Can we decrease the acute proctitis in prostate cancer patients using hyaluronic acid during radiation therapy: a prospective historically controlled clinical study | ЕВРОЛЕК
ЛЕКАРСТВЕННЫЕ СРЕДСТВА ЕВРОПЕЙСКИХ ПРОИЗВОДИТЕЛЕЙ

Can we decrease the acute proctitis in prostate cancer patients using hyaluronic acid during radiation therapy: a prospective historically controlled clinical study

A. STEFANELLI, G. PASCALE, E. RAINIERI, S. URSINO, M. COLELLA, G. ZINI, M. BERRETTA*, F. FIORICA


Department of Oncology Radiotherapy, Arcispedale S’Anna Universitary Hospital, Ferrara (Italy) *Department of Medical Oncology, National Cancer Institute, Aviano (Italy)

Abstract. — Background: The purpose of this study was to evaluate the ability of rectal sup­pository of hyaluronic acid to limit symptoms of acute radiation proctitis in patients with prostate cancer (PC).

Materials and Methods: From January 2011 to October 2011, 50 consecutive patients, undergoing radiotherapy with radical or adjuvant intent for PC, were invited to use rectal suppository of hyaluronic acid (HA: Cicatridina® suppository, Farma-Derma s.r.l., Sala Bolognese, BO, Italy) daily, before radia­tion delivering. An historical group was used as an external control. Acute rectal toxicity was scored weekly according to RTOG criteria. Time to occur­rence of acute rectal toxicity was taken as endpoint.

Results: Compliance was good. Only 2% of HA treated patients had a G2 acute proctitis versus 7% of historical group, globally a difference was ob­served in rate of acute proctitis between the experi­mental arm and the control group: 32% in experi­mental arm versus 45% in control group (p = 0.08). A delay in the onset of acute rectal toxicity in pa­tients treated with HA (p = 0.04) was showed.

Conclusions: Our findings suggested the role of HA in reducing acute proctitis in prostate can­cer patients treated with radiotherapy. Further trials are needed to confirm these results.

KeyWords: Acute proctitis, Radiotherapy prophylaxis, Hyaluronic acid.

Background

Prostate cancer (PC) is the second most frequent­ly diagnosed cancer among men and the sixth lead­ing cause of cancer death in men worldwide. From the available global statistics, in 2007, an estimated 782,600 new cases were diagnosed and 254,000 pa­tients died of PC1. Definitive external-beam radio­therapy (EBRT) represents an important treatment modality with curative intent for men with localized PC. Several randomized trials have shown that esca­lation of radiation dose improves outcomes in prostate cancer patients2-4. However, when a high dose is delivered, is likely that rectum toxicity in­creases. Indeed, rectal injury is a dose-limiting toxic­ity of radiotherapy for prostate cancer, it produces patient discomfort and reduces both patient compli­ance to treatment and quality of live5. Many pharma­cological agents have been used with prophylactic treatment for radiation rectal injuries: sucralfate6-9, 5- aminosalicylic acid (5-ASA) and its precursors610-12, corticosteroids1314; some studies showing a reduc­tion of rectal toxicity, but with others showing no ef­fect or possibly worsening of symptoms9. Hyaluron­ic acid (HA), a major mucopolysaccharide, is clini­cally used in prevention of radiation cystitis15 and skin reaction16. A recent study demonstrated a radio­protective effect of HA acid in intestinal mucosa17. HA reduces radiation induced apoptosis and in­creases crypt survival. However, no clinical trials have investigated the role of this mucopolysaccha­ride in the prevention of acute proctitis in prostate cancer during radiotherapy. The development of a non-toxic agent, that could simply be administered during radiotherapy to prevent toxicity, would be an important therapeutic advance in prostate cancer. In order to clarify this issue, we decided to analyze whether HA have any role in preventing acute proc­titis due to radiotherapy.

