DR. SUMANA MAITI

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CLINICAL FEATURES -EXAMINATION - DIAGNOSIS

INVASIVE DISEASE1. BLEEDING --- postmenopausal, metrorrhagia, menorrhagia, post coitalbleeding.

2. PAIN in the pelvis or hypogastrium 3. URINARY Symptoms 4. RECTAL Symptoms 5. DISTANT SITE SPECIFIC METASTATIC MANIFESTATIONSa. LYMPHATIC SPREAD --- to supraclavicular lns, para-aortic lymphadenopathy (non specific abdominal ymptoms) b. HEMATOGENOUS SPREAD---- to lungs (cough, respiratory distress, in 21% of patients in metastatic setting) ---- bone pain2

CLINICAL FEATURES -EXAMINATION - DIAGNOSISINTERNAL EXAMINATION (FOR BRACHYTHERAPY EXAMINATION UNDER ANAESTHESIA ADVISED) 1. INSPECTION --Cauliflower like growth --- exophytic nature Bleeding from the growth Serosanguineous vaginal discharge 2. PALPATION ---1) uterus ---- size, shape, position 2) cervix ---- bulky 3) growth might obliterate the vaginal fornices 4) friable growth, ulcerated , which bleeds to touch ---- blood present on finger tips 5) parametrium nodular thickening extending upto the lateral pelvic wall (by per rectal examination)

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CLINICAL FEATURES -EXAMINATION - DIAGNOSIS

1) Palpation, inspection, FIGO GUIDELINES 2) Colposcopy, 3) Endocervical curettage, 4)Hysteroscopy, 5) Cystoscopy, 6)Proctoscopy 7) Punch biopsy (edge of gross tumour,4quadrants), and

Radiologic examination1) Chest Xray of the lungs 2)Barium enema 3) intravenous urography,.5

DIAGNOSTIC WORK-UP ---FIGO statesSuspected bladder or rectal involvement should be confirmed by biopsy.

Findings of bullous edema or malignant cell in cytologic washings from the urinary bladder are not sufficient to diagnose bladder involvement.

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DIAGNOSTIC WORK-UP ---FIGO states

1)lymphangiography, 2)arteriography, 3)venography, and 4)laparoscopy Are of value for planning therapy but, because these are not generally available Interpretation of results is variable, the findings of such studies should not be the basis for changing the clinical stage.7

DIAGNOSTIC WORK-UP ADDITIONAL INVESTIGATIONS WHICH IS USED FOR TREATMENT

1.USG 2.MRI 3.CT Scan 4.PET Scan

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Conization:Removes a coneshaped piece of tissue Often allows for diagnosis and treatment Performed with local anesthesia in the office or under general anesthesia in the operating room9

STAGING --- FIGO STAGING 1) FIGO staging was based on anatomical compartmental spread of cervical cancer. 2) No inclusion of lymph nodal status 3) LVI not included because pathologists do not agree on status on presence of LVI 4) MRI, CT and PET Scan not included in formal staging.10

STAGING

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TNMDual system --- clinical (pretreatment) & post treatment (pathological) Separate classification for T NM, Clinical and pathological MRI, CT SCAN, ---Alters the clinical classification Definitive nodal classification

FIGOFIGO uses clinical --essentially anatomical Only stages and substages (I,II,III, IV, IA, IB) No role of optional investigations for FIGO clinical staging No role of LVSI , nodal status13

1) 2) 3) 4)

STAGEWISE MANAGEMENT RADIATION DETAILS --- EBRT + BT CHEMOTHERAPY COMPLICATIONS

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TREATMENT-Carcinoma in situ Conservative-Theraputic conization,Laser therapy,Cryotherapy. Irradiation. Surgery-TAH with or without small vaginal calf.

