Phase I-II study of neoadjuvant chemoradiotherapy followed by radical surgery in locally advanced cervical cancer 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. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy with no hysterectomy in patients with a (clinical and radiological) complete response after chemoradiation therapy for stage IB2 or II cervical cancer. Completion Surgery After Concomitant Chemoradiation in Locally Advanced Cervical Cancer: A Comprehensive Analysis of Pattern of Postoperative Complications Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. Radical radiotherapy versus brachytherapy plus surgery in carcinoma of the cervix 2A and 2B--long-term results from a randomized study 1968-1980. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. Neoadjuvant chemotherapy in locally advanced carcinoma of the cervix uteri. Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102) Potential Molecular Mechanisms for Improved Prognosis and Outcome with Neoadjuvant Chemotherapy Prior to Laparoscopical Radical Hysterectomy for Patients with Cervical Cancer
The usefulness of neoadjuvant chemotherapy ( NAC ) regimens has been reported ; however , the effect of NAC for advanced stages ( especially stage III-IVA ) is thought to be insufficient . We conducted a phase I-II study of neoadjuvant chemoradiotherapy consisting of intra-arterial ( i.a . ) infusion of carboplatin and intracavitary brachytherapy in patients with locally advanced cervical cancer to achieve the new NAC method . Sixteen eligible patients included those with previously untreated stage IIB , III or IVA cancer with bulky tumor .  Brachytherapy using iridium-192 was performed with concurrent i.a . chemotherapy with carboplatin ( 200 , 300 and 400 mg/m2 ) . Treatment was repeated every 4 weeks for a total of two cycles . Both hematologic and non-hematologic toxicities were generally mild . Grade 4 hematologic toxicity was observed in 12.5 % and there were no grade III or IV non-hematologic toxicities . The optimal dose of carboplatin was determined to be 400 mg/m2 . Among 16 patients , six showed complete response ( 37.5 % ) and nine showed partial response ( 56.3 % ) , for an overall response rate of 93.8 % . All 15 responding patients underwent radical surgery with a pelvic lymphadenectomy and postoperative radiotherapy . The combination of brachytherapy and i.a . chemotherapy with carboplatin is a promising regimen for NAC in locally advanced cervical cancer PURPOSE To determine whether the addition of cisplatin-based chemotherapy ( CT ) to pelvic radiation therapy ( RT ) will improve the survival of early-stage , high-risk patients with cervical carcinoma . PATIENTS AND METHODS Patients with clinical stage IA(2 ) , IB , and IIA carcinoma of the cervix , initially treated with radical hysterectomy and pelvic lymphadenectomy , and who had positive pelvic lymph nodes and /or positive margins and /or microscopic involvement of the parametrium were eligible for this study . Patients were r and omized to receive RT or RT + CT . Patients in each group received 49.3 GY RT in 29 fractions to a st and ard pelvic field . Chemotherapy consisted of bolus cisplatin 70 mg/m(2 ) and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles , with the first and second cycles given concurrent to RT . RESULTS Between 1991 and 1996 , 268 patients were entered onto the study . Two hundred forty-three patients were assessable ( 127 RT + CT patients and 116 RT patients ) .  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 . Grade s 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 lymphadenectomy for carcinoma of the cervix BACKGROUND Stage Ib and IIa cervical carcinoma can be cured by radical surgery or radiotherapy . These two procedures are equally effective , but differ in associated morbidity and type of complications . In this prospect i ve r and omised trial of radiotherapy versus surgery , our aim was to assess the 5-year survival and the rate and pattern of complications and recurrences associated with each treatment . METHODS 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 r and omised : 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 . 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 57 - 120 ) 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 = 0.0004 ) . 