1 Management of Carcinoma CervixCarcinoma cervix is the most common cancer in Indian women.The incidence rates range from 19-44 per 1 lakh women in variousCancer registries.The diagnostic workup includes a Thorough Clinical Historywith special emphasis on age at marriage, age at first pregnancy,parity, multiple sexual partners, sexually transmitted diseases andH/o smoking which is associated with increase in risk. Physical Examination consists of general examination as well asbimanual pelvic and rectal examinations. Examination underanesthesia can be done if required.Lab studies include a complete blood count, levels of blood ureaand serum creatinine to assess the renal function, liver functiontests , blood sugar analysis and analysis of urine.These are followed by Pap smears and Colposcopy withdirected biopsies in women with abnormal pap test. Endocervical Curettage is indicated in women with abnormalPap smear but having negative colposcopic findings or when theentire squamocolumnar junction is not visualized.Conization is indicated in patients who have inadequatecolposcopic findings but where the endocervical curettage shows ahigh grade lesion or when the biopsy suggests microinvasion.Punch biopsies are taken from the edges of any gross visibletumor.Cystoscopy and Rectosigmoidoscopy are indicated in cases ofsuspicion of bladder and bowel involvement.Radiologic studies include chest X-ray and IVP. Barium enema is done from stage III onwards, and earlier stages ifsymptoms are referable to colon or rectum.Various complimentary procedures that are of help in diagnosisand treatment planning are
2 Ultrasonography of abdomen and pelvis, CT or MRI scans, Recently PET scans have also been included and also the surgicalstaging. These procedures aid in treatment planning but cannot be used todetermine or alter the FIGO stage.The FIGO Staging includes stages from stage 0 to stage IV.Stage 0 is preinvasive carcinoma or carcinoma in Situ.Stage I tumors are confined to cervixstage IA is microinvasive cancer. It has again been divided into stages IA1 and IA2 based on the depth of invasion. Stage IA1 is stromal invasion less than 3 mm and IA2 is invasion between 3 to 5 millimeters.In both these stages, the horizontal spread should not be more than7 millimeters.Stage IB is any clinically visible lesion confined to cervix ormicroscopic disease greater than IA2.On the basis of size, it has again been divided into stages IB1 andIB2. Stage IB1 is a lesion 4cm or less in diameter. Stage IB2 is tumor more than 4 cm in size.Stage II:When the tumor spreads beyond uterus, but not upto the lateralpelvic wall or lower 1/3rd of vagina, it is classified as stage IItumor. Tumor with no parametrial invasion is IIA and if it invades theparametrium, it is classified as IIB.
3 Stage III is the tumor extending up to the lateral pelvic wall orlower 1/3rd of the vagina.Tumors associated with hydronephrosis or non-functioning kidneyare also classified as stage III. IIIA lesions are tumors invading the lower 1/3rd of vagina. IIIB tumors extend up to the lateral pelvic wall or are associatedwith hydronephrosis or nonfunctioning kidney.Stage IV tumors have been classified as either stage IV A or B. IV A tumors have invaded the mucosa of the bladder or rectum orextended beyond the true pelvis.IV B: Patients with distant metastases are classified as IV B.In FIGO 2008 system, Stage IIA is subdividedinto stage IIA1 and IIA2 based on size (≤4 vs.>4 cm).Pathology:Squamous cell carcinoma is the most common histologicalsubtype of carcinoma cervix and is diagnosed in over 90% ofcases. 7 to 10% are adenocarcinomas.Stage wise management of carcinoma cervix: 1.) Management of STAGE 0 or carcinoma in situ depends on whether the patient desires to preserve her fertility.In patients who desire fertility preservation,Ectocervical lesions can be managed with either of the followingprocedures ie., LEEP, laser therapy, cryotherapy or conization.
