Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02).

OBJECTIVE: Rikkunshito, an herbal medicine, is widely prescribed in Japan for the treatment of anorexia and functional dyspepsia, and has been reported to recover reductions in food intake caused by cisplatin. We investigated whether rikkunshito could improve chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients treated with cisplatin. METHODS: Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m² day 1) and paclitaxel (135 mg/m² day 0) as first-line chemotherapy were randomly assigned to the rikkunshito group receiving oral administration on days 0-13 with standard antiemetics, or the control group receiving antiemetics only. The primary endpoint was the rate of complete control (CC: no emesis, no rescue medication, and no significant nausea) in the overall phase (0-120 hours). Two-tailed p<0.20 was considered significant in the planned analysis. RESULTS: The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group (57.9% vs. 35.3%, p=0.175), as were the secondary endpoints: the CC rate in the delayed phase (24-120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed phases (63.2% vs. 35.3%, p=0.095; 84.2% vs. 52.9%, p=0.042; 84.2% vs. 52.9%, p=0.042, respectively), and time to treatment failure (p=0.059). Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6. CONCLUSION: Rikkunshito provided additive effect for the prevention of CINV and anorexia.

Relationship between removal of circumflex iliac nodes distal to the external iliac nodes and postoperative lower-extremity lymphedema in uterine cervical cancer.

OBJECTIVE: This study aimed to determine if there is a causal relationship between removal of the circumflex iliac nodes distal to the external iliac nodes (CINDEIN) and postoperative lower-extremity lymphedema (POLEL) after systematic lymphadenectomy in patients with cervical cancer. METHODS: A retrospective chart review was performed for all living cervical cancer patients who underwent lymphadenectomy and were managed at Hokkaido Cancer Center between 1993 and 2013. The type of lymphadenectomy gradually shifted from lymphadenectomy with removal of CINDEIN to without CINDEIN dissection during this period. The study period was divided into two phases: from 1993-2007 (first phase) and from 2008-2013 (second phase). We identified patients with POLEL. Logistic regression analysis was used to select the risk factors for POLEL. RESULTS: Implementation of CINDEIN-dissection lymphadenectomy (94.0% vs. 20.6%, p<0.0001) and adjuvant radiotherapy (26.1% vs. 4.5%, p<0.0001) was significantly higher in the first phase than in the second phase. Of 398 patients evaluated, POLEL was noted in medical records of 80 (20.1%) patients with a median follow-up period of 78.0months. The occurrence rate of POLEL was significantly higher in the first phase than in the second phase (32.2% vs. 8.0%, p<0.0001), despite no change in the number of dissected lymph nodes between the two phases. Multivariate analysis showed that adjuvant radiation therapy (odds ratio=2.6, 95% confidence interval=1.4-4.8) and removal of CINDEIN (odds ratio=4.6, 95% confidence interval=2.4-9.0) were independent risk factors for POLEL. CONCLUSION: Elimination of CINDEIN dissection is helpful for reducing the incidence of POLEL.

Close relationship between removal of circumflex iliac nodes to distal external iliac nodes and postoperative lower-extremity lymphedema in uterine corpus malignant tumors.

OBJECTIVE: The aim of this study was to confirm a causal relationship between removal of circumflex iliac nodes to the distal external iliac nodes (CINDEIN) and lower-extremity lymphedema after systematic lymphadenectomy in patients with uterine corpus malignancies. METHODS: A retrospective chart review was carried out for all patients with uterine corpus malignant tumor managed at Hokkaido Cancer Center between 1991 and 2013. All 318 patients underwent CINDEIN dissection as a part of initial surgery and 217 patients did not. Patients had undergone hysterectomy, bilateral salpingo-oophorectomy and lymphadenectomy and their medical records were reviewed. The type of lymphadenectomy gradually shifted from pelvic lymphadenectomy with removal of CINDEIN to full lymphadenectomy without CINDEIN dissection during this period. We identified patients with postoperative lower-extremity lymphedema (POLEL). Logistic regression analysis was used to select the risk factors for POLEL. RESULTS: Of 535 patients evaluated, POLEL was noted in the medical records of 126 patients (23.6%), with median follow-up of 71months. The occurrence of POLEL was significantly higher in the CINDEIN-dissection group than in the CINDEIN-sparing group (34.3% vs. 7.8%, P<0.0001). Multivariate analysis confirmed that adjuvant radiation therapy [odds ratio (OR)=6.3, 95% confidence interval (CI)=2.6-14.9], resection of more than 31 lymph nodes (OR=2.0, 95% CI=1.2-3.5), and removal of CINDEIN (OR=5.4, 95% CI=3.1-9.3) were independent risk factors for POLEL. CONCLUSIONS: Elimination of CINDEIN dissection can be helpful in reducing the incidence of POLEL.

