Role of the Naturopathic Physician in Gynecological OncologyMaking

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Role of the Naturopathic Physician in Gynecological Oncology-Making a difference Naini Kohli, ND, FABNO

Role of the Naturopathic Physician in Gynecological Oncology-Making a difference Naini Kohli, ND, FABNO Consultant, Naturopathic Oncology Cancer Treatment Centers of America Eastern Regional Medical Center, Philadelphia, PA 10/26/2021 Naini Kohli NYANP 1

Learning Objectives Ø Overview Ø Naturopathic adjunctive management for specific gynecological cancers Ø Evidence-based

Learning Objectives Ø Overview Ø Naturopathic adjunctive management for specific gynecological cancers Ø Evidence-based life style and naturopathic strategies for prevention Ø Clinical pearls for supportive care and managing aftermath of treatment. 10/26/2021 Naini Kohli NYANP 2

Gynecological Malignancies Endometrial(Uterine) Ovarian Cervical 10/26/2021 Vulvar Naini Kohli NYANP Vaginal Peritoneal and Fallopian

Gynecological Malignancies Endometrial(Uterine) Ovarian Cervical 10/26/2021 Vulvar Naini Kohli NYANP Vaginal Peritoneal and Fallopian Tubes (Rare types) 3

2015 projections for Gynecological Cancers 60000 50000 Series 1 new cases Series 2 anticipated

2015 projections for Gynecological Cancers 60000 50000 Series 1 new cases Series 2 anticipated deaths 40000 30000 20000 10000 0 Series 1 Series 2 10/26/2021 Endometrial 54870 10170 Ovarian 21290 14180 Naini Kohli NYANP Cervical 12900 4100 Vulvar 5150 1080 Vaginal 4070 910 4

Endometrial Cancer Ø Most common cancer of the female reproductive organs. Ø Primarily a

Endometrial Cancer Ø Most common cancer of the female reproductive organs. Ø Primarily a disease of postmenopausal women, 25% of cases occur in premenopausal patients, with 5% of cases in patients younger than 40 years Ø More common in white women, but more black women die from it. Ø There are over 600, 000 women who are survivors of this cancer. 10/26/2021 Naini Kohli NYANP 5

Predisposing factors Ø Exposure to high circulating levels of estrogens with low levels of

Predisposing factors Ø Exposure to high circulating levels of estrogens with low levels of progestogens. Ø 25% decline in mortality in last 30 years due to decreased use of unopposed estrogens. Ø Infertility, obesity, dysfunctional bleeding due to anovulation and patients with granulosa theca cell ovarian tumors are at high risk. Ø Diabetes mellitus, cigarette smoking, and less physical activity are related risk factors. Ø Tamoxifen use has been reported to increases endometrial cancer by 10%. Ø HNPCC increases risk by 20% 10/26/2021 Naini Kohli NYANP 6

Signs and Symptoms Postmenopausal women Ø 90% of patients complain of abnormal vaginal discharge,

Signs and Symptoms Postmenopausal women Ø 90% of patients complain of abnormal vaginal discharge, and 80% of these women experience abnormal bleeding. Ø 15% of postmenopausal women presenting with abnormal bleeding will be found to have endometrial carcinoma. Ø Signs and symptoms of more advanced disease include pelvic pressure and other symptoms indicative of uterine enlargement or extra uterine tumor spread. Ø Premenopausal women Ø The diagnosis of endometrial cancer may be difficult to make in premenopausal patients. The physician must maintain a high index of suspicion in this group of patients and perform endometrial sampling in any women who complain of prolonged, heavy menstrual periods or inter menstrual spotting 10/26/2021 Naini Kohli NYANP 7

Diagnosis Ø Trans vaginal Ultra sound (TVS) endometrial thickness Ø Endometrial biopsy Ø Pre-op

Diagnosis Ø Trans vaginal Ultra sound (TVS) endometrial thickness Ø Endometrial biopsy Ø Pre-op work-up CT/MRI Ø Staging – surgical / histological / nodes 10/26/2021 Naini Kohli NYANP 8

Treatment options-ASCO Guidelines Ø After total abdominal hysterectomy with or without lymph node dissection,

Treatment options-ASCO Guidelines Ø After total abdominal hysterectomy with or without lymph node dissection, it is reasonable to avoid radiation therapy if women have grade 1 or 2 cancers with either no invasion or less than 50% invasion of the myometrium Ø Vaginal cuff brachytherapy may be considered in cases of negative nodes with grade 3 tumor without myometrial invasion and in those with negative node dissection with grade 1 or 2 tumors with less than 50% myometrial invasion and higher-risk features, such as age older than 60 years and lymphovascular space invasion Ø Vaginal cuff brachytherapy is as effective as pelvic radiation at preventing vaginal recurrence for patients with grade 1 or 2 tumors with 50% myometrial invasion or with grade 3 tumors with less than 50% myometrial invasion Ø Patients with grade 3 cancer with at least 50% myometrial invasion or cervical stroma invasion could benefit from pelvic radiation to reduce the risk for pelvic recurrence 10/26/2021 Naini Kohli NYANP 9

Chemotherapy Options Combination Ø Carboplatin +Paclitaxel Ø Doxorubicin+Cyclophosph amide Ø Doxorubicin+Cisplatin Ø Doxorubicin+Paclitaxel+Ci splatin+