4Patients with Endocervical canal involvement can be treatedwith conization if they wish to preserve their fertility.For Post Menopausal women,The treatment of choice is either total abdominal or vaginalhysterectomy.Medically inoperable patients are treated with Intracavitaryirradiation alone up to a dose of 45 to 50 Gy to Point A. 2.) I A 1 ( No LV Invasion) Conization for those who wish to preserve fertility. Or, Total hysterectomy in other patients (also indicated in patients in whom cone margins are positive). Patients unfit for surgery: Intracavitary Brachytherapy alone is an option for patients who are unfit for surgery. Doses to Point A range from 60 to 70 Gy. Patients with LVS invasion are treated in a manner similar to stages I A2 and IB1
5 3.) IA2: Radical Hysterectomy with pelvic lymph node dissection. Women not fit for surgery are treated with Brachytherapy + EBRT to pelvis to a total dose of 75 to 80 Gy to point A. 4.) STAGE IB1 and IIA (<4 cm) Patients with Stage IB1 tumors and non bulky IIA lesions can be treated with either Radical Hysterectomy plus pelvic node dissection Or Pelvic RT plus Brachytherapy to a total dose up to 80 Gy to Point A. The results of either modality are equivalent.The ABS recommends that:Primary therapy should avoid the routine use of both radicalsurgery and radiotherapy to minimize the morbidity related tomultimodality treatment. 5.) STAGE IB2 and Bulky IIA(>4cm):Radical Radiotherapy + concurrent cisplatin based chemotherapywith a total Point A dose of 85 Gy or more.There is a lower level of evidence supporting radical surgery aloneas a treatment modality in this group of patients
6INDICATIONS OF ADJUVANT RADIOTHERAPY (Post Operative)In Node Negative Patients:i.) Any two of the following features:> 1/3rd Stromal Invasion LV space Invasion Large (>4 cm) tumorii.) Positive surgical margin & iii.) Positive parametrium (Tx of choice for options (ii.) & (iii.) is pelvic radiotherapy withconcurrent cisplatin based chemotherapy and vaginalbrachytherapy if vaginal margins are positive).In Pelvic Node Positive Patients:Pelvic radiotherapy with concurrent cisplatin based chemotherapyand vaginal brachytherapy if vaginal margins are positive.6). STAGES IIB/IIIA/IIIB: Pelvic RT + concurrent Cisplatin based chemotherapy
7 followed by Brachytherapy7.) STAGE IVA:The treatment of Stage IV A needs to be individualized based onthe extent of bladder or rectal involvement, Renal function,Parametrial involvement and performance status of the patient.Surgical exenteration can be tried in patients with no or minimalparametrial invasion and in patients with good performance status,in the form of anterior, posterior or total exenteration, based on theextent of bladder or rectal invasion. Concurrent RT/CT is an option in selected patients with goodgeneral and renal status who are not suitable for surgicalexenteration. But majority of patients in this stage have poor general conditionand have extensive disease and are best treated with palliative RTalone. A short regime of 30 Gy in 10 fractions for two weeks can be triedin these patients and those responding well can be followed upwith intracavitary application.8.) Stage IV B:Stage IV B patients are treated with palliative intent.Radiotherapy can be used for palliation of distant metastases inbrain and painful bony metastases.
8Symptoms due to extensive central disease like pain, bleeding andtenesmus can be effectively palliated with radiotherapy.There is no standard chemotherapy regimen for palliative treatmentBut combinations like cisplatin/paclitaxel, cisplatin/topotecan, andcisplatin/ifosfamide have been used with varying response rates.The ABS and NCI recommend the addition of ciplatin basedchemotherapy during the course of definitive irradiation from stageIB2 onwards.5 randomized trials have shown significant improvement in localcontrol as well as survival in these patients.Most of these trials were performed in affluent countries, inwomen with better nutritional and performance status, and betterrenal parameters.But patients in India are usually from lower socioeconomic statusand have more advanced disease with poor renal parameters andthere is a problem of doubtful compliance to treatment.Therefore radical RT alone can still be considered as an acceptabletreatment approach in our patients. INVASIVE CANCER FOUND AFTER SIMPLE HYSTERECTOMYTwo Treatment Options: 1. Immediate Resurgery- Radical Parametrectomy and Pelvic LND. 2. Post op RT:Another option is post op. radiotherapy in the form of wholepelvis radiotherapy 45-50 Gy, for patients with no disease or
9Pelvic RT with Concurrent Cisplatin based Chemotherapy forpatients with microscopic disease at margins followed by ICRT toboost the dose at vaginal apex to 60-65 Gy(total dose).For patients with gross residual disease in vault, whole pelvis doseof 40 Gy is followed by additional 20 Gy to parametrium withConcurrent Cisplatin based Chemotherapy and subsequent ICRTup to 65 Gy mucosal dose. RECURRENT DISEASE:The treatment of recurrent disease depends on whether it is a postRT recurrence or recurrence after surgery:Post RT:For small central recurrences after radiotherapy, either radicalhysterectomy or brachytherapy alone can be considered.For larger central lesions in patients with good performance status,pelvic exenteration is an option.For pelvic side wall recurrences, only treatment options includepalliative chemotherapy or symptomatic or supportive care.Post Surgery:Post surgical recurrences can be treated with definitive pelvic RTalong with cisplatin based chemotherapy.Extrapelvic/Distant Mets:
10Extrapelvic or distant metastases are treated with palliative intent. RADIOTHERAPYRadiotherapy for carcinoma cervix is delivered both as externalbeam treatment and Brachytherapy.EBRT treats the whole pelvis and parametria and intracavitarybrachytherapy primarily treats the central disease ie., cervix,vagina and medial parametria.EBRT is delivered before ICRT in the following circumstances:1. In case of bulky cervical lesions to improve the geometry.2. In exophytic easily bleeding tumors3. In tumors with necrosis and infection4. In cases with parametrial involvement.EBRT Portals for AP/PA fields are:Superior border is taken at L4-5 interspace in order to include thecommon iliac nodes.Inferior border is at lower border of obturator foramen. In case ofvaginal involvement, entire length down to introitus is included inthe portal.The lateral border is taken 2 cm lateral to the bony pelvis on eithersides. In cases of involvement of lower 1/3 rd vagina, inguinal nodesare covered.Lateral Portal:
11Anterior margin of the lateral portal is taken at cortex of thesymphysis pubis in order to adequately cover the external iliacnodes.Posterior margin covers at least 50% of the rectum in stage IB, andextends to sacral hollow in more advanced tumors.Lateral fields allow a decrease in dose to small bowel and a portionof the low rectum but care must be taken to include the allstructures of interest.Midline ShieldingMidline shielding may be used for part of pelvic RT to shieldbladder and rectum to allow a higher dose to be given bybrachytherapy.These can be made by simple rectangular blocks 4 cm wide atmidplane.Customized blocks can also be made based on radiographs.When inserted before 40 Gy, these should not extend to the top ofthe pelvic field otherwise the common iliac and presacral nodes donot receive adequate doses.BRACHYTHERAPY: ABS strongly recommends that: 1) Definitive Irradiation for cervical carcinoma must include brachytherapy as a component. 2) Precise applicator placement is essential for improved local control and reduced morbidity. 3) Interstitial brachytherapy should be considered for patients with disease that can’t be optimally encompassed
12 by intracavitary brachytherapy.4) Total treatment duration be less than 8 weeks when possible (exceeding beyond 8 wks can reduce local control and survival by about 1% per day of prolongation. Treatments Classified with respect to Source loading: 1) Preloading: The applicator is preloaded and contains radioactive sources at the time of placement into the patient. 2) Afterloading: The applicator is placed first into the target position and the radioactive sources are loaded later, either by hand (MANUAL) or by a machine ( REMOTE AFTERLOADING). Treatments Classified with respect to Dose Rate: LDR: 0.4 – 2 Gy/hr MDR: 2- 12 Gy/hr HDR: > 12 Gy/hr ( practically much higher dose rate used) Evolution Of Brachytherapy In Carcinoma Cervix: First application of Radium in treatment of uterine cancer- 1908 Three Basic Systems evolved:
13 The Stockholm System The Paris System The Manchester System Most systems used throughout the world are derived from these three basic systemsStockholm/Paris System- Applications reported interms of “mg.h”( milligram hours)- product of totalmass of Radium contained in the sources (in mg) andduration of the application (in hours).Manchester System: Designed to deliver a constant doserate to defined points near cervix, irrespective of variationin size and shape of uterus/vagina.Application specified in terms of “dose” in Roentgens deliveredat specific points ( Point A, Point B, Bladder Point, Rectal Point).Duration of implant based on the dose rate calculated at Point A.Optimal dose taken as 8000 R (72.8 Gy) in two sessions of 72 hrs.each, 4-7 days interval. POINT A: Originally defined as 2 cm superior tothe lateral vaginal fornix and 2 cm lateral to thecervical canal( later redefined as 2 cm superior tothe ext cervical os/cervical end of the tandem,and 2 cm lateral to the cervical canal).POINT B: Defined 3 cm lateral to Point A( intendedto quantify the dose delivered to the Obturator L.Ns.)Receives ~1/3–1/4 of dose to point A.Dose to Bladder and Rectum: Localization of
14bladder and rectum can be performed using radiographstaken with contrast media in bladder/rectum.Maximum dose to bladder/rectum: 80% or less thanthe dose to point A.MANCHESTER SYSTEM APPLICATORS: Two vaginal Ovoids- made of hard rubber Locked in position by spacer or a washer Ovoid Sizes: 2.0/2.5/3.0 cm Intrauterine Tubes- made of thin rubber Three different lengths for 1/2/3 radium tubes each about 2 cm long. Each tube is closed at one end and has a flange at the other. Manchester ovoid dimensions and applicator loadings were designed to ensure a dose rate of about 0.52 Gy/hr , which remained constant for all allowed applicator loadings and combinations. Vaginal contribution to point A was limited to 40% of the total dose. Current Practice- Point A dose is used to denote the average or minimum dose to the tumor.
15Manchester System: Definition of Points “A” and “B”
16Modern Fletcher-Suit Applicator Systems Adhered to the basic Manchester design. After loading capability was added to the Fletcher applicator by Suit and co-workers. Because of the similarity of Fletcher loadings to the Manchester loadings, Point A dose rates are nearly independent of the applicator dimensions. Use of Cs-137 instead of radium. Vaginal Cylinder Used in conjunction with an Intrauterine tandem to irradiate the vagina when the disease extends from the uterine cervix along the vaginal walls. Cylinder can be used alone after a radical hysterectomy if there is a close or positive vaginal margin.