Availability of tissue rinse liquid-based cytology for the rapid diagnosis of sentinel lymph node metastasis and improved bilateral detection by photodynamic eye camera.

OBJECTIVE: On sentinel lymph node navigation surgery for early invasive cervical cancers, to gain high sensitivity and specificity, the sentinel nodes should be detected bilaterally and pathological diagnosis should be sensitive to detect micrometastasis. To improve these problems, we tried tissue rinse liquid-based cytology and the photodynamic eye. METHODS: From 2005 to 2013, 102 patients with Stage Ib1 uterine cervical cancer were subjected to sentinel lymph node navigation surgery with Technetium-99 m colloid and blue dye. For the recent 11 patients with whom bilateral sentinel node detection was not available, the photodynamic eye was selectively examined. The detected sentinel node was cut along the minor axis into 2 mm slices, soaked in 10 ml CytoRich red and then subjected to tissue rinse liquid-based cytology at the time of surgery. RESULTS: With the accumulation of 102 Ib1 patients subjected to sentinel lymph node navigation surgery, the bilateral sentinel node detection rate was 67.7%. The photodynamic eye was examined for the recent 11 patients who did not have bilateral signals. Out of the 11, 10 patients obtained bilateral signals successfully. During the period of examining the photodynamic eye, a total of 34 patients were subjected to sentinel lymph node navigation surgery. Thus, the overall bilateral detection rate increased to 97% in this subset. Two hundred and five lymph nodes were available as sentinel nodes. The sensitivity of tissue rinse liquid-based cytology was 91.7%, and the specificity was 100%. False positivity was 0% and false negativity was 8.3%. Detection failure was observed only with one micrometastasis and one case of isolated tumor cells. CONCLUSION: Combination of photodynamic eye detection and tissue rinse liquid-based cytology pathology can be a promising method for more rewarding sentinel node detection.

Incidence of metastasis in the circumflex iliac nodes distal to the external iliac nodes in ovarian cancer.

OBJECTIVE: The circumflex iliac nodes distal to the external iliac nodes (CINDEINs) are included in the regional lymph nodes that are commonly dissected during systematic lymphadenectomy for ovarian cancer. Because in recent years CINDEIN dissection has been reported as a significant risk factor for postoperative lower limb lymphedema, we investigated the validity of omitting the CINDEIN dissection by evaluating the distribution pattern of positive lymph nodes in ovarian cancer, in order to improve postoperative quality of life (QOL). METHODS: We performed a retrospective chart review of 142 patients with ovarian cancer who had undergone systematic lymphadenectomy between 1995 and 2010. We assessed the distribution pattern of lymph node metastasis and the presence of CINDEIN metastasis according to the pT classification (pT1, pT2, and pT3). RESULTS: Of the 142 patients, 71, 21, and 50 were classified into pT1, pT2, and pT3, respectively. The lymph nodes most frequently involved were the para-aortic lymph nodes superior to the mesenteric artery (14%), followed by the obturator nodes (11%), the internal iliac nodes (9.4%), and the common iliac nodes (7.4%). Although the frequency of CINDEIN metastasis was 5.3% (6 of 114 cases with CINDEIN dissection), no metastasis to the CINDEINs was observed in pT1 patients. CONCLUSIONS: It may be acceptable to omit CINDEIN dissection during surgery for pT1 ovarian cancer in view of postoperative QOL.

Previous conization on patient eligibility of sentinel lymph node detection for early invasive cervical cancer.

