Integrated Cancer Treatment and Research Centre
Wagholi, Pune, INDIA
Recognized as “Center of Excellence” by Department of AYUSH, Govt. of India
Supported by Department of Atomic Energy (DAE), Government of India
Integrated Cancer Treatment and Research Center
Effectiveness of Ayurvedic treatment in alleviating side-effects of radiotherapy in
oropharyngeal cancer patients and its relationship with improvement in
immune status of the host
Vineeta Deshmukh, Sudha Gangal, Arvind Kulkarni, Shubha Chiplunkar*, Shweta
Gujar, Trupti Pradhan*, Shriram Agashe, Rupali Gaikwad, Sampat Navale and Sadanand
Sardeshmukh
Integrated Cancer Treatment and Research Center,
Pune, and* Advanced Center for Treatment Research and Education in Cancer (ACTREC), Tata Memorial
Center, Navi Mumbai
Introduction Ayurveda, an ancient Indian system of medicine is practised even
today for various illnesses especially those which are caused by reduced immune responses
Recently combinations of Ayurvedic drugs are recommended for cancer as an adjunct therapy
Non-toxicity of Ayurvedic drug combinations makes the drugs acceptable by patients
Oral cancer ranks in the top three of all cancers in India with an alarming increase in younger age. High incidence is associated with use of smokeless tobacco
The preference of treatment for oropharyngeal cancers is surgery followed by radiotherapy and / or chemotherapy depending upon grade and stage of disease
Introduction Side effects of Radiotherapy often affect immune system and
compromise quality of life of cancer patient
Side effects are also reflected in Quality of life as the treatment hampers intake of food
This major concern is being addressed worldwide
We have used selected Ayurvedic medicines, known to act on pathological conditions similar to side-effects of radiotherapy, as per Ayurvedic texts
In the first part of this study we have clinically assessed the efficacy of Ayurvedic drugs in alleviating side effects of radiotherapy
In the second part, we have assessed the possible improvement in immune status of these patients
Patient populationInclusion criteria: Patients with cancers of all sites in oropharynx,patients of all stages and grades eligible for radiation therapyAll patients had undergone surgery before radiation
Exclusion criteria: Oral cavity cancer patients who have received palliative radiotherapy, curative chemotherapy along with radiotherapy and those who have undergone Radiotherapy in the past
Treatment: Patients received radiation dose up to 6600 cGy in 30-35 fractions in 5-6 weeks
First part of the study:
Group 1: 35 patients treated with radiotherapy alone Group 2: 35 patients who received combinations of Ayurvedic drugs from the beginning of radiotherapy and continued for 3 months after radiotherapy
Ayurvedic medication for group 2
Ayurvedic medication –
• Mauktikyukta Kamadudha - 250 mg with milk twice a day
• Mauktikyukta Praval Panchamrut - 250 mg with milk twice a day
• Ananta Vati - 1 gm with water after both meals
• Yashtimadhu Ghruta - 5 gm before both meals • Yashtimadhu Ghrut - local application in the mouth
Assessment criteria for group 1 and 2 1) Common Toxicity Criteria (CTC, Designed by NIH/NCI) related to symptoms associated with oral cancers : Stomatitis , Trismus, Dysphagia, Xerostomia, Nausea, Excessive salivation and Weight loss - These symptoms were assessed at the end of radiotherapy and 3
months after radiotherapy- Symptoms are grades as 0 (No symptom) to 4 (Severe symptom) as