17 Also useful for a patient with a very narrow vagina. Available in various diameters(1-5 cm) and lengths to fit any vaginal width or length.CESIUM- 137 Most LDR intracavitary systems use Cesium as as the implanted radioisotope. Similar in size and shape and have an output similar to radium sources. Elimination of Radon gas leakage. Less required shielding for radiation protection (lower energy, 0.662 Mev)Characteristics of good insertion in brachytherapyA-P View:1) Tandem midline, unrotated2) Tandem midway between colpostats3) Colpostats high in the fornices along cervix (approx 1/3rd of the ovoid should be superior to the cervical collar and two-thirds should be inferior).Lateral View:1) Tandem bisects the colpostats2) Sufficient anterior and posterior packing3) Foley baloon firmly tugged down
18SIMULATION: After insertion of the applicator, dummy sources are loaded into the afterloading applicators and an orthogonal pair of radiographs are taken. The isocenter is set at the centre of the collar for Fletcher-Suit tandem and ovoid applications.ICRU BLADDER and RECTAL REF POINTS: Bladder Point- Foley balloon is filled with 7 cc of radiopaque fluid( Hypaque) and pulled down towards the bladder neck. On Lat radiograph, obtained by drawing a line through the center of the balloon and the posterior surface of the balloon is used as the reference point. On the anterior radiograph, the ref. point is taken at centre of the balloon. Rectal Ref Point: Lat radiograph- An AP line drawn from the lower end of the IU sources( or from the middle of the IV sources). The Rectal point is taken at a depth of 0.5 cm, posterior to the point where this line traverses the posterior vaginal wall( identified by intravaginal radiopaque gauge. AP radiograph- the Rectal point is at the lower end of the IU source or at the middle of thr IV sources at the midline.Dose Limitation:
19LDR: limit rectal point <70 Gy and bladder point<75 Gy.
20Advantages of HDR versus LDR :Presently there is a move towards HDR brachytherapy fromtraditional Low dose rate systems: 1. Eliminates radiation exposure hazard for caregivers and visitors. 2. Allows shorter treatment times. 3. Less risk of applicator movement during therapy. 4. Allows greater displacement of nearby normal tissues. 5. Possible to treat larger no. of patients. 6. Allows use of smaller diameter sources than are used in LDR 7. Reduces the need for dilatation of cervix and therefore, reduces the need for heavy sedation or GA every time. 8. Physically easier to insert applicator into the cervix. 9. Makes treatment-dose-distribution optimization possible.HDR Equipment: Source most commonly used: Ir-192 Half life- 74 days The encapsulated Ir-192 source is attached to the end of a cable, which can be advanced or retracted in precise increments using stepper motors ( stepping source) The ability to control the locations and dwell times permits greater flexibility modifying the dose distributions.The HDR dose to Point A is approximately about 60 % of the LDRdose.
21 Dose Limitation:HDR: limit bladder and rectal points to <70% of pointA dosewith HDR.The Ring Applicator: Particularly useful when the vaginal fornices are asymmetric or absent. It is popular because it has a reproducible geometry and is easy to insert. It is important that the plastic cap of the ring applicator be in place with each insertion, because excessive vagina mucosal doses would be delivered without them. Also important not to activate the entire ring circumference; usually the lateral 4 – 6 dwell positions are activated on each side of the ring, dependent on the ring diameter. SEQUELAE OF RADIATION THERAPY Acute: Nausea, diarrhea, abdominal cramping, rectal discomfort, Occasionally, rectal bleeding. Dysuria, frequency, nocturia, rarely hematuria; UTIs . Pruritus, erythema, pigmentation, dry/moist desquamation in perineum or intergluteal fold.
22 Radiation vaginitis/superficial ulceration of vagina/ vaginal stenosis HDR and LDR morbidity are equivalent: uterine perforation (<3%), vaginal laceration(<1%), DVT (<1%). Late: Rectovaginal/vesicovaginal fistula- 1to2% Proctitis/cystitis(3-5% stage I-IIA, 10-15% for stage IIB-III). ureteral stricture (1–3%) Intestinal obstruction or perforation(<5%) Vaginal stenosis, Anal Incontinence Femoral neck fractures/ lumbosacral plexopathy (extremely rare) FOLLOW UP: Every month- For first 3 months. Every 3 months- For remaining of the first year. Every 4 months- The 2nd year. Every 6 months- During the 3rd through 5th year. And yearly thereafter. Patients undergo Complete physical+ pelvic/rectal examination with Pap smear taken from 3 months onwards. Follow-up Pap smears controversial due to post-RT change.
23(+ chest X-ray annually for 5 years; CBC, Urea/creat. 6 monthly) Other investigations( USG/CT) as clinically indicated.