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 BACKGROUND Concomitant chemoradiation ( CRT ) ( including brachytherapy ) is considered the st and ard management for stage IB2 or II cervical cancer in many countries . Nevertheless , some of them discuss completion surgery ( hysterectomy [ HT ] ) after CRT . The aim of this study was to investigate the therapeutic impact of such surgery . METHODS A r and omized trial was opened in France in 2003 to evaluate the interest in HT after CRT . Inclusion criteria were : ( a ) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging ; ( b ) pelvic external radiation therapy ( 45 Gy with or without parametrial or nodal boost ) with concomitant cisplatin chemotherapy ( 40 mg/m2 per week ) followed by uterovaginal brachytherapy  ( 15 Gy to the intermediate risk clinical target volume ) ; and ( c ) complete clinical and radiological response 6 - 8 weeks after brachytherapy .  Patients were r and omized between HT ( arm A ) and no HT ( arm B ) . Unfortunately this trial was closed because of poor accrual : 61 patients were enrolled ( in 2003 - 2006 ) and are reported on here . RESULTS Thirty one and 30 patients were enrolled , respectively , in arm A and arm B. Twelve patients recurred ( five of them died ) : respectively , eight and four in arm A and arm B. The 3-year event-free survival rates were 72 % ( st and ard error [ SE ] , 9 % ) and 89 % ( SE , 6 % ) ( not significant [ NS ] ) in arm A and arm B , respectively . The 3-year overall survival rates were 86 % ( SE , 6 % ) and 97 % ( SE , 3 % ) ( NS ) in arm A and arm B , respectively . CONCLUSIONS Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT ( but this conclusion is limited by the lack of power ) Abstract Background We provided a comprehensive analysis of rate , pattern , and severity of early and late postoperative complications in a very large , single-institution series of locally advanced cervical cancer ( LACC ) patients administered CT/RT plus radical surgery ( RS ) . Methods A total of 362 consecutive LACC ( FIGO stage IB2-IVA ) patients were su bmi tted to RS after CT/RT at the Gynecologic Oncology Unit of the Catholic University ( Rome/Campobasso ) . At 4 weeks after CT/RT , patients were evaluated for objective response and triaged to radical hysterectomy and pelvic ± aortic lymphadenectomy . Surgical morbidity was classified according to the Chassagne ’s grading system . Results Most cases underwent type III – IV radical hysterectomy ( N = 313 , 86.5 % ) ; pelvic lymphadenectomy was performed in all patients , while 116 patients ( 32.1 % ) were also su bmi tted to aortic lymphadenectomy . A total of 93 patients ( 25.7 % ) experienced any grade postoperative complications , and 60 ( 16.6 % ) had ≥ grade 2 complications ; grade 3–4 complications occurred in 21 patients ( 5.8 % ) . Of all early postoperative complications ( N = 100 ) , 31 ( 31.0 % ) were urinary , 9 ( 9.0 % ) were gastrointestinal , and 45 ( 45.0 % ) were vascular . Of all late complications ( N = 31 ) , 20 ( 64.5 % ) were urinary , 7 ( 22.6 % ) gastrointestinal , and 2 ( 6.4 % ) were vascular . Multivariate analysis showed that not complete clinical response to treatment retained an independent , unfavorable association with risk of development of postoperative morbidity , while advanced stage , and aortic lymphadenectomy showed only a borderline value . Conclusions Failure to achieve clinical complete response to treatment and , to a lesser extent , more advanced stage , and aortic lymphadenectomy , were associated with a higher risk of developing any grade as well as ≥ grade 2 complications BACKGROUND AND METHODS On behalf of the Gynecologic Oncology Group , we performed a r and omized 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 r and omly 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 ) . 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 PURPOSE To compare the efficacy of neoadjuvant chemotherapy ( NAC ) followed by radical hysterectomy with that of radiotherapy ( R/T ) for bulky early-stage cervical cancer . PATIENTS AND METHODS Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were r and omly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) . The ratio of patient allocation was 6:4 for the NAC and R/T arms . Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative . RESULTS Of the 124 eligible patients , 68 in the NAC arm and 52 in the R/T arm could be evaluated . The median duration of follow-up was 39 months . Thirty-one percent of patients in the NAC arm and 27 % in the R/T arm had relapse or persistent diseases after treatment , and 21 % in each group died of disease . Estimated cumulative survival rates at 2 years were 81 % for the NAC arm and 84 % for the R/T arm ; the 5-year rates were 70 % and 61 % , respectively . There were no significant differences in disease-free survival and overall survival . CONCLUSION NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer . Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary OBJECTIVE To determine if three courses consisting of 50 mg/m2 cis-platinum , 1 mg/m2 vincristine , and 25 mg/m2 bleomycin ( day 1 - 3 ) at 10-day intervals can improve survival before Wertheim-Meigs + radiotherapy . MATERIAL Two hundred five unselected stage Ib patients ( having tumors > 2 cm in diameter ) were divided into two groups at r and om : ( 1 ) The group control consisted of 103 patients ( 56 bulky , > 4 cm diameter ) treated with Wertheim-Meigs ( if the tumor was resectable with free surgical margins ) + adjuvant radiotherapy to whole pelvis ( extended field radiation was used only in patients with paraaortic lymph node metastases ) . When the tumor was unresectable , a surgical staging was performed and radiotherapy was the chosen treatment . ( 2 ) Neoadjuvant ( 102 patients , 61 bulky ) had neoadjuvant chemotherapy and then the same treatment as the control patients . RESULTS After 67 ( 31 - 102 ) months of follow-up , no difference was seen in tumors > 2 and < 4 cm in both groups ( C = 77 % vs N = 82 % ) , but statistically significant differences were seen in survival and disease-free survival , in bulky tumors , and between patients with neoadjuvant chemotherapy + Wertheim-Meigs + radiotherapy ( 80 % ) and the control ( 61 % ) . This was due to an increased operability that was substantially improved in bulky tumors in the neoadjuvant chemotherapy group ( 61/61 , 100 % ) vs control ( 48/56 , 85 % ; P < 0.01 ) . After 7 years of follow-up , the outcome of the unresectable bulky control group of patients is significantly worse ( 14 % ) than that of the resectable group ( 69 % ; P < 0.001 ) . With regard to recurrences , a significant decrease in pelvic failures in the neoadjuvant chemotherapy group was observed ( P < 0.001 ) . Survival was improved in bulky resectable cases ( N = 81 % vs C = 69 % , P < 0.05 ) . Pathological findings for the surgical specimens revealed differences between both groups because all the risk factors such as parametrial and lymph node metastases , tumor bulk , and vascular embolism had been decreased ( P < 0.001 ) . CONCLUSION Neoadjuvant chemotherapy can improve survival because of increased operability with free survival margins and a decrease in pathologic risk factors in unselected , bulky ( > 4 cm diameter ) stage Ib patients BACKGROUND Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers . For the Gynecologic Oncology Group , we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer . METHODS Women with bulky stage IB cervical cancers ( tumor , > or = 4 cm in diameter ) were r and omly assigned to receive radiotherapy alone or in combination with cisplatin ( 40 mg per square meter of body-surface area once a week for up to six doses ; maximal weekly dose , 70 mg ) , followed in all patients by adjuvant hysterectomy .  Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement . The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A ( cervical parametrium ) and 55 Gy to point B ( pelvic wall ) . Cisplatin was given during external radiotherapy , and adjuvant hysterectomy was performed three to six weeks later . RESULTS 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 To investigate whether surgery or radiotherapy should be preferred in the early stages of carcinoma of the cervix a r and omized study was performed in which operable patients with small FIGO stage 2 squamous cell carcinoma were included . Of these patients , 122 were in stage 2A and 20 in stage 2B . The patients were treated with intracavitary