Advantages of low dose polyethylene glycol + ascorbate split-dose colonoscopy preparation for colorectal screening

Abstract

BACKGROUND

Colorectal cancer is the third occurring neoplasm type worldwide, with approximately two million people cases in 2020. Hence, activation of accurate screening and diagnostic protocols within the population is crucial for its prevention, contributing to public health improvement along with healthcare costs containment. Colonoscopy represents the gold standard for lesion detection, yet remains an invasive and distressful procedure, also due requiring appropriate intestinal prep through ingestion of laxative concoctions. For the Italian National Health System, this preparation is administered as 4-liter of polyethylene glycol (PEG), split in two rounds, which often results in insufficient bowel cleanliness to perform colonoscopy.

AIM

To implement a less distressful and more efficient preparation for colonoscopy preparation, to improve bowel cleansing.

METHODS

After obtaining the permission from the local National Health System management in 2022, 1-liter of PEG (1L-PEG) and ascorbate (ASC) was administered to patients as colonoscopy preparation, instead of the usual 4-liter of PEG.

RESULTS

The 1L-PEG + ASC gave improved results at the end of 2023, with 96.33% of acceptable cleansing among the screened population, of which 63.56% resulting in Optimal cleaning level for the Boston Scale. The colonoscopy adherence from patients increased in the period observed from 78.30% to 85.20%.

CONCLUSION

Implementing 1L-PEG + ASC gave better results than other preparations and diminished patient distress, leading to an increase in the operative colonoscopies percentage, and positively influencing the adherence to the screening protocol.

Key Words: Colorectal cancer; Colonoscopy preparation; Polyethylene glycol; Diagnostics; Colonoscopy; Preventive medicine; Oncological screening; Oncology; Drugs implementation; Medical protocols

Core Tip: The 1-liter of polyethylene glycol and ascorbate was introduced to enhance colonoscopy preparation from the standard (4-liter of polyethylene glycol, distressful for patients due to the volume and not operatively optimal due to poor bowel cleansing). Results from pilot study (426 patients) showed above 90% of the patients with adequate bowel cleansing (Boston Scale value ≥ 6). Provincial screening results from 2022 to 2023 after the renewed protocol resulted in 96.33% of the population having adequate bowel cleansing for colonoscopy, with 63.56% showing optimal cleaning. Patients’ compliance increased of +5.30% for 1^st and +3.90% for 2^nd level screening protocols.

INTRODUCTION

Diseases uncontrolled propagation is an extended health problem, not only for the individual but also from the social and economic standpoint. In particular, the occurrence of tumors has a major contribution to the general issue. Therefore, activating and properly endorsing screening protocols within the population, is crucial to prevent the harmful degeneration of neoplasms and contain healthcare financial burden.

Colorectal cancer (CRC) is the second occurring type of neoplasm by incidence on both sexes and third among cancers (breast and lung cancer, first and second respectively)[1]. As for 2020, more than 1.9 million of people worldwide suffered of CRC.

As per Xi and Xu[2], the incidence and deaths have been significant in that year, and by projection they appear to rise worldwide in the next two decades. In particular, the new cases increase between 2020 and 2040 was expected to be of 23.8% in Italy, of 18.6% in Russia, 32.9% in United States, of 64.3% in India, and of 64.2% in China. It is expected an increase in the Italian mortality rate on the order of 25.3%, of the Russian by 21.1%, of the American by 31.7%, of the Indian by 40.7%, and of the Chinese one by 47.6%. For what concerns Italy, in 2024, 48706 new cases (27473 males, 21233 females) were expected[3], which is close to the number of cases seen from 2017 to 2019 (44100) and anticipated yearly from 2038 to 2040 (47700) in United Kingdom[4]. United States, on the other hand, estimated 153020 new cases of CRC in 2023[5]. As per 2018 data, CRC appears more common in men than women, and with an higher incidence per 100000 individuals in Australia and New Zealand (41.7), Europe (37.5 overall, with local incidence being 40.4 for Southern Europe, 37.5 for Northern Europe, 37.5 for Central and Eastern Europe, and 34.5 for Western Europe), Eastern Asia (32.0), and North America (29.5), compared to a worldwide incidence per 100000 individuals of 23.6 cases[6].

