INTRAOPERATIVE PHOTODYNAMIC THERAPY IN GASTRIC CANCER PATIENTS ИНТРАОПЕРАЦИОННАЯ ФОТОДИНАМИЧЕСКАЯ ТЕРАПИЯ БОЛЬНЫХ РАКОМ ЖЕЛУДКА Intraoperative photodynamic therapy in gastric cancer patients

Results of intraoperative photodynamic therapy (IOPDT) in patients with gastric cancer are represented in the article. The study included 240 patients with gastric cancer stage II-IV ( Т 3-4N0-3M0-1) with evident or suspected peritoneal dissemination who underwent examination and treatment in P.Herzen Moscow Oncology Research Institute. The group 1, the study group, included 140 patients who underwent nominally curative or palliative surgery for locally advanced and disseminated gastric cancer with IOPDT as additional intraoperative intervention for antiblastics and cancer treatment. The group 2, the control group, included 100 patients who also underwent nominally curative or palliative surgery (equal to extent of surgery in patients from the study group) for locally advanced and disseminated gastric cancer and no intraoperative implication of physical or chemical treatment methods. IOPDT did not worsen a course of early post-operative period, did not impact on severity of post-operative complications and was not associated with increase of post-operative mortality. IOPDT allowed for improvement of 1-year and 3-year disease-speci ﬁ c survival rates: by 16.1% and 16.7%, respectively. For nominally curative resections, median survival, 1-year and 3-year disease-speci ﬁ c survival rates were improved by 14 months, 17.8% and 31.3%, respectively. For R1, R2 resections, IOPDT improved 1-year disease-speci ﬁ c survival rates by 16.4%. Additionally, for nominally curative resections IOPDT did not increase the recurrence rate and improved median recurrence-free survival, 1-year and 3-year recurrence-free survival rates by 16 months, 27.2% and 25.4%, respectively.


Introduction
Gastric cancer is one of the most common cancer digestive tract. In 2015 in Russia in structure of oncological diseases this pathological condition occupied 6th place (6.7%) after cancer of skin, breast and lung [1]. For gastric cancer peritoneal carcinomatosis is the most common type of metastasis [2,3,4] with incidence of 30-40% and median survival no more than 3.1 months without treatment [5].
The main method of treatment of resectable gastric cancer stage I-IV is curative surgery aimed at removal of primary tumor and all loco-regional metastases [6][7][8][9]. However, even for macroscopically complete cytoreduction the possibility of tumor cells diff usion over peritoneum cannot be excluded [10]; consequently surgical methods should be combined with additional antitumor methods. Considering disadvantages of systemic chemotherapy combined with cytoreductive resections for peritoneal carcinomatosis, there is necessity for development of new antitumor methods aimed at not only prevention of tumor cells from spreading over peritoneum but also at destruction of tumor cells. One of the promising directions is photodynamic therapy (PDT).
Results of IOPDT in patients with gastric cancer are represented in the article.

Materials and methods
The study included 240 patients with gastric cancer stage II-IV (Т3-4N0-3M0-1) with evident or suspected peritoneal dissemination who underwent examination and treatment in P. Herzen Moscow Oncology Research Institute from 2005 to 2012. In all patients gastric tumor invaded to serosa and infi ltrated adjacent organs and structures with no distant hematogenous and extraperitoneal lymphogenous metastases.
The group 1, the study group, included 140 patients who underwent nominally curative or palliative surgery for locally advanced and disseminated gastric cancer with IOPDT as additional intraoperative intervention for antiblastics and cancer treatment. The group 2, the control group, included 100 patients who also underwent nominally curative or palliative surgery (equal to extent of surgery in patients from the study group) for locally advanced and disseminated gastric cancer and no intraoperative implication of physical or chemical treatment methods.
The age of patients accounted from 20 to 73 y.o. The minimal age in the study group and in the control group was 20 and 27 y.o., respectively; the maximal age -72 and 73 y.o., respectively. The average age in the study group was 54.4±11.1 y.o., in the control group -57.1±11.2 y.o. More than a half of patients (133 patients (55.5%)) were in socially active age group of 20-59 y.o. There were no diff erences by age between groups (t-test, p=0.95).
According to full examination data, 180 (75%) of 240 patients had diff erent co-morbidity: 111 (79.3%) patients in the study group and 69 (69%) patients in the control group. There were no diff erences in the co-morbidity rate and structure between groups (F-test, χ 2 =3.29; p=0.07).

