone

Probiotics are generally preparations that contain sufficient numbers of viable bacteria that are able to exert beneficial effects [6]. A RCT in colorectal cancer patients treated with irinotecan-based chemotherapy investigated prevention of diarrhea using a mixed probiotic formulation [35]. Patients were instructed to take three capsules per day for 12 weeks, each containing 10 billion CFU of bacteria (Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium longum, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Streptococcus thermophilus, Lactobacillus brevis, Bifidobacterium infantis) and additives, inulin, maltodextrine, magnesium stearate, and ascorbic acid. Placebo capsules contained additives without probiotic bacteria. The study terminated due to slow accrual when 46 of 220 planned participants were recruited. Regardless, the authors reported that probiotics use was associated with significantly reduced incidence of severe and overall diarrhea.

Guidelines category: Suggestion for prevention of chemoradiotherapy-induced diarrhea in pelvic malignancy (LoE III)

In regard to pelvic cancer patients treated with radiotherapy or chemoradiotherapy, we have assessed one additional RCT [36]. The study investigated a mixed probiotic formulation called Bifilact® which includes Lactobacillus acidophilus and Bifidobacterium longum in two different doses and schedules; either twice daily 1 billion or thrice daily 10 billion CFU. The placebo group received capsules containing the excipients. The lower dose was associated with significant decreases in grade 4 diarrhea in patients that had received prior pelvic surgery. There was no change in the study primary endpoint, incidence of grade 2–3 diarrhea. Given the consistent positive results seen in this trial and in the trials included in our previous guidelines [6], the panel continues to suggest that probiotics containing Lactobacillus spp., may be beneficial for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy.

Sodium butyrate (enema)

Guideline category: No Guideline Possible

One RCT for prevention of radiation-induced proctitis using sodium butyrate enemas was identified [37]. The study recruited 166 patients who were allocated to a variety of rectal doses of sodium butyrate (placebo, 1, 2, or 4 g). This study found no evidence of efficacy in reduction of incidence, severity, or duration of acute radiation-induced proctitis.

No trials were identified that examined treatment of radiation-induced proctitis as covered in the previous guidelines [6] (Box 1).

Steroid (beclomethasone)

Guideline category: No Guideline Possible

The steroid beclomethasone dipropionate was investigated in a RCT for prevention of radiotherapy-induced GIM in patients with prostate cancer [38]. Patients received beclomethasone suppositories throughout radiation and for 4 weeks following completion of treatment. There was no significant improvement seen in bowel symptoms at 3 or 12 months, although rectal bleeding was reduced.

Sucralfate (oral)

Guideline category: No Guideline Possible

A single RCT investigated oral sucralfate for treatment of hemorrhagic proctitis in patients that had received chemoradiation for pelvic malignancy [39]. All 122 patients received argon plasma coagulation prior to receiving sucralfate or placebo. In this study, there was no evidence for improved benefit by adding sucralfate. In previous studies investigating oral sucralfate for treatment of radiation-related proctitis, there has been some evidence of effectiveness [47, 48]; however, due to a lack of evidence, no guideline is possible. In contrast, for prevention of radiation-induced gastrointestinal side effects, the panel has an existing recommendation not to use sucralfate [6] and no recent studies have been published for this indication (Box 1).

Discussion

Following a systematic review of the most recent clinical literature on interventions for the prevention and treatment of GIM, the panel assessed the evidence for 13 interventions to support clinical practice guidelines. Due to a lack of new evidence or conflicting evidence in each setting, no new guidelines were formed. For two interventions, where new studies were found, an existing guideline was retained: (1) The panel continues to suggest that probiotics containing Lactobacillus spp. may be effective for prevention of diarrhea during chemoradiotherapy and radiotherapy for pelvic cancers; (2) The panel continues to suggest that hyperbaric oxygen therapy is an effective way to treat radiation-induced proctitis. Several clinical studies investigating new interventions, fiber, famotidine, fat-modified diet, and beclomethasone were reviewed, but due to limited evidence were unable to form guidelines.

The existing guideline for probiotics was supported by one new RCT [36] in patients with pelvic malignancy treated with radiotherapy (46%) and chemoradiotherapy (54%). Probiotics given at a standard dose of Bifilact® decreased the incidence of life-threatening diarrhea in patients that underwent pelvic surgery as part of the treatment plan. No benefit was seen in patients that did not receive pelvic surgery or received high-dose Bifilact®. Overall, the effect was marginal, and it was unclear if patients treated by single modality or combined therapy were more protected. One additional RCT in colorectal cancer patients, treated with irinotecan-based chemotherapy [35], showed significant reductions in severe diarrhea. Since this is the first study to examine probiotics in the chemotherapy-alone setting, it could not be incorporated with the existing evidence or guideline. Limiting the evidence is that each study to date has included different strains and doses of bacteria, and has been conducted in heterogenic cancer treatment settings. As such, the panel is still unable to make a strong recommendation regarding probiotics. Further work is required to find the optimal strains and dose for maximal protection, and to evaluate effectiveness across settings of radiotherapy and chemotherapy, with and without prior surgery. Future studies should track changes in fecal microbial composition throughout treatment as a biomarker of response to probiotics.