per CTC2) Karnofsky score 3) QLQ C30 (EORTC – European Oraganization of Research and Treatment in Cancer) – Quality of Life Questionnaire - Functional, symptom and global score [the later indicating general well-being] Criteria 2 and 3 were assessed before and after radiationAll the criteria are internationally accepted outcome measures to assess side-effects and Quality of Life of cancer patients under treatment
Results - symptomsGraphical representation of mean values depicting side effects of
radiotherapy G
roup
2
Gro
up 1
Gro
up 2
Gro
up 1
Gro
up 2
Gro
up 1
Gro
up 2
Gro
up 1
Gro
up 2
Gro
up 1
Grade 0 Grade 0 Grad
e 1 Grade 1 Grade II Grade II Grad
e III Grade III Grade IV
Grade IV
0
5
10
15
20
25
30
StomatitisP=0.0002
XerostomiaP=0.0044
Excessive salivation
StomatitisP=0.0002TrismusP=0.0004DysphagiaP<0.0001XerostomiaP=0.0044NauseaP= 0.0025Weight Loss in % from base lineExcessive salivation
Graphical representation of mean values (35 samples) depicting Karnofsky score
A – Before Radiotherapy , B – After Radiotherapy
A B A BGroup 2 Group 1
68
70
72
74
76
78
80
82
78
79.1480
72
Karnofsky Score
p = 0.0031
Graphical representation of mean values depicting functional, symptom and global score of QLQ
A – Before Radiotherapy , B – After Radiotherapy
A B A BGroup 2 Group 1
0
20
40
60
80
100
120
84.12 84.5
97.78
57.558.81 58.81 83.33
40.724.76
19 17.95
32.67
Functionalp value - < 0.0001
Globalp value - < 0.0001
Symptomp value - < 0.0011
Conclusion
1. Ayurvedic treatment is effective in management of Radiotherapy side-effects in oral cavity cancer patients such as stomatitis, trismus, dysphagia, xerostomia and nausea
2. Karnofsky score representing ability to conduct daily activities, as judged by clinician, improved significantly with adjunct Ayurvedic treatment
3. Global score of QLQ indicative of general feeling of wellbeing, as assessed by patient was significantly reduced in group 1 patients while in group 2 patients the feeling of well being did nor worsen as reported by the patients themselves
Part 2Effect of Ayurvedic medicines on immune response of
Oral Squamous cell carcinoma (OSCC) patients: preliminary studies.
Relationship of oral Ayurvedic medicines (OAM) used in this study with immune response -
a) Rasayana: 4 drugs categorised as Rasayana are used in this study. They are known to boost up immunity as per Ayurvedic texts b) Two drugs used in this study are known to reduce inflammatory responses c) Selective Panchakarma procedures used for side-effects in OSCC include medicated oil treatments, local applications in mouth region and massage meant for systemic and local detoxification.This treatment was given to a group of patients treated with RT and OAM, who continued to show side effects 1 to 6 months post RT
Immunological criteria assessed
1) Immunophenotyping - Total T & B cells and T cells subsets in PBMC and mitogen induced proliferation of T and B cells2) Markers of tumor load: CD105 and Ki673) Assessment of cytokines carried out in saliva and serum, local responses were indicated by salivary samples, therefore data presented will be on salivary samples
Type 1 cytokines: IFN-γ and TNF-αType 2 cytokines: IL-1 β, IL-6, IL-8 and IL-10, indicative of
inflammatory status4) Immune complexes and IgA in saliva indicative of local immune response.
• Major limitation of the study: 1. small sample size.• Group 1a – controls: 1 normal healthy donor,
1 chewer with mild leukoplakia 1 chewer with severe leukoplakia
• Group 1b – OSCC patients treated with RT alone – 2• Group 2a – OSCC patients treated with RT and OAM – 5• Group 2b – OSCC patients treated with RT + OAM + Panchakarma -62. Large variation in test results in individual samples in 2a and 2b,
statistical analysis was therefore not conclusive although pattern of response was same
