RADIOTERAPIA EN CÁNCER CERVICO-UTERINO

Presentación del tema: "RADIOTERAPIA EN CÁNCER CERVICO-UTERINO"— Transcripción de la presentación:

1 RADIOTERAPIA EN CÁNCER CERVICO-UTERINO
DRA. RUBI RAMOS R2RT

2 TEMAS A REVISAR … GENERALIDADES RT ENFERMEDAD LOCALIZADA
RT ENF. LOCALMENTE AVANZADA CAMPO EXTENDIDO BRAQUITERAPIA OTRAS MODALIDADES DE TRATAMIENTO PALIACION TOXICIDAD

3 FR: IVSA TEMPRANA, MULTIPLES PAREJAS, SEXUALES, TABAQUISMO, VIH, VPH.
GENERALIDADES… 2ª CAUSA MUERTE MEXICO 3º CAUSA MUNDIAL VPH 98% (16-18) CCE 90% ADENOCARCONOMA 7-10% ADENOESCAMOSO 1-2% FR: IVSA TEMPRANA, MULTIPLES PAREJAS, SEXUALES, TABAQUISMO, VIH, VPH. Globocan 2012 (IARC) Section of Cancer Information Gunderson&Tepper Clinical Radiation Oncology, 3ra Ed 2012

4 AFECCION GANGLIONAR… ESTADIO PELVICOS (%) PARA-AÓRTICOS (%) IA1 0 – 3
5 – 8 IB 12 – 27 4 – 28 IIA 20 – 50 4 – 22 IIB 16 – 36 6 – 32 III 35 – 50 16 – 42 IVA 66 33 – 66 Ganglios regionales: parametriales, obturadores, ilíacos internos (hipogástricos), ilíacos externos, de la ilíaca común, sacros y presacros Metástasis a distancia Pulmón 21% Paraaórticos 11% Cavidad abdominal 8% SCV 7% Mets óseas 16% Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

5 FACTORES PREDICTIVOS Y PRONOSTICOS
Estadio clínico Enfermedad gg Raza (afroamericanos) ILV Estado márgenes postHTA Niveles de Hb y O2 Hb <11g/DL sv 3ª 27% VS 62% >11g/dl Tipo Histológico Tiempo de protracción Perdida 1% CL por día de prolongación de tto >30días En algunas series se dice k la edad no es un factor pronostico sin embargo para otros reportan una relación entre la edad y el estadio clínico asi como PTES ANCIANAS QUE POR SUS COMORBILIDADES SE DIFICULTA RECIBIR EL TTO. Afroamericanos tienen peores tasa de SV pacientes reciben transfusiones para mantener los niveles de hemoglobina> 12 a 12,5 g / dl. PO2 <10mmHg En ptes tratados con RT el tiempo total de tto debe ser lo mas corto posible por lo que la integración de EBRT + BQT Pelvic failure rate correlated with length of treatment in stages IB (A) and IIA (B) carcinoma of the uterine cervix. (From Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix: I. Impact of prolongation of treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275–1288; with permission from Elsevier.) es un factor importante par amejorar el control local. Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

6 ENFERMEDAD PREINVASIVA RT PELVICA +QT CONCOMITANTE + BQT
TRATAMIENTO CACU … ENFERMEDAD PREINVASIVA NIC 1 OBSERVACION NIC 2-3 CRIOTERAPIA ABLACION LASER ELECTROCIRUGIA ENFERMEDAD INVASIVA IA1 (s/ILV) CONO BIOPSIA IA1 (c/ILV) IA2 HTRM +LDN PELVICA Ó RT PELVICA +BQT IB1- IIA1 HTR+LDN PELVICA Ó RT PELVICA +BQT +-QT IB2-IVA RT PELVICA +QT CONCOMITANTE + BQT IV B QT RT ADYUVANTE CIN1 tiene una tasa de regresión espontánea en 1 a 3 años de> 50%, po lo tanto puede mantenerse en observación NCCN Guidelines 2014

7 ENFERMEDAD LOCALIZADA

8 CA IN SITU En CA IN SITU el tto de elección es QX la RT puede ser una opción para ptes con contraindicaciones medicas para poder realizar la Qx o carcinoma multifocal in situ en cérvix y vagina

9 Proctitis 1 pte (tto conservador)
CANCER IN SITU HIGH-DOSE-RATE INTRACAVITARY RADIOTHERAPY IN THE MANAGEMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA 3 AND CARCINOMA IN SITU PRESENTING WITH POOR HISTOLOGIC FACTORS AFTER UNDERGOING EXCISIONAL PROCEDURES. Kim et. al OBJETIVO: Evaluar efectividad BQT HDR en ptes con NIC3 y CIS con factores de pobre pronóstico para enf. Residual después de escisión dx. 140 ptes sobrevivieron (SVG 84.3%) 2 ptes recurrieron (RL 1.2%) 24 ptes fallecieron (por otras causas) Retrospectivo 166 ptes NIC 3 15 ptes CIS 151 ptes Dx conización 158 ptes y por biopsia por punción 8 ptes. 81.4% involucro cervical 44.5% márgenes + Tto: BQT HDR Co60 o Ir 192 a punto A 30Gy/6 fx (30-52Gy) RESULTADOS TOXICIDAD Proctitis 1 pte (tto conservador) BQT HDR ofrece buenos resultados por lo que puede considerarse como tto definitivo en ptes con NIC3 y CIS con alto riesgo de enf. Residual posterior a procedimientos escisiónales. Media de seguimiento 152 meses Int J Radiat Oncol Biol Phys Sep 1;84(1):e19-22

10 RT VS QX Hay pocos estudios que comparan los resultados de HT radical vs RT definitiva. Y no hay estudios que comparen QX vs QTRT. Los resultados entre la Qx vs RT es comparable

11 RESULTADOS RT VS QX EC TEMPRANOS
RT (n) SVG 5ª (%) Cx (n) VOLTERRANI 1983 127 91 123 89 INOUE 1984 59 80 362 CHANG 2000 52 61 68 70 Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

12 RT VS QX RANDOMISED STUDY OF RADICAL SURGERY VERSUS RADIOTHERAPY FOR STAGE IB-IIA CERVICAL CANCER. Landoni et. al CIRUGIA 169 ptes Milan Prospectivo Aleatorizado 327 ptes IB-IIA RT definitiva: Pelvis : 47Gy (40-53Gy) PA (+): 45Gy BQT HDR : Cs137 Punto A: 70 – 90Gy. RT adyuvante: >T2a, Estroma libre <3mm, márgenes+, gg +. Between September, 1986, and December, 1991, 469 women with newly diagnosed stage Ib and IIa cervical carcinoma were referred to our institute. 343 eligible patients were randomised: 172 to surgery and 171 to radical radiotherapy. Adjuvant radiotherapy was delivered after surgery for women with surgical stage pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive nodes. The primary outcome measures were 5-year survival and the rate of complications. The analysis of survival and recurrence was by intention to treat and analysis of complications was by treatment delivered. RADIOTERAPIA 158 ptes Media de seguimiento 87 meses Lancet Aug 23;350(9077):

13 GPO QX+RT > morbilidad Complicaciones urológicas
RT VS QX RESULTADOS… GPO QX+RT > morbilidad Complicaciones urológicas RT Cx p SVG 5ª 83% NDS SVLE 5ª 74% Complicaciones severas 12% 28% 0.0004 FINDINGS: 170 patients in the surgery group and 167 in the radiotherapy group were included in the intention-to-treat analysis; scheduled treatment was delivered to 169 and 158 women, respectively, 62 of 114 women with cervical diameters of 4 cm or smaller and 46 of 55 with diameters larger than 4 cm received adjuvant therapy. After a median follow-up of 87 (range ) months, 5-year overall and disease-free survival were identical in the surgery and radiotherapy groups (83% and 74%, respectively, for both groups), 86 women developed recurrent disease: 42 (25%) in the surgery group and 44 (26%) in the radiotherapy group. Significant factors for survival in univariate and multivariate analyses were: cervical diameter, positive lymphangiography, and adeno-carcinomatous histotype. 48 (28%) surgery-group patients had severe morbidity compared with 19 (12%) radiotherapy-group patients (p = ). INTERPRETATION: There is no treatment of choice for early-stage cervical carcinoma in terms of overall or disease-free survival. The combination of surgery and radiotherapy has the worst morbidity, especially urological complications. The optimum therapy for each patient should take account of clinical factors such as menopausal status, age, medical illness, histological type, and cervical diameter to yield the best cure with minimum complications. Landoni et al.35 published results of a prospective, randomized trial of radiation therapy versus surgery; 469 women with stage IB and IIA cervical carcinoma were referred for treatment and 343 were randomized (172 to surgery and 171 to radiation therapy). Postoperative irradiation was delivered after surgery for women with surgical stage pT2b or greater, <3 mm of cervical stromal invasion and cut-through margins or positive pelvic nodes. Scheduled treatment was delivered to 169 and 158 women, respectively; 62 of 114 women with cervical diameters of <4 cm and 46 of 55 women with >4 cm received radiation therapy. After a median follow-up of 87 months (range, 57 to 120 months), 5-year overall and disease-free survival rates were nearly Ovid: Perez and Brady's Principles and Practice of Radiation Oncology 20/07/13 01:39 Página 62 de 162 P.1384 identical in the surgery and radiation therapy groups (83% and 74%, respectively); recurrent disease developed in 86 women: 42 (25%) in the surgery group and 44 (26%) in the radiation therapy group (Fig ). Forty-eight patients (28%) in the surgery group had severe morbidity, compared with 19 (12%) in the radiation therapy group (p = .0004; Table 69.11). The combination of surgery and radiation therapy had the worst morbidity, especially urologic complications. A. MULTIVARIADO (SVG) Tamaño. Linfagiografía +. Adenocarcinoma. Lancet Aug 23;350(9077):

