Clinicopathological prognostic factors and the role of cytoreduction in surgical stage IVb endometrial cancer: A retrospective multi-institutional analysis of 248 patients in Japan

Objective

To evaluate clinicopathological prognostic factors and the impact of cytoreduction in patients with surgical stage IVb endometrial cancer (EMCA).

Methods

The records of 248 patients with stage IVb EMCA who underwent primary surgery including hysterectomy at multiple institutions from 1996 to 2005 were retrospectively analyzed. Data regarding disease distribution, surgical procedures, adjuvant therapy, and survival times were collected. Univariate and multivariate analyses were performed to identify factors associated with overall survival (OS).

Results

The median OS was 24 months. The most common histological types were endometrioid (grade 1: 15%, grade 2: 20%, grade 3: 24%) and serous (17%). The most common sites of intra-abdominal metastases were pelvis (65%), ovaries (58%), omentum (58%), retroperitoneal lymph nodes (52%), and upper abdominal peritoneum (44%). In 93 patients with extra-abdominal metastases, the most common site was the lung (n = 49). Complete resection of extra-abdominal metastases was achieved in only 13 patients. Complete resection of intra-abdominal metastases was achieved in 101 patients, 52 had ≤ 1 cm residual disease, and 95 had > 1 cm residual disease; the median OS times in these groups were 48, 23, and 14 months, respectively (p < 0.0001). Multivariate analysis showed that performance status, histology/grade, adjuvant treatment, and intra-abdominal residual disease were independent prognostic factors. Intra-abdominal residual disease was an independent prognostic factor in patients with and without extra-abdominal metastases.

Conclusions

Cytoreductive surgery and adjuvant therapy may improve survival in stage IVb EMCA, particularly in patients with favorable prognostic factors, even in the presence of extra-abdominal metastases.     

Randomized study of preoperative chemotherapy versus primary surgery for stage IB cervical cancer

AIM: To determine the most effective treatment and long-term outcome of patients with stage IB carcinoma of the cervix. METHODS: From January 1999 to December 2001, 106 women with cervical cancer stage IB received neoadjuvant chemotherapy (n = 52) or primary surgery (n = 54). These were randomly assigned. Clinical effects and pathological changes were simultaneously recorded. RESULTS: The overall clinical response rate was 84.6% and included a complete response (CR) in four patients (7.7%), partial response (PR) in 40 patients (76.9%), and stable disease (SD) in the remaining eight patients (15.4%). Surgery revealed positive nodes in 9.6% neoadjuvant chemotherapy group patients and in 29.6% primary surgery group patients (P = 0.014). Similar results occurred with vascular space involvement: 27.8% in the primary surgery group compared to 9.6% in the neoadjuvant chemotherapy group (P = 0.024). However, parametrial infiltration was found in 7.4% of the patients in the primary surgery group, while only 3.8% showed it in the neoadjuvant chemotherapy group (P = 0.679). The overall 5-year survival rate was significantly higher for all patients who received neoadjuvant chemotherapy (84.6%) than for the control group (75.9%) (P = 0.0112). The median survival time in patients with complete response and partial response to chemotherapy (83.3 months) was significantly higher than that of patients with stable disease to chemotherapy (55.2 months) (P = 0.0049). 27.3% of patients developed recurrent disease within 5 years of the primary treatment. The women with recurrence included partial response in six patients (60.0%), and stable disease in four patients (40.0%). For the other patients there was partial response and complete response in 38 patients (90.5%), and stable disease in the remaining four patients (9.5%) (P = 0.035). CONCLUSION: Neoadjuvant chemotherapy can effectively eliminate the pathological risk factors and improve long-term survival in patients with locally advanced cervical cancer.     