In respect to mortality in 2018[6], CRC is the second deadliest type of neoplasm worldwide, reaching in some countries the first place for male patients Saudi Arabia, EAU and Oman, in which it has also the highest incidence between cancers, and the first place for female patients in Spain, Japan, Portugal, Belarus and Algeria. Overall, the highest mortality on 100000 assisted between both sexes are registered in Hungary (male: 31.2, female: 14.8), Slovakia (male: 29.5, female: 14.4), and Croatia (male: 27.4, female: 12.7). As comparison, worldwide in the same year, the mortality rate for CRC on 100000 assisted was 10.8 for male patients and 7.2 on female patients.

Ultimately, if we consider the mortality trend for CRC in Italy[7], the timespan between 2010 and 2021 shows a mostly stable behavior (Figure 1), with an average value of 19095 deaths in said period of time. This, together with the increase in the incidence of CRC tumors in the youngest portion (40-54) of the population (while a decrease has been registered in the older one – 65 > years old)[8], urges the Italian National Health System (NHS) to promptly take action in order to reduce the toll taken from said pathology from the population.

Figure 1 Trend of mortality for colorectal cancer in Italy from 2010 to 2021. The behavior is mostly constant in the lapse of time observed. CRC: Colorectal cancer.

The main instrument to lower this trend is the use of promptly, reliable oncological screening protocols, while ensuring population undergoes said diagnostic pathways.

As the screening rounds progress, lesions diagnosed at an early-stage increase compared to advanced ones, allowing to intervene promptly with easier, less expensive interventions. Nevertheless, since with a positive fecal immunochemical test (FIT) the risk of carcinoma or adenoma is very high[9], it is essential to guarantee high levels of compliance within the successive colonoscopy analysis. Low adherence rates can negate the massive organizational effort of the abovementioned resources that screening entails. On the other hand, the national public screening protocol, endorsed on the population older than 50 years old, proved historically fruitful, by lowering both the incidence and the mortality rate on said segment of the population as registered from AIRC (Italian Association for the Research on Cancer), in particular with a decrease of -11% of the mortality between the years 2020 and 2025[10].

Colonoscopy is the recognized gold standard as 2^nd level test for CRC screening[11,12], and is a necessary procedure for polypectomy.

The Ferrara’s province Complex Operational Unit of Oncological Screening, proficient in both standardized[13] and experimental[14,15] screening protocols and technologies, follows the NHS-standardized colorectal screening protocol in two levels, with screening and diagnostic facilities organized as follows[13,15,16]: (1) 1^st level: Screening centers, 1^st level reading laboratories: FIT (24 test collection centers), 138 test distribution pharmacies; and (2) 2^nd level: 4 endoscopies, 3 radiology, and 1 surgeries.

The flow charts summarize the full course of the CRC screening protocols, for the 1^st level (Figure 2A) and 2^nd level (Figure 2B) of screening.

Figure 2 Flow chart schematizing the full course of the Italian national colorectal screening protocol. A: Fecal immunochemical test (1^st level) screening schematization; B: Colonoscopy (2^nd level) screening schematization. Shades of gray are used to highlight critical phases in the screening chain. FIT: Fecal immunochemical test.

The interventions in the existing medical protocol which allowed to develop and refine it are the following: (1) Guaranteeing an active offer, with periodical free tests to the entire population in the age group, mostly proved to contract the illness, which appeared to be vital to keep the positive trend going; (2) Identifying precancerous lesions and neoplasms at an increasingly early stage, which contributed to a significant reduction in mortality; and (3) Guaranteeing a quality diagnostic-therapeutic path by applying the defined protocols.

Colonoscopy quality, which affects diagnostic accuracy, depends on the adequate intestinal preparation. Optimal cleaning level improves adenoma detection rate, reduces procedural times, lowers probabilities of having to re-enact said intervention or procedure rescheduling, leading to reduction of adverse events probability and overall costs lowering, while improving patients’ compliance.

The state of cleanliness is for the most part not favorable to visual diagnostics, due to the presence of feces not yet expelled. The recognized scale for colorectal cleansing quality is the Boston-Bowel-Preparation-Scale (BBPS), a qualitative measurement that spans from 0 (not prepared for colonoscopy) to 3 (no solid residual, mucosa well visible), attributing one value for each colon three parts (right, transverse and left). Once summed, it gives the overall cleansing value of the complete colorectal tract (from a minimum of 0 to a maximum of 9)[17].

According to the Boston scale measurement, the cleaning success (CS) was defined as a total BBPS score ≥ 6, with a partial BBPS score ≥ 2 in each segment. High-quality cleansing of the right colon was defined as a partial BBPS score of 3. Values varying from 0 to 1, for single tracts, do not allow proper colonoscopy intervention. For this reason, adequate preparation of the patient bowel is required, by usage of proper medical concoctions.