Materials and Methods

Patients and Treatment

Men referred for pelvic radiotherapy for prostate cancer, as adjuvant or radical treatment, were considered for this study. The eligibility criteria includ­ed: signed informed patient consent; age less than 80 years; Karnofsky PS (Performance status) > 60; treatment with radiation doses more than 65 Gy. Pa­tients were ineligible if they had had more than two open pelvic or abdominal surgical procedures; if they had diabetes mellitus, inflammatory bowel dis­ease, active intraluminal gastrointestinal tumors, or a previous history of pelvic RT. Adjuvant hormonal therapy was permitted. The ACE-27 was used to take into account co-morbidities19 prospectively for experimental arm and retrospectively for historical control. In the presence of more than one co-mor­bidity related to an organ system the one with the highest severity was counted. The patients were di­vided in four subgroups: “no”, “mild”, “moderate” and “severe” co-morbidities. To test hypothesis that HA could be effective in preventing acute radiation proctitis, in these patients, rectal suppository of hyaluronic acid (Cicatridina® suppository, Farma- Derma s.r.l., Sala Bolognese, BO, Italy) was daily used concomitantly with radiation delivery. We eval­uated 50 consecutive patients: 19 received radiother­apy as adjuvant therapy, instead 31 with a radical in­tent. Due to the lack of both financial support and drug company interest, we did not have the possibil­ity to provide patients with a placebo product manu­factured in the same way as the medical device. In order to obtain a baseline level of proctitis for our center, we have used an historical control group re­ceived a radiotherapy program from January 2007 to March 2008, 38 patients treated postoperatively and 62 radically. The patient groups were comparable in terms of patient characteristics, radiation dose (total dose and fractionation dose) and radiation tech­nique. This is a case-versus historical control study. To obtain homogeneous data on toxicity, acute mor­bidity was classified according to the Radiation Therapy Oncology Group (RTOG) criteria (Table I)18 and recorded weekly  during radiation.

Radiation Treatment

All patients, experimental group and historical control, had conformal radiotherapy with 15 MV photon beams using CT-assisted three-dimen­sional treatment planning (Pinnacle3 Philips Healthcare P.O. Box10.000 5680DA Best TheNetherlands). When a radical radiation treat­ment was delivered, patients received a median prescription dose of 60 Gy (50-66 Gy) in 2 Gy fractions to the prostate and seminal vesicles plus a 1 cm margin, except posteriorly where the mar­gin was 0.5 cm. Then patients underwent a treat­ment to the prostate alone using a shrinking field technique with a 1 cm margin to a median pre­scription dose of 18 Gy (12-28 Gy) in 2.0 Gy fractions. Instead, in adjuvant setting, patients re­ceived 70 Gy in 2.0 Gy fractions to the surgical bed plus a 1 cm margin, except posteriorly where the margin was 0.5 cm. Dose was prescribed ac­cording to the ICRU 50 (International Commis­sion on Radiation Units & Measurements, 1993) guidelines. All treated patients, in experimental and historical control arm, had a low probability of toxicity, defined as a dose-volume histogram (DVH) below the reference DVH curve defined by the following points: V40 = 60%, V50 = 50%, V60 = 28%, V72 = 15%, V76 = 5%, where VX (%) is the percentage of volume receiving an X (Gy) dose5.

All patients were treated with radiotherapy im­age guided, acquiring 3D image weekly and two 2 D images daily.

Patient Evaluations

According to our policy, we evaluated PC pa­tients during radiotherapy weekly and scored ac­cording RTOG toxicity criteria for each of the following toxicities: proctitis, diarrhea, dysuria, fatigue, weight loss, nausea, and vomiting. Actu­al patient weight was also recorded at each evaluation. In experimental group, it was allowed to treat symptomatic patients with the same modali­ties than historical control in addition to supposi­tory of hyaluronic acid. Evaluations continued throughout RT and concluded with a 4-week post treatment visit. Historical control group included prostate cancer patients consecutively treated in our Radiation Department from 2007 to 2008 with definitive or adjuvant radiotherapy. Data were extrapolated from single case history.

Table I. Acute proctitis according to RTOG scoring system3. GI: gastrointestinal

Grade
0 1 2 3 4
No change Increased frequency or change in quality of bowel habits not requiring medication; rectal discomfort not requiring analgesics Diarrhea requiring parasympatolytic drugs/ mucus discharge not necessitating sanitary pads; rectal or abdominal pain requiring analgesics Diarrhea requiring parenteral support; severe mucus or blood discharge necessitating sanitary pads; abdominal distension Acute or subacute obstruction, fistula or perforation; GI bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion

Statistical Analysis

The primary endpoint of the study was the time to occurrence of acute rectal toxicity. Symp­tom data were analysed by one way analysis of variance and paired t-tests were used for estimat­ing group differences between experimental arm and historical control arm. Survival curves were calculated using the Kaplan-Meier method from the date of treatment start. Differences in acute toxicity rate were assessed by the log-rank test. Actuarial incidence of acute reactions was ana­lyzed in relation to clinical variables: age, comor­bidity, performance status and radiation dose, us­ing univariate and multivariate analyses.

All analyses were conducted with SPSS vers.13.0 (SPSS for Windows, Rel. 13.0 2004. SPSS Inc., Chicago, IL, USA).

Results

Features of Patients at Baseline

All patients in experimental group were eligible for the analysis. Ten out of 50 patients (20%) were over 75 years old, 30 (60%) ranged between 70-74 years and 10 (20%) between 65-69 years. In this co­hort, 19 patients (38%) received a postoperative ra­diotherapy treatment with a dose > 66 Gy with con­ventional fractionation and 31 patients (52%) re­ceived a radical radiotherapy with a dose > 74 Gy.

