Kohei Omatsu

Neoadjuvant chemotherapy followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for Stage IB2-IIB cervical cancer—Irinotecan and platinum chemotherapy

OBJECTIVE To evaluate the effectiveness of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for stage IB2-IIB cervical cancer. METHODS Forty-six consecutive patients with stage IB2-IIB cervical cancer were treated with NAC followed by radical hysterectomy plus postoperative chemotherapy. Median (range) body mass index (BMI) of the patients was 20.2 (16.2-26.4). Regimens for NAC and postoperative chemotherapy were irinotecan and cisplatin (CPT-11/CDDP) or CPT-11 and nedaplatin (CPT-11/NDP). A total of six cycles of NAC and postoperative chemotherapy were prescribed. No use of radiotherapy was scheduled, except in the case of a recurrence. RESULTS With a median follow-up period for survivors of 38.8 months (range 24-54 months), the 2- and 3-year progression-free survival rates were 91.2% and 86.1%, respectively. Overall response rate of NAC was 80.4%. Recurrence was observed in seven patients. In the absence of radiotherapy, pelvic recurrence was observed in only three patients; another two had para-aortic lymph nodes and the remaining two distant metastases. Toxicities due to chemotherapy were generally tolerable. Postoperative complications included urinary fistula (four patients, 8.7%) and bowel obstruction (two patients, 4.3%), all of which required surgical intervention. CONCLUSION The results indicate that NAC followed by surgery plus postoperative chemotherapy but no radiotherapy offers a viable option in the treatment of stage IB2-IIB cervical cancer. Although a relatively large incidence of postsurgical complications was observed among low-BMI patients, this treatment offers the advantage of minimizing radiation-induced morbidity, allowing radiotherapy to be reserved for the possible event of pelvic recurrence.

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma

BACKGROUND To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: an analysis of fully staged patients.

Objective Although postoperative adjuvant chemotherapy is generally recommended for early-stage ovarian cancer, it remains unclear whether adjuvant chemotherapy is also effective for clear cell carcinoma (CCC). Methods Seventy-three patients with stage I CCC of the ovary who had undergone complete surgical staging formed the study population (stage IA, 20 patients; stage IC, 53 patients). Survival and multivariate analyses were retrospectively performed to determine the effectiveness of postoperative chemotherapy in these patients. Results Of the total (73 patients), 30 patients received adjuvant chemotherapy (stage I C-positive), whereas 43 patients did not (stage I C-negative). The 5-year progression-free survival (PFS) and 5-year overall survival (OS) rates for the stage I C-positive group were 80.1% and 87.4% compared with 73.9% and 81.7% for the stage I C-negative group. The differences in survival between these groups were not significant (PFS: P = 0.610; OS: P = 0.557). Four of the patients with stage IA CCC underwent chemotherapy, whereas the remaining 16 patients received no additional therapy. No recurrence was observed in either group. Of the patients with stage IC CCC, 26 patients underwent chemotherapy (stage IC C-positive) and 27 received no additional therapy (stage IC C-negative). There was no statistical difference in PFS and OS between the stage IC C-positive and stage IC C-negative groups. Of the patients with stage IC without artificial rupture, the 5-year PFS rates of the C-positive and C-negative patients were 69.6% and 34.6%, respectively, but the 5-year OS rates were 75.0% and 70.0%, respectively (not significant). Multivariate analyses confirmed that the presence or absence of adjuvant chemotherapy was not a prognostic indicator. Conclusions The current study was performed only in fully staged patients, suggesting that postoperative adjuvant chemotherapy is not necessary for stage IA CCC patients. For patients with stage IC CCC patients, adjuvant chemotherapy suppressed recurrence, but the effectiveness was insufficient in our limited study. Further studies are required to clarify this.

Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma

BACKGROUND To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma

OBJECTIVE To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

Clinicopathologic features and treatment outcomes of primary extramammary Paget disease of the vulva.