International guidelines recommend the use of high-volume or low-volume polyethylene glycol (PEG)-based regimens, as well as validated non-PEG-based products in fractionated dosing modes. However, higher volume solutions may impact patient compliance and preparation adherence, and often result in suboptimal cleansing.

The old medical preparation protocol expected a two doses laxative intake of two liters each, for a total of 4-liter of PEG (4 L-PEG). In this paper is presented the benefit from the usage of a one-liter-volume new combination with ascorbate (ASC) and PEG [1-liter of PEG (1 L-PEG) + ASC], split in two doses of half liter.

The effectiveness of this new treatment has been investigated in multiple pilot studies and first cases of protocol implementations between 2021 and 2024[18-22], comparing 1 L-PEG + ASC split-dose with 4 L-PEG, 2-liter of PEG (2 L-PEG) and Patient, Intervention, Comparison, Outcome (PICO)-based, 2 L-PEG + ASC, and PEG + sodium picosulfate with magnesium citrate (SPMC) concoctions as colonoscopy preparation, with overall common better results on bowel cleansing for 1 L-PEG + ASC preparation[23-25].

Vassallo et al[18] compared efficacy, safety and tolerability of 1 L-PEG + ASC vs a 4 L-PEG-based high-volume preparations in both inpatients undergoing colonoscopy and outpatients (among 10 Italian centers from March 2022 to September 2022). Here, the focus is on the CS, being cleansing success the study target, with greater focus on reaching right colon high-quality cleansing, as well as improved patient compliance, tolerability and safety, and better detection rate for adenomas. 478 patients were randomized to 1 L-PEG + ASC (n = 236) or 4 L-PEG (n = 242). The 1 L-PEG + ASC approach gave a greater cleansing success (91.8% vs 83.6%; P = 0.01) and right colon high-quality cleansing (52.3% and 38.5%; P = 0.004) while compared to the 4 L-PEG. Thus, from the study of Vassallo et al[18], a higher quality right colon cleansing rate compared to the 4 L-PEG was observed, while the adenoma detection rate, tolerability, and incidence of adverse events are comparable between the preparations.

Repici et al[19] evaluated efficacy between 1 L-PEG + ASC preparation and a high-volume 4 L-PEG, using fractionated dosing over two days. Total 388 patients (average age: Approximately 60 years) were recruited in 2019: (1) 195 patients took 1 L-PEG + ASC; and (2) 193 patients took the 4 L-PEG. Successful bowel cleansing was achieved in approximately 97% of patients, while in the right colon segment, a cleansing success of 98% was obtained. The 1 L-PEG + ASC compliance, compared to 4 L-PEG protocol, was greater overall [178/192 patients (92.7%) vs 154/190 patients (81.1%)], while no difference regarding safety and detection rate was observed. High quality cleanliness (total BBPS 8-9) was achieved for 78.7% of patients in the 1 L-PEG + ASC group and in 64.5% of patients in the 4 L-PEG group.

Maida et al[20] compared 1 L-PEG-ASC to other bowel preparations (BPs). A random-effects model was applied to pool the results. The analysis showed significantly higher CS with 1 L-PEG-ASC: (1) Overall group: Odds ratio (OR) =1.50; 95%CI: 1.25-1.81, P < 0.01, I² = 0%, 6720 participants; and (2) Fractionated dosing subgroup: OR =1.44; 95%CI: 1.16-1.80, P < 0.01, I² = 0%, 5958 participants.

Results from a multicenter retrospective observational study from López-Jamar et al[21] were analyzed as well. Specifically, 13180 patients were recruited, but due to ineligibility criteria, the actual number of tested subjects was 13169. Of all the patients (n = 13169), those who took the split dose (n = 4316) are less than a half of those who took the single dose (n = 8853). For this reason, the total percentage of patients who achieved high-quality intestinal cleansing is lower than the average of the two, measured for the different individual treatments (obviously, the percentage with the highest number, at a single dose, weighs more on the total average).

The cleansing level values measured were: (1) Single dose (n = 8853): Right colon: Average BBPS score 2.28, patients achieving high-quality cleansing: 41.4%. Left colon: Average BBPS score 2.32, patients achieving high-quality cleansing: 42.0%. Transverse colon: Average BBPS score 2.36, patients achieving high-quality cleansing: 45.0%. Patients achieving adequate cleansing overall colon: 86.7%; (2) Split dose (n = 4316): Right colon: Average BBPS score 2.60, patients achieving high-quality cleansing: 65.4%. Left colon: Average BBPS score 2.71, patients achieving high-quality cleansing: 74.0%. Transverse colon: Average BBPS score 2.71, patients achieving high-quality cleansing: 73.0%. Patients achieving adequate cleansing overall colon: 94.7%; and (3) Total (n = 13169): Right colon: Average BBPS score 2.38, patients achieving high-quality cleansing: 49.3%. Left colon: Average BBPS score 2.45, patients achieving high-quality cleansing: 53.0%. Transverse colon: Average BBPS score 2.47, patients achieving high-quality cleansing: 54.0%. Patients achieving adequate cleansing overall colon: 89.3%.

