Neoadjuvant chemotherapy followed by radical hysterectomy and postoperative adjuvant chemotherapy in the treatment of carcinoma of the cervix uteri: long-term follow-up of a pilot study.

OBJECTIVE: The aim of the study was to determine if ACH given after NCH followed by RH could decrease the incidence of distant metastases in patients with locally advanced carcinoma of cervix uteri. MATERIAL: 56 pts (34 Ib, 18 IIb, 4 IIIb) with confirmed diagnosis of squamous cervical cancer were enrolled in this phase II trial. The methodology used was: 1) Figo clinical staging; 2) Ultrasonographic determination of tumor volume in < or > 4 cms; 3) V.B.P. scheme: cis-platinum 50 mg/m2/day 1; vincristine 1 mg/m2/day 1; bleomycin 25 mg/m2/days 1-2-3 (3 courses with 10 days interval); 4) Clinical and sonographic tumor response evaluation following U.I.C.C. response criteria; 5) Radical hysterectomy; 6) Pathological risk factor evaluation; 7) ACH with P.M.C. (cis-platinum 50 mg/m2, methotrexate 30 mg/m2, cyclophosphamide 500 mg/m2) 3 courses every 21 days; 8) Comparison and location of recurrences with a neoadjuvant group (NCH + RH + RT to whole pelvis), and with a control group treated with conventional radiotherapy were done. For statistical analysis the Chi-Square was used and D.F.S. and overall survival (O.S.) were calculated according to the Kaplan Meier and Log Rank Test. RESULTS: After a median follow-up of 75 months (range 42-108), O. S. for stage Ib was 88%, Stage IIb 78%, and 50% for IIIb. The recurrences were 12% (4/34) for Stage Ib (3 local and 1 distant); 28% for IIb (5/18) (4 pelvic and 1 distant); 50% (2/4) for IIIb (2 pelvic recurrences). When residual tumor volume was < 2 cm in the surgical specimen (n=39) there were 4 recurrences (3 pelvic and 1 distant), and 7 (6 pelvic and 1 distant) for tumors > 2 cm. (p<0.01 for pelvic recurrences). For the stage Ib with residual tumor <2 cm (n=14) there were no pelvic recurrences and only 1 distant. Comparing for Stage Ib with previous tumor volume >4 cm of the ACH Group (n=17) with a classical NCH (n=51) and control (n=51) groups, there were observed 2 (11.7%) pelvic and 1 (5,8%) distant relapses for the 1st Group, 3 (5.9%) pelvic and 3 (5.9%) distant relapses for the 2nd, and 11 (21.6%) pelvic and 5 (9.8%) distant relapses for the 3rd Group. From the comparison of locally advanced tumors (Stages IIb + IIIb) of ACH group (n=22), with a Stage IIIb surgically removed of classical NCH group (n=38) and with a control group of conventional RT (n=51), there were observed 6 (27%) pelvic and 1 (4.5%) distant relapses for the 1st Group, 4 (11%) pelvic and 7 (18.4%) distant relapses for the 2nd, and 31 (60.7%) pelvic and 5 (9.8%) distant for the 3rd one. CONCLUSION: ACH after NCH + RH could be used for stage Ib with tumor volume > 4 cm, with complete clinical response or residual tumor < 2 cm. The results of this group of tumors suggest the importance of going on phase III trials comparing NCH+RH alone vs. NCH+RH+ACH. ACH could also be used to try to obtain better control of distant metastases in Stages IIb and IIIb. In these cases radiotherapy to the whole pelvis must not be excluded.

Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results.

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 random: (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.

Quimioterapia y radioterapia en el cáncer de ovario: mitos y realidades / Drug therapy and radiotherapy in the ovarian neoplasm: myths and realitys