Chemotherapy Options Combination Ø Carboplatin +Paclitaxel Ø Doxorubicin+Cyclophosph amide Ø Doxorubicin+Cisplatin Ø Doxorubicin+Paclitaxel+Ci splatin+ Filgrastin Ø Cyclophosphamide + Cisplatin +Doxorubicin Ø Paclitaxel+Ifosfamide Ø Gemcitabine+ Cisplatin 10/26/2021 Naini Kohli NYANP Single agent Ø Doxorubicin Ø Megestrol Ø Paclitaxel Ø Topotecan 10

Ovarian cancer-Epidemiology Ø Fifth leading cause of cancer deaths among women and has the

Ovarian cancer-Epidemiology Ø Fifth leading cause of cancer deaths among women and has the highest mortality rate among all female reproductive cancers. Ø Primarily a disease of post menopausal women, mostly 50 -75 years with a peak at 61. 5 per 100, 000 women aged 75 -79 years. Ø Whites > Hispanic > Native American > Black > Asians and Pacific Islanders Ø Highest rate in industrialized nations and lowest in under developed nations except Japan- incidence is 3 per 100, 000 10/26/2021 Naini Kohli NYANP 11

Ø Inherited mutations in BRCA 1 and BRCA 2 increase the risk for ovarian

Ø Inherited mutations in BRCA 1 and BRCA 2 increase the risk for ovarian and breast cancers. Though are more common among women of Ashkenazi Jewish ancestry, they are not restricted to this population and can occur in women of any ethnicity. Ø Women with a BRCA 1 mutation have about a 40% lifetime risk for ovarian cancer. whereas with a BRCA 2 mutation the risk is about 10 – 20% (Lifetime ovarian cancer risk for women in the general public is about 1. 4%. ) Ø HNPCC. Women who have genetic mutations associated with hereditary non-polyposis colorectal cancer (HNPCC) have about a 12% lifetime risk of developing ovarian cancer 10/26/2021 Naini Kohli NYANP 12

Ovarian Screening Methods for Average-Risk Women CA-125: poor sensitivity in early stage disease Transvaginal

Ovarian Screening Methods for Average-Risk Women CA-125: poor sensitivity in early stage disease Transvaginal ultrasound: poor sensitivity in early-stage disease, cannot reliably distinguish benign from malignant changes. Pelvic exam 10/26/2021 Naini Kohli NYANP clinicaloptions. com/oncology 13

Primary treatment Ø Optimal cytoreduction or debulking Ø Residual tumor deposits should be less

Primary treatment Ø Optimal cytoreduction or debulking Ø Residual tumor deposits should be less than 1 cm in size. Ø Patients with optimally debulked disease have better chances of achieving complete clinical response to chemotherapy 10/26/2021 Naini Kohli NYANP 14

Standard of Care- 2006 ØMaximum attempt at surgical cytoreduction ØChemotherapy following surgery ØRegimen of

Standard of Care- 2006 ØMaximum attempt at surgical cytoreduction ØChemotherapy following surgery ØRegimen of choice Paclitaxel 175 mg/m 2/3 h , Carboplatin AUC 6 -7. 5 Repeat every 3 weeks x 6 cycles Intravenous (IV) with Intraperitoneal (IP) has been shown to give better results in Stage 3 and 4 patients 10/26/2021 Naini Kohli NYANP 15

Response Rate after Relapse 12 months 30% 24 months 57% Relapse 10/26/2021 Naini Kohli

Response Rate after Relapse 12 months 30% 24 months 57% Relapse 10/26/2021 Naini Kohli NYANP 16

Additional chemotherapy agents following failure of Cisplatin or Carboplatin with Paclitaxel or Docetaxel Ø

Additional chemotherapy agents following failure of Cisplatin or Carboplatin with Paclitaxel or Docetaxel Ø Doxorubicin (Doxil) Ø Gemcitabine(Gemzar) Ø Topotecan Ø Etoposide Ø Pemetrexel Ø Bevacizumab(Avastin) 10/26/2021 Naini Kohli NYANP 17

Cervical cancer Ø Cervical cancer was once one of the most common causes of

Cervical cancer Ø Cervical cancer was once one of the most common causes of cancer death for American women Ø Now gone down by more than 50% due to increased use of the Pap test and later on the introduction of the HPV vaccine. Ø Currently, an estimated 249, 496 women are living with cervical cancer in the United States. 10/26/2021 Naini Kohli NYANP 18

Pre disposing factors Ø Disease of midlife, most cases are found in women younger

Pre disposing factors Ø Disease of midlife, most cases are found in women younger than 50. It rarely develops before age of 20. Ø Hispanic women are most likely to get cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites. Ø American Indians and Alaskan natives have the lowest risk of cervical cancer in this country. 10/26/2021 Naini Kohli NYANP 19

Updated Cervical Cancer Screening Guidelines Ø Cervical cancer screening every 2 years - age

Updated Cervical Cancer Screening Guidelines Ø Cervical cancer screening every 2 years - age 21 -30 years. Ø 30 and older with three consecutive normal Pap tests can be screened every three years. Ø Women with risk factors like HIV positivity; immunosuppression; DES exposure in utero; or history of treatment for cervical intraepithelial neoplasia (CIN) 2, CIN 3, or cervical cancer may need to be screened more frequently. Ø Women who have had a total hysterectomy for benign conditions can stop being screened for cervical cancer unless they have a history of high-grade CIN. 10/26/2021 Naini Kohli NYANP 20