Neoadjuvant chemotherapy increases the 5-year overall survival of patients with resectable cervical cancer: A systematic review and meta-analysis

Cervical cancer is a global health challenge in women. Neoadjuvant chemotherapy (NACT) is a recent prospect for alternative cervical cancer treatments. This study investigated the efficacy of NACT against resectable cervical cancer based on the medium and long-term survival of patients with the disease. We searched through PubMed, Web of Science, EBSCO and Cochrane Library for relevant reports published by June 2020. The primary outcomes were 3-year and 5-year progression-free survival (PFS) and overall survival (OS) of patients with resectable cervical cancer. Overall, 22 publications encompassing 5627 patients fulfilled the inclusion criteria. We found NACT not to affect both 3-year PFS and OS as well as 5-year PFS of patients with resectable cervical cancer. However, NACT significantly improves the 5-year OS of patients with resectable cervical cancer (HR = 0.83, 95% CI: 0.73–0.94, p = 0.013). Subgroup analysis (RCTs, non-RCTs, NACT + surgery + AT vs. surgery + AT, NACT + surgery + AT vs. CCRT/RT/CRT) further revealed NACT had no significant effect on 5-year PFS of patients with resectable cervical cancer, converse to the 5-year OS subgroup analysis, which validated the beneficial effect of NACT in patients with resectable cervical cancer. In addition, the effect of NACT was most significant in the non-RCTs subgroup (p = 0.012). NACT may improve the long-term prognosis of patients with resectable cervical cancer. However, further large-scale multicenter studies are needed to validate this finding.     

Efficacy and prognostic implications of administering adjuvant chemotherapy to patients with endometrial cancer that is confined to the uterus

OBJECTIVE: The purpose of this study was to determine the value of prognostic factors and to assess the efficacy of adjuvant chemotherapy in patients with endometrial cancer confined to the uterus. STUDY DESIGN: Patients surgically stage IB, IC and II endometrial cancer according to the International Federation of Gynecology and Obstetrics were enrolled in this study. Stage IIIA tumors with positive peritoneal cytology, in the absence of other evidence of extra uterine disease, were also included. RESULTS: One hundred and sixty-seven patients fulfilled the eligibility criteria and 58 patients (34.7%) underwent combination chemotherapy. Disease recurrence occurred in 10 patients within a median time of 17 months. Histologic grade 3 was an independent prognostic factor for both disease-free and overall survival rates. Fourteen of 23 patients with histologic grade 3 tumors received adjuvant chemotherapy consisting of cyclophosphamide (or etoposide), epirubicin and cisplatin (in 1989-1999) or paclitaxel, pirarubicin and carboplatin (in 2000-2002). The 5-year disease-free and overall survival rates for these individuals was 92.3%, a value significantly higher than those in patients who had not undergone chemotherapy (50.0%). CONCLUSIONS: Histologic grade of 3 is an independent prognostic marker in patients with endometrial cancer confined to the uterus and adjuvant chemotherapy might improve the survival rates in these patients.     

Phase I trial of paclitaxel, doxorubicin, and carboplatin (TAC) for the treatment of endometrial cancer

Doxorubicin, platinum compounds, and taxanes represent the chemotherapeutic agents with the greatest activity in endometrial cancer. We conducted an optimal-dose determination of combination chemotherapy consisting of paclitaxel (TXL), doxorubicin, and carboplatin (CBDCA) (TAC) in patients with endometrial cancer. Patients with epithelial endometrial cancer requiring adjuvant therapy were enrolled between June 2003 and March 2005. No patients had received prior radiotherapy, and only two patients had previously undergone chemotherapy. Doxorubicin was infused on day 1, and TXL followed by CBDCA was administered on day 2. The starting dose was doxorubicin 35 mg/m(2), TXL 120 mg/m(2), and CBDCA area under the curve (AUC). The dose of each agent was gradually escalated. Patients were scheduled to receive at least four cycles of therapy. If patients experienced grade 4 neutropenia or neutropenic fever with grade 3 neutropenia, they were permitted to be administered granulocyte colony-stimulating factor after the second course. Twenty-seven patients were enrolled. Although four patients out of 27 experienced dose-limiting toxicities, a maximum tolerated dose was not established at the final dose level. Five patients (three for recurrent and two for advanced) had measurable lesions. There were four responders (three for partial response and one for complete response) in our series. The recommended dose of TAC therapy for endometrial cancer was doxorubicin 45 mg/m(2) for day 1, TXL 150 mg/m(2) and CBDCA AUC 5 for day 2.     