Scalvini et al[22] performed a real-world study between 2021 and 2022 involving 1779 patients comparing 1 L-PEG to 2 L-PEG and PICO-based (sodium picosulphate) mixtures, showed how the former provided better BP cleaning quality than the other two methods. In fact, 1 L-PEG preparation scored adequate BP cleanliness in 611 cases over 677 (90.3%), while 2 L-PEG scored it in 772 cases over 948 (81.4%) and PICO in 125 cases over 157 (81.2%). For what concerns right colon cleansing, again the best BP cleanliness was obtained with 1 L-PEG in 579 cases over 635 (91.2%), while with 2 L-PEG just 734 over 880 reached it (83.4%) and 119 over 144 (82.6%) with PICO preparation. The 1 L-PEG was the only preparation capable to exceed the European Society of Gastrointestinal Endoscopy minimum standard of 90% for adequate BP.

Nalankilli et al[23] presented a randomized study where a total of 164 patients were evaluated, allocated to 1 L-PEG + ASC (n = 82) or PEG + SPMC 1.25 L mixture (n = 82), and compared the BBPS between the two groups. The 1 L-PEG + ASC preparation was demonstrated not inferior to the PEG + SPMC, with 89% patients achieving successful preparation (total BBPS ≥ 6 and each sub-score ≥ 2) compared to 85.4% in the PEG + SPMC group (estimated difference of 3.7%, 95%CI: -6.6% to 13.9%). The median BBPS was non-inferior in all colon segments with 1 L-PEG + ASC [BBPS =3 (interquartile range 2-3)] vs PEG + SPMC [BBPS = 2 (interquartile range 2-3)].

The 1 L-PEG + ASC proved better for colorectal cleansing than higher volume doses of the same preparation. In their multicentered randomized study, Hong et al[24] tested 174 patients with 1 L-PEG + ASC and 172 with 2 L-PEG + ASC, and the former concoction showed non-inferior overall bowel cleansing success rates (93.10% vs 91.86%; difference, 1.24%; 1-sided 97.5% lower confidence limit, -4.31%; P_{noninferiority} < 0.0001; P_superiority = 0.661), while delivering greater high-quality bowel cleansing in overall and right-sided colon [49.43% vs 37.79% (P = 0.029) and 60.92% vs 48.84% (P = 0.024), respectively]. The polyp detection rate was greater with 1 L-PEG + ASC compared to 2 L-PEG (48.85% vs 37.79%, P = 0.038), while adenoma detection rate did not differ between the 2 groups (24.71% vs 20.35%, P = 0.331). Although treatment-emergent adverse events were slightly higher in the 1 L-PEG + ASC group than in the 2 L-PEG group (65.71% vs 52.91%, P = 0.015), most treatment-emergent adverse events were mild (85.55%) and most patients recovered without any management (99.23%).

Finally, as per Zessner-Spitzenberg et al[25], a study on 335466 colonoscopies, along 10 years (2012-2022), was conducted on Austrian patients. In this case, due to the starting year of the study, the Aronchick Scale, a graduation to determine colorectal tract cleaning antecedent to the Boston Scale, was used. Aronchick Scale is divided in five different grades: (1) Excellent; (2) Good; (3) Fair; (4) Poor; and (5) Inadequate. A Fair cleaning on Aronchick Scale equals a cleaning value of 6 in the Boston Scale. From this 10-year study, it was observed that adenoma detection capacity was not significantly lower between “excellent” and “good” level BP, while it was notably lower between “good” and “fair” level bowel cleaning. In particular, the statistics for the two conditions were: (1) “Excellent vs good” level cleaning: OR = 1.01, 95%CI: 0.9971-1.0329, P = 0.1023; and (2) “Good vs fair” level cleaning: OR = 0.97, 95%CI: 0.9408-0.9939, P = 0.0166.