Ø ACOG notes that women may be able to stop cervical cancer screening at

Ø ACOG notes that women may be able to stop cervical cancer screening at age 65 or 70 if they’ve had three or more normal Pap results in a row and no abnormal Pap in the previous ten years. Ø Women at high-risk of cervical cancer may need to continue screening beyond this age. Ø Women who have been vaccinated against human papillomavirus (HPV) should follow the same screening guidelines as unvaccinated women. 10/26/2021 Naini Kohli NYANP 21

Natural history of cervical carcinogenesis Ø Premalignant changes form a continuum from low to

Natural history of cervical carcinogenesis Ø Premalignant changes form a continuum from low to high grade SIL or cervical, vaginal or vulvar intraepithelial neoplasia 1, 2 or 3. Ø These lesions can persist, progress or regress. Ø Family history, HPV, cigarette smoking and nutrient deficiencies may be contributory Ø Inflammation, nutrition and other viruses are likely to be involved in affecting the outcome. Ø 90% of cancers are squamous and 10% adenocarcinomas 10/26/2021 Naini Kohli NYANP 22

Risk factors ØCIN ØMultiple sexual partners Ø HPV, HIV ØSmoking Ø Signs and symptoms

Risk factors ØCIN ØMultiple sexual partners Ø HPV, HIV ØSmoking Ø Signs and symptoms Ø Ø Post coital bleed, Intermenstrual bleed Discharge , Post menstrual bleeding. Ulcer / mass. visible / palpable Late stage – organ symptomss / mass 10/26/2021 Naini Kohli NYANP 23

Diagnosis Ø Biopsy Ø Staging – Clinical / Histological Ø Pre-op work-up Ø EUA

Diagnosis Ø Biopsy Ø Staging – Clinical / Histological Ø Pre-op work-up Ø EUA / Cystoscopy / CT / IVP 10/26/2021 Naini Kohli NYANP 24

Management Ø Ia 1 Microinvasion-Cone biopsy which could be diagnostic or therapeutic Ø I

Management Ø Ia 1 Microinvasion-Cone biopsy which could be diagnostic or therapeutic Ø I – IIa Surgery / Radiotherapy Ø Advanced , Radiotherapy, chemotherapy Ø Prognosis overall 65% 5 year 10/26/2021 Naini Kohli NYANP 25

Chemotherapy Combination Single Ø Cisplatin and XRT Ø Cisplatin and Topotecan Ø Bleomycin, Ifosamide,

Chemotherapy Combination Single Ø Cisplatin and XRT Ø Cisplatin and Topotecan Ø Bleomycin, Ifosamide, mesna and cisplatin/carboplatin(BIP/BI C) Ø Cisplatin and 5 FU/ vinorelebine/Irinotecan? gem citabine Ø Carboplatin, Taxotere( Docetaxel) Ø Paclitaxel Ø Docetaxel Ø Irinotecan Ø Topotecan Ø Pemetrexel 10/26/2021 Naini Kohli NYANP 26

Vulvar cancer Ø Accounts for 4% of cancers of the female reproductive organ malignancies

Vulvar cancer Ø Accounts for 4% of cancers of the female reproductive organ malignancies and 0. 6% of all cancers in women. Ø Average American woman has 1 in 333 chance of developing vulvar cancer at some point in life. Ø Predominantly a disease of postmenopausal women. Ø Ninety percent of cancers are squamous in origin, while melanomas, adenocarcinomas, basal cell carcinomas, verrucous carcinomas, sarcomas, and other rare malignancies also occur. 10/26/2021 Naini Kohli NYANP 27

Ø Commonly site is the labia majora but the labia minora but may occur

Ø Commonly site is the labia majora but the labia minora but may occur in clitoris, and perineum. Ø Vulvar intraepithelial neoplasia (VIN) III is a precursor lesion in some patients, and should be effectively treated by superficial excision, with or without laser therapy, when diagnosed (Jones & Rowan, 1994; Herod et al, 1996). Ø Treatment of invasive vulvar cancer needs an individualized multidisciplinary approach, . 10/26/2021 Naini Kohli NYANP 28

Investigations to assist diagnosis include: Ø Pap smear of the cervix to rule out

Investigations to assist diagnosis include: Ø Pap smear of the cervix to rule out Carcinoma insitu Ø Colposcopy of the cervix and vagina because of the common association with other squamous intraepithelial lesions Ø CT-scan of the pelvis and groins is often helpful to detect any enlarged lymph nodes in the groins or pelvis, particularly in the presence of palpable groin nodes Ø Routine full blood count, biochemical profile and chest x-ray (CXR) pre-operatively 10/26/2021 Naini Kohli NYANP 29

Treatment Ø Wide local excision ØRadical vulvectomy ØBilat groin lymphadenectomy+/- radiotherapy Ø Prognosis I

Treatment Ø Wide local excision ØRadical vulvectomy ØBilat groin lymphadenectomy+/- radiotherapy Ø Prognosis I >90% 5 yr, III/IV 40% 5 yrs 10/26/2021 Naini Kohli NYANP 30

Vaginal Cancer Ø Only about 1 of every 1, 100 women will develop vaginal

Vaginal Cancer Ø Only about 1 of every 1, 100 women will develop vaginal cancer in her lifetime Ø Age > 60 years Ø No specific risk factors Ø 95% squamous Ø Signs and Symptoms Pruritus , bleeding , discharge Ulcer , Mass, Inguinal lymphadenopathy 10/26/2021 Naini Kohli NYANP 31