Cost effectiveness of neoadjuvant chemotherapy followed by interval cytoreductive surgery versus primary cytoreductive surgery for patients with advanced stage ovarian cancer during the initial treatment phase

Objective

Advanced stage epithelial ovarian cancer (AEOC) can be treated with either neoadjuvant chemotherapy (NACT) or primary cytoreductive surgery (PCS). Although randomized controlled trials show that NACT is non-inferior in overall survival compared to PCS, there may be improvement in short-term morbidity. We sought to investigate the cost-effectiveness of NACT relative to PCS for AEOC from the US Medicare perspective.

Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregnancy: a series of nine cases and literature review

Objective

Treatment of locally invasive cervical cancer diagnosed during pregnancy in women who desire to retain their pregnancy is a major challenge to physicians. Neoadjuvant chemotherapy followed by radical hysterectomy has been reported to be an attractive option to delay delivery until fetal viability has been reached.

Methods

Between 1994 and 2009 9 patients were treated at San Gerardo Hospital (Monza, Italy) for cervical cancer during pregnancy.

Results

FIGO stage was IB1 in four patients and IB2 in five. Tumor diameter ranged between 20 and 70 mm. After neoadjuvant platinum-based chemotherapy partial response was achieved in 5 patients, while 4 had a stable disease. One patient received a second-line chemotherapy during pregnancy due to progressive disease, achieving a partial response. Median duration of therapy delay until cesarean section was 16 weeks. Between 30 and 36 weeks of gestation all patients underwent cesarean section. Piver II radical hysterectomy with pelvic lymphadenectomy was performed. Two children had mild perinatal morbidities and were discharged in good conditions after 14 and 40 days. Three patients received adjuvant therapy for pathological risk factors. Four patients relapsed (44%) and two of them (23%) died because of tumor progression.

Conclusion

During pregnancy, the oncological outcome of cervical cancer patients is similar to non-pregnant ones. Chemotherapy does not seem to affect fetal health and development, even if longer follow-up is required. Therefore, neoadjuvant chemotherapy for the treatment of locally invasive cervical cancer during pregnancy seems to be a reasonable option for delay definitive treatment until fetal viability is obtained.     

Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: A Phase II study of the Gynecologic Oncology Group

OBJECTIVES: The search for effective systemic chemotherapy for endometrial cancer is ongoing. Complete responses to current drugs or regimens are infrequent, and overall survival for patients with disease not amenable to surgery or radiation therapy is poor. Dactinomycin has proven activity against a wide variety of solid tumors but has not been tested against endometrial cancer. Using pharmacokinetic data supporting an intermittent, single-dose schedule, this Phase II Gynecologic Oncology Group study was conducted to determine the antitumor activity and toxicity of dactinomycin in patients with persistent or recurrent endometrial adenocarcinoma. METHODS: Eligibility was limited to patients with measurable disease, adequate renal, hepatic, and bone marrow function, and no more than one prior chemotherapy regimen. Treatment consisted of 2 mg/m(2) slow intravenous push of dactinomycin over 15 min with courses repeated every 4 weeks. RESULTS: A total of 27 patients were entered in this study between April 1996 and September 1996; all were evaluable for toxicity and 25 were evaluable for response. Overall, 12/25 (48%) patients had received prior radiation therapy and all had received prior chemotherapy. Sites of measurable disease were pelvis (9 patients) and distant (16 patients). There was 1 complete response and 2 partial responses for an overall objective response rate of 12%. Aside from emesis (grade 3, 2 patients; grade 4, 2 patients) significant nonhematologic toxicity was rare. The most common toxicity was neutropenia (grade 3, 2 patients; grade 4, 10 patients). CONCLUSION: Toxicity was deemed acceptable but the limited effectiveness of dactinomycin precludes further clinical development in this patient population.     

