Support Care Cancer DOI 10.1007/s00520-013-2051-9

ORIGINAL ARTICLE

Intravesical instillations with polydeoxyribonucleotides reduce symptoms of radiation-induced cystitis in patients treated with radiotherapy for pelvic cancer: a pilot study Pierluigi Bonfili & Pietro Franzese & Francesco Marampon & Maria Emilia La Verghetta & Silvia Parente & Manuela Cerasani & Daniela Di Genova & Marta Mancini & Francesca Vittorini & Giovanni Luca Gravina & Valeria Ruggieri & Mario Di Staso & Vladimir M. Popov & Vincenzo Tombolini & Ernesto Di Cesare

Received: 11 April 2013 / Accepted: 12 November 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose Chronic radiation cystitis (CRC) is a serious complication that can arise in patients with pelvic malignancies treated with radiotherapy. Polydeoxyribonucleotides (PDRNs) are known to reduce inflammation and improve tissue perfusion and angiogenesis. In this manuscript, we describe our observational experience regarding intravesical instillation of PDRNs in improving symptoms of CRC in subjects unresponsiveness to conventional medical therapy. Pierluigi Bonfili and Pietro Franzese equal contributed to this work. P. Bonfili (*) : P. Franzese : V. Ruggieri : M. Di Staso : E. Di Cesare Division of Radiotherapy, San Salvatore Hospital, 67100 L’Aquila, Italy e-mail: [email protected] F. Marampon : M. E. La Verghetta : S. Parente : M. Cerasani : D. Di Genova : M. Mancini : G. L. Gravina : E. Di Cesare Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy and Radiobiology Laboratory, San Salvatore Hospital, University of L’Aquila, 67100 L’Aquila, Italy F. Vittorini Department of Medical Physic, University of L’Aquila, 67100 L’Aquila, Italy V. Tombolini Department of Department of Radiotherapy, University of Rome “La Sapienza”, 00161 Rome, Italy V. M. Popov LIPOGEN LLC, Mount Laurel, NJ 08054, USA V. M. Popov Department of Cancer Biology and Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, 19107 Philadelphia, USA

Methods Eight patients with persistent and/or worsening CRC symptoms, despite conventional therapy, received biweekly intravesical instillation of PDRNs for two consecutive months. Symptoms were scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale, before, at the end, and after 4 months following the PDRNs treatment. Results Four months after instillations, a significant improvement in the subjective perception of CRC symptoms was experienced by participants. The mean LENT-SOMA score was reduced from 1.16+0.26 before to 0.34+0.035 after 4 months from instillations (p 41 ng/ml

Gleason 4+4=8 cT3a, cN0, M0 PSA of >28 ng/ml

cT3a, cN0, M0 PSA of >30 ng/ml

pT1a2, pN0, M0

pT1b, pN0, M0, G3

Cancer staging

Table 1 Demographic and clinical characteristics of selected subjects

0–45 Gy pelvis 45–50.4 Gy boost 0–45 Gy pelvis 25 Gy brachytherapy 0–45 Gy pelvis 45–65 Gy seminal vesicle + prostate 65–75 Gy prostate 0–45 Gy pelvis 45–65 Gy seminal vesicle + prostate 65–75 Gy prostate 0–45 Gy pelvis 45–65 Gy seminal vesicle + prostate 65–75 Gy prostate 0–45 Gy pelvis 45–54 Gy boost 0–45 Gy pelvis 45–54 Gy boost 0–45 Gy pelvis 45–54 Gy boost

Radiotherapy treatment dose/field

Capecitabine

Capecitabine

Capecitabine

Enantone Bicalutamide

Enantone Bicalutamide

Enantone Bicalutamide

Chemo or hormone therapy

18.27

23.6

15,8

18.9

12.7

21.4

27.3

16.4

10.1

Time interval between the end of radiotherapy treatment and the beginning of intravesical instillations (months)

17.1

17.7

12.8

19.1

18.3

15.4

16.7

21.2

15.9

Time of pharmacological treatment before intravesical instillations (weeks)

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acute (ARC) and chronic (CRC) form [1–4]. ARC symptoms can occur during and up to 3 to 6 months following the treatment, while CRC manifests approximately 6 months following the end of treatment. ARC symptoms are generally self-limiting and controlled with medical therapy, while CRC symptoms tend to be more difficult to manage [2–4]. Common CRC symptoms and clinical findings include urinary frequency, urgency, dysuria, hematuria, possible sphincter dysfunction, reduced bladder capacity, ulceration, and the potential for perforation and fistulation. Tissue injury induced by radiation is the result of progressive vascular changes which ultimately lead to tissue hypovascularity, hypocellularity, and tissue hypoxia, thereby compromising normal healing even after relatively minor trauma. The vascular changes include vascular endothelial hyperplasia, vascular occlusion, and perivascular fibrosis. Normal smooth muscle is replaced by fibroblasts, which lay down collagen, resulting in fibrosis as well as decreased bladder compliance and capacity [2–4]. Polydeoxyribonucleotide (PDRN) adenosine is a purine nucleoside that is released from a variety of cells in response to several types of stresses [5]. It has been suggested that adenosine regulates inflammation via interaction with one or more of its four known receptors (A1, A2A, A2B, and A3) [6, 7]. PDRNs, obtained from trout sperm by an extraction process [8] or from human placental extract [9], exert their antiinflammatory effects through the stimulation of the A2A receptor [8, 10], impact on vascular bed restoring blood flow [11], and improve angiogenesis [12]. PDRNs’ antiinflammatory action achieves maximum efficiency under pathologic conditions of low tissue perfusion, as occurs in the bladder wall of patients with CRC [2–4]. In the present study, we evaluate if PDRNs intravesically injected improve symptoms of subjects with persistent and/or worsening CRC symptoms and unresponsive to conventional medical therapy.

