IntroductionCarcinoma endometrium is the most common gynecological malignancy in the developed countries

IntroductionCarcinoma endometrium is the most common gynecological malignancy in the developed countries with age standardized incidence rate of 2.3 per 100,000 .(1) In India the total number of estimated cases of endometrial cancer in 2018 is 13,328 with an estimated 5010 deaths. The rise is attributed to change in lifestyle and reproductive profile of women especially in urban areas. The majority of patients present in 6th to 7th decade of life.According to WHO report, Cervical cancer is the fourth most frequent cancer in women with an estimated 570,000 new cases in 2017 , representing 6.6% of all female cancers. (2). In India, cervical cancer has increased from 0.11 million in 2000 to 0.16 million in 2010. Over 80% of cases are locally advanced and annually around 80,000 deaths are reported. More than 85% of cervical cancer cases are seen in developing countries, highlighting the disproportionately high burden of cervical cancer largely due to lack of screening and detection of precancerous lesions.Pelvic radiotherapy plays an important role in management of gynaecological malignancies. Pelvic RT includes external beam RT, brachytherapy. Brachytherapy can deliver high doses of radiation to cervix and paracervical tissues while avoiding severe bowel and bladder toxicity. Current treatment practice for FIGO Stage IB2- IVA cervical cancer includes CCRT followed by ICRT. FIGO Stage IA2, IB, IIA patients are treated with radical hysterectomy & bilateral lymph node dissection followed by adjuvant treatment. Adjuvant treatment includes external beam RT with concurrent chemotherapy followed by vaginal brachytherapy, in the presence of positive pelvic nodes, positive surgical margins, positive parametrial involvement. In case of negative nodes, negative surgical margins, no parametrial involvement, adjuvant radiotherapy is indicated for those tumours meeting Sedlis criteria. (3) The primary treatment modality of Endometrial carcinoma is surgery. FIGO stage I patients, require adjuvant radiotherapy in the presence of high-grade carcinoma (Grade III) or other adverse risk factors. The adjuvant treatment of FIGO stage II cases includes Pelvic RT with or without VBT and adjuvant chemotherapy. The adjuvant treatment of FIGO stage III, IV cases include systemic therapy with or without pelvic RT/VBT.(4)Vaginal stenosis is a notable side effect seen in women undergoing pelvic radiotherapy and is defined as an abnormal shortening and tightening of the vagina due to fibrosis (5). The reported incidence of radiation induced vaginal stenosis is largely inconsistent and can depend on patient related (age, inherent radiosensitivity of tissues) , tumour related (site of disease) and treatment related factors (Radiotherapy modality and dose, dose fractionation schedule, concurrent chemotherapy).(6)Brand H et al noted vaginal stenosis in 38% of post RT cervical cancer patients, with most cases occurring in 1st year. Stenosis of any grade was noted at a mean of 9.6months and median of 7.5months(Range- 26 days- 5.6yrs). (7) In a another study by Ken Yoshida et al, it was noted that VS increases with time and mild stenosis was noted within 1st year of follow up in more than half of the patients. The rates of Grade 1,2,3 VS at 3yrs post RT was 97.5%, 60.7%, 7.4% respectively. (8) Gondi et al noted that at 3 years, the probability of vaginal severe late toxicity(grade 3 VS) was 20.2% in RT alone arm and 35.1% in CCRT arm. Patients with moderate and poor dilator compliance were found to have higher vaginal severe late toxicity. (9)According to FIGO Cancer report 2012, the tolerance doses of the upper vagina and distal vagina are 140Gy and 100Gy, respectively. Threshold doses reported for vesicovaginal fistula and rectovaginal fistula are 150Gy and 80Gy, respectively. (10)The 〖EQD〗_2Gyfor the upper vagina in endometrial cancer is 43.2Gy with brachytherapy alone and 94Gy with EBRT and brachytherapy combined. For cervical cancer the 〖EQD〗_2Gy for upper vagina is 50.4Gy with brachytherapy alone and 100.8Gy with EBRT and brachytherapy combined. The 〖EQD〗_2Gyfor the distal vagina in endometrial cancer is 28.8Gy with brachytherapy alone and 79.2Gy with EBRT and brachytherapy combined. For cervical cancer the 〖EQD〗_2Gy for distal vagina is 33.6Gy with brachytherapy alone and 84Gy with EBRT and brachytherapy combined.In the EMBRACE study (11) the risk factors for vaginal stenosis included extension into vagina at diagnosis, External beam radiotherapy of dose more than 45Gy in 25 fractions and brachytherapy rectovaginal reference point dose. This has a negative impact on patients well being, particularly sexual dysfunction and dyspareunia. There is also the problem of excessive pain during medical pelvic examination leading to inadequate examination to monitor for changes in vaginal tissue.Evidence suggests that vaginal dilators can prevent the formation of adhesions and limit the development of fibrosis. Velaskar et al, (12) studied the efficacy of vaginal dilators in 89 patients who underwent radiotherapy for stage III cervical cancer. There was a significant increase in the vaginal length noted between 1st and 4th follow up. In another study it was noted that 82 % women maintained pre-RT VD size at 12 months. 