Takeo Otsuki

Evidence-based guidelines for treatment of cervical cancer in Japan: Japan Society of Gynecologic Oncology (JSGO) 2007 edition

Clinical practice guidelines for gynecologic cancers have been published by the National Comprehensive Cancer Network and the National Cancer Institute. Whereas these guidelines form the basis for the standard of care for gynecologic malignancies in the United States, it has proven difficult to institute them in Japan due to differences in patient characteristics, health-care delivery systems, and insurance programs. Therefore, evidence-based guidelines for treating cervical cancer specifically in Japan have been under development. The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer. Opinions from within and outside the Japan Society of Gynecologic Oncology (JSGO) were incorporated into the final draft, and the guidelines were published after approval by the JSGO. These guidelines are composed of ten chapters and comprise three algorithms. Each chapter consists of a clinical question, recommendations, background, objectives, explanations, and references. The objective of these guidelines is to clearly delineate the standard of care for cervical cancer treatment in Japan in order to ensure equitable care for all Japanese women diagnosed with cervical cancer.

Malignant transformation arising from mature cystic teratoma of the ovary: a retrospective study of 20 cases.

Objectives: Mature cystic teratoma (MCT) of the ovary rarely undergoes malignant transformation (MT). Malignant transformation carries a significantly worse prognosis than epithelial ovarian cancer, regardless of whether postoperative chemotherapy or radiotherapy is applied. The rarity of this tumor has posed a significant challenge to developing standardized postoperative management protocols. The aim of this study was to review our experience with MT and to describe our current treatment practices. Methods: A retrospective chart review of these patients was performed that identified 20 women treated for MT of MCT at our centers between 1988 and 2008. Results: The median age was 52.5 (range, 29-77) years. Fifteen patients had squamous cell carcinoma (SCC), and 5 patients had other histological subtypes. The International Federation of Gynecology and Obstetrics stage distribution was as follows: 11 were stage I, 4 were stage II, 4 were stage III, and 1 was stage IV. All patients underwent an initial laparotomy. Eleven patients received adjuvant treatment: 8 were treated with chemotherapy, 2 with concurrent chemoradiation therapy, and 1 with radiation therapy. Platinum-based chemotherapy was the first-line regimen. The overall 1-year survival rate was 70%. Significant correlations between overall survival and age, stage, and residual tumor were presented (P = 0.044, P = 0.0107, P < 0.0001, respectively). Eight patients with advanced stage died of their disease. Four patients, however, were treated with adjuvant chemotherapy or concurrent chemoradiation therapy and survived more than 1 year. One stage III patient had a disease-free interval of 2 years. Two cases of SCC treated with combination platinum/taxane chemotherapy temporarily responded. In the other 2 cases of SCC, concurrent chemoradiation therapy with nedaplatin also resulted in tumor regression. Conclusions: The prognosis of MT is highly dependent on age, stage, and optimal cytoreduction. Adjuvant treatment has not been standardized, although our experience supports the use of combination platinum/taxane chemotherapy.

Diagnosis, clinicopathologic features, treatment, and prognosis of small cell carcinoma of the uterine cervix; Kansai Clinical Oncology Group/Intergroup study in Japan

OBJECTIVES This is a multicenter, collaborative study to accumulate cases of small cell carcinoma of the uterine cervix (SmCC), to clarify its clinical and clinicopathologic features and prognosis, and to obtain findings to establish future individualized treatment. METHODS At medical centers participating in the Kansai Clinical Oncology Group/Intergroup, patients diagnosed with SmCC between 1997 and 2007 were enrolled. Clinicopathologic features and prognosis were retrospectively evaluated in patients with SmCC diagnosed at a central pathologic review. RESULTS A total of 71 patients were registered at 25 medical centers in Japan. Of these, 52 patients (73%) were diagnosed with SmCC based on a pathological review. These 52 patients diagnosed with SmCC were analyzed. The median follow-up period was 57 months. The 4-year progression-free survival (PFS) was: IB1, 59%; IB2, 68%; IIB, 13%; and IIIB, 17%. The 4-year overall survival (OS) was: IB1, 63%; IB2, 67%; IIB, 30%; IIIB, 29%; and IVB, 25%. For postoperative adjuvant therapy, postoperative chemotherapy (a platinum drug in all cases) was compared to non-chemotherapy. The 4-year PFS was 65% and 14%, and the 4-year OS was 65% and 29%. PFS was significantly better (p=0.002), and the OS tended to be better (p=0.073) in the group with postoperative chemotherapy. CONCLUSION Even in patients with early stage SmCC, the prognosis is poor. However, in early stage patients, by adding postoperative chemotherapy, the prognosis may improve. Currently, various treatment protocols are used at each medical center, but in the future, a standardized treatment protocol for SmCC will hopefully be established.

Prospective study of sentinel lymph node biopsy without further pelvic lymphadenectomy in patients with sentinel lymph node-negative cervical cancer.