contracture [2, 13, 14]. In order to exclude other conditions able to mimic CRC symptoms, a complete evaluation of the urinary tract was performed. The initial evaluation included urinalysis to assess hematuria and to measure urine pH, urine culture to confirm or rule out infection, urinary cytology to screen for bladder tumors, and bladder ultrasound to exclude papillary bladder tumors or bladder stones. In selected cases, patients with hematuria underwent a complete blood count (CBC), the coagulation status, and cystoscopy and renal imaging when clinically required. Indications for treatment with intravesical instillation of PDRNs, in association with pharmacological therapy, depended on the degree of symptoms present and the patient’s sense of needed to be treated. Grade 2 symptoms, according with RTOG scale, were treated only if the patient was bothered by them, while all patients with grade 3 and higher clinical presentations were always treated. All patients were subjected to a biweekly intravesical instillation of 10 ml of polydeoxyribonucleotide 50 % (Placentex® 50 %), added to 50 ml of physiologic solution containing 160 mg of gentamicin for a total of 8 weeks. Gentamicin was used to prevent superinfection related to the instillation procedure. A single-use catheter with an outer side diameter of 4 mm (12 Ch) was used to first empty the bladder and then fill the bladder with the 50 ml solution. Patients were asked not to void for at least 2 h after the instillation. Upon polydeoxyribonucleotide, the patients’ outcome was evaluated according to the Late Effects of Normal TissuesSubjective, Objective, Management, Analytic (LENTSOMA) scales on the basis of their documented signs and symptoms and were scored accordingly [15, 16]. This scale was preferred to other measures since it is highly sensitive and specific in measuring changes in genitourinary symptoms over time with respect to other scales commonly used in radiotherapy [15, 16]. LENT-SOMA scale was filled out, before the instillations, at the end of treatment and 4 months Table 2 Trend of improvement in the mean score of LENT-SOMA

Materials and methods This study was performed during the period between January 2012 and January 2013 at the Radiotherapy Unit of University of L’Aquila (L’Aquila, Italy) on eight patients affected by pelvic cancers who have previously received RT or CHT– RT treatments with curative intent. Demographic and clinical characteristics of selected subjects are presented in Table 1. Selection of patients was based on the presence of persistent and/or worsening CRC symptoms, and subjects were recruited only after failure of pharmacological treatments. Medical therapy used to control the genitourinary CRC symptoms was based on the individual or combined use of phenazopyridine (200 mg×2/day) for dysuria, oxybutynin (5 mg, 1 capsule (cps)×2/day) for urinary urgency, flavoxate (100 mg, 1 cps× 2/day), and tamsulosin (0.4 mg, 1 cps/day) for bladder neck

Patient number LENT-SOMA Before PDRNs End of PDRNs Four months after the treatment treatment end of PDRNs treatment 1 2 3 4 5 6 7 8 Mean + SD

0.91 1.22 1.16 0.92 1.23 1.18 0.94 1.71 1.16+0.26

0.61 0.93 0.85 0.61 0.81 0.88 0.82 0.84 0.79+0.11

One-way ANOVA test with post hoc analysis

0.43 0.41 0.37 0.31 0.29 0.31 0.28 0.36 0.34+0.035

Support Care Cancer Fig. 1 LENT-SOMA scores before, at the end, and after 4 months following intravesical instillations of PDRNs (average value ± standard deviation)

1.6 1.4 1.2 1 0.8 0.6

Mean

0.4

SD

0.2 0 Before PDRNs At the end of Four months Treatment PDRNs treatment after the end of PDRNs treatment ° One-Way ANOVA test with post hoc analysis

from the last instillation. Exclusion criteria were the following: (1) previous surgery of the lower urinary tract, (2) patients with a catheter in situ, (3) multiple metastases, (4) cachexia, and (4) bladder fistulas. The local medical ethics committee approved this study, and all participants signed an informed consent. Statistical methods Continuous variables were condensed by means and standard deviation (SD). Differences in continuous variables were analyzed by Student’s t test when two groups were compared or with one-way ANOVA test. The post hoc analysis significance level was adjusted using the Bonferroni method when one-way ANOVA test was used. p values of

Intravesical instillations with polydeoxyribonucleotides reduce symptoms of radiation-induced cystitis in patients treated with radiotherapy for pelvic cancer: a pilot study.

Chronic radiation cystitis (CRC) is a serious complication that can arise in patients with pelvic malignancies treated with radiotherapy. Polydeoxyrib...
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