Intraoperative photodynamic therapy technique
For PDT we used photosensitizer fotogem (produced by "Fotogem", Russia), a hematoporphyrin derivative. Fotogem was administered intravenously at a dose of 2.5 mg/kg body weight 48 h before surgery. Patients kept light regimen for 3-4 weeks after injection.
Surgical step was performed according to tumor distribution. If applicable, complete removal of primary tumor and all peritoneal metastases was done, where defi nitive treatment was impossible, palliative surgery with removal of primary tumor and maximal volume of peritoneal dissemination was carried out.
For both scenarios, IOPDT session was performed after completion of surgical step with sequential polypositional irradiation of all regions of parietal peritoneum at a dose of 6-10 J/cm 2 (Fig. 1). Exposure of visceral peritoneum was carried out by scattering irradiation and irradiation from a source of incoherent emission -operating lamp -for the duration of surgical procedure.

Results
Effi cacy of IOPDT in patients with gastric cancer was analyzed by comparing results of treatment in the study and control groups. For this purpose completeness of cytoreduction, rate and profi le of post-operative complications, mortality in early post-operative period and long-term results were assessed.

Characteristics of the surgical step
All patients had extended and combined surgery. The duration of surgical step accounted from 3 to 6.5 h.
The curative potential of gastric surgery was characterized using Japanese Classifi cation of Gastric Carcinoma, JGCA (1998) [11]. According to this classifi cation 3 types of resections are defi ned: А, В and С. Resection А implies curative surgery and appropriate for primary tumor T1 or T2 and for stage M0 (H0 -no liver metastases, P0 -no dissemination); N0 treated by D1, D2, D3 lymphadenectomy; N1 -D2, D3 lymphadenectomy; this type of resection is characterized by Cyt 0 -no tumor cells in peritoneal lavage, and also by proximal and distal margins clearance more than 10 mm. Resection B implies resections with no residual disease (R0) but not fulfi lling criteria for "Resection A". This type of resection was defi ned as nominally curative surgery. For resection С, there is micro (R1) or macro (R2) residual tumor, this type is equivalent to palliative surgery. If unresectable tumor is detected during the surgery and surgery is terminated on this step this surgical intervention is defi ned as exploratory surgery. There were no resections A and no exploratory surgeries in our study. Distribution of patients according to curative potential of gastric surgery is represented in table 1.
Thus, in the study and control groups rates of resections R0 and R1, R2 were approximately equal (rates of Intraoperative photodynamic therapy in gastric cancer patients  In the study and control groups the majority of surgical procedures were combined resections (61.4% and 61%, respectively) due to extent of tumor. Gastrectomy was combined with resection of transverse colon, pancreas, liver, diaphragm, spleen. D2, D3 lymphadenectomy was performed. There was no diff erence in extent of surgery between groups (F-test, for distal subtotal gastric resection -p=0.57; for gastrectomy -p=0.52; for combined resection -p=0.53).

Early post-operative period
To compare the study group with the control group for course of post-operative period we used follow-ing criteria: rate of acute post-operative complications, profi le of acute post-operative complications, grade of acute post-operative complications, necessity for surgical treatment of complications and mortality. Chosen criteria allow assessing feasibility of IOPDT with no risk of worsening of early results of treatment.
Acute post-operative complications were in 32 (22.9%) of 140 patients in the study group and in 26 (26%) of 100 patients in the control group. Statistical analysis of rates of post-operative complications in the study and control groups with F-test showed no diff erences (p=0.32).
In the profi le of acute post-operative complications there was no colon anastomotic leakage in the control group (p=0.58) comparing with the study group, but there were acute myocardial infarction (p=0.42) and intraabdominal hemorrhage (p=0.42). Statistic analysis using F-test showed no signifi cant diff erences in the profi le of acute post-operative complications. The p-values for necrotizing pancreatitis, anastomotic leakage, acute intestinal obstruction, infl ammation in lungs and pleura, thrombosis, wound infection when compared control group vs. IOPDT were 0.53, 0.21, 0.51, 0.39, 0.46, 0.65, respectively.
Surgical treatment for early post-operative complications was performed in 9 (28.1%) of 32 patients of the study group and in 8 (30.8%) of 26 patients of the control group. Statistic analysis of rates of surgeries for early post-operative complications using F-test showed no signifi cant diff erences between the study and control groups (p=0.52).
There were 3 (2.1%) deaths in the study group and 3 (3%) patients died in the control group. Causes of death were pulmonary thromboembolism and necrotizing pancreatitis. Statistic analysis of mortality using F-test showed no signifi cant diff erences between the study and control groups (p=0.32).