Diagnosis Ø Biopsy Ø Staging – surgical / histological Ø Pre-op work-up 10/26/2021 Naini

Diagnosis Ø Biopsy Ø Staging – surgical / histological Ø Pre-op work-up 10/26/2021 Naini Kohli NYANP 32

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Ø Primary prevention became possible with identification of human papilloma virus and creation of

Ø Primary prevention became possible with identification of human papilloma virus and creation of virus like particles in the laboratory Ø 20 different types have been isolated and implicated in vaginal, vulvar and oral cancers. Ø Majority of cervical cancers are caused by types 16 and 18. Ø Prophylactic vaccination has transformed the prospects for reducing the incidence of this disease on a global scale, achieving more than 98% protection in randomized clinical trials against precursor lesions such as CIN grade 2/3 and adenocarcinoma in situ 10/26/2021 Naini Kohli NYANP 34

Ø Gardasil is a quadrivalent vaccine approved by the FDA in 2006 for prophylactic

Ø Gardasil is a quadrivalent vaccine approved by the FDA in 2006 for prophylactic vaccination in girls and women aged 9 to 26 years, able to trigger an antibody response against the HPV types represented in the vaccine. Ø Cervarix is a bivalent vaccine also approved by the FDA to prevent cervical dysplasia and cervical cancer caused by HPV types 16 and 18 Ø CDC recommends 3 doses for all females aged 11 -26 years at 0, 2 and 6 months Ø A novel vaccine that covers five additional subtypes of HPV (31, 33, 45, 52, and 58) in addition to the 6, 11, 16, and 18, has completed phase III testing. 10/26/2021 Naini Kohli NYANP 35

Manipulating Estrogen metabolic pathways Ø Increasing the ratio of 2 Hydroxyestrone and 16 alpha

Manipulating Estrogen metabolic pathways Ø Increasing the ratio of 2 Hydroxyestrone and 16 alpha -hydroxyestrone. Ø Indoles ( DIM, I 3 C, Sulphoraphane) Ø Flavonoids Bazzan et al. Journal of Translational Medicine 2013, 11: 252 Page 3 of 4 http: //www. translational-medicine. com/content/11/1/252 10/26/2021 Naini Kohli NYANP 36

Retinoids Ø Vitamin A (natural), synthetic derivative –fenretinoid( 4 OH fenretinamid or 4 FHR)

Retinoids Ø Vitamin A (natural), synthetic derivative –fenretinoid( 4 OH fenretinamid or 4 FHR) Ø Control cell growth and differentiation at the level of gene expression through interaction with nuclear receptors Ø Inhibit proliferation, progression, induce terminal differentiation and stimulate intracellular communication Ø 13 cis retinoic acid has been shown to reverse or suppress oral leukoplakia and second primaries of the upper aero digestive tract. Ø Topical tretinoin 0. 372% has been shown to reverse low grade uterine cervical moderate dysplasia in a randomized clinical trial. 10/26/2021 Naini Kohli NYANP 37

Side effects Ø Beware of potential dose related toxicity Ø Tend to accumulate in

Side effects Ø Beware of potential dose related toxicity Ø Tend to accumulate in the liver and cause hepatic damage Ø Eye damage Ø Most relevant to prevention of gynecological cancers is that they are teratogens 10/26/2021 Naini Kohli NYANP 38

Anti-oxidants Ø Carcinogen blocking agents act by preventing conversion of a procarcinogen into an

Anti-oxidants Ø Carcinogen blocking agents act by preventing conversion of a procarcinogen into an active carcinogen- eg. inhibition of nitrosocarcingen formation by ascorbic acid, alpha tocopherol and the phenols. Ø Agents enhancing phase 2 carcinogen detoxifying enzymes including glutathione S transferase 10/26/2021 Naini Kohli NYANP 39

Target completed studies agent phase No of cases results CIN 1 -2 Folic acid

Target completed studies agent phase No of cases results CIN 1 -2 Folic acid 3 335 No effect on regression CIN 1 -2 Folic acid 3 331 No effect on regression CIN 2 -3 Retinoic acid(topical Beta carotene 3 301 Increased rate of regression of 2 but not 3 CIN 1 -2 Beta carotene 3 69 No effect on regression CIN 2 -3 Beta carotene 3 125 No effect on regression 10/26/2021 Naini Kohli NYANP 40

Prevention of Ovarian Cancer Ø Chemoprevention Ø Oral contraceptive pills Ø Limit clomiphene citrate

Prevention of Ovarian Cancer Ø Chemoprevention Ø Oral contraceptive pills Ø Limit clomiphene citrate Ø Surgical prevention Ø Oophorectomy: 80% risk reduction in high-risk women[1] Ø Bilateral tubal ligation: 72% risk reduction when used with oral contraception[2] 1. Finch A, et al. JAMA. 2006; 296: 185 -192. 2. Narod SA, et al. Lancet. 2001; 357: 1467 -1470. 10/26/2021 Naini Kohli NYANP clinicaloptions. com/oncology 41

Ovarian Cancer and Green Tea Ø No experimental human study assessing the effects of