14 RT VS QX PRIMARY SURGERY VERSUS PRIMARY RADIOTHERAPY WITH OR WITHOUT CHEMOTHERAPY FOR EARLY ADENOCARCINOMA OF THE UTERINE CERVIX. OBJETIVO: comparar la eficacia y seguridad de Qx 1ª vs RT/QTRT en CACU (AC) estadios tempranos Baalbergen et. al Revisión Cochrane Incluyeron 12 estudios retrospectivos de ptes EC tempranos CACU tratados con QX vs RT/ QTRT RESULTADOS En el análisis por subgrupo en 1 estudio mostró que la QX era mejor en Adenocarcinoma cervix EC tempranos sin embargo la mayoría requirió RT adyuvante lo que aumento la morbilidad. TECNICAS MODERNAS DE IMAGEN (IRM/ PET-CT) ayudan a una mejor selección de ptes para un tto más optimo QX es para EC tempranos en ptes seleccionados QTRT es la 2ª mejor opción para ptes no candidatos a cirugía QTRT 1ª elección en ptes con sospecha de gg + (IRM o PET-CT) BACKGROUND: For early squamous cell carcinoma of the uterine cervix, the outcome is similar after either primary surgery or primary radiotherapy. There are reports that this is not the case for early adenocarcinoma (AC) of the uterine cervix: some studies have reported that the outcome is better after primary surgery. There are no systematic reviews about surgery versus chemoradiation in the treatment of cervical cancer. This is an updated version of the original SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, MEDLINE (1950 to July week 5, 2009), EMBASE (1980 to week 32, 2009) and we also searched the related articles feature of PubMed and the Web of Science. We also checked the reference lists of articles. For this update, the searches were re-run in June 2012: MEDLINE 2009 to June week 2, 2012, EMBASE 2009 to 2012 week 24, CENTRAL Issue 6, 2012, Cochrane Gynaecological Specialised Register June 2012. Analysis of a subgroup of one RCT showed that surgery for early cervical AC was better than radiotherapy. However, the majority of operated patients required adjuvant radiotherapy, which is associated with greater morbidity. Furthermore, the radiotherapy in this study was not optimal, and surgery was not compared to chemoradiation, which is currently recommended in most centres. Finally, modern imaging techniques (i.e. magnetic resonance imaging (MRI) and positive emission tomography - computed tomography (PET-CT) scanning) allow better selection of patients and node-negative patients can now be more easily identified for surgery, thereby reducing the risk of 'double trouble' caused by surgery and adjuvant radiotherapy.   AUTHORS' CONCLUSIONS: We recommend surgery for early-stage AC of the uterine cervix in carefully staged patients. Primary chemoradiation remains a second best alternative for patients unfit for surgery; chemoradiation is probably first choice in patients with (MRI or PET-CT-suspected) positive lymph nodes. Since the last version of this review no new studies were found. Cochrane Database Syst Rev Jan 31;1:CD006248

15 RT O QTRT

16 RT VS QTRT EC TEMPRANAS CISPLATIN, RADIATION, AND ADJUVANT HYSTERECTOMY COMPARED WITH RADIATION AND ADJUVANT HYSTERECTOMY FOR BULKY STAGE IB CERVICAL CARCINOMA. OBJETIVO: Determinar si la adición QT (CDDP) a la RT pélvica mejora SVG en ptes EC tempranos de alto riesgo Keys et. al GOG 123 EC 1B (tumores voluminosos >4cm) 369 ptes QT/RT: 183 ptes RT: 186 ptes 3-6 semanas se realizó HT adyuvante RT Pelvis 45/1.8-2Gy + BQT LDR 30Gy QT: CDDP 40mg/m2 x6c RESULTADOS Riesgo Progresión RR: 0.51 (IC 95% ) SLP 4ª p < favor QTRT Riesgo Muerte : 0.54 (IC 95% ) SVG p = favor QTRT TOXICIDAD QTRT Mayor Toxicidad Grado 2-3 GI y hematológica La adición QT a la RT seguido de HT reduce significativamente el RR y muerte en EC tempranos CACU The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS: Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers. Media de seguimiento 36 meses N Engl J Med Apr 15;340(15):

17 Stehman et. Al SEGUIMIENTO GOG 123 A 101 meses
RT VS QX EC TEMPRANAS RADIATION THERAPY WITH OR WITHOUT WEEKLY CISPLATIN FOR BULKY STAGE 1B CERVICAL CARCINOMA: FOLLOW-UP OF A GYNECOLOGIC ONCOLOGY GROUP TRIAL. Stehman et. Al SEGUIMIENTO GOG 123 A 101 meses SVLP 5ª (%) SVG 5ª (%) RT 60 64 RT/QT 71 78 QT (CDDP) mejora significativamente la SLP y la SG a largo plazo vs RT sola sin aumentar los efectos tardíos graves. PROGRESIÓN: 0.61 (QT/RT) (IC 95% ) P < RIESGO MUERTE 0.63 (QT/RT) (IC 95% ) P < Am J Obstet Gynecol Nov;197(5):503.e1-6

18 PRINCIPALES FACTORES DE RIESGO
RT O QTRT ADYUVANTE GG positivos Márgenes positivos microscopicos Involucro parametrial ILV Invasión estroma Tamaño tumoral voluminoso Pacientes sometidos HT radical con fcatores de alto riegso son candidatos a recibir /QTRT adyuvante. Estudios han demostrado que la qtrt DISMINUYE SIGNIFICATIVAMENTE LAS RECURRENCIAS PELVICAS Y LAS METASTASIS A DISTANCIA , ASI COMO SVG, SIN DIFERENCIA SIGNIFICATIVA EN TOXICIDAD AGUDA O CRONICA GI, PRINCIPALES FACTORES DE RIESGO

19 RESULTADOS RT POSTOP EN EC TEMPRANOS DE CACU
AUTOR Nº PTS CL SV 5 a COMPLICACIONES SEVERAS ANDRAS ET. AL 80 89% 4 AMPIL ET. AL 27 70% SAIBISHKUMAR ET. AL 105 72% 55% 12 SHARMA ET. AL 83 62% 6 Gunderson L, editor.Clinical Radiation Oncology. 3 Ed. Elsevier 2012

20 REDUCCION DE RIESGO RECURRENCIA DEL 47% CON RT
RT ADYUVANTE A RANDOMIZED TRIAL OF PELVIC RADIATION THERAPY VERSUS NO FURTHER THERAPY IN SELECTED PATIENTS WITH STAGE IB CARCINOMA OF THE CERVIX AFTER RADICAL HYSTERECTOMY AND PELVIC LYMPHADENECTOMY: A GYNECOLOGIC ONCOLOGY GROUP STUDY. Seldis et. al OBJETIVO: Evaluar beneficio y riesgo de RT adyuvante en EC Ib CACU tratadas con HT +LDN pelvica. Cx + RT (%) Cx (%) Recurrencia 15 28 SVLR 2ª 88 79 Toxicidad Urologica Hematológica GI G 3/4 3.1 2.3 6 1.4 0.7 2.1 GOG 92 227 ptes QX= 140 ptes QX+RT 137 ptes FR: >1/3 invasión estroma, ILV, Tumores voluminosos RT: Cobalto, DT Gy 4-6 semanas postop RESULTADOS RT Pélvica adyuvante después de Qx radical reduce el numero de recurrencias en EC tempranos CACU con toxicidad aceptable. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group. REDUCCION DE RIESGO RECURRENCIA DEL 47% CON RT P= 0.008 Gynecol Oncol May;73(2):

21 Rotman et. Al SEGUIMIENTO GOG 92 RESULTADOS
RT ADYUVANTE A PHASE III RANDOMIZED TRIAL OF POSTOPERATIVE PELVIC IRRADIATION IN STAGE IB CERVICAL CARCINOMA WITH POOR PROGNOSTIC FEATURES: FOLLOW-UP OF A GYNECOLOGIC ONCOLOGY GROUP STUDY. Rotman et. Al SEGUIMIENTO GOG 92 HR IC 90% RECURRENCIAS 67 ptes 24(RT) vs 43 (OBS) 0.54 ( )  46% RR PROGRESION 0.58 ( ) P= 0.009 RESULTADOS Se OBSREVO UN RIESGO DE RERURRENCIA DEL 46% A FAVOR DEL GPO DE RT ADYUVANTE ASI COMO UNA DISMINUCION DEL IESGO DE PROGRESION Y MUERTE ESTADISTICAMENTE SIGNIFICATIVO A FAVOR DEL GPO RT. With RT, 8.8% of patients (3 of 34) with adenosquamous or adenocarcinoma tumors recurred vs. 44.0% (11 of 25) in OBS. Fewer recurrences were seen with RT in patients with adenocarcinoma or adenosquamous histologies relative to others (HR for RT by histology interaction = 0.23, 90% CI = 0.07 to 0.74, p = 0.019). After an extensive follow-up period, 67 deaths have occurred: 27 RT patients and 40 OBS patients. The improvement in overall survival (HR = 0.70, 90% CI = 0.45 to 1.05, p = 0.074) with RT did not reach statistical significance. CONCLUSIONS: Pelvic radiotherapy after radical surgery significantly reduces the risk of recurrence and prolongs progression-free survival in women with Stage IB cervical cancer. RT appears to be particularly beneficial for patients with adenocarcinoma or adenosquamous histologies. Circumstances that may have influenced the overall survival differences are considered. BENEFICIO EN LA TASA DE RECURRENCIA EN PTES CON HISTOLOGIA (ADENOCA. Y ADENOESCAMOSO) 8.8% (RT) vs 44% (OBS) P= 0.019 Int J Radiat Oncol Biol Phys May 1;65(1):169-76

22 Peters et. al RESULTADOS
QTRT ADYUVANTE CONCURRENT CHEMOTHERAPY AND PELVIC RADIATION THERAPY COMPARED WITH PELVIC RADIATION THERAPY ALONE AS ADJUVANT THERAPY AFTER RADICAL SURGERY IN HIGH-RISK EARLY-STAGE CANCER OF THE CERVIX. Peters et. al OBJETIVO: Determinar si la adición QT (CDDP) a la RT pélvica mejora SVG en ptes EC tempranos de alto riesgo RT Pelvis 49.3/1.7Gy PA 45/1.5Gy GOG 109/SWOG 8797 243 PTES EC 1 A2-IIA llevados a HT radial+LDN pélvica : * Parametrios (+) * Ganglios (+) * Márgenes (+) QT/RT: 127 ptes RT: 116 ptes RESULTADOS QT CDDP 70mg/m2 5FU 1000mg/m2/d x 4c J Clin Oncol Apr;18(8):

