**2. Clinical manifestations**

It should be noted that retroperitoneal tumor in children is primarily not clinically manifested and has no specificity during a long period of time. The primary tumor symptom complex is a variety of pathological manifestations caused by the influence of the tumor process on metabolism, immunity, and functional activity of the regulatory systems of the body. The most common symptoms are physical inactivity, lack of appetite, weight loss, lethargy, asthenia, rapid fatigability, moodiness, anemia, low-grade fever, and abdominal pain. The syndrome of minor signs of a tumor is present in most patients, but usually neither parents nor doctors attach significant importance to it. Usually, the first clinical manifestation is a palpable tumor in the abdomen, which is found accidentally. The tumor is smooth, sometimes coarse-grained, dense, painless, and moderately mobile. Macrohematuria occurs in less than 1/4 of patients and is considered a manifestation of tumor invasion into the renal pelvis system. Arterial hypertension is often observed [9].

Surgical treatment of both tumors is mandatory in antitumor therapy. In accordance with the recommendations of the SIOP (International Society of Pediatric Oncology) protocol used in European countries, chemotherapy is performed within 4 weeks before surgery in order to reduce the risk of intraoperative tumor rupture [10, 11].

Successful treatment of solid tumors involves early diagnosis, radical removal of the tumor with an extensive operative exploration of abdominal organs and regional lymph nodes, as well as neoadjuvant and adjuvant chemotherapy. The use of ablastic methods in the surgical treatment of tumors, which include photodynamic therapy (PDT), is becoming extremely important.

PDT is a treatment method based on the use of photosensitive substances, i.e., photosensitizers (FS) and light of a certain wavelength. FS selectively accumulates in the tumor tissue, then the affected tissues are illuminated with the light generated by special surgical laser units. As a result of subsequent cellular photochemical reactions, reactive oxygen species are released destroying pathological cells, causing nutrition disorders, leading to tumor apoptosis due to the damage to its micro-vessels. The antitumor effects of PDT in vivo result from three interrelated

#### *Photodynamic Therapy in Complex Therapy of Retroperitoneal Tumors in Children DOI: http://dx.doi.org/10.5772/intechopen.101884*

mechanisms, namely direct cytotoxic effects on tumor cells, damage to the tumor vascular network, and induction of a strong inflammatory reaction that can result in the development of a systemic immune response [12–15]. The established presence of an immunological component of photodynamic effect indicates the prospects of combining PDT and immunotherapy methods to improve the results of cancer treatment [16].

The use of photodynamic therapy in the treatment of oncological diseases has begun relatively recently. To date, the vast majority of works devoted to the use of PDT are studies carried out in the adult population, their purpose is to clarify the therapeutic effectiveness of PDT, identify priority FS and the scope of their application [17, 18].

However, the problem has been little studied in pediatric population, since it is associated with certain difficulties caused by limited technical capabilities and lack of application experience. Despite the great interest of researchers in this method, there are few data on the use of PDT in pediatric patients. There are only some works indicating the high efficiency of PDT application in pediatric dentistry, dermatology, and ophthalmology [19–22].

Nevertheless, the anatomical and physiological features of childhood require the development of specific therapeutic techniques: namely schemes and modes of use, taking into account the age and severity of the disease. We have not found data about the methodology and optimal modes of PDT, as well as the use of Radachlorine as FS for the treatment of solid tumors and the prevention of intraoperative metastasis in children in the literature review. This made it necessary to further study the possibilities of PDT in the treatment of solid tumors in children and determine the purpose and objectives of this study. Taking into account the data obtained during the preclinical study [23], we are to prove the effectiveness of PDT using Radachlorine photosensitizer aiming at increasing the clinical efficiency (5-year survival rate) of treatment of children with solid retroperitoneal tumors.

### **3. Materials and methods**

The study was performed in the surgical department and Oncologic Hematology Center for Children and Adolescents named after Professor V.I. Gerain of the State Budgetary Healthcare Institution "Chelyabinsk Regional Children's Clinical Hospital."

The studied group consisted of 93 patients with retroperitoneal tumors (48 boys and 45 girls), 66 patients with nephroblastoma, 27 patients with adrenal neuroblastoma. Taking into account the performed therapy, the patients were divided into two groups: the comparison group and the study group. The comparison group (control) received therapy according to the protocols SIOP 93, SIOP 2001, NB2004. The study group consisted of patients who received photodynamic therapy in addition to the standard treatment.

The comparison group included 47 patients with retroperitoneal tumors, including 35 patients with nephroblastoma and 12 patients with adrenal neuroblastoma. The study group included 46 children: 31 patients with nephroblastoma and 15 patients with adrenal neuroblastoma. The distribution of patients into treatment groups depending on the type of tumor is shown in **Table 1**.

The patients of the clinical groups were divided into age subgroups according to the age periodization according to A.V. Mazurin, I. M. Vorontsov [24]. **Table 2** shows the distribution of patients by age.

Depending on the gender, the patients of the studied groups were distributed in the following way as presented in **Table 3**.


#### **Table 1.**

*Distribution of patients into clinical groups depending on the type of tumor.*


#### **Table 2.**

*Distribution of patients in clinical groups by age.*


#### **Table 3.**

*Distribution of patients into clinical groups depending on gender.*

As can be seen from **Table 2**, in both clinical groups, the vast majority of patients are children of early age group from 0 to 3 years, that is, 62 children (66.7%). The next group is preschool-age children from 4 to 6 years, that is, 24 children (25.8%). Retroperitoneal tumors are revealed less frequently in older children, there are only seven patients in the age group older than 7 years (7.5%). The number of boys and girls in the clinical groups of patients is almost the same (**Table 3**): 48 boys (51.6%) and 45 girls (48.4%). The findings received by us do not contradict the literature data [10, 11, 25, 26], according to which retroperitoneal tumors develop more often in children aged 1–3 years, and in 90% of cases, the diagnosis is made before the age of 7. Our study also did not establish gender prevalence in the occurrence of tumor in children. The incidence among boys and girls was the same.