Additionally, “fair” or lower BP level patients at screening colonoscopy had higher hazards for PostColonoscopy CRC death. Statistics in this regard are: (1) “Fair vs excellent” hazard ratio (HR) = 2.56, 95%CI: 1.67-3.94, P < 0.001, showing significant correlation between CRC death in screening participants; and (2) “Fair” or inferior BP, with a risk that was more than twice as high as compared with individuals with “excellent” preparation. Looking at poorer BPs, HRs increase as: (1) “Poor vs excellent” HR = 2.88, 95%CI: 1.63-5.08, P < 0.001; and (2) “Inadequate vs excellent” HR = 4.66, 95%CI: 2.10-10.34, P < 0.001.

Further strengthening the suggestion that the biggest contributor to CRC mortality risk in individuals with insufficient BP might be a lower detection ability of adenomas, due to improper visualization of the whole colorectal’s mucosa. Coherently, in the same study, an increase of detected polyps’ number was observed with the worsening of BP.

In light of these previous studies, 1 L-PEG + ASC preparation was tested on a pilot study, and then fully implemented in the public colonoscopy protocol in 2022 from the U.O.C. Oncological Screenings of Local Health Agency of Ferrara. The results of this protocol variation are presented in this work.

MATERIALS AND METHODS

To improve the manuscript quality following major health protocols standards and enhancements procedures, SQUIRE 2.0 guidelines were used as reference checklist for this research[26]. They have been followed as framework during the manuscript development, and they are attached as Supplementary material to this publication. All authors had access to the study data and reviewed and approved the final manuscript.

As per European GDPR legislation and Italian privacy laws, data de-identification was carried out directly on the closed NHS platform Dedalus, anonymizing directly the data before the analysis from the team. Data were collected directly from said platform from the authorized physicians in the team.

The recruitment of the tested population was carried on under the Italian national screening program, with periodical invites every two years via ordinary mail and electronic patient record. People assisted by that program spans from 50 years to 69 years[27], and was recently expanded by law-decree in Emilia Romagna region (the one in which the experimental data have been acquired) to include also the 70-74 age group[28], and have thus their FIT carried out. If positive, the colonoscopy test is prescribed to verify the possible presence of neoplasms in the colorectal trait.

As by standard protocol for colonoscopy, 4 L-PEG concoction was prepared from the patient to drink, and either two liters have to be taken the evening before the colonoscopy and two liters in the morning, in case the exam is scheduled for the next afternoon, or both doses of two liters have to be drunk the day before in case the test is scheduled in the morning.

The split dose approach proposed in this work consists in a combination of PEG + ASC, with the preparation following the same timetable, but the dosage is half liters of solution each, way less stressful for the patient. The only setback of this second type of preparation is that patients affected from favism cannot consume it due to intolerance to the drug.

Following the abovementioned preparation, the patients underwent colonoscopy examination in Sant’Anna Hospital, Ferrara.

The degree of colorectal cleansing, and thus the capacity of the colonoscopy to properly inspect the colorectal tract, was defined by using the Boston Scale, which is graduated as follows[17]: (1) Cleaning impossible – Boston Scale value from 0 to 2 (colon segment not cleansed with mucosa not visible due to solid material that cannot be removed); (2) Inadequate cleaning – Boston Scale value from 3 to 5 (portion of mucosa visible, but other surrounding areas are not adequately visible due to opaque liquid and/or residual solid material); (3) Less than optimal cleaning – Boston Scale value from 6 to 7 (few residues remaining, small solid fragments and/or opaque liquid, however the mucosa is clearly visible); and (4) Optimal cleaning – Boston Scale value from 8 to 9 (entire segment of colon mucosa clearly visible without any residue, free of fragments and opaque liquid).

This scale considers preparation for the colonoscopy to be adequate/satisfactory (therefore not to be repeated) when all three scores of the colon sections considered are greater than or equal to 2 (level 2 cleaning corresponds to less than optimal and therefore good cleaning), thus having a total value equal or greater than 6.

A prospective pilot study was conducted on 426 assisted patients. All patients involved in the pilot study, where selected from the standardized NHS database Dedalus, as assisted included in the Italian NHS CRC screening program (male and female from 50 years to 70 years old, recently upgraded to 74 years old since 2024), in a lapse of time within one year.

The selection of the 426 patients was carried out by excluding assisted affected from different comorbidities, in order to focus the study on effectiveness of the protocol proposed in respect to CC without external influences. Criteria for the enrollment of the patients in this preparation phase were: (1) Type of sedation; (2) Whether or not the cecum was reached during colonoscopy; (3) Degree of intestinal tract cleansing (Figure 3); (4) Complications during the diagnostic examination; and (5) Number of polyps seen, removed, and recovered, and for each polyp, histological diagnosis, size, location, degree of dysplasia, and endoscopic description.