radium , followed by either radical surgery with pelvic lymphadenectomy ( Group A , 72 patients ) or high-voltage external irradiation 40 Gy to a pelvic field ( Group B , 70 patients ) . Postoperative irradiation 40 to 50 Gy was given in Group A if lymph node metastases were found at operation . Fourteen patients in Group A and 23 in Group B died of recurrent disease . The 5- , 10- , and 20-year survival in Group A was 87 , 84 and 81 % respectively compared with 72 , 69 , and 68 % in Group B , p < 0.05 . Twenty-three ( 34 % ) of 67 radically operated patients had metastases to pelvic lymph nodes . A high rate of pelvic and para-aortic recurrences accounts for the difference between Groups A and B. Young patients ( < 40 years ) with large tumours had a high risk of recurrent disease . Severe urinary and gastrointestinal complications were more common in Group A , especially among patients given postoperative radiotherapy .  Lymphoedema was seen almost exclusively in Group A. Two patients in Group A and one in Group B died of complications to treatment . The corrected 10-year survival of 69.5 % as achieved in the radiotherapy arm of this series is comparable to other reported studies . The high survival rate in the operated group , despite a very high metastases rate , suggests that surgery is applicable also in stage 2 patients PURPOSE In 1986 , a protocol comparing primary radiation therapy ( RT ) plus hydroxyurea ( HU ) to irradiation plus fluorouracil ( 5-FU ) and cisplatin ( CF ) was activated by the Gynecologic Oncology Group ( GOG ) for the treatment of patients with locally advanced cervical carcinoma . The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities . METHODS All patients had biopsy-proven invasive squamous cell carcinoma , adenocarcinoma , or adenosquamous carcinoma of the uterine cervix . Patients underwent st and ard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB , III , or IVA . Negative cytologic washings and para-aortic lymph nodes were required for entry . Patients were r and omized to receive either st and ard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU . RESULTS Of 388 r and omized patients , 368 were eligible ; 177 were r and omized to CF and 191 to HU .  Adverse effects were predominantly hematologic or gastrointestinal in both regimens . Severe or life-threatening leukopenia was more common in the HU group ( 24 % ) than in the CF group ( 4 % ) . The difference in progression-free survival ( PFS ) was statistically significant in favor of the CF group ( P = .033 ) . The sites of progression in the two treatment groups were not substantially different . Survival was significantly better for the patients r and omized to CF ( P = .018 ) . CONCLUSION This study demonstrates that for patients with locally advanced carcinoma of the cervix , the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU , and with manageable toxicity One hundred fifty-one patients ( 107 stage IIB and 44 stage IIIB ) who had completed 2 years of follow-up after treatment with neoadjuvant chemotherapy ( " Quick " VBP scheme ) , prior to st and ard therapy , are presented . Four groups of patients with different prognosis and operability status , according to tumor response , were identified . In the first group ( excellent responders ) 96 % of the patients had no evidence of disease ( NED ) , whereas in the fourth group ( no response ) , only 33 % had NED after 2 years of follow-up . In the first group , no pelvic failure was observed . On the other h and , of 21 patients in group 4 , 11 ( 52 % ) had pelvic recurrences . The response to neoadjuvant therapy is strongly associated with the initial tumor volume ecographically evaluated . The critical pretreatment volume for response was 84 cm3 ( 4.85 cm in diameter ) .  