Palliative Treatment of Advanced Cervical Cancer with Radiotherapy and Thai Herbal Medicine as Supportive Remedy-Analysis of Survival

Advanced carcinoma of the uterine cervix has been recognized to be the major malignant diseases problem in the developing countries and is a particular problem in Thai women (Sriamporn et al., 2004). For these advanced stages of disease, radiotherapy remains the most general treatment available for controlling inoperable tumors as the palliative treatment. The large tumors volume burden in addition to the advanced stage when presented plus the complication of radioresistant tumors were contributing factors to the ability to achieve effectiveness of radiation therapy. Currently, the new gold standard is concomitant chemoradiation for dealing with locally advanced cervical carcinoma (Thomas., 2000., Green et al., 2001; Toita et al., 2012). In addition, The advanced sophisticated radiation techniques such as 3D conformal radiotherapy , intensity modulated radiation therapy (IMRT) along with advanced imaging applications have increased in usage for locally advanced cervival cancer (Petsuksiri et al., 2012). Some of the patients were inaccessible to concurrent chemoradiation because of poor performance status,


Introduction
Advanced carcinoma of the uterine cervix has been recognized to be the major malignant diseases problem in the developing countries and is a particular problem in Thai women (Sriamporn et al., 2004).For these advanced stages of disease, radiotherapy remains the most general treatment available for controlling inoperable tumors as the palliative treatment.The large tumors volume burden in addition to the advanced stage when presented plus the complication of radioresistant tumors were contributing factors to the ability to achieve effectiveness of radiation therapy.Currently, the new gold standard is concomitant chemoradiation for dealing with locally advanced cervical carcinoma (Thomas., 2000., Green et al., 2001;Toita et al., 2012).In addition, The advanced sophisticated radiation techniques such as 3D conformal radiotherapy , intensity modulated radiation therapy (IMRT) along with advanced imaging applications have increased in usage for locally advanced cervival cancer (Petsuksiri et al., 2012).Some of the patients were inaccessible to concurrent chemoradiation because of poor performance status,
The reports of antioxidants combined with therapeutic modalities revealed the enhancement of the therapeutic effects of chemotherapy and/or radiotherapy, a decrease in side effects, protection of normal tissues and also increased survival (Simone et al., 2007).Most of the studies demonstrated evidences of a synergistic effect of antioxidants and radiotherapy and decreased adverse effects of the therapy (Moss, 2007).Based on this rationale, another alternative approach was tried using Thai herbal medicine (Vilac Plus G716/45) as supportive remedy.The Thai herbal tonic (Vilac Plus G716/45) are healthy tonic for all persons (sick or well) and it has been registered as a tonic, available without prescription by the Thai food and drug council.It was proven to have no acute oral toxicity in animal studies (Suntorntanasat et al., 2003).No traces of prednisolone or dexamethasone were detected (Amadi, 2004).In an in vitro study, the Vilac Plus (G716/45) demonstrated an important antioxidant capacity (Phillippe et al., 2006).The recipe of the ingredients of the Thai herbal tonic solution (Vilac Plus G716/45) consisted of three edible plants, the whole part of mushroom namely Ganoderma lucidum, leaves of Houttuynia cordata thunb and the roots of Boesenbergia Pandurata Holtt (Kra chai) which were found to have effective antitumor activities (Murakami et al., 1995;Wang et al., 1997).
The current authors therefore conducted a followup study to determine whether palliative treatment in advanced uterine cervical cancer using palliative radiotherapy and the Thai herbal medicine as supportive therapy, now designated as combined complementary palliative radiotherapy (CCPR) between March 2003 and June 2006 improved the survival rate.

Objectives
To evaluate the outcomes based on survival parameters of advanced stage IIIB cervical cancer by using CCPR in comparison with historic controls from the literature.

Materials and Methods
This study was performed at the Radiotherapy Division, Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen,Thailand 40002.Between March 2003 and June 2006, thirty patients in advanced cervical cancer stage IIIB-IV with poor performance status were treated by palliative radiotherapy along with the Thai herbal tonic solution (Vilac Plus G716/45) at a daily dose of 15-30 ml orally three times after meals as a supportive remedy.The staging of the diseases was classified by the tumor clinic committee of gynecologists and radiation oncologists according to the International Federation of Gynecologists and Obstetricians (FIGO) recommendations (International Federation of Gynecologists and Obstetricians, 1995).This project was approved by the Human Ethics Committee of Khon Kaen University (HE 480745).
The inclusion criteria were:(1) advanced stages IIIB-IV cervical cancer; (2) poor performance status; (3)minimal response of the tumors after radiotherapy 30-40Gy /3-4 weeks; (4) evidence of other underlying diseases; (5) advanced cervical cancer along with another malignancy; (6) informed of consent signed by the patients.The sole exclusion criterium was that the patients refused this treatment modality.All patients were followed until date of death or lost to follow -up.
Analysis: The results were analyzed for survival rates.The survival curve was estimated by the Kaplan -Meier method.
Radiotherapy: All patients were treated with a Linear accelerator (LINAC) 6 MV.The prescribed dose of teletherapy was 50 Gy/25 fractions, five fractions per week to the whole pelvis through AP and PA 15x15 cm 2 or a 16x16 cm 2port.In addition, the parametrial boosts of 200 cGy for 3-5 days after the completion of brachytherapy were used to treat stage IIIB patients with massive tumors at the parametrium.
Brachytherapy was performed by using high dose rate Ir-192 about 2-4 weeks after completion of teletherapy with doses range between 500-600 cGy/ fraction to point A for 4-5 fractions, once weekly fractionation.The point A dose was about 86 Gy.