Figure 3 Cleaning levels frequency distribution on a population of 426 patients from Sant’Anna Hospital (Cona, Ferrara, Italy). The vertical bold black lines divide good cleaning (colonoscopy possible) and bad cleaning (colonoscopy not viable).

Criteria of exclusion to the 1^st level of screening for assisted patients are: (1) Known presence of CRC; (2) Having undergone colonoscopy in the screening timeframe; (3) Being under hereditary-familiar observation for gene mutations known for causing CRC onset; and (4) Being already under observation and therapy due to chronical pathologies of the colorectal tract.

All patients were positive to FIT (1^st level of screening) and undergoing colonoscopy (2^nd level of screening) within 13 hours from the former exam.

The demographic correlated to the two GROUPS are here schematized: (1) Group 1: 213 patients (control: 106, test: 107), average age of 58.62, SD = 5.96, men: 12.68% (27), 4 L-PEG (control) 6.10% (13), 1 L-PEG + ASC (test) 6.58% (14), women: 87.32% (186), 4 L-PEG (control) 43.66% (93), 1 L-PEG + ASC (test) 43.66% (93); and (2) Group 2: 213 patients (control: 106, test: 107), average age 62.93, SD = 5.96, men: 79.34% (169), 4 L-PEG (control) 39.44% (84), 1 L-PEG + ASC (test) 39.90% (85), women: 20.66% (44), 4 L-PEG (control) 10.33% (22), 1 L-PEG + ASC (test) 10.33% (22).

The differentiation on biological sexes was carried out to verify the absence of possible trends due to this variable in the cleaning effectiveness.

Consequently to the results from this pilot study, a five years retrospective study was carried out between the years 2019 and 2023 on all the patients undergoing 2^nd level of colorectal screening (colonoscopy), in order to verify variations in bowel cleansing and assisted adherence due to 1 L-PEG + ASC implementation in the screening protocol (starting year 2022).

Statistical analysis

For what concerns the statistical analysis, SDs, P values and confidence intervals have been calculated and reported in the “RESULTS” section.

RESULT

In addition to the literature, data from a local pilot study, and consequently from the standard colonoscopy screening program, have been studied in order to verify the benefits from the implementation of 1 L-PEG + ASC in the Italian NHS scenario.

A prospective study was conducted from part of the team on a total population of 426 patients (Figure 3).

In the Y-axis, frequency from 0 (0%) to 0.8 (80%), indicates how the micro-groups are distributed in percentage of cleanliness. Example: 0.78 in abscissa group 2 for layer 2-stretch 2 (high dark green column) indicates that 78% of the patients tested, had a less-than-optimal level of cleanliness. Split dose gave better results than with traditional dose administration, showing higher percentage of patients with adequate cleansing, greater tolerability and a lower incidence of side effects. It is important to notice that the Y-axis value is not strictly definable as probability density from a statistical point of view, because on the X-axis there is not a continuous variable, but rather a discrete one, following a Boston Scale-based legend.

Complete data from the last five years (from January 1, 2019 to December 31, 2023) colonoscopy tests on 2^nd level CRC screening for the Sant’Anna Hospital (province of Ferrara), in respect to bowel cleaning levels following Boston Scale, are presented as a prospective study along said period of time (Figure 4).

Figure 4 Colonoscopy cleaning levels for the province of Ferrara. Number of patients treated are indicated between parentheses. CRC: Colorectal cancer.

As per the introduction of 1 L-PEG + ASC use in 2022, while the percentage of acceptable cleaning increased globally from 92.61% to 96.33% in 2023, the overall quality of the cleaning level increased, with “optimal” level reaching from 48.40% in 2019 to 63.56% in 2023, an increase of +15.16%, while “less than optimal” level dropped from 44.21% in 2019 to 32.76% in 2023. Both “inadequate cleaning” and “cleaning impossible” levels, and consequently “% of not acceptable cleaning” level, decreased more consistently from the 2022 in respect to the previous years, with the “% not acceptable cleaning” dropping from 7.39% in 2019 to 3.67% in 2023, and showing a notable gap due to the introduction of the 1 L-PEG + ASC protocol between 2021 (6.99%) and 2022 (4.20%). With a registered minimum at 3.67% of not performed colonoscopies due to not acceptable bowel cleaning in 2023, the trend shows promising results in reducing delays and/or requiring re-invitation for patients, reducing further distress to the assisted and increased costs for public medical structures.