Twenty-four (48%), 15 (30%) and 11 (22%) pa­tients had a Gleason score of < 6, 7 and > 7, re­spectively. In 37 (74%) patients was observed at least one co-morbidity. The patients’ classification of co-morbidities according to adult comorbidity evaluation-27 (ACE-27) index was 0 in 13 (26%) patients, 1 in 27 (54%), 2 in 9 (18%) and 3 in 1 (2%) patients, respectively. The Karnofsky PS score was: 60, 70-80 and > 90 in 4 (8%), 26 (52%) and 20 (40%) patients, respectively. Twenty-six pa­tients (52%) received radiotherapy in combination with 6 months of androgen suppression therapy. All patients completed the planned treatment. As historical control group, we analyzed retrospective­ly 100 prostate cancer patients treated in our Ra­diotherapy Department from 2007 to 2008, 62 pa­tients (62%) treated radically and 38 (38%) postop­eratively. Patient and treatment characteristics of experimental and historical control group are shown in the Table II. Seventeen out of 100 pa­tients (17%) were over 75 years old, 69 (69%) ranged between 70-74 years and 14 (14%) between 65-69 years. The patients’ classification of co-mor­bidities according to ACE-27 index was 0 in 28 (28%) patients, 1 in 52 (52%), 16 in 2 (16%) and 4 in 3 (4%) patients, respectively. The Karnofsky PS score was: 60, 70-80 and > 90 in 9 (9%), 54 (54%) and 37 (37%) patients, respectively.

Evaluation of Acute Toxicity

Compliance was good, with only one patient not completing the assigned rectal suppository of hyaluronic acid for an acute anal fissure. In experi­mental group, only 16 patients (32%) developed acute rectal toxicity, 14 of them (28%) reported in­creased frequency and rectal discomfort not requir­ing analgesics, therefore, a rectal toxicity classified as G1. Only a patient reported a G2 toxicity. None of the patients developed grade 3 or 4 acute reac­tions. In historical control group, 45 patients (45%) developed radiation toxicity, 38 patients a G1 rectal toxicity and 7 a G2 toxicity. No significant differ­ence (p = 0.21) was observed between experimental and historical group (Figure 1).

The acute toxicity-free rate at the end of treat­ment was 68% ± 6% in HA arm and 55 % ± 5% in historical control group (p = 0.04) (Figure 2). In arm treated with suppository of hyaluronic acid, radiation proctitis was recorded before 5 weeks in only 10% of patients.

The results of the univariate analysis are shown in the Table III, no variable showed pre­dictive value.

Discussion

Acute radiation proctitis is the most relevant acute side effect following external beam irradia­tion for prostate cancer. In literature, it occurrs in up to 75% of patients20-22 and results in bleeding, pain, abdominal cramping, mucoid discharge, and faecal urgency. The onset of symptoms reduces pa­tient compliance, therefore, also radiation efficacy. Consequently, an agent, administered during radio­therapy to prevent toxicity, would be an important therapeutic advance in prostate cancer.

Table II.  Clinical characteristics of the patients

Parameters Experimental group N (%) HA suppository Historical group N (%)
Age (years)
Range 66-80 67-82
Mean 72.06 72.20
Age-groups
65-69 10 (20%) 14 (14%)
70-74 30 (60%) 69 (69%)
> 74 years 10 (20%) 17 (17%)
ACE-27 overall comorbidity score
Grade 0 13 (26%) 28 (28%)
Grade 1 27 (54%) 52 (52%)
Grade 2 9 (18%) 16 (16%)
Grade 3 1 (2%) 4 (4%)
PS
90-100 20 (40%) 37 (37%)
70-80 26 (52%) 54 (54%)
60 4 (40%) 9 (9%)
PSA (ng/ml)
< 10 19 (38%) 39 (39%)
10-20 22 (44%) 42 (42%)
> 20 9 (18%) 19 (19%)
Gleasone score
< 6 24 (48%) 50 (50%)
7 15 (30%) 32 (32%)
> 7 11 (22%) 18 (18%)
Radiotherapy
Adjuvant 19 (38%) 38(38%)
Radical 31 (62%) 62 (62%)
Hormonal therapy
Yes 24 (48%) 51 (51%)
No 26 (52%) 49 (49%)

Table III. Univariate analysis of survival data according to various classifications.