Surgery and radiotherapy  were equally effective in those patients with initial tumor volume of 84 cm3 or less . But surgery appears to have a better outcome in those patients with tumors larger than the critical pretreatment tumor volume . Radiotherapy in this controversial group was ineffective in avoiding pelvic recurrences , especially when the tumor volume was not sufficiently reduced . The advantage of neoadjuvant chemotherapy is evident in stage IIB , with 79 % ( 85/107 ) of patients showing no evidence of disease as compared with 47 % ( 24/51 ) in a nonr and omized control group ( P less than 0.01 ) . Statistically significant differences were also obtained in stage IIIB ( 50 % vs 26 % in the control group ) BACKGROUND The aim of the present study was to demonstrate that radical hysterectomy ( RH ) leads to improved survival outcomes in FIGO stage IB2-IIB cervical cancer when compared with st and ard brachytherapy ( BCT ) after identical external beam chemoradiation ( EBRT-CT ) . PATIENTS AND METHODS EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m² and gemcitabine at 125 mg/m² per week concurrent with 50.4 Gy of radiation . In the BCT arm , EBRT-CT was followed by BCT to reach a point A dose of 85 Gy , whereas in the experimental arm , a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling ( RH ) was carried out within 4 - 6 weeks after EBRT-CT . RESULTS Between May 2004 and June 2009 , 211 patients were enrolled ( BCT , 100 and RH , 111 ) . At a median follow-up time of 36 months ( 3 - 80 ) , progression-free survival ( PFS ) and overall survival ( OS ) rates were similar in both the arms . PFS rates were 74.8 % and 71.7 % in the BCT and RH arms [ HR 0.6516 ( 95 % confidence interval ( CI ) 0.3504 - 1.2116 ) ] , P = 0.186 . OS rates were 76.3 % in the BCT versus 74.5 % in the surgical arm [ HR 0.6981 ( 95 % CI 0.3106 - 1.3439 ) ] , P = 0.236 . No differences were observed in the pattern of local and systemic failures . CONCLUSIONS This study failed to demonstrate that RH after EBRT-CT is superior to st and ard BCT BACKGROUND AND METHODS We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer . Between 1990 and 1997 , 403 women with advanced cervical cancer confined to the pelvis ( stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes ) were r and omly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin ( days 1 through 5 and days 22 through 26 of radiation ) . Patients were then to receive one or two applications of low-dose-rate intracavitary radiation , with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group . RESULTS Of the 403 eligible patients , 193 in each group could be evaluated . The median duration of follow-up was 43 months . Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone ( P=0.004 ) . Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group ( P<0.001 ) . The rates of both distant metastases ( P<0.001 ) and locoregional recurrences ( P<0.001 ) were significantly higher among patients treated with radiotherapy alone . The seriousness of side effects was similar in the two groups , with a higher rate of reversible hematologic effects in the combined-therapy group . CONCLUSIONS The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer PURPOSE Neoadjuvant chemotherapy ( NACT ) and radical surgery ( RS ) have emerged as a possible alternative to conventional radiation therapy ( RT ) in locally advanced cervical carcinoma . In 1990 , a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity . PATIENTS AND METHODS Patients with squamous cell , International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study . They received cisplatin-based NACT followed by RS ( type III to V radical hysterectomy plus systematic pelvic lymphadenectomy ) ( arm A ) or external-beam RT ( 45 to 50 Gy ) followed by brachyradiotherapy ( 20 to 30 Gy ) ( arm B ) . RESULTS Of 441 patients r and omly assigned to NACT+RS or RT , eligibility was confirmed in 210 and 199 patients , respectively . Treatment was administered according to protocol in 76 % of arm A patients and 72 % of arm B patients . Adjuvant treatment was delivered in 48 operated patients ( 29 % ) . There was no evidence for any significant excess of severe morbidity in one of the two arms . The 5-year overall survival ( OS ) and progression-free survival ( PFS ) rates were 58.9 % and 55.4 % for arm A and 44.5 % and 41.3 % for arm B ( P = .007 and P = .02 ) , respectively . Subgroup survival analysis shows OS and PFS rates of 64.7 % and 59.7 % ( stage IB2-IIB , NACT+RS ) , 46.4 % and 46.7 % ( stage IB2-IIB , RT ) ( P = .005 and P = .02 ) , 41.6 % and 41.9 % ( stage III , NCAT+RS ) , 36.7 % and 36.4 % ( stage III , RT ) ( P = .36 and P = .29 ) , respectively . Treatment had a significant impact on OS and PFS . CONCLUSION Although significant only for the stage IB2 to IIB group , a survival benefit seems to be associated with the NACT+RS compared with conventional RT There were 732 evaluable patients with primary , previously untreated , histologically confirmed stage I squamous carcinoma of the cervix with greater than or equal to 3-mm invasion . Of these , 645 had no gross disease beyond the cervix/uterus , had negative paraaortic lymph nodes , and had undergone a radical hysterectomy with pelvic lymphadenectomy .  