Ovarian Cancer and Green Tea Ø No experimental human study assessing the effects of green tea in EOC progression is available Ø Post-diagnosis green tea intake with EOC progression 1 observational cohort study. Ø Post-diagnostic tea intake and 3 -year survival was assessed in 244 women with EOC. Ø Compared to non-drinkers, women who drank more than one cup of tea daily after EOC diagnosis had a lower risk of mortality (HR: 0. 43, 95% CI: [0. 20; 0. 92]) when standard risk factors for EOC progression were taken into account. 10/26/2021 Naini Kohli NYANP 42

Ø 10 year Meta-analysis of the correlation between drinking green tea and the risk

Ø 10 year Meta-analysis of the correlation between drinking green tea and the risk of female ovarian tumors. Ø 6 case control studies and cohort studies with 9113 participants, 3842 cases, and 5271 control cases were included. Ø Drinking green tea was found to decrease the risk of ovarian cancer (odds ratio = 0. 81; 95% confidence interval = 0. 73 -0. 89; P <. 0001). 10/26/2021 Naini Kohli NYANP 43

Green tea and prevention 10/26/2021 Naini Kohli NYANP 44

Green tea and prevention 10/26/2021 Naini Kohli NYANP 44

Mainly focuses on supporting healing and repair Surgery Chemotherapy Side effect management Immune support

Mainly focuses on supporting healing and repair Surgery Chemotherapy Side effect management Immune support Improving effectiveness The Naturopathic Physician’s supportive role Follow up and Secondary Prevention 10/26/2021 Naini Kohli NYANP Radiation Therapy Radiation sensitization Side effect management Immune support Dealing with sequel of treatments QOL issues Secondary prevention 45

Evidence based naturopathic strategies- areas of focus • Surgical menopause and related problems •

Evidence based naturopathic strategies- areas of focus • Surgical menopause and related problems • Ureteral Stricture and hydronephrosis • Nausea, vomiting diarrhea • PNP • Fatigue • Low blood counts Surgery Chemotherapy Radiation Hormonal treatment • Skin rashes • Diarrhea, nausea • Dysuria • Fatigue • Radiation enteritis 10/26/2021 Naini Kohli NYANP • Vasomotor symptoms • Osteoporosis • Weight gain 46

�General surgical support Ø Good multi-vitamin and mineral formula Ø Arnica Ø Modified Citrus

�General surgical support Ø Good multi-vitamin and mineral formula Ø Arnica Ø Modified Citrus Pectin Ø Probiotics Ø Adaptogenic herbs after surgery to help with recovery 10/26/2021 Naini Kohli NYANP 47

Side effects of chemotherapy Nausea Ø Ginger encourages movement through the bowels while decreasing

Side effects of chemotherapy Nausea Ø Ginger encourages movement through the bowels while decreasing intestinal spasm Ø Digest Dis Sci 2005 Oct 1; 50(10) Ø Treatment of nausea with use of ginger root produced similar results as compared to a popular anti-nausea medication Ø J Ethnopharmacol. 1998 Aug; 62(1): 49 -55. Ø Reduced nausea in women receiving Cisplatin for gynecologic cancers. Ryu SY, et. Al. Major clinical research advances in gynecologic cancer 2009. J Gynecol Oncol. 2009 Dec; 20(4): 203 -9. Ø Peppermint essential oil (Lua PL, Zakaria NS. J Altern Complement Med. 2012. ) 10/26/2021 Naini Kohli NYANP 48

IVC Ø Reduction in treatment related toxicity with paclitaxel/carboplatin + IVC (13 patients) vs.

IVC Ø Reduction in treatment related toxicity with paclitaxel/carboplatin + IVC (13 patients) vs. standard treatment alone (12 patients). Ø Patients were followed for 5 years. Ø Overall survival tended toward improvement. (median time to progression was 8. 75 months longer in the Cp+Pax+IVC arm than in the Cp+Pax arm. These results did not achieve statistical significance because the study was not statistically powered to detect efficacy. 10/26/2021 Naini Kohli NYANP 49

Cisplatin Vinca alkaloids Dorsal root ganglion Chemotherapy induced Peripheral neuropathy- sites of action. Ø

Cisplatin Vinca alkaloids Dorsal root ganglion Chemotherapy induced Peripheral neuropathy- sites of action. Ø Ø Ø Taxanes- Stocking & glove distribution & perioral numbness suggests DRG neuropathy Cisplatin- accumulates in DRG Carboplatin Oxaliplatin - – impairs voltagegated sodium channels Vinca alkaloids- – mitotic inhibitor, impairs axonal transport & impairs regeneration – mixed motor, sensory & autonomic 10/26/2021 Naini Kohli NYANP 50

Chemotherapy induced peripheral neuropathy Nutraceutical Chemotherapy drug End results Vitamin E Cisplatin +ve results

Chemotherapy induced peripheral neuropathy Nutraceutical Chemotherapy drug End results Vitamin E Cisplatin +ve results in 3 RCT in decreasing PNP and ototoxicity. Phase 3 trial showed no effect on sensory neuropathy Carboplatin, Taxanes, Oxa liplatin Calcium and Magnesium Oxaliplatin Initial positive results but three subsequent clinical trials were negative Lipoic Acid oxaliplatin Open label study, n=15, showed trend towards reduction in PNP Glutathione Cisplatin Oxaliplatin I/V infusion prior to chemotherapy reported reduction in PNP, 1+2 studies. 10/26/2021 Naini Kohli NYANP 51

Nutraceutical Chemotherapy drug End results Glutamine- 1 cohort, 1 case control Paclitaxel 1 study