23 Mayor en gpo QTRT principalmente GI y hematológica
QTRT ADYUVANTE RESULTADOS… SVLP 4 años 63% (RT)vs 80% (QTRT) SVLP 4 años 83% (AC/AEC)vs 79% (CCE) La QT/RT adyuvante mejora los resultados globales en ptes EC tempranos con factores de alto riesgo Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT 􏰀 CT arm are 2.01 (P 􏰁 .003) and 1.96 (P 􏰁 .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT 􏰀 CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT 􏰀 CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT 􏰀 CT group. Conclusion: The addition of concurrent cisplatin- based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymph- adenectomy for carcinoma of the cervix. SVG 4 años 71% (RT)vs 81% (QTRT) TOXICIDAD G3-4 Mayor en gpo QTRT principalmente GI y hematológica J Clin Oncol Apr;18(8):

24 Okazawa et. al RESULTADOS
QTRT ADYUVANTE IMPACT OF THE ADDITION OF CONCURRENT CHEMOTHERAPY TO PELVIC RADIOTHERAPY IN SURGICALLY TREATED STAGE IB1-IIB CERVICAL CANCER PATIENTS WITH INTERMEDIATE-RISK OR HIGH-RISK FACTORS: A 13-YEAR EXPERIENCE Okazawa et. al OBJETIVO: Evaluar el beneficio de QTRT adyuvante en EC tempranos CACU 316 ptes IB1-IIB Postop HTR Riesgo alto 187 ptes Riesgo intermedio 129 ptes RT: 124 ptes QTRT: 192 ptes RESULTADOS Gpo Alto riesgo la QTRT fue superior en SLP, SVG y recurrencias Gpo Riesgo Intermedio la QTRT fue superior en ptes con 2 o más factores de riesgo. Sin diferencia en beneficio SVG en ptes con 1 FR intermedio Beneficio SLP a favor de adyuvancia en ptes con invasión estroma profundo p= 0.012 La QT/RT adyuvante mejora el pronostico de EC tempranos en ptes con factores de alto riesgo y riesgo intermedio We reviewed the medical records of 316 patients with FIGO stage IB1-IIB cervical cancer who had been treated with adjuvant radiotherapy (RT) (n = 124, RT group) or adjuvant CCRT (n = 192, CCRT group) after radical hysterectomy between January 1996 and December Of these, 187 patients displayed high-risk prognostic factors (high-risk group), and 129 displayed intermediate-risk prognostic factors (intermediate-risk group). Sixty patients with 1 intermediate-risk prognostic factor who received no adjuvant therapy were also identified and used as controls (NFT group). Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: In the high-risk group, adjuvant CCRT was significantly superior to RT alone with regard to recurrence rate, progression-free survival (PFS), and overall survival. In the intermediate-risk group, CCRT was superior to RT with regard to recurrence rate and PFS in patents with 2 or more risk factors. Among the patients with only 1 intermediate-risk factor, although no survival benefit of CCRT over RT was observed, addition of adjuvant treatment resulted in significantly improved PFS compared with the NFT group in patients with deep stromal invasion (log-rank, P = 0.012). CONCLUSIONS: Postoperative CCRT improved the prognosis of FIGO stage IB1-IIB cervical cancer patients in the high-risk group and patients who displayed 2 or more intermediate-risk factors. Patients who displayed deep stromal invasion alone also derived clinical benefit from adjuvant treatment. Int J Gynecol Cancer Mar;23(3):

25 CONCLUSIONES ENF. LOCALIZADA …
En Ca IN SITU el tto de elección es QX sin embargo la RT es una opción para ptes con contraindicaciones médicas Para EC tempranos (IA1-IB1) CACU el tto de elección es la cirugía La RT ofrece resultados similares a la QX en ptes medicamente inoperables con tasas de curación 85-95% EC tempranos La RT adyuvante esta indicada en ptes con invasión profunda al estroma, enf. Voluminosa, ILV QT/RT adyuvante esta indicada para ptes con invasión a parametrios, márgenes positivos, gg positivos IRM/ PET-CT ayudan a una mejor estatificación y selección del tto más optimo

26 ENFERMEDAD LOCALMENTE AVANZADA
EC IB2 - IVA

27 QTRT LOCALMENTE AVANZADO
CONCURRENT CISPLATIN-BASED RADIOTHERAPY AND CHEMOTHERAPY FOR LOCALLY ADVANCED CERVICAL CANCER. Rose et. al RT+CDDP GOG 120 EC IIB-IVA 526 ptes RT: DT Gy BQT 30-40Gy QT: CDDP 40-50mg/m2 5FU 4g/m2 HU 2-3 gr/m2 ALEATORIZACION RT+CDDP+5FU+HU BACKGROUND AND METHODS: On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens -- cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone -- in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 micromol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3). RT+HU Media de seguimiento 35 meses N Engl J Med Apr 15;340(15):

28 QTRT LOCALMENTE AVANZADO
CDDP: 0.61 (IC95% ) CDDP + 5Fu + HU: 0.58 ( ) 65 vs 47%(HU) P= 0.001 SVG RESULTADOS… QTRT basada en CDDP mejora las tasas de SVG y SLP en EC localmente avanzados CACU SVG CDDP: Riesgo Progresión: 0.57 (IC95% ) CDDP + 5Fu + HU: 0.55 (IC95% 0.40 – 0.75) 65 vs 46% (HU) P <0.001 SVLP Triple esquema > toxicidad (p=0.001). GI Hematológica. Para ambos gpos que recibieron CDDP tuvieron mejores tasas de SVLP y SVG vs el gpo con HU RESULTS: The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively. CONCLUSIONS: Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer. N Engl J Med Apr 15;340(15):

29 QTRT LOCALMENTE AVANZADO
LONG-TERM FOLLOW-UP OF A RANDOMIZED TRIAL COMPARING CONCURRENT SINGLE AGENT CISPLATIN, CISPLATIN-BASED COMBINATION CHEMOTHERAPY, OR HYDROXYUREA DURING PELVIC IRRADIATION FOR LOCALLY ADVANCED CERVICAL CANCER: A GYNECOLOGIC ONCOLOGY GROUP STUDY SVG Rose et. Al SEGIMIENTO GOG 120 A 106 meses SVG EC III RIESGO DE PROGRESIÓN O MUERTE CDDP: (95% CI, 0.43 to 0.75) Combinado : 0.51 (95% CI, 0.38 to 0.67) SVG EC III SVG ia largo plazo favor QTRT basada CDDP en CACU Localmente avanzado sin aumento en la toxicidad TOXICIDAD G3-4 GI O UROLÓGICA 19.1% (CDDP) 16.85% (HU) TOXICIDAD TADIA XRT 1.7% (CDDP) vs 1.2% (HU) PURPOSE: We report the long-term survival and toxicity of a randomized phase III study comparing cisplatin alone with cisplatin, flurouracil, and hydroxyurea versus hydroxyurea concurrent with pelvic irradiation for patients with locally advanced cervical cancer with pathologically negative para-aortic nodes. PATIENTS AND METHODS: Comparisons of progression-free (PFS) and overall survival (OS) between treatment arms utilized Kaplan-Meier and log-rank statistics. Relative risk estimates adjusting for prognostic factors were determined using the Cox proportional hazards regression model. Pearson's 2 test was used to assess differences in adverse events. RESULTS: The analysis included 526 patients. The median follow-up among surviving patients was 106 months. Consistent with the original report, improvement in PFS and OS was evident for both cisplatin-containing arms compared with hydroxyurea (P < .001). Analogous results were seen for stage IIB and for stage III disease (each P < .025). The relative risk of progression of disease or death was 0.57 (95% CI, 0.43 to 0.75) with cisplatin and 0.51 (95% CI, 0.38 to 0.67) with cisplatin-based combination chemotherapy compared with hydroxyurea. Among 518 patients who received radiation, acute (grade 3 or 4) gastrointestinal or urologic toxicities occurred in 66 with cisplatin (19.1%) and 29 with hydroxyurea (16.8%). Delayed radiation toxicity occurred in six patients who received cisplatin (1.7%) and two who received hydroxyurea (1.2%; P = .680). CONCLUSION: Cisplatin-based chemotherapy during pelvic radiation therapy improves long-term PFS and OS among locally advanced cervical cancer patients collectively and for stage IIB and III disease, individually. There was no observed increase in late toxicity with cisplatin-based chemoradiotherapy. SVG SVG EC IIB J Clin Oncol Jul 1;25(19):

30 QTRT LOCALMENTE AVANZADO
CONCOMITANT CHEMOTHERAPY AND RADIATION THERAPY FOR CANCER OF THE UTERINE CERVIX. Green et. al 13 Estudios Aleatorizados Total : 3578 Pacientes para SV y SLP 3694: Recurrencia local y Distancia. Metaanálisis Cochrane Ensayos a partir 1980 CACU EC IB-IVA Estudios que compararan QT/RT vs RT (Con o sin Cirugía) En el Brazo experimental se permitió el uso de QT adyuvante además de QT/RT. RESULTADOS La QT/RT disminuye el Riesgo de muerte en 31% Beneficio absoluto SG 10% Aumenta un 34% la SLE. Disminuye las tasas de RL y MD. Cochrane Database Syst Rev Jul 20;(3):CD002225