236 pacientes con carcinoma epitelial del ovario fueron estadificadas y reestadificadas según la clasificación de la FIGO de 1985. Objetivos: 1) valorar la quimioterapia como adyuvante en estadios iniciales y terapéutica en estadios avanzados usando esquemas de mono o poliquimioterapia. 2) Evaluar la radioterapia como terapia de consolidadción rescate. 3) Comparar la utilidad de la quimioterapia de segunda línea vs. la radioterapia en pacientes con second look positivo. Como esquemas de monoquimioterapia se utilizó melfalán y como poliquimioterapia de segunda línea, esquemas basados en platino en aquellas pacientes respondedoras al mismo. Resultados: cuando se realiza la comparación para la muestra global no se hallaron diferencias significativas con respecto a la sobrevida y al período libre de enfermedad con mono o poliquimioterapia. En los estadios avanzados si se halló diferencia significativa con respecto al período libre de enfermedad en las pacientes que fueron tratadoas con poliquimioterapia (p<0,025). En los estadios IAB, se registraron diferencias estadísticamente significativas en la sobrevida de las que hicieron adyuvancia (78 vs. 31 por ciento) y las que hicieron seguimiento (p<0,005). En los estadios IIIc no se hallaron tampoco diferencias significativas en ambos grupos (MQT vs. PQT) con respecto a la sobrevida pero sí en el período libre de enfermedad (p<0,025). Radioterapia como arma de consolidación rescate. Al comparar los casos con cirugías completas con posterior quimioterapia adyuvante y second look negativo que realizaron seguimiento posterior (n=19) con las que consolidaron con radioterapia (n=9), no se hallaron diferencias estadísticamente significativas con respecto a la sobrevida ni al TLE. En las que tuvieron LR < 0 > de 2 cm. con quimioterapia posterior y second look negativo y que hicieron seguimiento (n=30), la sobrevida fue del 24 por ciento, en las que consolidaron con RT ésta fue del 66 por ciento (p<0,02) y el TLE fue de 29 y 70 por ciento respectivamente. Al comparar en los estadios avanzados con LR < 0 > de 2 cm. que realizaron quimioterapia posterior y tuvieron Second look positivo, las terapias de rescate (QT vs. RT) se registraron diferencias estadísticamente significativas entre ambos grupos, con respecto a la sobrevida: QT (n=18): 10 por ciento vs. RT (n=20): 37 por ciento (p<0,025). Conclusiones: 1) no hemos comprobado diferencias estadísticamente significativas en la sobrevida global de todas las pacientes tratadas con mono o poliquimioterapia. En los estadios avanzados tratados con esquemas basados en platino hallamos diferencias significativas con respecto al TLE. En los estadios iniciales (IAB), se registró un beneficio en términos de sobrevida en las que realizaron quimioterapia adyuvante. 2) La radioterapia demostró ser de utilidad en aquellas pacientes con LR menores de 1 cm., confinadas a la pelvis o microscópicas en abdomen. 3) Las alternativas terapéuticas de consolidación rescate o salvataje no aseguran mejoría de la sobrevida o un TLE aceptable (AU)

Quimioterapia y radioterapia en el cáncer de ovario: mitos y realidades / Drug therapy and radiotherapy in the ovarian neoplasm: myths and realitys

236 pacientes con carcinoma epitelial del ovario fueron estadificadas y reestadificadas según la clasificación de la FIGO de 1985. Objetivos: 1) valorar la quimioterapia como adyuvante en estadios iniciales y terapéutica en estadios avanzados usando esquemas de mono o poliquimioterapia. 2) Evaluar la radioterapia como terapia de consolidadción rescate. 3) Comparar la utilidad de la quimioterapia de segunda línea vs. la radioterapia en pacientes con second look positivo. Como esquemas de monoquimioterapia se utilizó melfalán y como poliquimioterapia de segunda línea, esquemas basados en platino en aquellas pacientes respondedoras al mismo. Resultados: cuando se realiza la comparación para la muestra global no se hallaron diferencias significativas con respecto a la sobrevida y al período libre de enfermedad con mono o poliquimioterapia. En los estadios avanzados si se halló diferencia significativa con respecto al período libre de enfermedad en las pacientes que fueron tratadoas con poliquimioterapia (p<0,025). En los estadios IAB, se registraron diferencias estadísticamente significativas en la sobrevida de las que hicieron adyuvancia (78 vs. 31 por ciento) y las que hicieron seguimiento (p<0,005). En los estadios IIIc no se hallaron tampoco diferencias significativas en ambos grupos (MQT vs. PQT) con respecto a la sobrevida pero sí en el período libre de enfermedad (p<0,025). Radioterapia como arma de consolidación rescate. Al comparar los casos con cirugías completas con posterior quimioterapia adyuvante y second look negativo que realizaron seguimiento posterior (n=19) con las que consolidaron con radioterapia (n=9), no se hallaron diferencias estadísticamente significativas con respecto a la sobrevida ni al TLE. En las que tuvieron LR < 0 > de 2 cm. con quimioterapia posterior y second look negativo y que hicieron seguimiento (n=30), la sobrevida fue del 24 por ciento, en las que consolidaron con RT ésta fue del 66 por ciento (p<0,02) y el TLE fue de 29 y 70 por ciento respectivamente. Al comparar en los estadios avanzados con LR < 0 > de 2 cm. que realizaron quimioterapia posterior y tuvieron Second look positivo, las terapias de rescate (QT vs. RT) se registraron diferencias estadísticamente significativas entre ambos grupos, con respecto a la sobrevida: QT (n=18): 10 por ciento vs. RT (n=20): 37 por ciento (p<0,025). Conclusiones: 1) no hemos comprobado diferencias estadísticamente significativas en la sobrevida global de todas las pacientes tratadas con mono o poliquimioterapia. En los estadios avanzados tratados con esquemas basados en platino hallamos diferencias significativas con respecto al TLE. En los estadios iniciales (IAB), se registró un beneficio en términos de sobrevida en las que realizaron quimioterapia adyuvante. 2) La radioterapia demostró ser de utilidad en aquellas pacientes con LR menores de 1 cm., confinadas a la pelvis o microscópicas en abdomen. 3) Las alternativas terapéuticas de consolidación rescate o salvataje no aseguran mejoría de la sobrevida o un TLE aceptable