Immunohistochemical expression of Annexin A2 and S100A proteins in patients with bulky stage IB-IIA cervical cancer treated with neoadjuvant chemotherapy

Objective

Abnormal expression of Annexin A2 and S100A proteins has been reported to induce sensitivity/resistance to chemotherapy in a variety of cancers. The aim of this study was to evaluate the significance of Annexin A2 and S100A protein expression to predict response to neoadjuvant chemotherapy and prognostic significance of these protein expressions in bulky stage IB-IIA cervical cancer patients.

Methods

Paired tumor samples (pre- and post-chemotherapy) were obtained from 68 patients who were treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy at our hospital from 2006 to 2011. The expression of Annexin A2 and S100A proteins was analyzed by immunohistochemistry.

Results

Thirty-six patients were identified as chemotherapy-response and 32 were non-response. (a). Protein expression in tumor cells: (1). Exposure of tumor cells to chemotherapy results in a change of Annexin A2 and S100A expression (P < 0.05). (2). Annexin A2, S100A8 and S100A9 protein expression correlates with tumor response to chemotherapy (P < 0.05). (b). Protein expression in stromal cells: (1). Expression of Annexin A2, S100A8 and S100A9 was increased, but S100A2 and S100A4 was decreased after exposure to chemotherapy (P < 0.05). (2). Only S100A4 expression was associated with response to chemotherapy (P < 0.05). Multivariate analysis revealed that tumor size (P = 0.022), differentiation (P = 0.000), Annexin A2 expression in stromal cells (P = 0.009), and S100A8 expression in tumor cells (P = 0.008) were independent prognostic factors for progression-free survival of cervical cancer patients.

Conclusions

Expression of some of the measured proteins in tumor and stromal cells correlates with chemotherapy exposure, response to therapy, and progression-free survival.     

Postoperative vaginal brachytherapy alone is the treatment of choice for grade 1–2, stage IC endometrial cancer

The aim was to determine outcome and toxicity in grade 1-2, FIGO stage IC endometrial cancer patients treated with external beam radiotherapy plus vaginal cuff brachytherapy or vaginal cuff brachytherapy alone. Between 1986 and 1999, a total of 132 patients were diagnosed with FIGO stage IC endometrial carcinoma. The median age was 67.5 years (range, 36-88). Median follow-up was 54 months (range, 6-157). Grade 1 disease was present in 64 patients, grade 2 in 45 patients, and grade 3 in 23 patients. Patients with grade 3 disease usually received external radiotherapy and were excluded from this analysis. Of the patients with grade 1-2 disease, 31 received brachytherapy alone and 78 received both external radiotherapy and brachytherapy. Ten (8%) patients experienced failure. Isolated pelvic relapse occurred in five patients. Three patients experienced both distant and local relapse. Two patients had isolated distant relapse. Nine failures occurred in patients treated with both external radiotherapy and brachytherapy. Only one failure occurred in those treated with brachytherapy alone. Overall survival and disease-free survival at 5 years were 85% and 92%, respectively. For those treated with both external radiotherapy and brachytherapy, 5-year locoregional control was 95%. For those treated with brachytherapy alone, 5-year locoregional control was 96.4%. There was no significant survival or local control difference between the two groups. Nine patients (9%) treated with both external radiotherapy and brachytherapy developed Radiation Therapy Oncology Group grade 3-4 toxicity. No patient treated with vaginal cuff brachytherapy alone developed grade 3-4 toxicity (P < 0.001). In patients with well-differentiated (grade 1-2) stage IC endometrial cancer, external beam radiotherapy plus brachytherapy versus vaginal cuff brachytherapy alone achieved equivalent local control and survival. However, vaginal cuff brachytherapy alone produced significantly less toxicity.     