31 CAMPO EXTENDIDO

32 CAMPO EXTENDIDO PROPHYLACTIC EXTENDED-FIELD IRRADIATION OF PARA-AORTIC LYMPH NODES IN STAGES IIB AND BULKY IB AND IIA CERVICAL CARCINOMAS. TEN-YEAR TREATMENT RESULTS OF RTOG OBJETIVO:Evaluar resultados RT campo extendido en ptes con factores de alto riesgo vs RT pelvica Rotman et. al RTOG 79-20 IIB N(-) 337 ptes Pelvis 167 ptes Pelvis+PA 170 ptes Dosis RT Pelvis: 40-50Gy BQT LDR 30-40Gy PA 45Gy Pelvis Pelvis + PA SVG 10ª 44% 55% (p=0.02) CLR 65% 69% (p=0.44) Metástasis 30% 25% Toxicidad 4% 8% (p=0.06) OBJECTIVES: To investigate whether irradiation to the standard pelvic field only improves the response rate and survival in comparison with pelvic plus para-aortic irradiation in patients with high-risk cervical carcinoma, and to investigate patterns of failure and treatment-related toxicity. DESIGN: Randomized controlled trial from November 1979 to October 1986, with stratification by histology, para-aortic nodal status, and International Federation of Gynecology and Obstetrics (FIGO) stage. SETTING: Radiation Therapy Oncology Group (RTOG) multicenter clinical trial. PATIENTS: A total of 367 patients with FIGO stage IB or IIA primary cervical cancers measuring 4 cm or greater in lateral diameter or with FIGO stage IIB cervical cancers were randomized to RTOG protocol to receive either standard pelvic only irradiation or pelvic plus para-aortic irradiation. INTERVENTION: Pelvic only irradiation consisted of a midplane pelvic dose of 40 to 50 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. Pelvic plus para-aortic irradiation delivered 44 to 45 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. A total dose of 4000 to 5000 mg/h of radium equivalent or 30 to 40 Gy was provided by intracavitary brachytherapy to point A. MAIN OUTCOME MEASURES: Response rate, overall and disease-free survival, patterns of failure, and treatment-related toxicities. RESULTS: Ten-year overall survival was 44% for the pelvic only irradiation arm and 55% for the pelvic plus para-aortic irradiation am (P = .02). Cumulative incidence of death due to cervical cancer was estimated as significantly higher in the pelvic only arm at 10 years (P = .01). Disease-free survival was similar in both arms; 40% for the pelvic only arm and 42% for the pelvic plus para-aortic arm. Locoregional failures were similar at 10 years for both arms (pelvic only, 35%; pelvic plus para-aortic, 31%; P = .44). In complete responders, the patterns of locoregional failures were the same for both arms, but there was a lower cumulative incidence for first distant failure in the pelvic plus para-aortic irradiation arm (P = .053). Survival following first failure was significantly higher in the pelvic plus para-aortic arm (P = .007). A higher percentage of local failures were salvaged long-term on the pelvic plus para-aortic arm compared with the pelvic only arm (25% vs 8%). The cumulative incidence of grade 4 and 5 toxicities at 10 years in the pelvic plus para-aortic arm was 8%, compared with 4% in the pelvic only arm (P = .06). The death rate due to radiotherapy complications was higher in the pelvic plus para-aortic arm (four [2%] of 170) compared with the pelvic only arm (one [1%] of 167) (P = .38). The proportion of deaths due to radiotherapy complications in the pelvic plus para-aortic arm was higher than in the pelvic only arm (four [6%] of 67 vs one [1%] of 85; P = .24). If the patient had abdominal surgery prior to para-aortic irradiation, the estimated cumulative incidence of grade 4 and 5 complications was 11%, compared with 2% in the pelvic only arm. CONCLUSIONS: The statistically significant difference in overall survival at 10 years for the pelvic plus para-aortic irradiation arm, without a difference in disease-free survival, can be explained by the following two factors: (1) a lower incidence of distant failure in complete responders and (2) a better salvage in the complete responders who later failed locally. Beneficio significativo en SVG a 10ª a favor gpo campo extendido se asocio a una baja incidencia de fallas a distancia en RP y a mejores tasas de salvamento en RC después de fallas local Media de seguimiento 8 años JAMA Aug 2;274(5):

33 RT pelvis (45gy) /QT CDDP+5FU x3c +BQT
CAMPO EXTENDIDO PELVIC RADIATION WITH CONCURRENT CHEMOTHERAPY COMPARED WITH PELVIC AND PARA-AORTIC RADIATION FOR HIGH-RISK CERVICAL CANCER. Morris et. al RT pelvis y PA (45Gy) + BQT Gy Punto A 193 ptes RTOG 90-01 386 ptes IIB-IVA IB-IIA con tumor >5cm ó gg+ RESULTADOS SV 5ª 73% (QTRT) vs 58% (RT) p= 0.004 SLE 5ª 67% (QTRT) vs 40% (RT) p<0.001 La tasa metástasis distancia y RLR fueron mayores en gpo RT SOLA p <0.001 Toxicidad similar en ambos gpos con > tasa de efectos hematológicos en gpo QTRT RT pelvis (45gy) /QT CDDP+5FU x3c +BQT 193 ptes Media de seguimiento 43 meses N Engl J Med Apr 15;340(15):

34 Eifel et. Al SEGUIMIENTO RT 90-01 Resultados a 8 años
CAMPO EXTENDIDO PELVIC IRRADIATION WITH CONCURRENT CHEMOTHERAPY VERSUS PELVIC AND PARA-AORTIC IRRADIATION FOR HIGH-RISK CERVICAL CANCER: AN UPDATE OF RADIATION THERAPY ONCOLOGY GROUP TRIAL (RTOG) Eifel et. Al SEGUIMIENTO RT 90-01 Resultados a 8 años QT/RT mejoró SVG 8ª (67 vs 41%) p <0.0001 SLE (61 vs 46%) QT/RT disminuyó RL (18 vs 35%) MD (20 vs 35%) Toxicidad tardía similar en ambos gpos de tto The median follow-up time for 228 surviving patients was 6.6 years. The overall survival rate for patients treated with CTRT was significantly greater than that for patients treated with EFRT (67% v 41% at 8 years; P <.0001). There was an overall reduction in the risk of disease recurrence of 51% (95% CI, 36% to 66%) for patients who received CTRT. Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (P <.0001); 116 patients with stage III to IVA disease had better disease-free survival (P =.05) and a trend toward better overall survival (P =.07) if they were randomly assigned to CTRT. The rate of serious late complications of treatment was similar for the two treatment arms. CONCLUSION: Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects. Confirma beneficio de QTRT en SVG ptes con CACU localmente avanzado sin aumentar toxicidad tardia Media de seguimiento 6.6 años J Clin Oncol Mar 1;22(5):

35 Aguda G3 2 ptes (GI),1 pte (GU), 19 ptes (hematológica)
CAMPO EXTENDIDO LOW-DOSE, PROPHYLACTIC, EXTENDED-FIELD, INTENSITY-MODULATED RADIOTHERAPY PLUS CONCURRENT WEEKLY CISPLATIN FOR PATIENTS WITH STAGE IB2-IIIB CERVICAL CANCER, POSITIVE PELVIC LYMPH NODES, AND NEGATIVE PARA-AORTIC LYMPH NODES. OBJETIVO: Evaluar RT profilactica campo extendido, IMRT +CDDP ptes EC IB2-IIIB, gg pelvicos (+) y PA (-) Lianget. al Prospectivo 32 ptes IB2-IIIB Gg pelvicos (+) y PA (-) Evaluación gg PETCT Compararon 2gpos IMRT vs Control histórico 3D IMRT pelvis 45Gy + campo extendido PA 40Gy+BQT(24Gy) QT CDDP 40mg/ m2 SVG 3ª 87% (IMRT) vs 62% p= o,o2 SVLE 3ª 82% (IMRT) vs 54% p= 0.02 SLMD 3ª 79% (IMRT) vs 57% p= 0.01 Recurrencias fuera de campo 5 ptes IMRT campo extendido +QT (CDDP) concomitante tiene excelentes resultados y control de enfermedad subclínica. OBJECTIVE: The objective of this study was to assess prospectively the clinical outcomes of low-dose prophylactic extended-field, intensity-modulated radiotherapy (IMRT) plus concurrent weekly cisplatin for patients with stage IB2-IIIB cervical cancer, positive pelvic lymph nodes (PLNs), and negative para-aortic lymph nodes (PALNs). METHODS: Thirty-two patients with stage IB2-IIIB cervical cancer with positive PLN and negative PALN were included prospectively. All lymph nodes were assessed with positron emission tomography. The PALN field, including lymphatics from the superior border of L1 to the L4-L5 interphase, was irradiated concurrently with pelvic IMRT with a prescribed dose of 40 Gy in 25 fractions. Chemotherapy consisted of cisplatin delivered weekly at a dose of 40 mg/m. Using historical controls treated with pelvic radiotherapy, the survival curves were compared to assess the difference between the 2 treatment periods. RESULTS: Thirty-one patients completed the allocated extended-field IMRT, and all finished the planned pelvic IMRT and brachytherapy. Acute ≥ grade 3 gastrointestinal, genitourinary, and hematologic toxicities were seen in 2, 1, and 18 patients, respectively. During a median follow-up of 33 months, 5 patients developed out-field distant recurrences. One patient had a late grade 3 gastrointestinal complication, and 1 patient had genitourinary toxicity. The 3-year actuarial overall survival, disease-free survival, and distant metastasis-free survival for the study cohort and historic controls were 87% versus 62% (P = 0.02), 82% versus 54% (P = 0.02), and 79% versus 57% (P = 0.01), respectively. CONCLUSIONS: Extended-field IMRT of 40 Gy to the PALN plus concurrent cisplatin can effectively eradicate subclinical disease at the PALN and improve the outcome for patients with PLN-positive stage IB2-IIIB cervical cancer. TOXICIDAD Aguda G3 2 ptes (GI),1 pte (GU), 19 ptes (hematológica) Tardía G3 : 2 ptes Media de seguimiento 33 meses Int J Gynecol Cancer Jun;24(5):901-7

36 CAMPO EXTENDIDO NTENSITY-MODULATED RADIATION THERAPY VERSUS PARA-AORTIC FIELD RADIOTHERAPY TO TREAT PARA-AORTIC LYMPH NODE METASTASIS IN CERVICAL CANCER: PROSPECTIVE STUDY. OBJETIVO:Evaluar resultados IMRT en ptes con CACU y gg PA metastasicos Du et. al Prospectivo 60 ptes cacu previamente tratados con QX o RT C/GG PA mets sin evidencia de mets a distancia. Sometidos QT previa x 3CDDP/etoposido IMRT: Gy RT conv: 45-50Gy RESULTADOS Aim To compare dosimetry, efficacy, and toxicity of intensity- modulated radiation therapy (IMRT) with para-aortic field radiotherapy in patients with para-aortic lymph node (PALN) metastasis of cervical cancer. Methods This prospective study examined 60 patients with cervical cancer with PALN metastasis who underwent whole-pelvis radiotherapy followed by brachytherapy between November 1, 2004 and May 31, After 3 cycles of chemotherapy, patients were serially allocated into two groups and treated with IMRT or para-aortic field RT at doses of Gy and Gy, respectively. Treatment response was evaluated and toxicities were assessed. Patients in the IMRT group were treated with both para-aortic field RT and IMRT in order to compare the exposure dose of organs at risk. Results In the IMRT group, the mean dose delivered to the planning target volume was 67.5 Gy. At least 99% of the gross tumor volume received effective coverage and radical dose (median, 63.5 Gy; range, ) during treatment. IMRT plans yielded better dose conformity to the target and better sparing of the spinal cord and small intestine than para-aortic field RT. The IMRT patients experienced less acute and chronic toxicities. The IMRT group also had higher 2- and 3-year survival rates than the para-aortic RT group (2-year, 58.8% vs 25.0%, P = 0.019; 3-year, 36.4% vs 15.6%, P = 0.016). However, no significant difference was found in 1-year survival (67.7% vs 51.3%, P =0.201). The median survival in the IMRT group was 25 months (range, 3 to 37 months). The actuarial overall survival, disease-free survival, and locoregional control rates at 2 years were 67%, 77%, and 88%, respectively, in the IMRT group. Conclusions IMRT provides better clinical outcomes than para-aortic field radiotherapy in patients with PALN metastasis. However, cervical local and distal recurrence remain a problem. Long-term follow-up and studies involving more patients are needed to confirm our result Croat Med J Jun;51(3):229-36