Nutraceutical Chemotherapy drug End results Glutamine- 1 cohort, 1 case control Paclitaxel 1 study case control study oxaliplatin Less weakness, better vibrational sense and less parasthesiae reduction in neuropathy across all grades as compared to controls. Acetyl L Carnitine-3000 mg daily, n=409, DBRCT Paclitaxel enrolled in double-blind, placebocontrolled trial. . Vitamin B 6 1 DBRCT Cisplatin Reduced CIPN but high dose 100 mg may affect response duration and needs further investigation Omega 3 Fattyacids DBRCT Paclitaxel Reduced CIPN incidence by 70% 10/26/2021 Naini Kohli NYANP Study group showed worsening CIPN and decreased functional status at 24 weeks. 52

Radiation Ø Radical radiotherapy is commonly used (alone, or in conjunction with surgery and/or

Radiation Ø Radical radiotherapy is commonly used (alone, or in conjunction with surgery and/or chemotherapy) to treat pelvic cancers such as cervical, endometrial, bladder. Ø Commonly reported side-effects include: abdominal pain, Ø Urgency, diarrhea, faecal incontinence and bloating. Ø During the course of treatment around 80% of patients will experience bowel symptoms often referred to as ‘Acute Radiation Enteritis’. 10/26/2021 Naini Kohli NYANP 53

Naturopathic Recommendations To prevent/treat Diarrhea Ø Probiotics-Lactobacillus acidophilus, Sacro-B, Culturelle (Lactobacillus GG), Ultra. Flora

Naturopathic Recommendations To prevent/treat Diarrhea Ø Probiotics-Lactobacillus acidophilus, Sacro-B, Culturelle (Lactobacillus GG), Ultra. Flora Plus DF Ø GI-ENCAP (Thorne) (DGL, Slippery elm, Marshmallow root, and Plantain Ø Berberine , 2 caps bid to tid has been reported to help with radiation induced intestinal syndrome 10/26/2021 Naini Kohli NYANP 54

Ø Radiation-induced dermatitis Ø Calendula Lotion Ø Fatigue Ø Nutrients: B-vitamins Ø Herbs- Ginseng

Ø Radiation-induced dermatitis Ø Calendula Lotion Ø Fatigue Ø Nutrients: B-vitamins Ø Herbs- Ginseng (Pommier P, et al. J Clin Oncol. 2004) (Barton DL, et al. Support Care Cancer. 2010) 10/26/2021 Naini Kohli NYANP 55

Enhance Effectiveness of Treatment Ø Chemotherapy Ø Curcumin (Rocks N, et al. Br J

Enhance Effectiveness of Treatment Ø Chemotherapy Ø Curcumin (Rocks N, et al. Br J Cancer. 2012; Yin H, et al. Acta Biochim Biophys Sin (Shanghai). 2012) (Synergistic with gemcitabine and 5 FU) Ø Radiation Ø Curcumin (Shi HS, et al. Int J Nanomedicine. 2012; Lee JC, et al. Radiat Res. Ø 10/26/2021 2010) Fish oil (Murphy RA, et al. Cancer. 2011) Naini Kohli NYANP 56

Preventing Cardiotoxicity Ø Clinical trial: 79 patients treated with Adriamycin Ø Co. Q 10

Preventing Cardiotoxicity Ø Clinical trial: 79 patients treated with Adriamycin Ø Co. Q 10 administered along with chemo (40 pts) Ø 30% reduction in EKG changes in Co. Q 10 group compared with controls, and this was true for 29 patients who received chemotherapy for at least 8 weeks. Ø Gan To Kagaku Ryoho. 1984 Jul; 11(7): 1420 -7. Ø Does not interfere with the anti-cancer activity of Adriamycin Ø Prevents damage to mitochondria found in heart tissue Conklin KA. Coenzyme Q 10 for prevention of anthracycline-induced cardiotoxicity. Integr Cancer Ther. 2005 Jun; 4(2): 110 -30. ØL-carnitine - 1000 mg BID � Carnitine deficiency aggravates cyclophosphamide-induced cardiotoxicity in rats Chemotherapy. 2010; 56(1): 71 -81. 10/26/2021 Naini Kohli NYANP 57

End Result- Loss of Estrogens Vasomotor Symptoms Aftermath of treatment Bone Health 10/26/2021 Naini

End Result- Loss of Estrogens Vasomotor Symptoms Aftermath of treatment Bone Health 10/26/2021 Naini Kohli NYANP Sexual Health 58

Ø Estrogens are critical in defining metabolic function in hepatic and adipose tissues Ø

Ø Estrogens are critical in defining metabolic function in hepatic and adipose tissues Ø Compared to age matched men premenopausal women have a lower mortality due to protective effects of estrogens. Ø Results in significant loss of skeletal muscle, bone cardiovascular and brain function. 10/26/2021 Naini Kohli NYANP 59

Factors leading to loss of Estrogens Ø Surgery for the cancer itself Ø Prophylactic

Factors leading to loss of Estrogens Ø Surgery for the cancer itself Ø Prophylactic RRSO Ø Chemotherapy Ø Radiation therapy Ø Estrogen receptor antagonists. 10/26/2021 Naini Kohli NYANP 60

Potential side effects of estrogen blockade Ø Increased risk of osteoporosis and bone fractures.