IA----- Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion 5 mm and largest extension 7 mm IA1 ----- Measured stromal invasion of 3.0 mm in depth and extension of 7.0 mm

Stage IA1---- SURGERY ---- RADIOTHERAPY RESTRICTED TO PATIENTS WHO ARE NOT CANDIDATES OF SURGERY THEN WHO ARE THE CANDIDATES OF SURGERY ???? OPTIONS 1) SIMPLE HYSTERECTOMY (provided there is no LVSI) 2) CONIZATION 3) CLOSE OBSERVATION 4) BRACHYTHERAPY http://icmr.nic.in/guide/cancer/CcMG.pdfThere is no need to remove pelvic lymph nodes when treating IA116

IA2 ----- Measured stromal invasion of 3.0 mm and not 5.0 mm with an extension of not 7.0 mm

OPTIONS SURGERY ---- RADIOTHERAPY RESTRICTED TO PATIENTS WHO ARE NOT CANDIDATES OF SURGERY THEN WHO ARE THE CANDIDATES OF SURGERY ????

1. 2. 3.

total abdominal or modified radical hysterectomy, Vaginal trachelectomy with pelvic lymphadenectomy. Intracavitary radioactive sources alone (6,500 to 8,000 mgh, 60 to 75 Gy to point A, in two LDR insertions, respectively). With HDR brachytherapy the dose is approximately 36 to 45 Gy in 6 to 8 fractions, depending on tumor volume and depth of stromal invasion.

If fertility is desired, options are: i large cone biopsy plus extra peritoneal or laparoscopic pelvic lymphadenectomy, ii radical trachelectomy and extra peritoneal or laparoscopic pelvic lymphadenectomy.

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FIGO stage

IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IA . IB1 Clinically visible lesion 4.0 cm in greatest dimensionTREATMENT OPTIONS ----1) Radical hysterectomy (type III) with pelvic node dissection 2) Radical Radiation Therapy [ EBRT + BRACHYTHERAPY] [ DOSE --- 80 Gy LDR equivalent dose to Point A]

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Stage IB2 and IIA: IB2 Clinically visible lesion N4.0 cm in greatest dimension Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvicwall or to the lower third of the vagina IIA Without parametrial invasion IIA1 Clinically visible lesion 4.0 cm in greatest dimension IIA2 Clinically visible lesion N4 cm in greatest dimension

The treatment options include 1. Radical hysterectomy (Type III) and bilateral pelvic lymphadenectomy 2. Radical Radiation therapy (External plus intracavitary). 3. Concomitant chemo radiation (Radiation therapy + Weekly Cisplatin).19

POST OPERTAIVE MANAGEMENT.1) Type of surgery ---- ADEQUATE ??????????? A. HST (simple or radical or modified radical) B. Conization / LEEP C. PELVIC lymphadenectomy ????

2) PROGNOSTIC FACTORS A. HIGH RISK FACTORS FOR RECURRNT TUMOURS (recurrence rate 40% within 3 years) 1) POSITIVE or CLOSE MARGINS 2) POSITIVE LYMPH NODES 3) MICRCOPIC PARAMETRIAL INVOLVEMENT B. INTERMEDIATE RISK FACTORS (recurrence rate 30% within 3 years) 1) LARGE TUMOR SIZE 2) CERVICAL STROMAL INVASION TO MIDDLE OR DEEP 1/3RD 3) LYMPHO-VASCULAR INVASION20

POST OPERTAIVE MANAGEMENT.2) PROGNOSTIC FACTORS A. HIGH RISK FACTORS FOR RECURRNT TUMOURS CT+RT

B. INTERMEDIATE RISK FACTORS RT

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STAGE IIB TO IVAStage IIB With obvious parametrial invasion Stage III The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney. IIIA Tumor involves lower third of the vagina, with no extension to the pelvic wall IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning Kidney.

Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to Stage IV. IVA Spread of the growth to adjacent organs

CONCURRENT CHEMORADIATION

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STAGE IV B (Distant metastasis) CISPLATIN BASED CHEMOTHERAPY RADIATION DIRECTED TO PELVIS TO CONTROL SYMPTOMS AND LOCAL PELVIC DISEASE.