Depending on the therapy to be carried out, the patients were divided into two groups. Patients of the comparison group underwent surgical treatment in combination with chemotherapy and radiation therapy according to the protocol. Patients of the study group received therapy according to the SIOP protocol in combination with PDT.

All children with an identified oncological condition underwent a complex of mandatory diagnostic tests, in accordance with the Clinical Recommendations of the Ministry of Health of the Russian Federation. Patients with retroperitoneal tumors necessarily underwent a physical examination to determine density of the tumor surface, mobility, and size of the growth. Palpation of all accessible groups of peripheral lymph nodes was performed. Blood pressure measurement and neurological status assessment were mandatory.

Laboratory tests included clinical blood analysis, common urine analysis, biochemical blood analysis (electrolytes, whole protein, liver samples, creatinine,

#### *Photodynamic Therapy in Complex Therapy of Retroperitoneal Tumors in Children DOI: http://dx.doi.org/10.5772/intechopen.101884*

urea, lactate dehydrogenase, alkaline phosphatase) and a study for tumor markers of NB catecholamines in urine and serum, NSE (to exclude NB).

Studies of molecular biological markers (N-MYC oncogene amplification and 1p deletion) and histological examination were carried out, and histomorphologic diagnosis in all patients with WT and NB was made. Taking into account the data obtained, the tumor process was staged according to SIOP and NWTS.

Instrumental methods of examination included ultrasound of the abdominal cavity organs and retroperitoneal space with blood flow mapping, CT of the abdominal cavity organs and retroperitoneal space with intravenous contrast, MRI of the abdominal cavity and retroperitoneal space with and without contrast enhancement. If necessary, angiography and a radioisotope study of the kidneys were performed to assess kidney function. Compulsory examinations were electrocardiography and echocardiography.

Special attention was paid to safety and ethical issues of the study.

The study was approved by the local Ethics Committee of GBUZ CHODKB— Protocol No. 17 of 20.03.2015. The sampling of patients was carried out on a voluntary basis. The clinical trial was conducted in accordance with the scientific and moral principles set out in the Helsinki Declaration of the World Medical Association and reflected in OST 42-511-99 "Rules for Conducting Qualitative Clinical Trials in the Russian Federation," ICH GCP rules and current regulatory requirements. All patients were provided with written information about the drug prior to the study. Legal representatives and patients were informed in detail by the doctor who conducted the study about the procedure of introducing a photosensitizer. Before starting the study, the parents signed an informed consent form confirming their voluntary participation.

The inclusion criteria in the study on the effectiveness of PDT in retroperitoneal tumors in children were:


Based on the results of a comprehensive examination, an "Individual Case Record" was filled in for each patient, including a complete anamnesis, laboratory data, and diagnostic studies.

An assessment was carried out in both groups of patients after PDT and complex treatment within two months. The effectiveness of therapy was evaluated according to standard criteria (WHO), taking into account the dynamics of surgical treatment, tumor recurrence, as well as the patient's condition. Later, postoperative follow-up was carried out on an outpatient basis for 5 years, every 6 months (10 visits). The tumor was monitored, dynamic data control of laboratory findings, ultrasound, and CT were carried out.

To assess the effectiveness of PDT, the operational characteristics of the test were used in accordance with the principles of evidence-based medicine. Criteria for the effectiveness of the conducted PDT:


The safety of the participants was ensured:


There were no valid data on adverse medical consequences published. Spectral fluorescence examination of patients was carried out before the injection of Radachlorine, every hour after the injection of Radachlorine and after the end of the PDT procedure. The accumulation of photosensitizer in the tumor was measured using a laser electron spectral device LESA-01-Biospec. During the measurement, the spectrum was determined by analyzing its shape and amplitude of the signal, the integral intensity of Radachlorine fluorescence at various sites of the tumor and adjacent tissues, and the fluorescent boundaries of the tumor. Also, the intensity of fluorescence of the normal skin of the hands and face and oral mucosa of patients was evaluated. The ratio between the values of fluorescence intensity in the tumor and normal tissue, which characterized the selectivity of accumulation in the tumor tissue, was determined.

PDT with Radachlorine was performed intraoperatively after removal of the tumor by means of a high-intensity laser "Lakhta Milon" (Russia), using laser illumination in the range of 0.1–0.8 W/cm<sup>2</sup> . Depending on the depth of infiltrating tumor growth, various doses of light energy were used—from 150 to 400 J/cm2 , wavelength 650–670 nm, adjusted during an experimental study [23]. The photosensitizer was administered intravenously, at the rate of 0.6–0.8 mg/kg 2–3 hours prior to illumination. The duration of illumination depended on the size of the tumor and averaged 20 minutes.

Statistical data processing was carried out using IBM SPSS Statistics 19 package. The analysis of qualitative characteristics in the studied groups was done by means of construction of cross-tabulation tables and calculation of significance by χ2 -Pirson criterion. The differences were considered statistically significant for p values <0.05, which corresponded to 95% probability of an accurate prediction. To analyze the data of overall 5-year survival and relapse-free survival Kaplan-Meier curves were constructed calculating average survival time, its standard error, and 95% significance interval. A long-range criterion was applied to identify statistical

*Photodynamic Therapy in Complex Therapy of Retroperitoneal Tumors in Children DOI: http://dx.doi.org/10.5772/intechopen.101884*

differences in the survival curves. The differences were considered statistically significant for p values <0.05.