49% of patients with decrease in VD size at 1 month post-RT, 71% returned to pre-RT VD size at 12 months (13). Vaginal dilator use has been recommended as a standard practice once the acute inflammatory phase has settled by the American cancer society and the UK National Forum of Gynaecological Oncology Nurses (14). They recommend to initiate use at 6 weeks post RT and dilators are to be used for about 3 minutes twice a week for the first 6 months, upto 10minutes and twice daily. This should be continued once a week thereafter and then occasionally after a year.(15) The Sydney Gynecological Oncology Group 2012, suggests a minimum use of 3 times weekly for 5-10 minutes each for an indefinite time period. (16)A recent Delphi consensus among professional experts recommended that dilator use should commence 4 weeks post-RT and it is to be used two to three times per week for 1–3 minutes and continued for 9–12 months. Plastic dilator sets were the most appropriate device. Frequency of dilator use can be decreased once sexual activity is resumed. (5)Usage of dilators during radiotherapy is discouraged since it is plausibly associated with greater scar formation, causes psychologic sequelae and also there is no good evidence supporting the same (17)There exists no uniformly adopted grading system for assessment of vaginal stenosis. However, the two most commonly used grading systems include LENT SOMA grading and CTCAEThe principle of using vaginal dilatation is to break the adhesions formed and stretch out the vagina in order to maintain vaginal patency. Regular sexual intercourse also does prevent the same.Poor compliance can be expected due to emotional distress and lack of information provided regarding dilator use. A study regarding sexual function and vaginal changes after RT for cervical cancer by Jensen et al. showed that patients who are disease free after RT for locally advanced, recurrent, or persistent cervical cancer experience persistent sexual dysfunction and adverse vaginal changes during the first 2 years after RT with only small changes over time. The sexual and vaginal problems could not be attributed to active disease, because the patients were disease free at all assessmentsAnatomy Uterus is a pear shaped, hollow, thick walled muscular organ normally located in the pelvis posterior to bladder and anterior to the rectum. The uterus measures 7.5 cm. in length, 5 cm. in breadth. It is divided into 3 parts (from superior to inferior):- fundus, corpus, cervix.The major supports of the uterus are the broad, round, uterosacral and cardinal ligaments.Cervix is the lower constricted segment of the uterus. The cervix projects through the anterior wall of the vagina, which divides it into upper supravaginal portion and lower vaginal portion. The supravaginal portion is separated anteriorly from the bladder by fibrous tissue(parametrium) which extends to its sides and between the layers of the broad ligament. Posteriorly its covered by peritoneum which is reflected on to the anterior rectal wall forming the rectouterine pouch. The external os is located on the vaginal portion of the cervix and is bounded by the anterior and posterior lips of the cervix.The vagina extends from the vestibule to the uterus and is directed upward and backwards. Its length is 6-7.5 cm along its anterior wall and 9cm along its posterior wall. It is constricted at its commencement, dilated in the middle and narrowed near its uterine extremity. Superiorly it is attached to the anterior and posterior wall of the uterus leading to the formation of 4 recesses around the cervix – anterior, posterior and two lateral fornices. The anterior surface of the vagina is in relation with the fundus of the bladder and urethra. Its posterior surface is separated from the rectum by the rectouterine pouch in upper portion and separated from the anal canal by the perineal body in the lower portion. Its sides are enclosed between the levator ani muscles.Lymphatic drainage Common iliac group of nodes are 4-6 in number and lie along the sides of the common iliac artery (1-2 nodes placed below aortic bifurcation in front of 5th lumbar vertebrae). They drain the hypogastric and external iliac nodes & pass their efferents to lateral aortic nodes.External iliac group of nodes are 8-10 in number and lie along the external iliac vessels. They receive afferents from inguinal nodes, deep lymphatics of abdominal wall below the umbilicus and the adductor region of the thigh , glans penis, clitoris, membraneous urethra, prostate, fundus of bladder, cervix uteri and upper part of vagina. Internal iliac group of nodes (Hypogastric) surround the hypogastric vessels. It received afferent lymphatics from all the pelvic viscera, deeper parts of perineum, membraneous/ cavernous portions of urethra, buttock, back of thigh.Lateral aortic group of nodes (Paraaortic) – They receive afferents from common iliac nodes, lymphatics of testis, ovary, corpus uteri, fallopian tube, kidney, suprarenal gland, lymphatics draining lateral abdominal muscles. Most of the efferent vessels converge to form right and left lumbar trunks that join the cysterna chyli, whereas a few are seen to enter the preaortic and retroaortic nodes.LYMPHATIC VESSELSUterus- lymphatic