13. Photodynamic Therapy of Vater Papilla Cancer and
Common Bile Duct Cancer

E.Ph.Stranadko, A.I.Lobakov, A.V.Mokin

Abstract

Success which has been achieved in treating cancer of outer and inner localizations with photodynamic therapy (PDT) is a basis for applying this technique for treating cancer in extrahepatic bile ducts and in the periampullary area.

Out of 1500 patients who have been treated a particular attention has been paid to those with malignant tumors of hard-to-get-at localizations. This problem cannot be considered solved up to now. Cancer of the large duodenal papilla (LDP) and common bile duct has just such localization.

Currently, we have gained experience of treating 17 patients with LDP cancer and cancer of the common bile duct which in some cases had extended to the duodenal wall and to the pancreas head.

17 patients had 24 PDT courses. Seven PDT courses were made repeatedly at various time intervals after the first PDT course (from 2 years to 1 year 9 months) because of continuing tumor growth. Out of 12 patients followed-up for more than 6 months after PDT 9 patients are still alive. The life span of 7 patients who had PDT treatment more than one year ago varies from 14 to 60 months. The medium life span is 2.5 years.

Introduction

PDT is a well-known organ-sparing technique for treating a number of various diseases and, first of all, of malignant tumors. For this a photosensitizer which is selectively accumulated in tissues with increased metabolism is used. Then these pathologically changed tissues with accumulated photosensitizer are locally irradiated with the light having the wavelength corresponding to the peak of this photosensitizer absorption. The reaction which develops in presence of oxygen triggers production of singlet oxygen and other active oxygen forms which damage tumor cells. As a result we can see tumor resorption [3, 9, 21, 32, 42]. The effect produced by active oxygen forms looks like either direct cytotoxic damage [24, 29, 32] or destruction of vessels delivering blood to the tumor [25, 31]. Most of all antitumoral PDT reactions affect vascular mechanisms (about 60 %). PDT also stimulates immune responses of the organism directed against the tumor due to the direct inflow of lymphocytes, neutrophiles and macrophages to irradiated tumor tissues (even this fact alone inhibits tumor growth) and due to the effect produced by cytokines (interleikin 6 and interleikin 10) which are responsible for antitumoral PDT effect [27, 34-36, 38].

PDT opens a wide range of possibilities for various curative effects of radical and palliative character when other curative methods are ineffective or are not applicable at all.

The aim of the present work is to develop techniques which could be used for treating one of the most aggressive cancers having hard-to-get-at localization as well as to evaluating effectives of PDT technique when being applied for cancer of the large duodenal papilla and common bile duct.

Materials and methods

Currently, PDT is widely used mostly for treating skin cancer, lower lip cancer, cancer of the tongue, cancer of oral mucosa; less frequent - for treating esophagus cancer, lung cancer, uterine cervix cancer, bladder cancer; very rarely - for treating malignant brain tumors, breast cancer, cancer of colon and rectum as well as cancer of pancreas, bile ducts, primary and metastatic tumors in the liver [6, 7, 10, 42, 45-49). Modern technical possibilities which have appeared in medicine recently have made PDT available for practical application as well as rather effective for treating LDP cancer and bile ducts cancer [8, 11, 13, 14, 17, 18, 23, 39-41].

LDP cancer is a rarely seen malignant tumor. LDP cancer in combination with tumors of the distal parts of pancreas ducts (Virsung duct) and of the common bile duct and of the duodenal mucous in the area of Vater papilla is called “Vater papilla cancer” or “periampullary cancer” [1, 5, 13].

In statistical analyses and in multiple publications cancer of the periampullary area is included into the chapter “Cancer of Pancreas”. It is true, while progressing this cancer extends, first of all, to the pancreas head; moreover, the most radical surgical methods for treating cancer of periampullary area and cancer of pancreas head imply one and the same surgery – gastropancreaticoduodenal resection. We would like to mention here some statistical data taken from the book by A.M.Garin and I.S.Bazin “Ten the most wide-spread malignant tumors” (Moscow, 2006). According to the world’s oncologic statistics in 2002 pancreas cancer by morbidity rate ranked the 13th place and by mortality – 8th. In absolute figures there were 232306 diagnosed patients, 227023 of them died. Ratio “death-to-disease” is approaching 1 – 0.98. Such formidable ratio has not been described to any other forms of cancer. Practically, morbidity and mortality rates are equal.