Objective The aim of the present study was to evaluate the incidence of lymphedema and cancer recurrence rate in patients with cervical cancer who undergo sentinel lymph node (SLN) biopsy alone in the absence of SLN metastases. Patients and Methods The study included 35 consecutive patients with cervical cancer scheduled for radical hysterectomy at Tohoku University Hospital between May 2006 and July 2009. All patients had International Federation of Gynecology and Obstetrics stages IA1 to IIA1 disease. Patients in whom SLNs were detected unilaterally or not detected and/or whose lymph nodes were diagnosed intraoperatively as positive metastasis underwent systemic pelvic lymphadenectomy. Patients who were found negative for SLN metastasis did not undergo further pelvic lymphadenectomy. Results The mean number of detected SLNs was 4.1 (range, 1–11). True lymph node metastasis could be detected in 11 (31%) of the 35 cases. Intraoperative frozen section identified correctly in 8 of 11 metastatic patients. Twenty-three patients underwent SLN biopsy alone without systematic pelvic lymphadenectomy. None of the 23 patients diagnosed with negative SLNs have experienced a lymph node recurrence in the pelvic cavity. New symptomatic lower extremity lymphedema was identified in 2 (8.7%) of the 23 patients who underwent SLN biopsy alone and in 5 (42%) of 12 patients who underwent systematic lymphadenectomy. Conclusion Radical hysterectomy with SLN biopsy alone seems to be a safe and effective strategy for detection of lymph node metastasis and for reducing the number of patients with lower extremity lymphedema, but a more convenient and sensitive procedure for intraoperative diagnosis needs to be established.

Clinicopathologic features of brain metastases from gynecologic malignancies: A retrospective study of 139 cases (KCOG-G1001s trial)

OBJECTIVE Although brain metastases from gynecologic malignancies are rare, such cases have been gradually increasing in number. The aim of the present study was to evaluate the clinicopathologic features and prognostic factors of brain metastases from gynecologic malignancies. METHODS Retrospective analysis of 139 patients with brain metastases from gynecologic malignancies was carried out as a multi-institutional study. The clinicophathological data of the patients were collected from medical records. RESULTS Median survival time of the patients with brain metastases was 12.5 months for the ovarian cancer group, 6.2 months for the corpus cancer group, and 5.0 months for the cervical cancer group; two-year overall survival rates were 19.7%, 6.1%, and 4.8%, respectively. Multivariate analysis revealed ovarian/tubal/peritoneal origin, KPS >70, single brain metastasis, absence of extracranial disease, cranial surgery, cranial radiotherapy, and chemotherapy to be independent favorable prognostic factors associated with overall survival. CONCLUSION It is considered that aggressive multimodal therapy is warranted in the treatment of brain metastases from gynecologic malignancies in carefully selected patients. The present study may provide a platform for the discussion of management strategies in these rare clinical scenarios.

Detection of sentinel lymph node metastases in cervical cancer: Assessment of KRT19 mRNA in the one-step nucleic acid amplification (OSNA) method

OBJECTIVE The purpose of this study was to examine the utility of the one-step nucleic acid amplification (OSNA) assay using cytokeratin (CK) 19 (KRT19) messenger RNA (mRNA) for the detection of sentinel lymph node (SLN) metastases in cervical cancer patients. METHODS To determine a cutoff value, KRT19 mRNA was assessed by OSNA assay using 239 lymph nodes (LNs) (217 histopathologically negative LNs and 22 positive LNs). A cutoff value was determined by statistical analysis of the copy numbers obtained by OSNA assay. Subsequently, performance evaluation of the OSNA assay (applying the cutoff value above) on 130 SLNs (32 patients) was used to investigate (through concordance) whether the OSNA assay exhibited diagnostic performance equivalent to the two-mm interval histopathological examination. RESULTS Two hundred fifty copies/μL of KRT19 mRNA in the OSNA assay appeared to be an optimal cutoff value. In performance evaluation of the OSNA assay, we identified five positive SLNs and 125 negative SLNs by OSNA assay using KRT19 mRNA, exhibiting 96.2% agreement with two-mm interval histopathological examination. CONCLUSIONS Our results indicated that the KRT19 mRNA OSNA assay can detect LN metastases as accurately as two-mm interval histopathological examination and thus may be an effective additional or alternative method for a rapid intra-operative examination of SLNs in cervical cancer.

Individualized radical hysterectomy procedure using intraoperative electrical stimulation for patients with cervical cancer.