Long-term results
To evaluate effi ciency of IOPDT long-term results in the study and control group were analyzed. For disease-    specifi c survival the end-point was a death of a patient from cancer disease. For recurrence-free survival the end-point was a recurrence or progression of cancer in patients who underwent nominally curative surgery. Patients who died in early post-operative period from complications (n=6) were excluded from the analysis. Long-term results were obtained in 97.5% of patients.
For the study group, maximal follow-up period was 72 months with median survival of 20 months. One-year disease-specifi c survival accounted for 70.6±3.9%, 3-year -39.6±4.3%. For the control group, maximal follow-up period was 58 months with median survival of 13 months.
For the study group, in patients with nominally curative resections maximal follow-up period was 72 months with median survival of 41 months. One-year disease-specifi c survival accounted for 96.1±2.2%, 3-year -71.4±5.5%. For the control group, maximal fol-low-up period was 58 months with median survival of 27 months. One-year disease-specifi c survival accounted for 78.3±5.5%, 3-year -40.1±6.8%. Statistic analysis using Log-Rang Test showed signifi cant diff erence between groups (p=0.05) (Fig. 3).

Intraoperative photodynamic therapy in gastric cancer patients
For the study group, in patients with R1, R2 resections maximal follow-up period was 21 months with median survival of 8 months. One-year disease-specifi c survival accounted for 38.3±6.3%. For the control group, maximal follow-up period was 20 months with median survival of 7 months. One-year disease-specifi c survival accounted for 21.9±6.4%. Statistic analysis using Log-Rang Test showed signifi cant diff erence between groups (p=0.04) (Fig. 4).
For the study group, in patients with nominally curative resections the recurrence diagnosed in 52 (66.7%) of 78 patients, in the control group -in 43 (74.1%) of 58. Statistic analysis using Log-Rang Test showed no signifi cant diff erence between groups (F-test, p = 0.23).
For the study group, in patients with nominally curative resections maximal follow-up recurrence-free period accounted for 72 months with median recurrence-free survival of 37 months. One-year recurrence-free survival accounted for 89.4±3.5%, 3-year -51.9±6.1%. For the control group, maximal follow-up recurrence-free period accounted for 58 months with median recurrence-free survival of 21 months. One-year recurrence-free survival accounted for 62.2±6.5%, 3-year -26.5±6.2%. Statistic analysis using Log-Rang Test showed signifi cant diff erence between groups (p=0.03) (Fig. 5).

Discussion
Historically methods of additional antitumor methods developed from irrigation with solutions and instillation of radioactive substances to implication of photosensitizing agents for photodynamic destruction of tumor implants and also to implication chemotherapeutical agents injected to peritoneum at doses exceeding standard ones for systemic treatment [12]. Toxicity of intraperitoneal chemotherapy may be high and effi ciency of disease control depends considerably on histological structure of the tumor [13,14]. Despite the active development of intraperitoneal chemotherapy treatment results in patients with gastric cancer with peritoneal carcinomatosis remain unsatisfactory: post-operative complications are up to 40%, post-operative mortality -20%, median survival rates -6-15.4 months, 1-year survival rates by Kaplan-Meier -up to 50.7% [15][16][17].
In our study, IOPDT did not worsen a course of early post-operative period, did not impact on severity of post-operative complications and was not associated with increase of post-operative mortality when comparing the study and control groups (p=0.32). IOPDT allowed for improvement of median survival, 1-year and 3-year disease-specifi c survival rates: by 7 months, 16.1% and 16.7%, respectively (p=0.07). For nominally curative resections, median survival, 1-year and 3-year diseasespecifi c survival rates were improved by 14 months, 17.8% and 31.3%, respectively (p = 0.05). For R1, R2 resections, IOPDT improved median survival and 1-year diseasespecifi c survival rates by 1 month and 16.4% (p=0.04), respectively. Additionally, for nominally curative resections IOPDT did not increase the recurrence rate (p=0.23) and improved median recurrence-free survival, 1-year and 3-year recurrence-free survival rates by 16 months, 27.2% and 25.4%, respectively (p =0.03).

Conclusion
Intraoperative photodynamic therapy is an effi cient and safe method of intraoperative intervention in patients with gastric cancer with high risk or confi rmed peritoneal dissemination. Widespread implementation of the method into clinical practice will promote improvement of oncological treatment results in this group of patients.