• Time point of assessment 2a: A - beginning of RT + OAM, B – at the end of RT + OAM, C – 1 month post RT + OAM2b: A – beginning of Panchakarma (OAM continued), B – at the end of Panchakarma (OAM continued), C – 1 month post Panchakarma (OAM continued)
Grouping of patients
A B C0
10
20
30
40
50
60
70Total CD 3 in PBMC
Healthy Mean
Con-trol OC Mean
Test Pt Rep-re-sen-tative
% o
f Lym
phoc
ytes
A B C0
5
10
15
20
25
30
35
40
45
50
Total CD 4 in PBMC
Healthy Mean
Control OC Mean
Test Pt Repre-sentative
Pan-chakarma Pt Repre-senta-tive
% o
f Lym
phoc
ytes
A B C0
5
10
15
20
25Total CD 8 in PBMC
Healthy MeanControl OC MeanTest Pt Repre-sen-tative
% o
f Lym
phoc
ytes
A B C0
2
4
6
8
10
12
14Total CD 19 in PBMC
Healthy Mean
Con-trol OC Mean
Test Pt Repre-senta-tive
Pan-chakarma Pt Rep-resen-tative
% o
f Lym
phoc
ytes
A B C0
10000
20000
30000
40000
50000
60000
70000
80000T Cell Proliferation ( PHA)
Healthy Mean
Control OC Mean
Test Pt Repre-sentative
Pan-chakarma Pt Repre-sentative
Mea
n CP
M
A B C0
5000
10000
15000
20000
25000
30000
35000
B Cell Proliferation (PWM)
Healthy Mean
Control OC Mean
Test Pt Repre-sentative
Pan-chakarma Pt Repre-senta-tive
Mea
n CP
M
A B C0
0.5
1
1.5
2
2.5
3
3.5
4CD 105 in Serum
Healthy Mean
Con-trol OC Mean
Test Pt Rep-re-senta-tive
ng/m
l
A B C0
2
4
6
8
10
12
14
16
18
20Ki 67 in Serum
Healthy MeanCon-trol OC MeanTest Pt Rep-re-senta-tivePan-chakarma Pt Rep-re-senta-tive
ng/m
l
Tumor markers
A B C0
20
40
60
80
100
120
140IGA in Saliva
Healthy Mean
Control OC Mean
Test Pt Repre-senta-tive
Pan-chakarma Pt Rep-resen-tative
ng/m
l
A B C2.42
2.43
2.44
2.45
2.46
2.47
2.48
2.49
2.5IC in Saliva
Healthy Mean
Con-trol OC Mean
Test Pt Rep-re-senta-tivePan-chakarma Pt Rep-re-senta-tive
Abso
rban
t OD
at 4
50 W
avel
engt
h
Local immune response
A B C0
10
20
30
40
50
60
70
80IFN g in Saliva
Healthy MeanCon-trol OC MeanTest Pt Repre-senta-tivePan-chakarma Pt Rep-resen-tative
pg/m
l
A B C0
10
20
30
40
50
60
70
80
90
TNF a in SalivaHealthy Mean
Con-trol OC Mean
Test Pt Rep-re-sen-tative
pg/m
l
Type 1 cytokines in saliva
A B C.
020406080
100120140 IL 1 in Saliva Hea
lthy Mean
Control OC Mean
pg/m
l
A B C0
20
40
60
80
100
120
140
160IL 6 in Saliva
Healthy Mean
pg/m
l
A B C0
50
100
150
200
250
300
350IL 8 in Saliva
Healthy Mean
Control OC Mean
pg/m
l
A B C0
2
4
6
8
10
12 IL 10 in SalivaHealthy Mean
Control OC Mean
pg/m
l
Type 2 cytokines in saliva
Tentative conclusionBased on the preliminary data, the trends indicate-1) Local immune response in saliva shows better association with treatment outcome2) Immune recovery in the form of a) phenotypes in peripheral blood b) proliferative responses in T and B cells c) oral mucosal immunity d) type 1 cytokines e) reduction in circulating tumour markers is seen in patients treated with oral administration of Ayurvedic drugs along with RT.3) The pro inflammatory cytokines showed decrease after radiation. In both 2a and 2b patients this response appears to be related to Ayurvedic treatment4) Type 1 cytokines IFN-Ƴ and TNF-α show low levels initially which are increased in both 2a and 2b after 1 month of radiotherapy, which is perhaps indicative of polarization towards TH1 response
Further research leads require inclusion of larger cohort and extended follow-up with OAM to confirm the findings
1) 4 parameters compared in 3 normal donors
Name of GroupProliferation T
cell CD3IL 10 in Saliva
CD 105 in Saliva
Healthy 65187 35 4.3 1.8Tobacco chewer with mild
leukoplakia 33506 29 0.9 3.2Tobacco chewer with severe
leukoplakia 73356 27 1.4 2.1
Mean - Healthy 57350 33 2.2 2.4
2) Responses of T1/T2 Vs T3/T4 patients
Stage Mean values
Stage I + II 65437 41 2.6 2.5
Stage III + IV 54132 53.8 5.1 2.62
Controls and TNM classification