OBJECTIVE: Sentinel lymph node (SLN) detection has been accepted as a common strategy to preserve the quality of life of the patients with gynecologic cancers. However, the feasibility of SLN detection after conization is not yet clarified. Accuracy of SLN after conization was evaluated. METHODS: Eighteen cases with prior conization (cone group) and 32 cases without conization (noncone group), all of which belonged to IB1 except 1 case in IA stage, underwent SLN detection. Systemic pelvic and para-aortic lymphadenectomy was coincidently performed for the estimation of negative and positive predictive values. RESULTS: Detection rate in which at least unilateral nodes were identified or bilaterally identified was 100% and 72.2% in the cone group, 90.6% and 71.9% in the noncone group, respectively. The average number of the detected SLN was 2.4 in the cone group and 2.1 in the noncone group. Negative and positive predictive value was 100% in both groups. On the distribution of sentinel node stations, most of the detected nodes were internal iliac and obturator node in both groups. Less frequent detection was observed in superficial common iliac node (5.4% in the cone group, 3.1% in the noncone group), external iliac node (2.7% and 9.5%), and parauterine artery node (5.4% and 1.6%).In both groups, no other lymph nodes were identified as SLN except 1 case in the cone group with the node in cardinal ligament. CONCLUSIONS: No significant difference was observed on detection rate, predictive value, and the distribution of sentinel node between the cone and noncone groups. Sentinel lymph node detection after conization can be performed with a certain reliability.

Incidence of metastasis in circumflex iliac nodes distal to the external iliac nodes in intermediate- and high-risk endometrial cancer.

OBJECTIVE: The aim of this study was to elucidate the incidence of metastasis in circumflex iliac nodes distal to the external iliac nodes (CINDEIN), which are also called suprainguinal nodes, in intermediate- and high-risk endometrial cancer. Removal of these nodes needs to be discussed from the viewpoint of patient's quality of life because removal of CINDEIN is strongly related to lower extremity lymphedema. METHODS: A retrospective chart review was carried out for 508 patients with intermediate- and high-risk endometrial cancer who were included in this study. We identified patients with lymph node metastasis. Lymph node sites were classified into four groups: (1) CINDEIN, (2) external iliac nodes, (3) Group A consisting of circumflex iliac nodes to the distal obturator nodes, internal iliac nodes, obturator nodes, cardinal ligament nodes (including deep obturator nodes), and sacral nodes, and (4) Group B consisting of common iliac nodes and para-aortic nodes. Logistic regression analysis was used to select risk factors for CINDEIN metastasis. RESULTS: In an analysis of 508 patients with intermediate- and high-risk disease, CINDEIN metastasis was found in fourteen (2.8%) of the patients. Multivariate analysis confirmed that high-risk histology (OR=5.7, 95% CI=1.2-16.1) and Group A node metastasis (OR=9.7, 95% CI=2.9-31.4) were independent risk factors for CINDEIN metastasis. None of the patients with G1 endometrioid adenocarcinoma had CINDEIN metastasis. Three (2.5%) of the patients with G2 endometrioid adenocarcinoma had CINDEIN metastasis and all of these three patients had other pelvic node metastasis. CONCLUSION: Removal of CINDEIN can be eliminated in patients with G1 endometrial cancer and patients with G2 endometrial cancer who have no pelvic node metastasis.

Risk factors for lower-limb lymphedema after surgery for cervical cancer.

BACKGROUND: Lower-limb lymphedema (LLL) is a prevalent complication that is encountered after treatment for gynecological malignancies. The aim of this study was to evaluate the risk factors for postoperative LLL in patients with cervical cancer. METHODS: We conducted a retrospective chart review for patients who had undergone surgery, including systematic lymphadenectomy, for cervical cancer. Patients who died of cancer, were evaluated for short periods of time (<2 years), had missing medical records, or were suffering from deep venous thrombosis were excluded. We utilized the International Society of Lymphology staging of lymphedema severity as the diagnostic criteria for LLL, and patients with stage II or III lymphedema, as objectively determined by physicians, were included in the group of patients with LLL. Multivariate analysis was performed to confirm independent risk factors. RESULTS: A total of 155 patients with cervical cancer were evaluated. Thirty-one patients (20.0%) contracted LLL with a median follow-up of 6.1 years. Suprafemoral node dissection (odds ratio, 9.5; 95% confidence interval, 1.2-73.3; P = 0.031) and adjuvant radiotherapy (3.7; 1.2-10.9; P = 0.019) were identified as independent risk factors. CONCLUSION: Given that the effectiveness of the above two therapeutic options for cervical cancer is currently controversial, the clinical benefits of these therapies should be reevaluated specifically to conserve the quality of life for patients with this disease.