The optimal method for treating Vater papilla cancer is thought to be gastropancreaticoduodenal resection (GPDR). However, despite of advances in surgical techniques, anesthesiology and resuscitation GPDR is still accompanied by severe complications and high postoperative mortality (25 – 40 %). Because of this GPDR is done mostly to the patients with Vater papilla cancer only at its early stages when patients have no contraindications for extended surgical interventions. Sometimes a local tumor resection is used as a less invasive and relatively safe approach; however, it is accompanied with a high recurrence rate. Radical surgeries for bile duct cancer are also accompanied with a high recurrence rate up to 80 % [17, 18]. An average survival period after radical surgery is 1.5 - 2 years. Five-year survival period does not exceed 10 – 20 % [4, 5, 16].

Patients who have contraindications for GPDR and obturated jaundice are usually prescribed palliative interventions: draining endoscopic procedures with embedding endoprosthetic devices or with applying bypass anastomosis. However, tumors rather quickly invade endoprosthetic device with restenosing and jaundice followed. An average survival period after palliative surgeries is 6 - 12 months.

Radiotherapy - both external and intralumenal - for malignant tumors in this zone is technically difficult, little effective and thus, rarely used.

Successful treatment of malignant tumors of various localizations with PDT which has been achieved for the last two decades has enabled researchers to make attempts to use PDT in pancreaticoduodenal area and in extrahepatic bile ducts and, as a result, some publications about it have appeared in medical literature [17, 30, 39, 50, 51, 54].

The first successful PDT application with hematoporphyrin derivatives in the drug dose of 2 mg/kg has been described in the work [39]. In 1985 during cholecystectomy surgery the common bile duct adenocarcinoma was revealed in 50-year old female. The T-like drainage was left in the wound and 2 months later the first PDT session during laparotomy was performed. A light-guiding fiber with a cylindrical diffuser was inserted via a choledochoscope. After PDT session the U-like tube was left in the duct so as to prevent jaundice. Later during the following four years six more PDT sessions have been performed. A choledochoscope was inserted via the U-like drainage. Two years later after beginning PDT treatment of the common bile duct adenocarcinoma, the endometrium cancer was revealed in the same patient. She was operated on for it and had radiotherapy. The patient died 4.5 years later because of metastases in the pleural cavity. It has remained unclear if these metastases were from cholangiocarcinoma or from the endometrium. However, publication of this case has enabled researchers to implement PDT technique into clinical practice for treating the bile ducts cancer.

Having some experience of PDT application for treating cancer of this localization we have decided to present here our preliminary results of treating 17 patients with LDP cancer and the common bile duct cancer extended for some of them to the duodenal wall and to the head of pancreas (see the Table).

Table. Parameters and effectiveness of photodynamic therapy for LDP cancer and common bile duct cancer

Notes:

LDP - large duodenal papilla; Chd – choledoch (common bile duct); PH – pancreas head; Hms – liver metastases; PST – papillosphincterotomy; THD - transhepatic drainage; ChdD – choledoch drainage; LT - laparotomy; ChECT – cholecystectomy; ChES – cholecystoeunostomy; ChdS – choledochostomy; ChS – cholecystostomy; HES – hepaticoeunostomy; TDPECT – transduodenalpapillectomy; ESI - endoscopic superficial irradiation; EILI - endoscopic intralumenal irradiation; ILI - intralumenal irradiation; TDILI - transdrainage intralumenal irradiation; CR - complete tumor resorption; PR - partial tumor resorption; NR – no response (process stabilization); PhS - photosensitizer; PhSS – Photosense; PhDZ - Photoditazine; FSc - Foscan; PhTL – Photolon; DLI – drug-light interval.

In all patients diagnosis has been verified hystologically: 14 patients had adenocarcinoma of various degree of differentiation; 3 patients had a cancer - unfortunately, no additional information about them. Photosensitizers were administrated intravenously for all patients. 17 patients had 24 PDT courses. Seven courses were made repeatedly because of continuing tumour growth at different terms after the first PDT course (from 2 months till 1 year and 9 months).

Depending on tumor localization, its extension and previous curative procedures several delivery routes for light were used:

• superficial irradiation of LDP tumor from the duodenum side with use of a light-guiding fiber, that was inserted via a biopsy channel of the endoscope;

• intralumenal irradiation of the terminal part of the common bile duct with use of a light-guiding fiber with a cylindrical diffuser of 10 - 20 mm long, that was inserted via either the LDP duct or a papillosphincterotomic hole;

• intralumenal irradiation of a tumor-stenosed part of the common bile duct with use of a light- guiding fiber with a cylindrical diffuser of 40 - 50 mm long, that was inserted via a catheter after transcutaneous, transhepatic drainage or via the drainage after palliative surgeries;

• a combined approach for light delivery: superficial irradiation of the common bile duct from the duodenum side and intralumenal irradiation of the terminal part of the choledoch with the light-guiding fiber inserted via a drainage catheter.