Objective The aim of this study was to identify the clinicopathologic features and treatment outcome of primary extramammary Paget disease of the vulva (EMPDV). Materials and Methods We performed a retrospective analysis of 14 patients who were treated at our center from April 1994 to November 2010. Results The mean age of patients in our sample was 64.4 years (range = 47–83 y). We observed intraepithelial and invasive EMPDV in 11 (78.6%) and 3 (21.4%) patients, respectively. Moreover, we observed a positive incision margin in 9 patients (64.3%). During a median follow-up period of 69.5 months (range = 32–221 mo), we observed recurrence in 3 patients (21.4%), 2 of whom had invasive EMPDV and 1 had intraepithelial EMPDV. Time to recurrence was 16 and 18 months for patients with invasive EMPDV and 98 months for patients with intraepithelial EMPDV. The recurrence rate of intraepithelial EMPDV and invasive EMPDV was significantly different (9.1% and 66.7%, respectively, p < .028). Local recurrence occurred in all 3 patients, necessitating further surgical resection. One patient with recurrence of invasive EMPDV received adjuvant radiotherapy but died 101 months after the initial treatment. The other 2 patients remained alive without recurrence. We did not observe distant recurrence. Conclusions The recurrence rate of invasive EMPDV was high. However, because distant metastasis is rare, repeat surgical excision for recurrent EMPDV and long-term observation are necessary for a good prognosis.

Recurrence patterns of advanced ovarian, fallopian tube, and peritoneal cancers after complete cytoreduction during interval debulking surgery.

Objectives Similar to primary debulking surgery, complete resection of all macroscopic diseases during interval debulking surgery (IDS) is the primary objective while using neoadjuvant chemotherapy followed by IDS for advanced ovarian, fallopian tube, and peritoneal cancers. However, most patients develop recurrent disease even after complete cytoreduction during IDS. This study aims to identify recurrence patterns of the ovarian, fallopian tube, and peritoneal cancers in patients who underwent complete cytoreduction during IDS. Methods We retrospectively reviewed data of patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers who were treated at our hospital from January 1, 2005, to December 31, 2011. Results In this study, 105 patients underwent neoadjuvant chemotherapy followed by IDS and achieved complete cytoreduction. The median follow-up period was 42.1 months. Recurrence was documented in 70 patients (66.7%), and 35 (33.3%) showed no evidence of disease. Peritoneal dissemination was the most common recurrence (60.0%) observed. In multivariate analysis, positive peritoneal cytology (P = 0.0003) and elevated pre-IDS serum CA125 levels (P = 0.046) were independent risk factors for recurrence. Conclusions After complete cytoreduction during IDS in patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers, positive peritoneal cytology at IDS and elevated pre-IDS CA125 levels are associated with an increased risk of cancer recurrence. Positive peritoneal cytology during IDS is a particularly strong predictive factor for poor outcomes in these patients.

Platinum-free interval in second-line chemotherapy for recurrent cervical cancer.

Objective The purpose of this study was to determine whether the platinum-free interval (PFI) was a predictive indicator in second-line treatment of cervical cancer in patients who had undergone prior platinum-based chemotherapy. The role of the PFI in selecting the second-line regimen in other gynecologic malignancies is also discussed. Methods In this retrospective study, we examined the clinical records of patients with recurrent or metastatic cervical cancer who had received platinum-containing combination regimens as second-line chemotherapy. All patients had received prior platinum-containing chemotherapy or concurrent chemoradiotherapy. Results The overall response rate to second-line chemotherapy was 25.8%; 7 patients achieved a complete response and 17 a partial response. The median progression-free survival (PFS) was 5.1 months and median overall survival (OS) was 13.5 months. The response rate was 12.5%, 14.2%, 20.0%, 22.2%, and 55.0%; median PFS was 4.0, 5.1, 4.4, 5.8, and 7.4 months; and median OS was 10.2, 14.4, 11.9, 16.3, and 19.7 months when PFI was within 3, 3 to 5, 6 to 11, 12 to 23, and more than 24 months, respectively. Age (>50 years), size (>3 cm), prior radiotherapy, and PFI (>24 months) were identified as prognostic factors in the multivariate analysis for PFS and OS. Conclusions The results indicate that a PFI of more than 24 months is the discriminating point between platinum-sensitive and platinum-resistance cervical cancer. This indicates that PFI offers a useful tool in selecting agents for second-line chemotherapy in a wide range of gynecologic malignancies.

Survival outcome of women with stage IV uterine carcinosarcoma who received neoadjuvant chemotherapy followed by surgery

To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy.

Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma

OBJECTIVE To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P<0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P=0.02). When stratified by disease-free interval, women with a disease-free interval ≥6months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P=0.002); conversely, in women with a disease-free interval <6months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P=0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P=0.019). CONCLUSION Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6months.