For palifermin, one RCT provided evidence that 60 μg/kg/day palifermin for 3 days before and after induction chemotherapy for AML was effective in decreasing incidence of severe GIM following chemotherapy [32]. In contrast, a case-matched cohort study found that palifermin was ineffective in reducing GIM related to BEAM chemotherapy and HSCT in patients with lymphomas [33]. Finally, a study that retrospectively assessed GIM in two groups of patients (9 that received palifermin and pegfilgrastim, and 10 that received neither) found palifermin treatment was associated with significantly fewer days with grade 2 or worse diarrhea [34]. A previous study by Johannson et al. reported protective effects on mucosal barrier, but not clinical symptoms, of palifermin in the setting of autologous HSCT after conditioning chemotherapy for lymphomas using the same dose and schedule of palifermin [49]. However, since the three studies are not in agreement regarding the effectiveness of palifermin in high-dose chemotherapy for hematological cancers, no guideline is possible. Furthermore, the previous guidelines reviewed the paper by Rosen et al. that found palifermin to be ineffective against GIM following 5-FU-based chemotherapy for metastatic colorectal cancer [50]. This differs from the extensive preclinical evidence that reported reduced GIM with palifermin following chemotherapies used for colorectal cancer [51, 52]. As such, the effectiveness of palifermin appears to be related to the type of chemotherapy and the addition of total body irradiation.

Hyperbaric oxygen therapy continues to be investigated as an intervention for radiation-induced proctitis, especially in the context of chronic hemorrhagic disease. While there is a relative lack of RCTs in this setting, the cumulative evidence does support its use in over 10 studies spanning 20 years. The one exception noted is the recent RCT by Glover et al. which included patients with long-standing symptoms resistant to optimal therapy. They found hyperbaric oxygen therapy was ineffective at resolving rectal bleeding or bowel symptoms at 12 months [29]. This RCT is the first to oppose the existing evidence and indicates that radiation morbidity refractory to standard management may not be effectively treated with this approach. However, additional RCTs are urgently required given the now conflicting results.

The current review evaluated sodium butyrate enemas for the prevention of radiation-induced proctitis. The included trial was a relatively large, well-designed study [37] that examined increasing doses of sodium butyrate throughout radiation treatment. However, there was no evidence of effectiveness in reducing the incidence, severity, or duration of proctitis. In contrast, the previous guidelines included a number of studies that investigated the use of sodium butyrate for treatment of radiation-induced proctitis [6], and topical sodium butyrate was considered effective for treatment of existing acute radiation proctitis. However, the panel noted the studies were relatively small with a combined evidence level of III [6]. As such, there is conflicting evidence for effectiveness in the prevention and treatment setting, and no guideline is possible for either.

In January 2019, the literature search was repeated in an effort to capture late-breaking evidence published July 2016 to December 2018. This identified a further 4 relevant studies investigating prevention and treatment of GIM but did not impact on existing guidelines or lead to any new guidelines. A double-blind RCT investigated 3% Aloe vera ointment for treatment of acute radiation-induced proctitis [53]. Nine patients received 1 g Aloe vera twice daily for 4 weeks, while 11 patients received placebo ointment. Aloe vera was effective at reducing diarrhea and fecal urgency, but was not able to reduce hemorrhage or rectal pain. A randomized non-blinded and non-controlled study investigated high protein (36 g daily) oral nutritional supplement in pre-cachectic patients treated with chemotherapy for colorectal cancer [54]. The study recruited 47 to the supplement group and 48 to the control group, and found no significant differences in toxicity between groups. An elemental diet, consisting predominantly of amino acids, for prevention of gastrointestinal toxicity in patients receiving stem cell transplant for hematological cancers was evaluated in a prospective cohort study [55]. Elemental diet was received by 52 consecutive patients and results were compared with previous 21 consecutive patients. Severe diarrhea incidence was not significantly different between the diet (50%) and non-diet (26%) groups (p = 0.08). Finally, a randomized study compared enteral nutrition with high levels of omega-3 fatty acid (900 mg/day) with lower levels of omega-3 fatty acid (250 mg/day) supplementation for prevention of toxicities during neoadjuvant chemotherapy for esophageal cancer [56]. A total of 31 patients were randomized to the high omega-3 group and 30 to the lower omega-3 group. The incidence of severe diarrhea was 16% vs 37% (p = 0.068) in favor of the high-dose group.

A limitation of this review was the exclusion of papers that included targeted therapies; a decision made a priori to allow direct comparison with previous recommendations. In future reviews, inclusion of emerging multimodal regimens will be critical. Further, the classical definition of GIM will need to move with the field, to broaden its definition to include biological therapy-specific toxicities [57, 58]. Finally, as the combination use of chemotherapy and radiotherapy with targeted agents or immunotherapy will increase the risk of GIM, so will the need for tailored preventative and therapeutic interventions grow.