Parameters Groups P ± S.E.M. P = HR (95% CI)
Age category 0:65-69 1: 70-84 2: >75 -0.088 0.197 0.654 0.916 (0.623-1.346)
Comorbidity 0: none 1: mild 2: moderate 3: severe 0.122 0.153 0.425 1.130 (0.837-1.524)
PS 0: 90-100 1: 70-80 2: 60 -0.018 0.207 0.931 0.982 (0.655-1.473)
PSA (ng/ml) 0: < 10 1: 10-20 2 > 20 -0.144 0.179 0.421 0.866 (0.610-1.229)
Gleason score
0: < 6 1: 7 2: > 7
-0.110 0.168 0.515 0.896 (0.645-1.246)
Radiotherapy 0: aduvant 1: radical 0.450 0.281 0.109 1.568 (0.904-2.719)

cicatridina-13-1-1

Figure 1Distribution of no rectal toxicity and of G1 and G2 toxicity for all patients.

Since there are conflicting results in trials avail­able comparing the existing treatment options, firm guidelines cannot be made. Attempts to re­duce radiation-induced proctitis using various agents such as steroids, mesalazine, sucralfate and other have not met with success, probably for mul­ti-factorial genesis of radiation proctitis.

Withers and Mason, in 1974, first identified crypt depletion and deep inflammatory infiltrate in the colon mucosa as a major effect of radiation23.

Disepithelization of the gut mucosa allows intesti­nal contents, e.g., microorganisms, foreign anti­gens, and proteolytic enzymes, access to stromal tissue compartments. This elicits inflammatory and fibrogenic responses that may further damage the mucosa and possibly set the stage for chronic changes in the deep layers of the bowel wall24. Hyaluronic acid is a major mucopolysaccharide found widely in the connective, epithelial and neural tissues. It exhibits a variety of properties that could explain a prophylactic mechanism of pathogenesis of radiation proctitis: inhibition of immune complexes, adherence to polymorphonu­clear cells, inhibition of leucocyte migration, regu­lation of fibroblast and endothelial cell prolifera­tion, enhancement of connective tissue healing, etc25. A recent study17 showed that hyaluronic acid, in animal model, reduces radiation apoptosis and increases intestinal crypt survival. Riehi et al17 clearly demonstrated that HA, administering be­fore radiotherapy, could prevent radiation injury through a bond with tool-like receptor 4 (TLR 4) and an increase in expression of cyclo-oxygenase- 2 (COX-2) and prostaglandin E2 (PGE2). This ap­pealing theory could explain molecular mecha­nism under protection of radiation injury in hu­mans too. Nevertheless, HA is clinically used to treat radiation cystitis15 and other radiation injuries1626 with beneficial results. The aim of the present study was to analyze whether HA has any role in preventing acute proctitis due to radiothera­py in prostate cancer patient. HA is topically ad­ministered by suppository to protect rectal mucosa normally irradiated only for geometrically and dosimetric reasons.

cicatridina-13-1-2

Figure 2. Time to occurrence of acute rectal toxicity for all patients evaluated: 50 treated with HA rectal suppository and 100 historical control.

We did not have the possibility to provide pa­tients with a placebo product manufactured in the same way, so we did not have possibility to test HA in a double-blind randomized study. There­fore, we decided to use an external control con­sisting of patients treated at an earlier time in our Radiotherapy Department. This historical control group has characteristics very similar to patient group treated with HA and have been treated in a similar setting (adjuvant and radical radiothera­py) and in a similar manner (same dose, fraction­ation and machines). Furthermore, the rate of acute proctitis after radiotherapy, to treat prostate cancer, is well known and vary little in literature. In this study, the rate of acute proctitis is 40.7%, with a G2 rate of 5%, these values are compara­ble with literature data using image guided radio­therapy and same dose of radiotherapy27.

In our analysis, rectal suppository of hyaluron­ic acid administered before radiation is well tol­erated, only one patient discontinued treatment. Globally, a difference was observed in rate of acute proctitis between the experimental arm and the control group: 32% in experimental arm ver­sus 45% in control group, although only 2% of HA treated patients had a G2 acute proctitis ver­sus 7% of historical group. Furthermore, analysis of time to occurrence of acute rectal toxicity shows a delay in the onset of symptoms in pa­tients treated with HA (p = 0.04). This effect could be used to increase compliance of prostate cancer patients to radiation therapy. The use of image guided radiotherapy, reducing inadvertent dose deposition in the adjacent rectal tissues28, decreases the rate of acute proctitis. However, in most radiotherapy department image guided radi­ation therapy is not standard treatment, therefore, rectal toxicity has a rate higher than observed in this study. So, improved results could be expect­ed from HA rectal suppositories to prevent acute radiation induced proctitis.

In conclusion, our findings suggested the role of HA in reducing acute proctitis in prostate can­cer patients treated with radiotherapy. It’s impor­tant validate these results with other clinical trials.

Acknowledgements

Grant support: The Authors want to thank Farma-Der- ma s.r.l. for supply suppository.


of-www-cicatridina

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