Optimizing the treatment of ovarian cancer: Neoadjuvant chemotherapy and interval debulking versus primary debulking surgery for epithelial ovarian cancers likely to have suboptimal resection

Objective

To: a) identify prognostic factors in patients with epithelial ovarian cancer treated with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS), and b) compare post-surgical survival between patients treated with NACT/IDS for presumed unresectable disease and stage IIIC/IV patients who underwent suboptimal primary debulking surgery (PDS).

Role of salvage cytoreductive surgery in the treatment of patients with recurrent ovarian cancer after platinum-based chemotherapy

OBJECTIVES: The role of cytoreductive surgery, which is well established in the primary treatment for epithelial ovarian cancer, is controversial in recurrent disease. The aim of this study was to assess the clinical benefit of salvage surgical cytoreduction in patients with recurrent ovarian cancer after platinum-based chemotherapy. METHODS: We conducted a retrospective analysis of 46 patients with recurrent epithelial ovarian cancer treated at our department between 1988 and 2003. Twenty-three patients underwent salvage cytoreductive surgery (cytoreductive group), and the other 23 patients were treated without surgery (control group). RESULTS: Patients in cytoreductive group had a median survival of 41.7 months after recurrence, which was significantly longer than control group (18.8 months; P < 0.01). The duration of stay at home and the period oral intake was preserved were significantly longer in the cytoreductive group. In the cytoreductive group, survival was influenced by the residual disease after surgery (residual tumor diameter, <2 cm vs >2 cm; median survival, 50 months vs 35.2 months; P < 0.05). However, the number of recurrent sites (solitary vs multiple) and the lengths of treatment-free intervals after primary treatment (<6 months vs >6 months) showed no significant influence on survival. CONCLUSIONS: The application of cytoreductive surgery might improve the prognosis of patients with recurrent ovarian cancer if the tumor was resectable. Preserved prognoses of platinum-resistant disease with short treatment-free interval demonstrated in this study suggest that the concept of maximum cytoreduction might be introduced in the treatment of recurrent disease in the future.     

Comparison of laparoscopic surgery and conventional laparotomy for surgical staging of patients with presumed low-risk endometrial cancer: The current state of Japan

Objective

National health insurance coverage for the laparoscopic staging surgery for patients with stage IA endometrial cancer started from April 2014 in Japan. We conducted this retrospective study to evaluate the surgical outcomes of the laparoscopic surgery for patients with low-risk endometrial cancer compared with those of the laparotomy.

Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study

PURPOSE: To determine overall survival and progression-free survival among patients with high-risk, stage III and IV endometrial cancer who receive paclitaxel and carboplatin (TC) after complete tumor resection. PATIENTS AND METHODS: Patients with stage III/IV endometrial cancer with less than 2 cm of disease after surgical resection who received TC in the adjuvant setting were retrospectively identified and are the subject of this analysis. Data were extracted from electronic medical records. Disease recurrence was documented by radiologic progression or pathologic tissue review. We obtained Institutional Review Board approval before initiating this study. RESULTS: Forty-eight patients were eligible for analysis--24 (50%) with stage IV disease, 29 (60%) with serous or clear cell tumor histology and 43 (90%) with FIGO grade 3 tumors. All patients underwent surgical resection; 10 (21%) of the 48 patients received adjuvant radiation therapy in addition to chemotherapy. Forty-three patients (90%) received 6 cycles of paclitaxel (175 mg/m(2)) and carboplatin (area under the curve of 5-6) every 3 or 4 weeks, and 44 (92%) completed all planned cycles of treatment. With a median follow-up of 20 months (range, 6-92), 29 patients (60%) recurred, with a 3-year overall survival rate of 56%. The median time to progression for all patients was 13 months (95% CI 10, 18) with a median OS of 47 months (95% CI, 30--upper limit not achieved). CONCLUSION: TC is a well tolerated, active regimen in the treatment of resected, high-risk stage III and IV endometrial cancer that warrants further investigation.