Objective In this study, by monitoring the varied distributions of nerve fascicles using intraoperative electrical stimulation (IES), we sought to establish an individualized operation based on the patient’s unique nerve distribution pattern, and to determine whether this technique would result in a higher preservation rate. Materials/Methods Radical hysterectomy was performed from 2002 to 2010. Patients in group A are the 48 cases from 2002 to 2007 in which nerve-sparing radical hysterectomy using IES as our previous report was performed. Patients in group B are the 38 cases from 2008 to 2010 in which we used our new method, which was individualized to each patient. Urodynamic study (UDS) was used to confirm nerve preservation. Nerve preservation was defined as confirming distinct detrusor contraction during urinary voiding. Results In group B, nerve preservation rate was higher than in group A (75% vs 9 0%, P = 0.067). We classified the case-by-case nerve anatomy as whether the nerve fascicle was mainly on the medial side or on the lateral side of the deep uterine vein. The lateral type anatomy was observed unilaterally in 6 cases and bilaterally in 1 case. In summary, the lateral type anatomy was observed in 8 (29%) of 28 sides. In the cases evaluated by UDS, the positive predictive value of IES was 95% in group A and 100% in group B. Conclusions Our method of IES showed a high positive predictive value of nerve preservation as confirmed by UDS. By delineating the nerve tract in detail using IES, it is possible to individualize the operation based on each patient’s anatomy, with an improved nerve preservation rate.

Investigation of the clinicopathological features of fallopian tube malignancy.

The present study investigated the clinico-pathological features of fallopian tube malignancy (FTM) and elucidated the biological behavior of this disorder. Data were compiled concerning FTM from 68 patients from 7 institutes. The patients included 60 cases with fallopian tube carcinoma and 8 cases with fallopian tube carcinosarcoma. The clinical stage was stage III or higher in 72% of the cases. A complete response or partial response was achieved in 56 and 10 of the 68 patients with FTM, respectively, indicating a response rate of 97.1%. The median observation period for FTM was 41 months (3 to 126 months). Three of the 19 patients with stage I/II disease (16%) and 31 of the 49 patients with stage III/IV disease (63%) experienced recurrence, with a median progression-free survival of 17.5 months, and a 3-year overall survival of 77.2%. Regarding the site of recurrence, local intraperitoneal recurrence (26.2%) and solitary recurrences in lymph nodes (19.0%) and in the liver (16.7%) were relatively frequent. Secondary debulking surgery (SDS) was performed in 15 patients (44%) out of the 34 recurrent FTMs. Conversely, recurrence was associated with ascites (carcinomatous peritonitis) in 4 of the 34 recurrent patients, but all 4 patients died. The median survival period after recurrence was 28 months: 7.5 and 30 months with and without ascites, respectively (P<0.001). A univariate analysis showed that prognosis was significantly correlated only with whether SDS could be performed. These results suggest that since FTM frequently results in solitary recurrence, aggressive recurrence treatment including SDS could improve prognosis.

Leptomeningeal metastasis from gynecologic cancers diagnosed by brain MRI

Leptomeningeal metastasis (LM) is rarely observed in gynecologic cancers. As gadolinium-enhanced magnetic resonance imaging (Gd-MRI) is highly effective for diagnosing LM, the aim of this study is to describe the clinical behaviors and outcomes of LM patients who were diagnosed by Gd-MRI. After securing institutional review board approvals, we retrospectively reviewed patient records. Eight patients were found to have LM from gynecological malignancies. Primary tumors included three ovarian cancers, one tubal cancer, one peritoneal cancer, two endometrial cancers, and one cervical cancer. Gd-MRI of the brain and the spine is indicated as the high-priority inspection for the diagnosis of this devastating complication.

Recurrent cerebral infarction synchronous with menorrhagia caused by endometrial stromal sarcoma

A 42-year-old woman developed paraphasia and acalculia on the third day of menstruation. She had a two-year history of periodic menorrhagia, and was diagnosed as having a uterine tumor, suspected to be leiomyoma, whose diameter had enlarged from 1.0 to 7.0 cm in two years. Brain magnetic resonance imaging (MRI) showed an old infarction in the right frontal lobe and a fresh infarction in the left temporoparietal lobe (Fig. 1A,B). She was administered intravenous unfractionated heparin; subsequently, the medication was switched to oral clopidogrel (75 mg/day), resulting in amelioration of her symptoms. At the third day of the next menstruation, she noticed numbness in the left side of her body. Brain MRI showed a small fresh infarction in the right thalamus. As an infarction recurred despite antiplatelet therapy, the clopidogrel was switched to oral dabigatran (110 mg/day). During her next menstruation, the dabigatran was switched to warfarin because of severe menorrhagia. No infarction recurred in this menstrual period. She was then transferred to our hospital to undergo further examinations. On the third day of the next menstruation, she developed dizziness. Brain MRI showed a fresh infarction in the left occipital lobe (Fig. 1C). Whole-body computed tomography (CT) showed a splenic infarction and pulmonary emboli, indicating systemic arterial and venous embolism. Pelvic MRI showed an inhomogeneous mass in the uterine fundus (Fig. 1D,E). At the third stroke, her blood hemoglobin (Hb) level decreased (6.9 g/dl) and Ddimer (17.9 μg/ml; normal range b 1.0) and carboxyhydrate antigen 125 (CA-125) (433 U/ml; normal range b 35) levels increased compared with the levels at the previous menstruation without infarction