The patients randomized for this study were followed-up to evaluate their dynamic picture. For this aim their general condition was examined, laboratory analyses were done in 1 – 2 weeks, 1 – 2 months, 6 months, etc. Their bilirubin levels in blood serum were assessed. The patients also had esophagogastroduodenoscopy with biopsy from the accessible parts of LDP tissues, from the duodenal mucosa. They also had ultrasound examination of the abdominal cavity, computerized tomography with contrasting extrahepatic bile ducts.

Out of 12 patients who were followed-up for more than 6 months after PDT, 9 patients are still alive. In 7 patients who were treated one year ago the survival period was within 14 – 60 months. An average survival period was 2.5 years.

The actuarial survival rate (by Culter-Ederer, 1958) was: 1 – 3 – 5 years per 17, 11, 1 patients and was equal to 77.8 %, 63.6 % and 38.2 %. A small number of cases involved in the study doesn’t allow to consider such survival rate as representative one; however, it gives promising information for further studies in this field.

Discussion

Modern techniques for treating billiopancreaticoduodenal cancer and the results depend on tumor localization and process extension. For better convenience we would like to specify three main lesion areas:

• large duodenal papilla and periampullary area;
• head and body of the pancreas;
• extrahepatic bile ducts.

At the first period of the disease curative modalities and, consequently, results of the treatment depend on the primary localization or on the original point of tumor growth. The most favourable cancer localization for treating in this zone is LDP cancer because it often causes mechanical jaundice, and patients seek for a medical aid at a relatively early stage. That is why radical surgeries are made most often just for this type of localization [5]. When cancer is spreading more to the front, more palliative surgeries and other nonsurgical modalities are applied.

As it is seen from the literature [32, 42, 56] and from our own experience PDT effectiveness depends on the whole number of factors. First of all, it is tumor type (its histological structure) – basically because of various optic properties of the tissue. Then, it is a degree of tumor differentiation and metabolic intensity which predispose photosensitizer’s capture and accumulation in tumoral cells as well as its hold-up duration in the tumor. Besides, these factors also predispose an interaction activity of the photosensitizer used with other photochemical agents which are formed during PDT process; they also determine sensitivity of separate tumor cells and the whole tumor to damaging effects.

That is why even if energetic parameters of laser radiation (power density, energy density) are identical, sensitivity to PDT should be determined for every type of tumor, for organ structure and for tumor localization inside the organ. Moreover, we should take into account that during tumor growth metabolic processes are changing (as a rule, the lower is the degree of differentiation, the more intensive are metabolic processes). The stage of the disease has its impact as well. Unfortunately, up to now there are no tables which could consider all these parameters and multivariate analyses. That is why the type of photosensitizer, its dosage and parameters of photodynamic influence are chosen by a doctor who should use his personal experience and knowledge so as to work out the most optimal treatment modality which could consider individual particularities of the given patient and peculiarities of the given tumor.

PDT is a highly precision technique which selectively affects on tumor due to two factors:

• tumor tissue captures and accumulates photosensitizer and holds it in higher concentration and for longer time than normal tissues;

• cytotoxic effect of photosensitizer is manifested only under its activation by the light of a definite wavelength and in presence of oxygen; that is why one can avoid damaging the adjacent tissues if the light is directed locally to the tumor and if basic dosimetric principles are used.

Up to now the question if additional radio- and chemo- therapy procedures produce favourable effects in case of LDP, pancreatic and bile duct cancer or not has not been answered yet. Prospective and randomized trials have been conducted in small (in numbers) groups of patients. As the majority of authors state the application of one of these additional treating modalities does not prolong survival period in patients after conditionally radical surgeries [44]. Only their combination – chemo-radiotherapy is effective to some extent after radical surgeries if there are no tumor cells at the resection margins. However, the survival period in these patients increases only slightly while the quality of life because of repeated courses, adverse reactions and complications the number of which increases by 30 % decreases significantly [33, 52].

All the arsenal of modern approaches for treating LDP and bile duct cancer cannot provide recovery in all patients. Even extended and combined surgeries which include complete removal and transplantation of the liver do not prolong the life span in patients with this cancer localization [43 and references there], while PDT may be effective even in patients who cannot have a radical surgery with liver transplantation.

Conclusion

Lately, PDT has grown from an experimental technique to a highly effective organ-sparing modality for treating malignant tumors even in the most hard-to-get-at visceral cancer localizations.

PDT decreases cholestasis symptoms, improves the quality of life of patients with Vater papilla cancer and common bile duct cancer.

Results of PDT treatment for cancer of this localization are quite comparable with the results obtained after radical surgeries and are even better for palliative surgeries.

Less rapid tumor growth and longer survival period in patients with residual, nonresorped tumor after PDT treatment are determined, in our opinion, by vascular mechanisms produced by PDT which lead to vascular thrombosis and impaired blood supply in this residual tumor - factors which provide long-term process stabilization.

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