Results
Thirty cases of patients in advanced cervical cancer stage IIIB-IV with a poor performance status were treated using CCPR.The overall 1, 3, and 5 year survival rates for stage IIIB were 88 %, 60% and 52%.The following results are summarized in accordance with Tables 1-2 and Figure 1.
The enhancing effect of Vilac Plus ® on radiotherapy to prolong the survival of these patients may be explained under the principle that antioxidants have an antitumor effect and offer normal tissue protection.The Vilac Plus ® tonic revealed antioxidant activity (Phillippe et al., 2006) being bioavailable at the subcellular level.The hypothesis of radical-scavenging activity of the tonic against excess free radicals of the radiotherapy may be explained by specific protection against DNA of normal cells.This is the key and crucial evidence for the possible scientific explanation of the mechanism and pharmacological action of CCPR, therefore, further research will be needed test this hypothesis.The ingredients of the Vilac Plus ® tonic consisting of antitumor mushroom, LingZhi (Ganoderma lucidum), Houttuynia corda Thunb and Boesenbergia pandurata Holtt (Krachai) were used as adjuvant therapy.The tonic was prepared by fermentation using Lactobacillus casei spp.(Genebank Reg.No. AF 320255) and Lactobacillus plantarum spp.(GenebankReg.No. AF The promising supportive adjuvant actions contributed from the composition of the 3 ingredients in Vilac Plus ® plus the microorganism used in the fermentation that should be recognized as a probiotic is a key component in the biotechnological production.The herbal ingredients of the mushroom,widely recognized in world literature, Ling Zhi (Ganoderma lucidum) or Reishi, has been found to contain 119 different terpinoids, about 80 of which biologically active (Van der Hem 1995; Kim et al., 1999).The possibility to have a supportive role in cancer treatment appears to be immunomodulation by protection DNA damage of normal cells through its powerful antioxidant mechanism and inhibition of tumor necrosis factor (TNF).There are a number of reports that have mentioned the benefit of this mushroom on various cancers (Wang et al., 1997;Sliva, 2003;Wu et al., 2006).The other herbs are the edible plants, Houttuynia cordata thunb (Hayashi et al., 1995) and the root of Boesenbergia pandurata Holtt (Murakami et al., 1995).The role to contribute as supportive therapy is perhaps because of the presence of phytosterols such as flavonoids and volatile oil, of which the strongest one is linalool, that have essential antiproliferative activity on cancer cells (Cherng et al., 2007;Banjerdpongchai et al., 2011).The co-operative actions of these herbs are reported to be as "interferon-inducing herbs" that may contribute some important role to play as antitumor -antiviral activity through the interferon molecule (Hayashi et al., 1995;Chang et al., 2001).
The Lactobacillus plantarum, Lactobacillus casei, antioxidants actions on the possible role in cancer therapy might be summarized as follows: 1) The antioxidants combined with therapeutic modalities produce enhancement of the therapeutic effects of chemotherapy and/or radiotherapy, decrease side effects, protect normal tissues and therefore increase survival (Moss, 2007;Simone et al., 2007).2) Heat-killed Lactobacillus plantarum L-137 demonstrated an antitumor effect in tumor -bearing mice (Murosaki et al., 2000).3) Antitumor and antimetastatic effects by induction or stimulation of the synthesis of several cytokines that have been known to be an immunomodulation factors.The small molecule weight cytokines such as IFN-gamma IL-1 beta and TNF alpha being some of the enhancement transfer factors to work effectively has been reported (Matsuzaki., 1998).4) Immunomodulation enhancement through LC 9018, a biologic response modifier prepared from heat-killed Lactobacillus casei YIT9018 that results in the delayed or inhibited process of metastases in various cell types of cancers and the delayed process of cancer recurrences have been reported (Okawa et al., 1993;Matsuzaki, 1998).5) The clinical reports of LC9018 as an adjuvant with radiotherapy demonstrated an enhancement of tumor regression, prolonged survival and relapse -free survival compared with radiotherapy alone (Okawa et al., 1993).
To demonstrate the potential advantages of integrating complementary therapies into cancer care, future areas of research will need to include improvement of the following aspects, such as access for patients, symptom control for patients, assessment of patient well-being, patient satisfaction, and cost effectiveness (Barnett, 2001).
In conclusion, the overall 5 year survival rate for stage IIIB with poor performance status was 52% compared with 34-54.8% of historic controls.The CCPR demonstrated low rates of radiation morbidity.It was a simple feasible technique, and could be the alternative option for the palliative cancer cases with poor performance status for developing countries.The pilot study was limited by the small number of patients.The treatment of cancer patients has many interrelated and confounding factors that have to be sorted out and further research will be necessary.