37 RESULTADOS… ORGANOS DE RIESGO
IMRT logro el 99% de la dosis al PTV (DOSIS MEDIA 67.5Gy) Mejor preservacion de dosis a organos de riesgo (ME, intestino) Menores tasas de toxicidad aguda y tardía Se necesita un seguimiento a largo plazo Croat Med J Jun;51(3):229-36

38 CONCLUSIONES ENF. LOCALMENTE AVANZADA …
La RT/QT en enfermedad localmente avanzada es el tratamiento estándar ( SV y CL). La RT a PA está indicada en pacientes con ganglios positivos ( SVG). No esta indicada RT profiláctica a PA Se prefiere IMRT en PA ya que permite escalar dosis y disminución de dosis a órganos riesgo, y < toxicidad

39 BRAQUITERAPIA LDR 0.4-2Gy/hr (Cesio 137) Media 2-12Gy/hr
HDR >12Gy/hr ( iridio 192) La braquiterapia es una parte importante del tto en Ca. LA despues de EBRT Y su uso como tto primario para casos seleccionadps en EC tempranos En general los resultados son similares independientemente de la tasa de dosis. Posible administrar dosis altas al tumor con una caída rápida de la dosis hacia tejidos normales adyacentes

40 LDR HDR VENTAJAS Dosis estandarizadas Plan y tiempo de tto estándar
Máximo 2 aplicaciones DESVENTAJAS Requiere hospitalización Exposición Radiación del equipo médico Disponibilidad limitada de fuentes Reposo cama prolongado HDR Tto ambulatorio Desplazamiento mínimo de aplicadores Dosimetría más adecuada Reduce o elimina exposición del personal Fracciones grandes en tiempos cortos no permiten la reparación del daño subletal en tejidos normales Falta de protocolos establecidos Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

41 ESPECIFICACION DE DOSIS PUNTO A
BRAQUITERAPIA ESPECIFICACION DE DOSIS PUNTO A Son puntos de referencia en el tratamiento de BQT que anatomicamente se describen como 2cm hacia el cervix y 2 centrimetroa lateral. tradicionalmente cruzan el uréter y la arteria uterina en el triángulo paracervical y es considerado un punto crítico en la tolerancia de radiación. Esta definición de puntos "A" provee una planeación de dosis de BQT Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

42 ESPECIFICACION DE DOSIS PUNTO B
BRAQUITERAPIA ESPECIFICACION DE DOSIS PUNTO B Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

43 HDR VS LDR AUTOR # PTS SV TOXICIDAD TARDÍA COMENTARIO PATEL 482 5ª
3% 0% No hubo diferencias significativas TESHIMA 171 LDR: 93%-47% HDR:85%-53% HDR 10% Pacientes de edad avanzada en HDR HAREYAMA 129 LDR: 60-87% HDR: 51-87% 13% 10% No dif. Significativas LERTSANGUANSINCHAI 221 LDR: 70% HDR: 70% 7% No diferencias significativas NAYARAN 217 LDR: 60% HDR: 60% 58% 32% Guiada por iRM ayudo disminución toxicidad tardia HDR Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

44 BRAQUITERAPIA HIGH DOSE RATE VERSUS LOW DOSE RATE INTRACAVITY BRACHYTHERAPY FOR LOCALLY ADVANCED UTERINE CERVIX CANCER. Wang et. al HR SVG 3ª 0.95 (95% CI 0.79 to 1.15) SVG 5ª 0.93 (95% CI 0.84 to 1.04) SVG 10ª 0.79 (95% CI 0.52 to 1.20) SVCE 5ª 0.95 (95% CI 0.84 to 1.07) SVCE 10ª 1.02 (95% CI 0.88 to 1.19) SVLR 3ª 1.04 (95% CI 0.71 to 1.52) SVLR 5ª 0.96 (95% CI 0.81 to 1.14) Mets PA 0.99 (95% CI 0.72 to 1.35) TOXICIDAD GU 1.33 (95% CI 0.53 to 3.34) Rectal 1.00 (95% CI 0.52 to 1.91) Intestino 3.37 (95% CI 1.06 to 10.72) HDR Revision Cochrane 4 estudios BQT HDR vs LDR 1256 ptes CACU LA Sin diferencias estadisticamente significativas en los resultados globales entre ambas modalidades. Se observo un incremento en complicaciones con HDR p= 0.04 Cochrane Database Syst Rev Jul 7;(7):CD007563

45 RECOMENDACIONES DE DOSIS
No se a establecido un esquema de dosis y tiempo de fraccionamiento òptimo para la BQT Las metas tto a punto “A” LDR 80-85Gy para EC tempranos LDR 85-90Gy para EC avanzados Dosis a pared pélvica lateral 50-55Gy EC tempranos y Gy EC avanzados. Mantener dosis a vejiga <100Gy y recto <75 Fraccionamiento 5-6Gy x 5fx 10Gy x 2 7Gy x 3 Pearcy et. al Revisión de 24 tipos de fx de HDR publicadas en las 3 últimas décadas, no observó relación de dosis en CL o morbilidad tardía. Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

46 BRAQUITERAPIA INTERSTICIAL…
Indicaciones Tumores voluminosos residuales Tumor residual con extensión a la pared lateral, vaginal, parametrial Presencia de fístula y/o invasión organos adyacentes. Histerectomía supracervical previa. Su uso esta limtado A: El cuadro de explorador anterior tomografía computarizada que muestra una intersticial basado en plantillas aplicación de braquiterapia. B: La resonancia magnética durante la inserción de la aguja intersticial en un paciente con estadio IIIB cáncer de cuello uterino asegura la colocación correcta de los catéteres adyacentes a la tándem. El 100% isodose línea está en amarillo. Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

47 BRAQUITERAPIA TRIDIMENSIONAL
No utiliza el sistema manchester La planeación tridimensional se realiza con TAC o IRM Proporciona información sobre el volumen blanco y órganos de riesgo (Histograma dosis volumen) Menor toxicidad intestinal y vesical. La planeación 3D permite la evaluación de la distribución de dosis aplicada a cierto volumen como GTV, CTV u órganos de riesgo.2 Esta ventaja es debida a que se puede delinear adecuadamente el volumen blanco así como los órganos de riesgo, mejorando considerablemente la conformidad de la dosis que con RTE convencional. Perez and Brady's Principles and Practice of Radiation Oncology, 6th Edition. 2013

48 OTRAS MODALIDADES DE TRATAMIENTO
Este término se refiere a ptes con EC III de ca. Mama, otra categoria es el el ca inflamatorio. Estas caracteristicas de la enfermedad deben tomarse en cuennta al tomar las decidiones de tratamiento. Por la modalidad de tto que se utiliza para ptes T3n0m0 LA incluiremos en este apartado.

49 IMRT

50 IMRT Autor n EC QTc Tox. GI 3 – 4 Tox. GU 3 – 4 SVLE 3ª (%) SVG 3ª (%)
Chen, et al. (1) 54 IB – IIA - 2 78 98 Hasselle, M. et al. (2) 89 I – IVA PO CDDP O 5FU 1 4 73 12 I – IIA 100 33 3 81 84 44 IIB – IVA 7 58 63 Estos articulos incluyeron ptes con CACU I-IVA tratados con IMRT el segundo en concomitancia con QT reportando excelentes tasas de SVLE Y SVG asi como toxicidad aguda y tardia aceptable. Cancer J. 2008;14:200–206. (1) Int. J. Radiation Oncology Biol. Phys., Vol. -, No. -, pp. 1–10, (2)

51 Mejor cobertura de PTV en gpo IMRT 61.55 vs 50.8% p= 0.046
IMRT CACU INTENSITY-MODULATED RADIATION THERAPY FOR ADVANCED CERVICAL CANCER: A COMPARISON OF DOSIMETRIC AND CLINICAL OUTCOMES WITH CONVENTIONAL RADIOTHERAPY. Du et. al Mejor cobertura de PTV en gpo IMRT vs 50.8% p= 0.046 Mejor protección con IMRT a órganos de riesgo (recto, vejiga, intestino delgado) IIB-IIIB 60 ptes : IMRT (30Gy pelvis+boost 30Gy ) 62 ptes RT convencional Ambos recibieron QT concomitante +BQT IMRT produce mejor distribución de dosis con toxicidad mas baja , con resultados clínicos comparables. Sin diferencia significativa en SVG a 3 y 5 años SLP fue mayor gpo IMRT P= 0.031 OBJECTIVE: The aim of this study is to evaluate the dosimetry, efficacy and toxicity of reduced field intensity-modulated radiation therapy (RF-IMRT) for patients with advanced cervical cancer. METHODS: From August 2005 to August 2010, 60 patients with stage IIB-IIIB cervical cancer underwent reduced field IMRT (RF-IMRT group) and 62 patients treated with conventional radiotherapy (c-RT group) were enrolled. The RF-IMRT plans were as follows: whole pelvic IMRT plan was performed to deliver a dose of 30Gy firstly, then the irradiated volume was reduced to lymphatic drainage region as well as paracervix and parametrium for an additional 30Gy boost. Intracavitary brachytherapy and concurrent chemotherapy were performed during external irradiation. The tumor coverage and normal tissue avoidance were evaluated. Treatment response, toxicities and survival were assessed. RESULTS: The mean dose delivered to the planning target volume was significantly higher in RF-IMRT group than in c-RT group (61.5 vs. 50.8Gy, P=0.046). IMRT plans yielded better dose conformity to the target and better sparing of the rectal, bladder and small intestine. The RF-IMRT patients experienced significantly lower acute and chronic toxicities with comparable short-term effects than did those treated with conventional RT (CR: 87.7% vs. 88.3%, P=0.496; PR: 7.0% vs. 6.7%, P=0.440). No significant differences were found between treatment groups for 1year, 3year, and 5year overall survival (OS) levels, although the latter approached statistical significance in favor of IMRT, while a significantly higher progression-free survival (PFS; P=0.031) was seen for IMRT. CONCLUSIONS: RF-IMRT yields improved dose distributions, with lower toxicities, while providing comparable clinical outcomes. The increased PFS may be an advantage. Toxicidad aguda 87.7% vs 88.3% p= 0.496 Gynecol Oncol Apr;125(1):151-7

