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