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Hysterectomy1) SUBTOTAL HST 2) Simple or extrafasical (????) ---- TYPE 1---- appropriate for stage Ia1 tumours without LVSI, who are not desirous of future fertility. 3) Modified radical HST (WERTHIEMS) --- TYPE 2 ---- appropriate for stage Ia1 (LVSI +), stage Ib onwards 4) RADICAL HST (MEIGS) ----- TYPE 3 ---- alternative to type 2 5) EXTENDED RADICAL ----- TYPE 4 (periureteral tissue, superior vesicle artery, of vagina) 6) EXTENDED RADICAL ----- TYPE 5 (portions of distal ureter and bladder are resected)

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ROLE OF LYMPHADECTOMY1. SENTINEL LN 2. SAMPLING 3. DEFINITIVE SURGICAL EXCISION 4. ADEQUACY 5. TREATMENT BASED ON (+) PARA-AORTIC LNS [ If during surgery for early stage, first search for para-aortic nodes --- if frozen section is negative --- go to pelvic nodes ---- sample and dissect along different HST subtypes.]

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RADIATION1) Can be used to treat all stages of cervical cancer. 2) Cure rates with radiation about 70% for stage I, 60% for stage II, 45% for stage III and 18% for IV. 3) EBRT + BRACHY 4) FOR stage IA1 & 2 ---- Brachy only 5) For all higher stages ----- Combination favoured as tumour load increases. 6)CURATIVE INTENT ----- STAGE SPECIFIC 7)PALLIATIVE DOSE ----- TO CONTROL SYMPTOMS27

External irradiation is used to treat the whole pelvis and the parametria including the common iliac and para-aortic lymph nodes,

Central disease (cervix, vagina, and medial parametria) is primarily irradiated with intracavitary sources.

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TIMING OF RADIATION1) ADJUVANT RADIATION OR CHEMORADIATION. 2) RADICAL RADIATION OR CHEMORADIATION.

3) NEOADJUVANT . A. combination of preoperative irradiation and radical hysterectomy has been used in the treatment of patients with bulky stage IB and IIA tumors. B. Sometimes a LDR intracavitary insertion alone before surgery has been used (5,000 to 6,000 mgh). C. The rationale for use of an operation has been the alleged inability of irradiation to eradicate completely the metastatic tumor in the pelvic lymph nodes29

SEQUENCING EBRT & BRACHYTHERAPYExternal-beam pelvic irradiation is delivered before intracavitary insertions in patients with ----1)Bulky cervical lesions or tumors beyond stage IIA to improve the geometry of the intracavitary application; 2)Exophytic, easily bleeding tumors; 3)Tumors with necrosis or infection; or 4)Parametrial involvement.30

SEQUENCING EBRT & BRACHYTHERAPYA. TOTAL TREATMENT ----- 56 DAYS B. SO IF EBRT and BRACHY ---1. AFTER 20 Gy, start Brachytherapy ----- why? 2. Brachytherapy can be started before EBRT ----- when ? 3. If Brachytherapy after completion of EBRT ----- then plan for interdigitation. 4. Avoid use of concurrent chemotherapy with HDR BT 5. Always check the dose of EBRT with shielding ? ---- why?

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PLANNING OF EBRTDETERMINE THE DOSE TO BE PESCRIBED. Point A: LDR equivalent of 80-85 Gy (early stage disease, nonbulky Stage I-II) or 85-90 Gy (advanced stage, Stage IIIB or > 4 cm). Pelvic Sidewall: LDR equivalent of 50-55 Gy (early stage) or 55-60 Gy (advanced stage)

A. AVAILABILITY OF ENERGY SOURCE ---- Co60 or LINAC (6 -10MV) --- Box technique B. IFD ( > 18 cm ?) C. SHIELDING --- WIDTH ? ---- HOW DOES IT AFFECT THE BT DOSE ?32

PLANNING OF EBRTD. PARAMETRIAL BOOST E. PARA-AORTIC IRRADIATION [If para-aortic node metastases are present or suspected, patients are treated with 45 to 50 Gy to the para-aortic area plus a 5 to 10 Gy boost to enlarged lymph nodes through reduced lateral or rotational portals. With conventional techniques, the para-aortic lymph nodes are irradiated either with an extended field that includes both the para-aortic nodes and the pelvis or through a separate portal] F. ALTERED FRACTIONATION. G. 3D & IMRT IN CANCER OF CERVIX

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Superior border of the pelvic portal should be at the L4-5 interspace to include all of the external iliac and hypogastric lymph nodes. This margin must be extended to the L3-4 interspace if common iliac nodal coverage is indicated.