Risk factors for postoperative lower-extremity lymphedema in endometrial cancer survivors who had treatment including lymphadenectomy.

OBJECTIVE: The aim of this study was to determine the incidence rate of lower-extremity lymphedema after systematic lymphadenectomy in patients with uterine corpus malignancies and to elucidate risk factors for this type of lymphedema. METHODS: A retrospective chart review was carried out for all patients with uterine corpus malignant tumor managed at Hokkaido Cancer Center between 1991 and 2007. Patients who did not undergo lymphadenectomy as a treatment or died of cancer/intercurrent disease were excluded from this study. All living patients included in this study had hysterectomy, bilateral salpingo-oophorectomy and lymphadenectomy and their medical records were reviewed. We identified patients with postoperative lower-extremity lymphedema (POLEL). Logistic regression analysis was used to select the risk factors for POLEL. RESULTS: Of 286 patients evaluated, 103 (37.8%) had POLEL. Multivariate analysis confirmed that adjuvant radiation therapy (OR=5.2, 95% CI=2.1-12.7), resection of more than 31 lymph nodes (OR=2.6, 95% CI=1.4-4.9), and removal of circumflex iliac nodes to the distal external iliac nodes (CINDEIN) (OR=6.1, 95% CI=1.3-28.2) were independent risk factors for POLEL. CONCLUSION: Adjuvant radiation therapy should be avoided in patients who undergo systematic lymphadenectomy if an alternative postoperative strategy is possible. Although reducing the number of resected lymph nodes is not appropriate from a therapeutical point of view, elimination of CINDEIN dissection may be helpful in reducing the incidence of POLEL. The clinical significance of CINDEIN dissection needs to be investigated by a randomized controlled trial.

Survival and failure pattern of patients with endometrial cancer after extensive surgery including systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy.

We investigated the survival and the failure pattern of 288 patients with endometrial cancer treated with extensive surgery including systematic pelvic and para-aortic lymphadenectomy followed by cisplatin-based chemotherapy from 1982 to 2002. We correlated the failure pattern with various clinicopathologic factors to find the predictors of recurrence sites. The 5-year overall survival rates were 97.5% for stage I, 87.5% for stage II, 85.2% for stage III, and 12.5% for stage IV. Notably, the 5-year survival rate was 76.5% for patients with stage IIIC disease. Among patients with a low risk (n = 92) for recurrence who received no adjuvant chemotherapy, 2 (2.2%) showed recurrent disease. Among those with intermediate (n = 98) and high (n = 98) risks for recurrence who received adjuvant chemotherapy, 9 (9.2%) and 20 (20.4%) showed recurrent disease, respectively. The recurrence sites were described as follows: distant (n = 12), vaginal (n = 8), peritoneal (n = 7), pelvic (n = 2), and lymphatic (n = 2). Lymphatic failure was found beyond the area of lymphadenectomy. Architectural and nuclear grades; myometrial, lymph-vascular space, and cervical invasions; and lymph node metastasis were predictors of distant failure. Cervical invasion and lymph node metastasis were predictors of vaginal failure. For patients with stage I/II cancer, the architectural and nuclear grades were related to distant failure. Seven (63.6%) of 11 patients with a low or intermediate risk survived after relapse, whereas only 1 (4.8%) of 21 patients with a high risk survived after a recurrence. We conclude that we need to further test the efficacy of systemic adjuvant therapy using new chemotherapeutic regimens to prevent distant failure and to improve the survival of patients with endometrial cancer.