52 IMRT CACU CLINICAL OUTCOMES OF DEFINITIVE INTENSITY-MODULATED RADIATION THERAPY WITH FLUORODEOXYGLUCOSE-POSITRON EMISSION TOMOGRAPHY SIMULATION IN PATIENTS WITH LOCALLY ADVANCED CERVICAL CANCER Kidd et. al Se observó una correlación en la respuesta del PET-CT con riesgo de recurrencia y SVCE Hallazgos PET-CT sin diferencia en ambos grupos Prospectivo 452 ptes CACU 135 ptes IMRT 317 ptes : Convencional EBRT+BQT 85% recibió QT concomitante IMRT se les realizo PET-CT simulación RESULTADOS IMRT guiada por PET-CT mejoró SV con menores tasas de toxicidad A 3 meses postRT se realizo un nuevo PET-CT 178 ptes con recurrencia 29% (IMRT) vs 43%( no IMRT) SVLR P= NS IMRT mejores tasas de SVCE p <0.0001 Toxicidad G3 ó > GI, GU: 62 ptes (IMRT) y 54 (no IMRT) P= PURPOSE: This study aimed to evaluate the toxicity and clinical outcomes for cervical cancer patients treated definitively with intensity-modulated radiation therapy (IMRT) compared with non-IMRT treatment. METHODS AND MATERIALS: This prospective cohort study included 452 patients with newly diagnosed cervical cancer treated with curative intent (135 IMRT and 317 non-IMRT). Treatment involved external irradiation and brachytherapy, and 85% of patients received concurrent chemotherapy. All IMRT patients underwent an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET/CT) simulation. A 3-month post-therapy PET was obtained to evaluate treatment response. Toxicity was scored by the Common Terminology Criteria for Adverse Events Version 3.0. RESULTS: The IMRT and non-IMRT groups had similar stage distribution and histology. For all patients, the post-therapy FDG-PET response correlated with overall recurrence risk (p < ) and cause-specific survival (p < ). Post-treatment FDG-PET findings were not significantly different between the IMRT and non-IMRT patients (p = ). The mean follow-up for all patients alive at the time of last follow-up was 52 months (72 months non-IMRT, 22 months IMRT). At last follow-up, 178 patients (39 IMRT, 139 non-IMRT) had developed a recurrence. The difference in recurrence-free survival between the two groups did not reach statistical significance (p = ), although the IMRT group showed better overall and cause-specific survivals (p < ). Of the patients, 62 patients (8 IMRT and 54 non-IMRT) developed Grade 3 or greater bowel or bladder complications, and by cumulative hazard function analysis the risk was significantly less for patients treated with IMRT (p = ). CONCLUSION: Cervical cancer patients treated with FDG-PET/CT-guided IMRT have improved survival and less treatment-related toxicity compared with patients treated with non-IMRT radiotherapy. Media de seguimiento 52 meses Int J Radiat Oncol Biol Phys Jul 15;77(4):

53 RT + HIPERTERMIA La hipertermia es un tipo de tto en la cual el cuerpo esta expuesto a altas temperaturas (42-43ªC= lo que provoca destruccion celulas tumorales y tambien sea planteado que actua como radiosensibilizador para la RT Los resultados positivos son principalmentes de una sola institucion lo que dio lugar a su aplicación clinica sin embargo la evidencia de su papel en cacu LA es insuficiente

54 BENEFICIO ABSOLUTO EN EL GPO DE PTES QUE RECIBIERON RT+HT
HIPERTERMIA Y RT COMBINED USE OF HYPERTHERMIA AND RADIATION THERAPY FOR TREATING LOCALLY ADVANCED CERVIX CARCINOMA. OBJETIVO: Evaluar si la adición de hipertermia a RT para CACU LA tiene impacto en SVG, CL. Lutgens et. al Revisón Cochrane 7 Estudios aleatorizados que compararon RT sola vs RT+hipertermia en ptes CACU LA (74% EC IIIB) HR (IC) p RC 0.56 ( ) <0.001 RL 3ª 0.48 ( ) SVG 3ª 0.67 ( ) 0.05 Tox. Aguda 0.99 ( ) Tox. Crónica 1.01 ( ) 0.96  Una revision de los articulos publicados hasta el momento debido a las incosistencias de los resultados. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 4 to 6). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p < 0.001), a significantly reduced local recurrence rate (hazard ratio (HR) 0.48; 95% CI 0.37 to 0.63; p < 0.001) and a significantly better overall survival (OS) following the combined treatment with RHT(HR 0.67; 95% CI 0.45 to 0.99; p = 0.05). No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30 to 3.31; p = 0.99) or late grade 3 to 4 toxicity (RR 1.01; CI 95% 0.44 to 2.30; p = 0.96) between both treatments. AUTHORS' CONCLUSIONS: The limited number of patients available for analysis, methodological flaws and a significant over-representation of patients with FIGO stage IIIB prohibit drawing definite conclusions regarding the impact of adding hyperthermia to standard radiotherapy. However, available data do suggest that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervix carcinoma without affecting treatment related grade 3 to 4 acute or late toxicity. BENEFICIO ABSOLUTO EN EL GPO DE PTES QUE RECIBIERON RT+HT Sin embargo existen varias limitantes en el estudio (# ptes, metodología, > EC IIIB) lo que dificulta conclusiones sobre su impacto . Cochrane Database Syst Rev Mar 17;(3):CD006377

55 RADIOTERAPIA GUIADA POR IMAGEN (IGRT)
IGRT CACU RADIOTERAPIA GUIADA POR IMAGEN (IGRT) Instituciones de protocolo utilizan cone beam CT Ptes Útero móvil grande Verificar que se encuentre dentro del campo de tto. Boost principalmente a nivel de gg paraaorticos.

56 RADIOTERAPIA CORPORAL ESTEREOTÁCTICA (SBRT )
SBRT CACU RADIOTERAPIA CORPORAL ESTEREOTÁCTICA (SBRT ) Fraccionamientos grandes otorgando altas dosis de radiación dirigida al tumor con alta precisión con un efecto ablativo en el tumor lo que produce un impacto similar a la qx. Boost gg aislado Opción ptes seleccionadas con CACU recurrente pared lateral pélvica : tumores pequeños y sin otras opciones de tto disponible Paliativo: alivia el dolor por masa pélvica recurrente

57 Tiempo de protracción Niveles de HB Histología
FACTORES QUE INFLUYEN EN EL TRATAMIENTO Tiempo de protracción Niveles de HB Histología

58 Tiempo total de RT Externa + BQT con QT NO debe exceder 56 días.
PROTRACCION Tiempo total de RT Externa + BQT con QT NO debe exceder 56 días. Devlin, Phillip M. Title: Brachytherapy: Applications and Technique, 1st Edition,2007 Lippincott Williams El tiempo total del tto debe ser tan corto como sea posible y evitar cualquier retraso para lograr un buen control local ya que algunos estudios han reportado pérdida de CL %/ día de prolongación de tto.

59 52-62 días: 20% 62-73 días: 13% CL 10ª  1.1% después del día 52
TIEMPO DE PROTRACCION OVERALL TREATMENT TIME IN ADVANCED CERVICAL CARCINOMAS: A CRITICAL PARAMETER IN TREATMENT OUTCOME. Grinsky et. al Tiempo RL (RR) p Muerte (RR) < 52d 1 <0.005 ≥ 52d 1.6 52-62 días: % 62-73 días: % CL 10ª  1.1% después del día 52 Retrospectivo 386 ptes EC IIB-III RT pelvis 50Gy BQT 10Gy Protraccion 52 días RESULTADOS El tiempo global de tto es un factor pronóstico significativo en CACU LA La pérdida de control local y la supervivencia global, cuando el tratamiento excedió 52 días, fue de aproximadamente 1% por día en ambos casos. Int J Radiat Oncol Biol Phys Dec 1;27(5):