Potential side effects of estrogen blockade Ø Increased risk of osteoporosis and bone fractures. Ø Anxiety Ø Insomnia Ø Arthralgia Ø Depression Ø Fatigue Ø Weight gain Ø Sexual dysfunction 10/26/2021 Naini Kohli NYANP 61

Supporting loss of estrogens Support Bone Health Calcium Magnesium Vitamin D Omega 3 fatty

Supporting loss of estrogens Support Bone Health Calcium Magnesium Vitamin D Omega 3 fatty acids Multi-vitamin with micro-minerals and vitamin K Arthralgia Omega 3 fatty acids Glucosamine Bromelain Depression/Anxiety 5 HTP Inositol Magnesium EFA’s B 6 Hot Flashes • Omega 3 fatty acids • Magnesium • Black Cohosh (does not appear to be any CYP interactions with metabolism of aromatase inhibitors based on previous In vivo studies noted ) • Hesperidin 10/26/2021 Naini Kohli NYANP Insomnia Melatonin Inositol Homeopathic Coffea Cruda Improved Sleep Habits 62

Case study Vaginal cancer Aftermath of treatment Ø JS, 48 yrs female presented with

Case study Vaginal cancer Aftermath of treatment Ø JS, 48 yrs female presented with h/o stage 3 b Vaginal Cancer in Oct 2013, having completed treatment with chemo-radiation in July 2012 Ø Histopathologically moderately differentiated carcinoma arising out of bartholin cyst. Ø Patient presented to ERMC with complains of chronic pelvic pain, poor appetite, weight loss of about 20 lbs in 2 months, xerostomia, fatigue and insomnia Ø Patient was referred to the pain clinic but terminated from the practice due to positive drug screen 10/26/2021 Naini Kohli NYANP 63

Ø Lab results were wnl and scans did not show any concrete evidence of

Ø Lab results were wnl and scans did not show any concrete evidence of cancer except for the presence of 2 thickened areas in the pelvis which could be due to radiation induced changes. Ø Pelvic examination performed by oncologist was not very helpful since patient was in extreme pain and was anxious, all he could see was a necrotic area in the lateral vaginal wall from where smear was taken and revealed chronic inflammation. Ø Patient was referred to pain management where she received a script for Oxycodone 15 mg every 6 hours. 10/26/2021 Naini Kohli NYANP 64

Naturopathic evaluation Ø History and family dynamics- lives with husband son, no family stressors

Naturopathic evaluation Ø History and family dynamics- lives with husband son, no family stressors or h/o drug seeking behavior. Ø Anxiety and frustration with her current situation Ø Constipation due to opioid use leading to poor appetite worsened by anxiety and depression Ø Painful defecation Ø Fatigue, vasomotor symptoms 10/26/2021 Naini Kohli NYANP 65

Management Plan ØContrast sitz bath 3 mins Observation warm and 45 seconds cold x

Management Plan ØContrast sitz bath 3 mins Observation warm and 45 seconds cold x 3 Follow up in 3 ending with cold. months Plan for EUA and biosy of suspicious areas Pain Control 10/26/2021 Naini Kohli NYANP 66

ND recommendations continued Ø Vitamin A 25000 iu twice daily to support differentiation of

ND recommendations continued Ø Vitamin A 25000 iu twice daily to support differentiation of squamous epithelium Ø Omega 3 1200 mg (combined EPA+DHA) twice daily to decrease inflammation and to support overall health Ø Curcumin Phytosome 500 mg twice daily to support antiapoptotic and anti-inflammatory pathways Ø Theanine 200 mg twice daily to help with anxiety Ø Melatonin 10 mg at bed time to help with sleep Ø CDE vaginal suppositories at bed time 10/26/2021 Naini Kohli NYANP 67

Follow up visit 2 Jan th 15 2013 Ø Subjected to EUA and biopsies

Follow up visit 2 Jan th 15 2013 Ø Subjected to EUA and biopsies Ø Biopsies negative for cancer Ø Patient subjectively better Ø Pain is better controlled , takes Oxycodon only on as needed basis Ø Vaginal dryness is still there Ø Vasomotor symptoms better Ø Constipation managed with smooth move tea daily 10/26/2021 Naini Kohli NYANP 68

Ø Decreased Vitamin A to 25000 iu daily x 3 months and discontinue Ø

Ø Decreased Vitamin A to 25000 iu daily x 3 months and discontinue Ø Decrease Theanine to 200 mg daily x 3 months and discontinue Ø Continue Omega 3, Meriva , Vitamin D 3 and melatonin with recommendations to recheck vitamin D levels in 6 months. Ø Vitamin E suppositories as needed for dryness Ø Added Cal Mag for supporting bone health 10/26/2021 Naini Kohli NYANP 69

Bone health in Cancer Care Ø Treatment related bone loss may lead to osteopenia,

Bone health in Cancer Care Ø Treatment related bone loss may lead to osteopenia, osteoporosis and related complications like fractures, pain and diminished QOL (quality of life) Ø Complications of bone metastasis including pain, hypercalcemia and pathological fractures 10/26/2021 Naini Kohli NYANP 70

Risk Factors for Osteoporosis in Cancer Patients Ø Removal of ovaries Ø Chemotherapy induced

Risk Factors for Osteoporosis in Cancer Patients Ø Removal of ovaries Ø Chemotherapy induced ovarian failure Ø Hormonal therapy with aromatase inhibitors Ø Glucocorticoid therapy Ø Proton pump inhibitors, anticoagulants, certain antidepressants Ø Skeleton is a common site of metastatic recurrence Ø Family history Ø Life style like smoking and alcohol 10/26/2021 Naini Kohli NYANP 71