From these histograms it is shown a substantial improvement in intestinal cleansing with split dose compared to the traditional dose. Patients taking split dose show, unlike other patients, a higher percentage of good intestinal cleaning, according to the Boston Scale. Since the cleaning levels are comparable between the two micro-groups, it can be stated that patients’ biological sex does not appear to influence the preparation.

For what concerns the obtained data (Figures 3 and 4), the following P value statistical analysis has been carried out: (1) Group 1: 213 participants, 106 control subgroup, acceptable cleaning: 58, not acceptable cleaning: 48, 107 test subgroup, acceptable cleaning: 104, not acceptable cleaning: 3, SD = 0.05851, Z-value: 7.21670, P < 0.00001; (2) Group 2: 213 participants, 106 control subgroup, acceptable cleaning: 52, not acceptable cleaning: 54, 107 test subgroup, acceptable cleaning: 103, not acceptable cleaning: 4, SD = 0.06095, Z-value: 7.70567, P < 0.00001; (3) Total pilot study: 426 participants, 212 control subgroup, acceptable cleaning: 110, not acceptable cleaning: 112, 214 test subgroup, acceptable cleaning: 207, not acceptable cleaning: 7, SD = 0.04227, Z-value: 10.54954, P < 0.00001; and (4) Total screened (5 years, from 2019 to 2023): 8286 participants, 4863 control subgroup, acceptable cleaning: 4524, not acceptable cleaning: 339, 3423 test subgroup, acceptable cleaning: 3288, not acceptable cleaning: 135, SD = 0.00518, Z-value: 5.83245, P < 0.00001.

After the implementation within the local colonoscopy protocol of 1 L-PEG + ASC preparation, the adherence to the 2^nd level of screening (colonoscopy) improved as follows (data from various yearly surveys)[29,30].

Since the implementation of the reduced dosage in 2022, the overall adherence rose steadily to over 85% from that moment, compared to the previous years where the adherence was around 78%-82% (Figure 5). At the first year of 1 L-PEG + ASC protocol introduction (2022, with adherence at 85.10%), it is observable and increase of +3.90% in the adherence to colonoscopy testing in respect to previous year (2021, adherence 81.20%).

Figure 5 Colonoscopy adherence data (2^nd level testing), comparison for the province of Ferrara and Emilia Romagna region. An increasing trend has been verified along the years of observation.

The data considered regard only colonoscopy adherence, since computer assisted detection colonoscopy and computed tomography scan exams dictates a different type of preparation (sodium amidotrizoate and meglumine amidotrizoate), and thus the patients assisted with those medical protocols were not included in this study.

Data for adherence to 1^st level screening (FIT) adherence for Ferrara’s province CRC screening are provided (Figure 6). The whole year 2020 was regionally considered as a standalone for data collection, in respect to the two years periods, due to the variations (and limitations) in the national screening protocol during the coronavirus disease 19 pandemic. With the adoption of low volume intestinal preparation in a fractionated dosing regime, a substantial increase was observed in the colorectal 1^st from 53.30% in 2021-2022 a 56.20% in 2023-2024 for Ferrara’s province, compared to 53.20% and 52.80% for the regional average in Emilia Romagna, as well as patients’ compliance and responsibility. Being the increase parallel to the one observed with the previous observed, with a coherent spike in the trend (+5.30%) between 2020 (48.00% of adherence) and 2021-2022 (53.30% of adherence), and its positive trend of further +2.90% in 2023-2024 (56.20% of adherence), partly correlated to the new protocol implementation, it is implied that the update in the medical protocol with reduced doses of concoction per patient had its beneficial effect on compliance also in this part of the screening, with the knowledge of lower distress for the patients undergoing eventual required colonoscopy.

Figure 6 Data of fecal immunochemical test adherence (1^st level testing), comparison for the province of Ferrara and Emilia Romagna region. Adherence to fecal immunochemical test for Ferrara’s province colorectal cancer screening. An increasing trend has been verified along the years of observation. FIT: Fecal immunochemical test.

DISCUSSION

The usage of PEG and ASC, combined with low volume formulations, the dose’s fractional administration, and the few hours of “runaway time” between the preparation end and the colonoscopy beginning, seem to be the determinant factors of an effective, safe and less distressing preparation for the patient.

Bowel cleaning levels in the closed study showed above 90% values, while after implementation the percentage of acceptable colorectal cleaning level in the second level screening patients reached 96.33%, together with an increase of the overall quality of said cleaning (up to 63.56% of “Optimal cleaning” patients in 2023).