The 3-year disease-free interval ( DFIs ) for the 545 patients with negative pelvic nodes was 85.6 % , and for the 100 with positive pelvic nodes , 74.4 % . A large number of pelvic nodes involved with tumor was not correlated with a poorer prognosis ; the DFIs were 72.1 , 86.4 , and 64.6 % for one , two , and three or more positive pelvic nodes , respectively . DFI correlated strongly with depth of tumor invasion , both in absolute terms ( mm ) and infractional thirds . The DFI was 94.6 % for less than or equal to 5 mm , 86.0 % for 6 - 10 mm , 75.2 % for 11 - 15 mm , 71.5 % for 16 - 20 mm , and 59.5 % greater than or equal to 21 mm . In fractional terms , the DFI was 94.1 % for superficial third , 84.5 % for middle third , and 73.6 % for deep third invasion . With respect to clinical tumor size , the DFIs were 94.8 , 88.1 , and 67.6 % for occult , less than or equal to 3 cm , and greater than 3 cm , respectively . The DFI was 77.0 % for those with positive capillary-lymphatic spaces ( CLS ) and 88.9 % for those with negative CLS . Tumor grade and parametrial status correlated with DFI . DFI was not significantly different for age , disease status of the surgical margins , tumor description ( e.g. , exophytic ) , quadrant involved with tumor , uterine extension , and keratinizing status of tumor cells . Clinical tumor size , CLS , and depth of tumor invasion were independent prognostic factors OBJECTIVE To evaluate , in a r and omized clinical trial , the role of adjuvant hysterectomy after st and ardized radiation in improving progression-free survival and survival for patients with " bulky " stage IB cervical cancer . METHODS A total of 256 eligible patients with exophytic or " barrel " shaped tumors measuring > or = 4 cm were r and omized to either external and intracavitary irradiation ( RT , N = 124 ) or attenuated irradiation followed by extrafascial hysterectomy ( RT + HYST , N = 132 ) . Twenty-five percent of patients had tumors with a maximum diameter of > or = 7 cm . RESULT Tumor size was the most pronounced prognostic factor followed by performance status 2 and age at diagnosis . Hysterectomy did not increase the frequency of reported grade 3 and 4 adverse effects ( both groups , 10 % ) . The majority of these adverse effects were from the gastrointestinal or genitourinary tracts exclusively . There was a lower cumulative incidence of local relapse in the RT + HYST group ( at 5 years , 27 % vs. 14 % ) . There were no statistical differences in outcomes between regimens except for the adjusted comparison of progression-free survival , although all indicated a lower risk in the adjuvant hysterectomy regimen ( unadjusted relative risk [ URR ] of progression , 0.77 , P = 0.07 ; URR of death , P = 0.26 , both one tail ) . CONCLUSION Overall , there was no clinical ly important benefit with the use of extrafascial hysterectomy . However , there is good evidence to suggest that patients with 4- , 5- , and 6-cm tumors may have benefitted from extrafascial hysterectomy ( URR of progression ; 0.58 ; URR of death , 0.60 ) Background : A phase III trial was conducted to determine whether neoadjuvant chemotherapy ( NACT ) before radical surgery ( RS ) improves overall survival . Methods : Patients with stage IB2 , IIA2 , or IIB squamous cell carcinoma of the uterine cervix were r and omly assigned to receive either BOMP ( bleomycin 7 mg days 1–5 , vincristine 0.7 mg m−2 day 5 , mitomycin 7 mg m−2 day 5 , cisplatin 14 mg m−2 days 1–5 , every 3 weeks for 2 to 4 cycles ) plus RS ( NACT group ) or RS alone ( RS group ) . Patients with pathological high-risk factors received postoperative radiotherapy ( RT ) . The primary end point was overall survival . Results : A total of 134 patients were r and omly assigned to treatment . This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group . Patients who received postoperative RT were significantly lower in the NACT group ( 58 % ) than in the RS group ( 80 % ; P=0.015 ) . The 5-year overall survival was 70.0 % in the NACT group and 74.4 % in the RS group ( P=0.85 ) . Conclusion : Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival , but reduced the number of patients who received postoperative RT Background : The p53:miR-34a : E2F positive feed-forward loop and the p53:miR-605:Mdm2 positive feed-back loop have been identified to be crucial oncogenesis/tumor suppressor-regulating signaling pathways . In this study , we sought to examine the hypothesis that neoadjuvant chemotherapy ( NAC ) is a better approach with improved prognosis and outcomes after  laparoscopical radical hysterectomy ( LRH ) on patients with cervical cancer and to eluci date the potential roles of the p53:miR-34a : E2F1 and the p53:miR-605:Mdm2 signaling pathways in this therapy . Methods : Twenty-one patients with stage IIB cervical cancer were recruited to this study and they were r and omly divided into two groups : LRH ( n=10 ) and NAC+LRH ( n=11 ) groups . The NAC+LRH group consisted of 4 cycles of cisplatin , paclitaxel and carboplatin .  Complication rates and NAC outcomes ( tumor size changes , 2-year disease-free survival rate , and 2-year overall survival rate ) were compared between the two groups . Expression of p53 , Mdm2 , E2F1 , miR-34a , and miR-605 at mRNA and protein levels from the tumor tissues was analyzed . Results : We observed that the diameter of tumors following chemotherapy was substantially smaller in the NAC+LRH patients than in LRH patients . No recurrence or metastasis after surgery was observed in the NAC+LRH patients , whereas 2 out of 10 LRH patients had recurrences and 1 had metastasis . The 2-year disease-free and overall survival rates were apparently higher in the NAC+LRH group than in the LRH group . Furthermore , molecular biology analyses revealed that the protein and mRNA levels of p53 were both markedly increased in patients who received NAC than those who did not , and oppositely , the levels of E2F1 and Mdm2 were significantly lower in the NAC+LRH patients than in the LRH patients . The levels of miR-34a and miR-605 were considerably higher with NAC relative to without NAC . Among the three anti-cancer drugs included in NAC , cisplatin was found to be the main component that caused increases in p53 protein levels , miR-34a and miR-605 miRNA levels , and decreases in Mdm2 and E2F1 protein levels . Furthermore , ERK1/2 inhibitor U0126 or TAB1 siRNA mitigated these changes induced by cisplatin . Conclusion : These findings not only indicate NAC as a rational approach for better treatment of cervical cancer with improved therapeutic outcomes , due partly to the ability of cisplatin to promote the p53:miR-34a : E2F1 positive feed-forward loop and the p53:miR-605:Mdm2 positive feedback loop
BACKGROUND Cervical cancer is the second commonest cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide .
Sources suggest that a very high proportion of new cervical cancer cases in developing countries are at an advanced stage ( IB2 or more ) and more than a half of these may be stage III or IV .
Cervical cancer staging is based on findings from clinical examination ( FIGO ) staging ) .
St and ard care in Europe and US for stage IB2 to III is non-surgical treatment ( chemoradiation ) .
However in developing countries , where there is limited access to radiotherapy , locally advanced cervical cancer may be treated with a combination of chemotherapy and hysterectomy ( surgery to remove the womb and the neck of the womb , with or without the surrounding tissues ) .
It is not certain if this improves survival .
Therefore , it is important to systematic ally assess the value of hysterectomy in addition to radiotherapy or chemotherapy , or both , as an alternative intervention in the treatment of locally advanced cervical cancer ( stage IB2 to III ) .
OBJECTIVES To determine whether hysterectomy , in addition to st and ard treatment with radiation or chemotherapy , or both , in women with locally advanced cervical cancer ( stage IB2 to III ) is safe and effective compared with st and ard treatment alone .