60 QTRT LOCALMENTE AVANZADO
CARCINOMA OF THE UTERINE CERVIX. I. IMPACT OF PROLONGATION OF OVERALL TREATMENT TIME AND TIMING OF BRACHYTHERAPY ON OUTCOME OF RADIATION THERAPY. ≤ 7 semanas. 7.1 – 9 semanas. > 9 semanas. Perez et. al Washington EC IB-III 1224 ptes RT 50GY Boost 10Gy (IIB-III) BQT LDR 30-40GY RESULTADOS Correlación importante entre tiempo de protracción y EC, así como un impacto en CL . FL a 10 años IB 7% (< 7 sem), 22% (7.1-9 sem), 36% >9 sem p= 0.01 IIA 14% (< 7 sem), 27% (7.1-9 sem), 36% >9 sem p= 0.08 IIB 20% (< 7 sem), 28% (7.1-9 sem), 34% >9 sem p= 0.09 III 30% (< 7 sem), 40% (7.1-9 sem), 50% >9 sem p= 0.08 SVCE 10 a IB 86% (< 7 sem), 78% (7.1-9 sem), 55% >9 sem p= <0.01 IIA 73% (< 7 sem), 41% (7.1-9 sem), 48% >9 sem = 0.01 IIB 72% (< 7 sem), 60% (7.1-9 sem), 70% >9 sem p= 0.01 III 45% (< 9 sem), 36% >9 sem p= 0.16 PURPOSE: Some studies have described decreased pelvic tumor control and survival rates in invasive carcinoma of uterine cervix when the overall time in a course of definitive irradiation is prolonged. We attempt to confirm or deny these observations and evaluate the impact of timing of brachytherapy on outcome. We also explore the hypothesis that more extensive tumors technically require prolongation of the course of irradiation; thus, decreased tumor control and survival in these patients may not necessarily be the result of time/dose factor. METHODS AND MATERIALS: Records of 1,224 patients (Stage IB to III) treated with definitive irradiation (combination of external beam and two intracavitary insertions to deliver doses of 70 to 90 Gy to point A) were reviewed. Follow-up was obtained in 97% of the patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationship between outcome and overall treatment time and time of intracavitary insertions was analyzed in each stage and according to tumor size/extent. RESULTS: There was strong correlation between overall treatment time (OTT) and tumor stage (< or = 7 weeks: 81% for Stage IB; 74% for Stage IIA; 52% for Stage IIB; and 47% for Stage III). Interruptions of therapy accounting for prolongation of treatment time occurred in 25-30% of patients, most frequently because of holidays and weekends and side effects of therapy. Overall treatment time had a major impact on pelvic tumor control in Stages IB, IIA, and IIB; in Stage IB 10-year actuarial pelvic failure rates were 7% with OTT < or = 7 weeks, 22% with 7.1 to 9 weeks, and 36% with > 9 weeks (p < or = 0.01). For Stage IIA the corresponding values were 14%, 27%, and 36% (p = 0.08), and in Stage IIB pelvic failure rates were 20%, 28%, and 34%, respectively (p = 0.09). In Stage III, pelvic failure was 30%, 40%, and 50%, respectively (p = 0.08). There was also a strong correlation between OTT and 10-year cause-specific survival (CSS); in Stage IB rates were 86% with OTT of < or = 7 weeks, 78% for 7.1 to 9 weeks, and 55% for > or = 9 weeks (p < 0.01). The corresponding rates in Stage IIA were 73%, 41%, and 48% (p < or = 0.01). For patients with Stage IIB, CSS rates were 72% for OTT < or = 7 weeks, 60% for 7.1 to 9 weeks, and 70% for > 9 weeks (p = 0.01). Patients with Stage III disease had 45% 10-year CSS when treatment was delivered in 9 weeks or less and 36% for longer overall times (p = 0.16). In multivariate analysis of patients with Stage IB and IIA, OTT and clinical stage were the most important prognostic factors for pelvic tumor control, disease-free survival, and CSS. Tumor size was a prognostic factor for CSS. In Stages IIB and III, OTT, clinical stage, unilateral or bilateral parametrial invasion, and dose to point A were significant prognostic factors for pelvic tumor control, disease-free survival, and CSS. Prolongation of time had a significant impact on pelvic tumor control and CSS regardless of tumor size, except in Stage IB tumors < or = 3 cm. Regression analysis confirms previous reports that prolongation of OTT results in decreased pelvic tumor control rate of 0.85% per day for all patients, 0.37% per day in Stages IB and IIA, 0.68% per day in Stage IIB, and 0.54% for Stage III patients treated with > or = 85 Gy to point A. Performance of all intracavitary insertions within 4.5 weeks from initiation of irradiation yielded decreased pelvic failure rates in some groups of patients (8.8 vs. 18% in Stage IB and IIA tumors < or = 4 cm and 12.3 vs. 35% in Stage IIB) (p < or = 0.01). CONCLUSIONS: Prolongation of treatment time in patients with Stage IB, IIA, IIB, and III carcinoma of the uterine cervix has a significant impact on pelvic tumor control and CSS. The effect of OTT was present regardless of tumor size except in Stage IB tumors < or = 3 cm. Media de seguimiento 12 años Int J Radiat Oncol Biol Phys Jul 30;32(5):

61 TIEMPO DE PROTRACCION THE ADVERSE EFFECT OF TREATMENT PROLONGATION IN CERVICAL CANCER BY HIGH-DOSE-RATE INTRACAVITARY BRACHYTHERAPY. Chen et. al MULTIVARIADO (SVCE y RL ) EC P <0.001 Respuesta del tumor tto RT p= 0.001 Tiempo de protracción p=0.006 257 ptes IB-IVA EBRT +BQT HDR (2-4) DTM 65.6Gy( Gy) EBRT 44-45Gy x 5 sem + boost hasta 54-58Gy para EC IIB-IVA BQT HDR Ir 192 intervalo 1 semana 7.2Gy a punto A x 3 6 Gy a punto A x 4 La prolongación del tiempo de protracción resulto en disminución en la tasa diaria de CL global 0.67% y para EC IB-IIA 0.57% y 0.73% EC III Media tiempo de tto 63 días Para todos los estadios : SVCE 5ª 83% (<63d) vs 65%(>63d)p= 0.004 RPC a 5ª 93% (<63d) vs 87% >63 d p= 0.02 EC IB/IIA SVCE 5ª 97% (<63d) vs 79%(>63d)p= 0.01 RPC a 5ª 100% (<63d) vs 87% >63 d p= 0.02 Sin diferencia significativa para EC IIB Y III MATERIAL AND METHODS: From September 1992 to December 1997, 257 patients diagnosed with uterine cervical cancer (35 Ib, 26 IIa, 122 IIb, 10 IIIa, 57 IIIb, 7 IVa), who underwent external radiotherapy combined with between two and four courses of HDRICB and a minimum of 3 years of follow-up (median 57 months), were analyzed. Treatment consisted of irradiation of the whole pelvis with Gy consisting of fractions by 5 weeks, with the dose boosted to Gy (with central shielding) for patients diagnosed as FIGO stage IIb-IVa bilateral parametrial disease. HDRICB was performed using an Ir-192 remote afterloading technique at 1-week intervals. The standard prescribed dose for each course of HDRICB was 7.2 Gy to point A for three insertions (before July 1995), or 6.0 Gy to point A for four insertions (after July 1995). Total prescribed point A doses (external beam radiotherapy+HDRICB) ranged from 58 to 71.6 Gy (median, 65.6 Gy) for stage IB-IIA, while analogous dosage for larger lesions (stage IIb-IVa) ranged from 59 to 75.6 Gy (median, 65.6 Gy). Kaplan-Meier and multivariate analyses were used to test the effect of treatment time on pelvic control rate (PCR) and cause-specific survival (CSS) at 5 years. RESULTS: Median treatment time was 63 days. For all stages of disease, the 5-year CSS and PCR were significantly different comparing treatment times of less than and greater than or equal to 63 days [83% and 65% (P=0.004], 93% and 83% (P=0.02), respectively]. These associations were also significant for stage Ib/IIa [97% and 79% (P=0.01), and 100% and 87% (P=0.02), respectively), but not for stage IIb [75% and 72% (P=0.79), and 93% and 87% (P=0.83), respectively] or stage III [66% and 49% (P=0.2), and 83% and 72% (P=0.21), respectively]. Multivariate analysis identified three prognostic factors for CSS, stage (P<0.001), tumor response to external RT (P=0.001), and overall treatment time (OTT; P=0.006). Prognostic factors for pelvic failure were stage (P<0.001), tumor response to external RT (P=0.001), and OTT (P=0.03). Prolongation of treatment time resulted in a daily decrease in pelvic control rate of 0.67% overall, and 0.43% for stage Ib-IIa, 0.57% for stage IIb, and 0.73% for stage III patients. CONCLUSION: Analysis of the data from the current study demonstrates that the adverse effect of treatment prolongation was observed later in the treatment course for the high-dose rate (HDR) series compared to the LDR analog, however, treatment-time prolongation still negatively influenced the cause-specific survival and pelvic control rate for both dosage groups. Media de seguimiento 57 meses Radiother Oncol Apr;67(1):69-76.

62 NIVELES DE HB

63 NIVELES DE HB EVALUATION OF THE EFFECT OF ROUTINE PACKED RED BLOOD CELL TRANSFUSION IN ANEMIC CERVIX CANCER PATIENTS TREATED WITH RADICAL RADIOTHERAPY. OBJETIVO: Determinar impacto de transfusión PG en ptes con HB <11g/dl en ptes sometidos a RT radical por CACU Kapp et. al Retrospectivo 204 ptes EC IB-IVA RT 46Gy+bqt 18-35gy Hb inicial Corregida 2-3 días de la RT Hb semanal. RESULTADOS Hb (gr) n SVE 5ª (%) p CL SVLM (%) PRESENTACIÓN ≥ 11 150 71 <0.0001 76 85 0.0003 < 11 54 35 44 58 TRATAMIENTO 160 26 37 48 PURPOSE: It is well established that anemia predicts diminished radiocurability in cervix cancer. However, the therapeutic benefit of measures to correct the anemia remains controversial. The objective of this study was to determine the impact of routine transfusion in patients with hemoglobin level (hb-l) < or =11 g/dl. METHODS AND MATERIALS: Since 1985, it has been departmental policy to attempt to correct hb-l < or =11 g/dl before and/or during radiotherapy by red blood cell transfusion (RBCT) in patients undergoing radical radiotherapy for primary cervix cancer. To assess the benefit of RBCT, the charts of 204 patients (FIGO: IB-IV) treated until 1997 were reviewed. Parameters analyzed for their impact on disease-specific survival (DSS), pelvic control (PC), and metastases-free survival (MFS) included pretreatment hb-l, treatment hb-l, stage, tumor size, and lymph node status. To determine any differences in outcome according to type of anemia, a separate analysis was performed, grouping patients by cause of anemia (tumor vs. other medical illness related). RESULTS: Each of the parameters tested was significantly correlated with the end points studied in univariate analysis. Patients whose hb-l were corrected (18.5%) had an outcome that did not differ significantly from that of nontransfused patients, whereas DSS, PC, and MFS (all: p < 0.001) were significantly decreased in nonresponders to RBCT. Subgroup analysis showed no impact of hb-l in patients with other medical illness-related anemia (n = 12). In multivariate analysis treatment, but not pretreatment, hb-l remained predictive for DSS, PC, and MFS. Persistent anemia was associated with a significantly increased risk of death (relative risk: 2.1) and pelvic failure (relative risk: 2.4) compared with nontransfused patients. If only patients with tumor anemia were considered, the respective risks increased (2.7; 3.6). None of the patients with other causes of anemia recurred, whether or not their hb-l was maintained. Assessment of the therapeutic gain in patients who responded to RBCT showed improved PC (p = 0.02) and a trend toward increased DSS (p = 0.06), but no effect on MFS after adjustment for tumor size and lymph node status. CONCLUSION: Treatment hb-l, in addition to tumor size and lymph node status, independently predicted outcome. Although our final multivariate analysis showed a therapeutic benefit for patients whose hb-l was corrected, the response to RBCT was disappointing. Results of our subgroup analysis suggest that the cause of anemia in patients with cervical cancer warrants in-depth investigation. Int J Radiat Oncol Biol Phys Sep 1;54(1):58-66