Speaking of the CRC treatment expenses, Bhimani et al[31] reviewed how for a private Health-Care System the costs of treating CRC varied substantially between different studies and countries, despite the medical treatment having similar clinical settings and perspectives. The average cost per patient (2018 United States dollars) ranged relevantly between: (1) Surgical costs: $1149-$34606; (2) Chemotherapy: $1883-$18021; and (3) Radiotherapy: $2037-$5347.

FIT is a standardized, user friendly, non-invasive, repeatable and economical test with which patients’ fecal material is monitored for traces of blood. In Italy, this screening is standardized under NHS management, with invites every two years from the 50^th year of age for each citizen, in search for signs of neoplasia. This approach allowed to lower CRC mortality in the Italian state of approximately 62% among men and approximately 54% among women[32]. These results were obtained because of the increased early-stage lesion diagnoses through progression of the screening rounds, allowing early detection and therapeutic treatment. As per year 2023, cost of screening and treatment of CRC at an A1 grade public medical structure (University Hospitals, Scientific Hospitalization and Treatment Institutes headquarters with three-year clinical faculty training period of medicine and surgery, and hospitals with more than 300 beds with the presence of functions 2^nd level Emergency-Urgency), are below schematized. These costs are intended as maximum refunding from the NHS toward the hospital institute to cover services delivered to the patient, as per regional legislation[33].

Benign neoplasms screening and intervention: (1) FIT + colonoscopy + polypectomy = €126 per case treated; and (2) FIT + colonoscopy + hemicolectomy = €7685.36 per case treated.

Computer assisted detection colonoscopy can be used as non-invasive alternative to colonoscopy, but it is more expensive, and in any case, in presence of benignant neoplasms, invasive intervention would be required for the removal.

Malignant neoplasms intervention: (1) Hemicolectomy + adjuvant chemotherapy = €12110.13-€14758.37 + chemotherapy costs per case treated (variable); (2) Hemicolectomy + palliative chemotherapy = approximately €25000-€45000 to increase survival by 12-30 months; and (3) Palliative chemotherapy + biological drugs (targeted therapies) = approximately €40000-€60000 to increase survival by 12-30 months.

Metastasis onset alters significantly the overall costs, due to eventual additional surgeries on secondary cancer and personalized pharmaceutical treatment, as well as other criticalities or complications that may occur. For this reason, the esteemed costs are calculated on a conservative approach, as per literature and the research group experience.

On that matter, preventive screening allows to heavily cut these costs by enacting early intervention on still benignant cases, reducing malignant neoplasms onset and the requirement of the abovementioned treatments.

As per data observation, a positive trend in the adherence was registered, as seen for the 1^st (+5.30% in the first year of introduction) and 2^nd (+3.90% in the first year of introduction) level CRC screening, due to the reduction of the distress given from the lower volume concoction ingested for colonoscopy preparation. This consequentially increased early intervention neoplasms, cutting operating costs in case of their future possible degeneration into cancers.

In respect to previous works, it has been observed how 1 L-PEG + ASC improved the bowel cleansing as predicted, both in precedent pilot studies[19,21,23,24] and screening campaigns[18,20,22,25], with more patients showing high levels cleansing values and enhanced overall acceptable cleansing levels after the implantation of the drug.

Limitations on the study are given by the provincial nature of the implementation itself (even thou multiple hospitals in the Ferrara’s province are involved, the screening center remains a single-center institution), while waiting for the regional and national entities to expand the protocol into other cities and institutes, to strengthen the data with a regional observation of the effects of 1 L-PEG + ASC implementation. Also, due to the coronavirus disease outbreak in 2020, with all the institutes having their delays and closures, a longer window of observation might be required to observe a standardized screening population adherence, rather than just the years from 2019 to 2023.

As future improvements to the protocol, it will be mandatory to increase the advertisement of the implementation of the drug within the screened population, in order to increase the knowledge about the less stressful preparation and thus encourage the assisted to adhere to the 2^nd level of screening. It will be also required to continue in the next years the observation in both bowel cleansing quality and adherence trends, in order to verify in the long run the effective contribute of the introduction of 1 L-PEG + ASC to CRC screening protocol. Finally, it is required a study to verify, as per Zessner-Spitzenberg et al[25], if the enhancement in bowel cleansing (and assisted adherence) actually brought also with the passing of time a variation in the detection of early adenomas with reduction of CRC cases.

CONCLUSION

The new drug’s implementation proved to be functional to both the betterment of bowel cleaning of the assisted patients and to the population participation to all levels of colorectal screenings and diagnostics.