Integrated Cancer Treatment and Research CentreWagholi, 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 NavalePradhan*, 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� 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 population

Inclusion 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• 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 CTCas per CTC

2) 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 radiation

All the criteria are internationally accepted outcome measures to

assess side-effects and Quality of Life of cancer patients under

treatment

Results - symptoms

Graphical representation of mean values depicting side effects of

radiotherapy

Excessive salivation

5

10

15

20

25

30 Stomatitis

P=0.0002

Trismus

P=0.0004

Dysphagia

P<0.0001

Xerostomia

Stomatitis…

Trismus…

Dysphagia…Xerostomia…Nausea…Weight Loss…Excessive salivation

0

Group

2Group

1Group

2Group

1Group

2Group

1 Group

2Group

1 Group

2Group

1

Grade

0Grade 0

Grade

1Grade 1

Grade

IIGrade II

Grade

IIIGrade III

Grade

IVGrade

IV

Xerostomia

P=0.0044

Nausea

P= 0.0025

Weight Loss

in % from base line

Excessive

salivation

Graphical representation of mean values (35 samples)

depicting Karnofsky score

A – Before Radiotherapy , B – After Radiotherapy

78

79.1480

78

80

82

78

72

68

70

72

74

76

A B A B

Group 2 Group 1

Karnofsky Score

p = 0.0031

Graphical representation of mean values depicting

functional, symptom and global score of QLQ

A – Before Radiotherapy , B – After Radiotherapy

84.12 84.5

97.78

57.558.81 58.81 83.3360

80

100

120

Functional

p value - <

0.000157.558.81 83.33

40.724.76

19 17.95

32.67

0

20

40

60

A B A B

Group 2 Group 1

Global

p value - <

0.0001

Symptom

p 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 treatmentadjunct 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 2

Effect 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 cells

2) Markers of tumor load: CD105 and Ki67

3) Assessment of cytokines carried out in saliva and serum, local

responses were indicated by salivary samples, therefore data

presented will be on salivary samplespresented will be on salivary samples

Type 1 cytokines: IFN-γ and TNF-α

Type 2 cytokines: IL-1 β, IL-6, IL-8 and IL-10, indicative of

inflammatory status

4) 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

Grouping of patients

• Group 2a – OSCC patients treated with RT and OAM – 5

• Group 2b – OSCC patients treated with RT + OAM + Panchakarma -6

2. 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 + OAM

2b: A – beginning of Panchakarma (OAM continued), B – at the end of Panchakarma (OAM continued), C – 1 month post Panchakarma(OAM continued)

0

10

20

30

40

50

60

70

A B C

% o

f Ly

mp

ho

cyte

sTotal CD 3 in PBMC

Healthy

Mean

Control

OC Mean

Test Pt

Represen

tative

Panchaka

rma Pt

Represen

tative0

5

10

15

20

25

30

35

40

45

50

A B C

% o

f Ly

mp

ho

cyte

s

Total CD 4 in PBMCHealthy

Mean

Control OC

Mean

Test Pt

Representati

ve

Panchakarm

a Pt

Representati

ve

0

5

10

15

20

25

A B C

% o

f Ly

mp

ho

cyte

s

Total CD 8 in PBMCHealthy

Mean

Control

OC

Mean

Test Pt

Represe

ntative

Panchak

arma Pt

Represe

ntative0

2

4

6

8

10

12

14

A B C

% o

f Ly

mp

ho

cyte

s

Total CD 19 in PBMC

Healthy

Mean

Control OC

Mean

Test Pt

Represent

ative

Panchakar

ma Pt

Represent

ative

0

10000

20000

30000

40000

50000

60000

70000

80000

A B C

Me

an

CP

M

T Cell Proliferation ( PHA)

Healthy Mean

Control OC

Mean

Test Pt

Representative

Panchakarma

Pt

Representative

0

5000

10000

15000

20000

25000

30000

35000

A B C

Me

an

CP

M

B Cell Proliferation (PWM)

Healthy

Mean

Control OC

Mean

Test Pt

Representati

ve

Panchakarm

a Pt

Representati

ve

2.5

3

3.5

4

CD 105 in Serum

Healthy

Mean

Control

OC Mean12

14

16

18

20

Ki 67 in SerumHealthy

Mean

Control

OC Mean

Tumor markers

0

0.5

1

1.5

2

A B C

ng

/ml

Test Pt

Represen

tative

Panchaka

rma Pt

Represen

tative0

2

4

6

8

10

12

A B C

ng

/ml

Test Pt

Represent

ative

Panchaka

rma Pt

Represent

ative

100

120

140

IGA in Saliva

Healthy

Mean

Control OC

Mean 2.47

2.48

2.49

2.5

Ab

sorb

an

t O

D a

t 4

50

Wa

ve

len

gth

IC in SalivaHealthy

Mean

Control

OC Mean

Local immune response

0

20

40

60

80

A B C

ng

/ml Mean

Test Pt

Representa

tive

Panchakar

ma Pt

Representa

tive

2.42

2.43

2.44

2.45

2.46

2.47

A B C

Ab

sorb

an

t O

D a

t 4

50

Wa

ve

len

gth

OC Mean

Test Pt

Represent

ative

Panchaka

rma Pt

Represent

ative

50

60

70

80

pg

/ml

IFN g in Saliva

Healthy

Mean

Control

OC Mean 50

60

70

80

90

pg

/ml

TNF a in SalivaHealthy

Mean

Control

OC Mean

Type 1 cytokines in saliva

0

10

20

30

40

A B C

pg

/ml

Test Pt

Represent

ative

Panchakar

ma Pt

Represent

ative

0

10

20

30

40

50

A B C

pg

/ml

Test Pt

Represen

tative

Panchaka

rma Pt

Represen

tative

0

20

40

60

80

100

120

140

A B C

pg

/ml

IL 1 in Saliva Health

y Mean

Control

OC

Mean

2

4

6

8

10

12

pg

/ml

IL 10 in SalivaHealthy

Mean

Control

OC

Mean

Type 2 cytokines in saliva

A B C

0

20

40

60

80

100

120

140

160

A B C

pg

/ml

IL 6 in SalivaHealt

hy

Mean

Contr

ol OC

Mean

0

50

100

150

200

250

300

350

A B C

pg

/ml

IL 8 in SalivaHealthy

Mean

Control

OC Mean

Test Pt

Represe

ntative

0

A B C

Tentative conclusionBased on the preliminary data, the trends indicate-

1) Local immune response in saliva shows better association with

treatment outcome

2) 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 3) The pro inflammatory cytokines showed decrease after radiation. In

both 2a and 2b patients this response appears to be related to Ayurvedic

treatment

4) 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 Group

Proliferation T

cell CD3

IL 10 in

Saliva

CD 105 in

Saliva

Healthy 65187 35 4.3 1.8

Tobacco chewer with mild

leukoplakia 33506 29 0.9 3.2

Tobacco chewer with severe

Controls and TNM classification

Tobacco 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