Results of a prospective randomized trial with neoadjuvant chemotherapy in stage IB, bulky, squamous carcinoma of the cervix.

A prospective randomized trial was carried out in patients with squamous carcinoma of the cervix uteri, stage Ib bulky. The protocol considers two arms: the control group (75 patients) and the neoadjuvant one (76 patients). All the patients were classified according to the FIGO staging system and in order to determine the tumor size objectively, an ultrasound scanning was done. After this a Wertheim-Meigs operation followed by adjuvant whole-pelvis irradiation was performed. In the neoadjuvant group the same procedures were carried out but three courses of chemotherapy with the "quick" VBP scheme were given before the treatment. The new therapeutic strategy proved to be very useful in bulky tumors in which the clinical examination showed a cervix increased in size and the ultrasound scanning a volume larger than 60 c.c. (> 4 x 4 x 4 cm). In those cases statistically significant differences were found between both groups when free disease interval and survival were considered. These were due to the fact that operability has been improved and the parametrial extension has been decreased as well as other risk factors such as vascular embolism, lymph node involvement, tumor-cervix quotient, and tumor volume. The use of this new strategy is not justified in small tumors (< 3-4 cm in diameter) because in those cases, survival is not improved with neoadjuvant therapy.

Lymph node metastases in carcinoma of the cervix uteri: response to neoadjuvant chemotherapy and its impact on survival.

One hundred and sixty-nine patients with squamous cancer of the cervix uteri treated with three courses of neoadjuvant chemotherapy with the modified VBP scheme are presented. All were subjected to a Wertheim-Meigs operation with paraaortic lymph-adenectomy. The incidence of lymph node metastases is analyzed according to clinical stage, tumor volume, residual tumor in the surgical specimen, and clinical response to neoadjuvant chemotherapy. A significant decrease in the incidence of lymph node involvement was observed in good responders. Survival rates, after 2 years of follow-up, improved in those cases with small residual tumor, negative parametria, and negative nodes.

Neoadjuvant chemotherapy in locally advanced carcinoma of the cervix uteri.

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 standard 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 hand, 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 nonrandomized control group (P less than 0.01). Statistically significant differences were also obtained in stage IIIB (50% vs 26% in the control group).

Is subradical surgical treatment for carcinoma of the cervix uteri stage IB logical?

Twenty-eight patients with squamous carcinoma of the cervix FIGO stage Ib were treated with three courses of neoadjuvant chemotherapy with a VBP modified scheme. Clinical responses showed that the percentage of complete and moderate responses exceeds 95% of the cases. Clinical response was also related to tumor bulk measurement by ultrasound scanning. Twenty-three of the patients were then subjected to the Wertheim-Meigs operation. Pathological findings of surgical specimens showed absence of residual lesion in 6 patients (26.1%) and carcinoma smaller than 0.5 cm in 5 patients (21.7%). Tumor response to neoadjuvant chemotherapy was excellent in NG3, MG3 tumors when lymphoplasmomonocytic infiltration was present. In accord with this result a new protocol was developed.

Results of a phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix uteri.

Results of a Phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix uteri (VBP modified scheme) show that 85.7% of patients given this therapy were NED in Stage IIb versus 54% of a nonrandomized control group given conventional therapy. In Stage IIIb the averages are 66.6% vs. 31% in the control group. Analysis of the ecographic data has shown that if a critical prechemotherapy volume (120 cm3) is exceeded, the prognosis is unfavorable, especially in cases treated with radiotherapy as second-line treatment.

A possible new trend in the management of the carcinoma of the cervix uteri.

Thirty-three patients with locally advanced carcinoma of the cervix were treated with chemotherapy as first line treatment. Great emphasis was applied to document, in the most objective manner, the tumor size response. The first 8 patients received a conventional scheme composed of vincristine, bleomycin and cis-platinum (VBP) at 21-day intervals. The results were not as satisfactory as expected. In the other 25 patients a more aggressive VBP scheme was used, at 10-day intervals. Surprisingly satisfactory results and tolerance were observed. In many instances verified tumor reduction allowed surgical radical treatment in prechemotherapy inoperable cases.