64 RESULTADOS… SV 5ª SVCE 5ª SVG 5ª
NIVELES DE HB RESULTADOS… SV 5ª SVCE 5ª Se observó una reducción en las tasas de SVCE, CL, SVLM en ptes no transfundidos p <0.001 La anemia persistente se asoció a > mortalidad RR 2.1 y RL RR 2.4 Ptes que respondieron transfusión mostraron una mejoría CL (p 0.02) y un aumento SVCE p Sin efecto en SVLM. SVG 5ª Int J Radiat Oncol Biol Phys Sep 1;54(1):58-66

65 Niveles HB durante RT fue el FP mas importante par CL y SVG
NIVELES DE HB ANEMIA IN CERVICAL CANCERS: IMPACT ON SURVIVAL, PATTERNS OF RELAPSE, AND ASSOCIATION WITH HYPOXIA AND ANGIOGENESIS. Dunts et. al SVG 3 a 57% 72% EC IIB, 60% IIIB, 22% IVA Niveles HB previa tto tuvo impacto significativo en tasa de recurrencia Niveles HB a los 19.8Gy también tuvo impacto FL 3ª p= : 6% HB >13 SVG 795 15% SVG 64% 67% <11 SVG 32% Niveles O2 23 tumores con hipoxia (<15mmHg) antes del tto y a los 19.8Gy SVG a 3ª 38% (hipoxia) vs 68% p= 0.02 También se observo un aumento significativo en la densidad de la microvasculatura en ptes con tumor hipóxicos. 87 ptes IIB-IVA RT (45-50Gy) + BQT HDR (5x7Gy) Niveles de O2 y de HB antes de RT y después RT (19.8Gy) RESULTADOS Niveles HB durante RT fue el FP mas importante par CL y SVG La persistencia de hipoxia durante RT , niveles bajos HB y aumento de angiogénesis muestra pobre pronóstico PURPOSE: The prognostic impact of anemia in cervical cancers is well established. We have investigated the impact of anemia on prognosis and patterns of relapse in cervical cancers. Furthermore, we analyzed the relationship between anemia, tumor hypoxia, and angiogenesis. METHODS AND MATERIALS: Eighty-seven patients (mean age 58 years) with squamous cell cancer of the cervix (Stage IIB: n = 19; Stage IIIB: n = 59; Stage IVA: n = 9) were prospectively enrolled in the study from 1995 through Patients underwent definitive radiotherapy with a combination of external beam radiotherapy ( Gy) and high-dose-rate brachytherapy (5 x 7 Gy). Tumor oxygenation was measured with the Eppendorf pO(2)-histograph before radiotherapy and after 19.8 Gy. Angiogenesis was determined by measuring the microvessel density in pretreatment biopsies in 46 patients. The impact of tumor oxygenation (at 0 Gy and 19.8 Gy), hemoglobin (hb) level (at 0 Gy and 19.8 Gy), angiogenesis and clinical parameters on survival and relapse was investigated. RESULTS: The 3-year overall survival rate (after a median follow-up of 42 months) was 57% for the whole group of patients, 72% for Stage IIB, 60% for Stage IIIB, and 22% for Stage IVA. The presence of pretreatment anemia had a significant impact on the relapse rate. However, the midtherapy hb level (at 19.8 Gy) had the strongest impact on local failure rate and survival: 3-year local failure rate was 6% in 20 patients with a hb > 13 g/dL at 19.8 Gy, 15% in 47 patients with an hb between 11 and 13 g/dL, and 67% in 20 patients with an hb < 11 g/dL, p = This was associated with a significant impact on the 3-year overall survival, 79% vs. 64% vs. 32%. Twenty-three tumors were poorly oxygenated at both measurements (oxygen pressure [median pO(2)] < 15 mm Hg before therapy and at 19.8 Gy). This group had a significantly lower 3-year overall survival as compared with patients with high pO(2) before and/or at 19.8 Gy (38% vs. 68%, p = 0.02), and these poorly oxygenated tumors had also a significantly increased microvessel density. In a multivariate model, the midtherapy hb level maintained an overwhelming impact on local failure rate and survival. CONCLUSION: Hemoglobin level during radiotherapy was the strongest prognostic factor for local control and survival. We could further identify a poor prognostic subgroup with persisting hypoxia during radiotherapy, low hb levels, and increased angiogenesis. According to these findings, an association between anemia, poor tumor oxygenation, and angiogenesis is likely. Media de seguimiento 42 meses Int J Radiat Oncol Biol Phys Jul 1;56(3):

66 HISTOLOGIA

67 HISTOLOGIA COMPARISON OF CLINICAL OUTCOMES OF ADENOCARCINOMA AND ADENOSQUAMOUS CARCINOMA IN UTERINE CERVICAL CANCER PATIENTS RECEIVING SURGICAL RESECTION FOLLOWED BY RADIOTHERAPY: A MULTICENTER RETROSPECTIVE STUDY (KROG 13-10). Noh et. al OBJETIVO: Evaluar influencia pronostica del tipo histológico en EC IB-IIA tratados con HT radical+ RT adyuvante o QT/RT Retrospectivo Multicentrico 1323 ptes Histologias CCE, Adenoca, Adenoescamoso EC IB-IIA Postop HTR+LDN + RT postop >45Gy BQT (24Gy) : 219 ptes QTRT 492 ptes RESULTADOS SVLR 5ª 83.7%( CCE) 79.6% (AC) 79.6% (AEC) P= <0.0001 Histología adenocarcinoma se asocio a SV pobre en EC IB-IIA que recibieron RT adyuvante o QTRT To evaluate the prognostic influence of adenocarcinoma (AC) and adenosquamous carcinoma (ASC) in patients with FIGO stage IB-IIA cervical cancer who received radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). METHODS: We analyzed 1323 patients who satisfied the following criteria: histologically proven squamous cell carcinoma (SCC), AC, or ASC of the uterine cervix; FIGO stage IB-IIA disease; no history of neoadjuvant chemotherapy; and a history of radical hysterectomy with pelvic lymph node (PLN) dissection, followed by postoperative pelvic RT at a dose ≥ 45 Gy. The median age was 50 years. Median RT dose delivered to the whole pelvis was 50.4 Gy, and 219 (16.6%) patients received brachytherapy at a median dose of 24 Gy. Concurrent chemotherapy was delivered to 492 (37.2%) patients. RESULTS: Pathologic risk factors were not different according to pathologic subtype. The median follow-up duration was 75.7 months. Locoregional recurrence-free survival, relapse-free survival (RFS), and overall survival were significantly affected by histology, tumor size, PLN metastasis, parametrial invasion, lymphovascular invasion, and deep stromal invasion. The 5-year RFS rates were 83.7%, 66.5%, and 79.6% in patients with SCC, AC, and ASC histology, respectively (P<0.0001). By multivariate analysis, AC histology was the only significant prognostic factor affecting all survival outcomes. CONCLUSIONS: AC histology was associated with poor survival outcomes in patients with FIGO stage IB-IIA cervical cancer who received adjuvant RT or CCRT. Prognosis of ASC histology was closer to that of SCC histology than that of AC histology. FACTORES ASOCIADOS A SVLRLR, SVG Histología Tamaño tumor Metástasis Invasion parametrial ILV Invasión profunda al estroma MULTIVARIDO (SVG) Histología adenocarcinoma Media de seguimiento meses Gynecol Oncol Mar;132(3):618-23

68 CONCLUSIONES TECNICAS DE TRATAMIENTO …
IMRT tiene ventajas técnicas sobre RT convencional sin embargo en tumores ginecológicos no a sido evaluada como en otros sitios IMRT mejora el indice terapeutico permitiendo reducción de dosis a tejidos sanos y mayor dosis al tumor , < toxicidad CL y SVG similares en BQT LDR vs HDR No hay dosis ni fx estándar para BQT Los resultados con el uso de hipertermia +RT no son consistentes y faltan estudios con mayor cantidad de ptes para valorar resultados a largo plazo . La protracción óptima es <8 semanas , > de esta duración se asocia con disminución de tasas de CL y SV de 1% por día Niveles HB >10 se asocia a a mejor SVG y CL . La persistencia de hipoxia durante RT , niveles bajos HB y aumento de angiogénesis muestra pobre pronóstico

69 PALIACIÓN Los pacientes con cáncer de cuello uterino localmente avanzado son a menudo muy deterioradas con incesante sangrado vaginal, secreción ofensiva y dolor pélvico

70 17 ptes lesiones sintomáticas (1ª o gg mets regionales)
SHORT-COURSE PALLIATIVE RADIOTHERAPY FOR UTERINE CERVICAL CANCER. MONTHLY PALLIATIVE PELVIC RADIOTHERAPY IN ADVANCED CARCINOMA OF UTERINE CERVIX. Mishra et. al 100 ptes IIIB-IVB y mets 67% STV 48% dolor pélvico RT 30Gy/3fx mensual Kim et. al 17 ptes lesiones sintomáticas (1ª o gg mets regionales) Sangrado vaginal y dolor pélvico RT 20-25Gy/5 fx RT paliativa ofrece un control satisfactorio de los síntomas con complicaciones aceptables RESPUESTA Sangrado 100% Dolor 33-40% Buena tolerancia al tto SVM 7 meses RESPUESTA Sangrado 93.8% Dolor 66.7% Toxicidad aguda: G1-2 :7 ptes Toxicidad tardía <G3 : 4 ptes SVM 7.8 meses J Cancer Res Ther Oct-Dec;1(4): Radiat Oncol J Dec;31(4):

71 TOXICIDAD

72 AGUDA TARDIA TOXICIDAD… Estenosis vaginal Epitelitis
Nausea Cistitis Vaginitis Colitis TARDIA Estenosis vaginal Constricción uretral 1.3% Fistula RV (<2%) Obstrucción o perforación intestinal (<5%) Fractura (5%) Segundas neoplasias Perez and Bradys. Principles and practice of radiation oncology. 6th Ed Hansen, E. Evidence-Based radiation Oncology. Springer. 2nd Ed

73 Gracias…