The width of the pelvis at the level of the obturator fossae averaged 12.3 cm, and the distance between the femoral arteries at the level of the inguinal rings averaged 14.6 cm.

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If there is no vaginal extension, the lower margin of the portal is at the inferior border of the obturator foramen. When there is vaginal involvement, the entire length of this organ should be treated down to the introitus 35

The lateral ports anterior margin is placed at the pubic symphysis

the posterior margin usually is designed to cover at least 50% of the rectum in stage IB tumors, and it should extend to the sacral hollow in patients with more advanced tumors

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BRACHYTHERAPY1. TYPES ---- INTRACAVITARY or INTERSTITIAL 2. RADIONUCLIDE ----- Cs 137, Ir -192. 3. DOSE RATE ---- LDR, PDR, HDR. 4. LOADING --- MANUAL/ REMOTE -- PRE / AFTERLOADING

INTRACAVITARY 1. Paris system 2. Stockholm system 3. Manchester system Todd & Meredith 4. Madison system (HDR)

INTERSTITIAL 1. Patterson Parker Manchester 2. Paris 3. Quimby 4. Computer

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INDICATIONS OF BRACHYTHERAPY INTRACAVITARY FOR ALL STAGES EITHER 1) AS STANDALONE (stage IA 2) COMBINATION WITH EBRT INTERSTITIAL 1. when parametrial extent of the tumor cannot be encompassed by

standard intracavitary brachytherapy. 2. A second indication is a narrow vagina not allowing the use of appropriate vaginal applicators toarrive at a sufficient dose distribution due to poor geometric conditions. 3. A third indication is represented by patients who had prior hysterectomy with the impossibility of a tandem placement. 4. A fourth indication includes patients with a recurrence inside an area previously irradiated restricting the use of further external irradiation.38

Intracavitary brachytherapyAPPLICATORS A. (TANDEM OVOID [FULL / HALF] or B. RING or C. VAGINAL CYLINDER D. VIENNA applicator [intracavitary/ interstitial]

Tandem and ovoids variations 1. 2. 3. 4. 5. 6. FLETCHER FLECHTER SUIT FLETCHER SUIT DELCLOS FLETCHER WILLIAMSON WEEKS & MONTANA CT SCAN COMPATIBLE MRI COMPATIBLE

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Good Insertion Characteristics of ICT [AP View] o Tandem midline, unrotatedo Tandem midway between colpostats o Keel (flange) in close proximity to gold seed markers o Colpostats high in the fornices along cervix

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Good Insertion Characteristics of ICT [lateral view]1) 2) 3) 4) 5) 6) 7) Tandem - 1/3 of the way between S1 S2 and the symphysis pubis The tandem - midway between the bladder and S1 - S2 Marker seeds should be placed in the cervix Ovoids should be against the cervix (marker seeds) Tandem should bisect the ovoids The bladder and rectum should be packed away from the implant Foley balloon firmly tugged down

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CONVERSION ----HDR & LDRHDR dose 6 Gy x 4 6 Gy x 5 LDR equivalent 32 Gy 40 Gy

i. Always consider dose fractionation when converting the LDR to HDR. ii. For simplified calculation conversion factors are 0.54 to 0.6 for 3 to 5 HDR #s. iii. For higher number of #s (6-8), conversion factors is 0.75. iv. Radiobiological principle --- late tissue toxicity

DOSE LIMITATIONSKeep dose to rectum and bladder points below 80% of dose to Point H (ABS recommendation) Or, maximum dose to rectum, 75 Gy (avg dose 68 Gy); bladder, 80 Gy (avg 70 Gy); vagina, 120-140 (avg 125 Gy).42

Concepts of DOSE PRESCRIPTION PARIS, MANCHESTER SYSTEMS --- used to pescribe dose to Point A, B. ICRU recommends a system for comparison of dose prescriptions but do not have guidelines on how to achieve it. ABS recommendations on LDR and HDR brachytherapy dose pescriptions with general guidelines on brachytherapy use. GEC ESTRO in 2005 proposed an IMAGE GUIDED BT using MRI to define the high risk and intermediate risk to guide the dose pescriptions.