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Pre clinical studies on natural products Ø Common vegetables, including onion, garlic and parsley,

Pre clinical studies on natural products Ø Common vegetables, including onion, garlic and parsley, can inhibit bone resorption in ovariectomized rats. Ø Essential oils derived from sage, rosemary, thyme and other herbs inhibit osteoclast activity in vitro leading to an increase in bone mineral density. Ø Soy has shown promising results and epidemiological evidence to support use in maintaining bone health. Ø Recently, cannabinoids have been described as having positive effects on osteoblast differentiation. 10/26/2021 Naini Kohli NYANP 73

Managing vasomotor symptoms Ø Magnesium: Of 25 patients, 14 (56%) had a >50% reduction

Managing vasomotor symptoms Ø Magnesium: Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Doses ranged from 400 – 800 mg of magnesium oxide daily. Ø EPA: Of 120 women supplemented with E-EPA omega -3 fatty acid they had a reduced HF frequency and improved the HF score relative to placebo. 10/26/2021 Naini Kohli NYANP 74

Black Cohosh Ø Black Cohosh appears to be one of the most effective botanicals

Black Cohosh Ø Black Cohosh appears to be one of the most effective botanicals for relief of vasomotor symptoms, while St. John’s wort can improve mood disorders related to the menopausal transition. Ø It was presumed to have estrogenic activity, however, recent studies show no effect on serum hormone levels. Ø Two recent studies of black cohosh for women on tamoxifen have shown a significant reduction in number and severity of hot flashes as compared to placebo as well as improvement in sleep, fatigue levels and abnormal sweating 10/26/2021 Naini Kohli NYANP 75

Wild yam (Dioscorea villosa) Only 1 RCT of topical wild yam cream showed no

Wild yam (Dioscorea villosa) Only 1 RCT of topical wild yam cream showed no difference in alleviation of menopausal symptoms or serum/salivary hormone levels compared to placebo. (Komesaroff PA, Black CV, Cable V, Sudhir K. Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women. Climacteric 2001; 4: 144– 50. [Pub. Med: 11428178] 10/26/2021 Naini Kohli NYANP 76

Vitex Agnus Castus and EPO Ø The only study of Chaste tree alone in

Vitex Agnus Castus and EPO Ø The only study of Chaste tree alone in peri-and postmenopausal women reported improvement in mood and hot flashes, although the study had no placebo or comparison group. Ø Most often, when the herb is used for menopause it is in a combination with black cohosh and other botanicals. Ø The only RCT of evening primrose for menopausal symptoms found no differences in the reduction of hot flashes between the placebo and evening primrose groups. 10/26/2021 Naini Kohli NYANP 77

Acupuncture and TCM, RCT Ø Enrollment of 40 post menopausal women reporting at least

Acupuncture and TCM, RCT Ø Enrollment of 40 post menopausal women reporting at least 20 hot flashes per week. . Ø They received traditional Chinese medicine (TCM) AP, sham AP, verum CHM, or placebo CHM for 12 weeks. RESULTS: TCM AP induced a significant decline in all outcome measures from pretreatment to posttreatment compared with sham AP (hot flush frequency, P = 0. 016; hot flush severity, P = 0. 013; MRS, P < 0. 001). TCM AP group a larger decrease in MRS scores persisted from pretreatment to follow-up (P = 0. 048). 10/26/2021 Naini Kohli NYANP 78

Lifestyle adaptation Ø Avoid triggers such as spicy food, alcohol, hairdryers and anxiety. Ø

Lifestyle adaptation Ø Avoid triggers such as spicy food, alcohol, hairdryers and anxiety. Ø Dress in layers so that clothes can easily be removed during hot flushes. Ø Weight control Ø Exercise Ø Quit smoking Ø Use of Non-hormonal lubricants during intercourse to avoid vaginal rubbing and trauma. Ø Vaginal moisturizers like Emu oil, coconut oil can be helpful 10/26/2021 Naini Kohli NYANP 79

Clinical trials in cervical cancer chemoprevention Ø Butterworth et al. Oral folic acid supplementation

Clinical trials in cervical cancer chemoprevention Ø Butterworth et al. Oral folic acid supplementation for cervical dysplasia : a clinical intervention trial. Am J Obstet Gynecol 1992; 166: 803 Ø Childers JM, et al. Chemoprevention of cervical cancer with folic acid: a phase 3 SWOG intergroup study. Cancer Epidemiol Biomarkers prev. 1995; 45: 489 Ø Meyskens et al. Enhancement of regression of cervical intraepithelia neoplasi 11 with topically applied all-trans-retinoic acid: a randomised trial. J Natl Cancer Inst 1994; 86: 539 Ø Romney SL, et al. Effects of beta-carotene and other factors on outcome of cervical dysplasia and HPV infection. Gynecol Oncol. 1997; 65: 483 Ø Keefe KA, et al. A randomized, double blind, phase 111 trial using beta-carotene supplementation for women with high grade CIN. Cancer Epidemiol Biomarkers prev. 2001; 10: 1029 -1035. 10/26/2021 Naini Kohli NYANP 80

THANK YOU “If I have seen a little further it is by standing on

THANK YOU “If I have seen a little further it is by standing on the shoulders of Giants”-Isaac Newton 10/26/2021 Naini Kohli NYANP 81