drainage of body of uterus is mainly to obturator and internal and external iliac vessels. Lymphatics from fundus of the uterus pass laterally into broad ligaments and continue up with the ovarian vessels to the lateral aortic and preaortic nodes. Cervix – lymphatics run in three directions- transversely to external iliac nodes, posterolaterally to the hypogastric nodes and posteriorly to common iliac nodes.Vagina- lymphatics are carried in three directions, those of the upper part to external iliac nodes, middle part to hypogastric nodes and those of the lower part to common iliac nodes. Some lymphatics from the lower part of vagina join those of the vulva and pass to the superficial inguinal nodes. AetiologyCarcinoma endometrium is said to arise due to hormonal stimulation by endogenous or exogenous estrogen which exacerbates endometrial growth without progesterone stimulated maturation and cyclic menstrual shedding. Risk factors include obesity, Insulin resistance, Type II diabetes mellitus which lowers the level of sex hormone binding globulin resulting in higher circulating levels of free estrogen. Moreover large amounts of subcutaneous adipose tissue leads to more conversion of androgens to estrogen. This leads to a state of persistent estrus due to negative hypothalamic feedback which in turn interferes with the mid cycle LH, FSH surge leading to anovulation. Other risk factors include early menarche, late menopause, use of estrogen only hormone replacement therapy, Tamoxifen(18). Familial syndromes like Lynch syndrome (mutations in MMR genes) and PTEN mutations also increase the risk of endometrial carcinomas as well as a multitude of other tumours.More than 90% of cervical cancers are related to presence of HPV (Human Papilloma virus) and are contracted via sexual intercourse (19)Other risk factors include early age of sexual intercourse, high parity, multiple sexual partners or male partner with multiple sexual partners, tobacco smoking, history of sexually transmitted disease, including chlamydia, Herpes simplex virus type 2, HIV, cigarette smoking, low socioeconomic status, poor hygiene (20)HPV is a double-stranded DNA virus. Virions access basal and parabasal cells in areas of erosion and viral DNA enters the host cell nucleus and finally viral DNA integration occurs. (24) < 15% of women exposed to HPV virus develop persistant infection leading to dysplasia whereas majority clears the infection within 2 years. (21). The lag period between HPV infection and development of invasive cervical cancer is 15-20 years.HPV virus codes for six early and two late open reading frame proteins, out of which E5, E6, E7 alters cellular proliferation. The E6 protein inactivates p53, a major tumour suppressor gene and causes chromosomal instability, inhibits apoptosis and activates telomerases. The E7 protein inhibits Rb gene (Retinoblastoma gene) and results in dysregulated cell proliferation and immortalisation. The most frequent subtype is HPV 16 and 18 and the less frequent subtypes include HPV 31, 33, 35, 39, 45, 51, 52, 56, and 58. HPV vaccination- All the vaccines are recombinant vaccines composed of viral like particles and are not infectious since they do not contain viral DNA. A quadrivalent Human papilloma virus recombinant vaccine for HPV types 6, 11, 16, and 18 is available for girls and women of ages 9 to 26 years and for boys of ages 9 to 26 years. The rationale being to eradicate HPV related gynaecologic, penile, anal, cancers. The bivalent HPV vaccine targeting HPV types 16 and 18 is available for girls aged 9 to 25 years old. HistologyThe most frequent types of cervical cancer are squamous cell carcinoma (90%) and adenocarcinoma(7 to 10%) which develop from distinct precursor lesions -cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (22).The presence of precursor lesions and the possibility of its early detection on cytological smears (PAP smear) has reduced the incidence of cervical carcinoma.Squamous cell carcinoma of cervix is divided into large cell keratinizing, non-keratinizing and small cell carcinomas) and according to the level of differentiation is divided into well, moderate or poorly differentiated. Adenocarcinoma of the cervix includes Mucinous, Endometrioid, Clear cell, serous subtypes and arises from the cylindrical mucosa of the endocervix or mucus secreting endocervical glands. The other less common histological subtypes include Adeno squamous carcinoma, Adenoid cystic carcinoma, Neuroendocrine and Undifferentiated carcinoma. The two main clinicopathological types of endometrial carcinoma include Type 1 – estrogen dependent endometroid carcinoma and Type 2- estrogen independent non endometroid adenocarcinoma. Type I category tumours are often low grade with minimal myometrial invasion and it affects premenopausal and perimenopausal women. The most frequently altered molecular pathway is PI3K/PTEN/ AKT pathway. Type II category includes high grade histology , serous/ clear cell carcinoma with deep myometrial invasion, advanced stage of presentation. There is often alteration in p53 pathway. About 80% of endometrial carcinoma constitute endometroid adenocarcinoma. Other subtypes include – serous carcinoma (11.4%), clear cell carcinoma (3.5%), mucinous, squamous, undifferentiated, mixed histology. (4)