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American Brachytherapy Society (ABS)Recommend prescribing to Point H Draw a line connecting the mid-dwell positions of the ovoids and find the point this line intersects the tandem. Follow 2 cm superior (along the tandem) plus the radius of the ovoids, then 2 cm perpendicular to the tandem. Note: This is basically 2 cm above the top of the ovoids.50

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LYMPHATIC TRAPEZOID

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Three-dimensional (3D) imaging

Ultrasound Computed tomography (CT) Magnetic resonance imaging (MRI) Positron emission tomography (PET) scans

The location of the uterus, cervix, and vagina, or the organs at risk (OAR), including the sigmoid, rectum, bladder, and small bowel.55

Since the 1990s, Implementation of CT simulation for EBT planning in radiation oncology departments has enabled physicians to contour and perform dose volume histogram (DVH) analysis of the OAR.

In 2004, The American Brachytherapy Society (ABS) published guidelines for image-guided gynecologic brachytherapy.56

In 2005, the Groupe Europe en Curietherapy European Society of Therapeutic Radiation Oncology (GEC-ESTRO) has advocated the implementation of MR evaluation in cervical cancer brachytherapy because of the superiority of MR imaging in identifying the cervix and residual tumor.Haie-meder, 2005 Poetter, 200657

At a consensus conference in July 2005, the ABS and GEC-ESTRO leadership in gynecologic brachytherapy agreed to adopt the GEC-ESTRO guidelines and to advocate 3D image based planning for cervical cancer.

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Clinical Target Volumes A first target related to the extent of GTV at diagnosis : with an intermediate dose prescribed to this target (60 Gy)Intermediate risk CTV A second target related to the extent of GTV at time of BT : taking into account tumor extent at diagnosis. with a high dose prescribed to this target (80-90 Gy) -High risk CTV

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HIGH RISK CTVDerived from point A use GTV at the time of BT CTV defined for brachytherapy if TO ERADICATE ALL RESIDUAL MACROSCOPIC TUMOUR major response : limited to cervix and adjacent structures with presumed residual disease (~30-60 cc)

Intent : 80 to 90 + Gy total dose to CTV in definitive radiotherapy in advanced disease Dose comparable with dose to point A61

HIGH RISK CTV

GTV at time of brachytherapy

Includes: Whole cervix Presumed tumor extension Clinical assessment Residual grey zones on MRI

NO SAFETY MARGINS DOSE HIGH ENOUGH TO STERILIZE MACROSCOPIC TUMOUR

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INTERMEDIATE RISK CTVICRU 38 recommendations GTV at diagnosis CTV at time of brachytherapy

CTV including safety margins with regard to dimensions of GTV at diagnosis TO CURE SIGNIFICANTT MICROSCOPIC DISEASE IN CERVIX CANCER, WHICH CORRESPONDS TO A DOSE OF AT LEAST Intent : 60 Gy total dose to CTV in definitive radiotherapy 60Gy. advanced disease in

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DOSE PESCRIPTION BY GEC ESTRO1) Dose at point A (right, left, mean) 2) D100, D90 for GTV and HR CTV and IR CTV, respectively 3) Dose to bladder and rectum for ICRU reference points 4) D0.1cc, D1cc, D2cc for organs at risk (e.g. rectum, sigmoid, bladder) (vagina) 5) D5cc, D10cc for organs at risk if contouring of organ walls is performed 6) Complete description of time dose pattern: physical and biologically weighted doses.

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INTRA OPERATIVE (IORT)

RADIOTHERAPY

INDICATIONS Tumour bed at risk ,isolated unresectable residual , in recurrent disease within a previously radiated volume. Source- Electron or KV X-ray.

COMPLICATION OF RTACUTE Rectal, Urinary, GI

CHRONIC Bladder, Bowel, Spinal cord, Vagina.

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CHEMORADIATION

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Concomitant chemo-radiationAt an NCI sponsored consensus conference in April 1995 the panel concluded that there was no evidence that hydroxyurea or any other concomitant chemotherapy agent should be incorporated into standard practice

Only 3 years later a series of five randomized trials in a variety of cervical cancer stages conducted in the United States in the mid and late 1990s became mature.

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22/2/1999: NCI Clinical Announcement:The results of 5 large studies have shown that women with invasive cervical cancer have better survival when they receive chemotherapy which includes the drug cisplatin along with radiation therapy.

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Phase III trials with concurrent chemoradiotherapy in stage IB2-IVa CERVICAL CANCER: Dose of Cisplatin/m2GOG 85 GOG 120 GOG 120 GOG 123 SWOG8797/ GOG 109 RTOG 9001 NCIC Cisplatin 50 mg day 1, 29 + FU infusion Cisplatin 50 mg day 1, 29 + FU infusion HU Cisplatin 40 mg weekly Cisplatin 40 mg weekly Cisplatin 70 mg day 1, 22 + FU infusion Cisplatin 70 mg day 1, 22 + FU infusion Cisplatin 40 mg, weekly

Metanalysis: Results for overall survivalTwenty four trials (21 published and 3 unpublished) 4921 randomised patients 61-75% of patients were available for The meta-analysis supported the NCI consensus and confirms analysis concurrent chemoradiation is superior to radiotherapy alone in terms of higher local control, decreased incidence was the commonest agent used Cisplatin of distant relapses and improved OS with both platinum and nonplatinum chemotherapy

Green J, Cochrane Database Syst Rev 2005 Jul 2005 Green JA, THE LANCET Sept 2001

Choice of concurrent chemoradiationA number of newer chemotherapy agents including carboplatin, paclitaxel, tirapazamine, topotecan and vinorelbine are candidates for study as concurrent chemotherapy agents with radiation therapy in cervical cancer.

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NEOADJUVANT CHEMOTHERAPYNACT RATIONAL1)Tumor size reduction may facilitate local therapy: radiotherapy or surgery 2)Possible transformation of inoperable tumor in radically resectable one 3)Treatment of micrometastatic disease 4)Response to NACT has been identified as an important prognostic factorBenedetti-Panici E J Cancer 1998, Buda JCO 2005

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NACT DISADVANTAGES1)Delay in curative treatment (20-30% of patients who dont respond to NACT), 2)The development of radioresistant cellular clones, 3)Crossresistance with radiotherapy.75

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CHEMOTHERAPY (for recurrent or metastatic disease) Ist line combination chemotherapy :

Cisplatin/Paclitaxel, Carboplatin/Paclitaxel, Cisplatin/Topotecan, Cisplatin/Gemcitabine.

CHEMOTHERAPY- Contd. Possible first line single agent therapy : Cisplatin(preferred), Carboplatin, Paclitaxel. Second line therapy : Bevacizumab / Docetaxel / 5FU / Gemcitabine / Iphosphamide / Irinotecan / Mitomycin / Topotecan / Pemetrexad / Vinoralbine.

SURVEILANCEInterval H&P, Cervical / vaginal cytology every 3-6 months for 2 yrs,then every 6 months for 3-5 yrs, then annually. Chest X-ray annually. CBC,BUN, creatinine every 6 months. PET CT as clinically indicated. Patient education regarding symptoms.

RELAPSE:LOCAL No prior RT or failure outside previousely treated field : Options are ---

1. Surgery+/_ IORT followed by Adjuvent RT & brachytherapy. 2. Chemotherapy, 3. Clinical trial.

RELAPSE : localHISTORY OF PRIOR RT : CENTRAL DISEASE : Pelvic exenteretion +/IORT. NON CENTRAL DISEASE : Resection witth IORT, Chemotherapy, Best supportive care, Clinical trial.

RELAPSE : distant Multiple sites or unresectable : Chemotherapy or best supportive care. Resectable metastasis : Resection +/-IORT,

Palliative RT, Chemotherapy.

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