Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy.

OBJECTIVE: Gynecologic cancer chemotherapy impacts the quality of life (QOL) of patients, with lasting adverse events that may require treatment adjustments or discontinuation. Consequently, real-time symptom monitoring before outpatient visits has resulted in improved QOL for patients and extended survival times. This study investigated whether there are differences between electronic patient-reported outcomes (e-PRO-CTCAE) and physician-assessed outcomes (NCI-CTCAE) evaluated in an outpatient setting in gynecologic cancer chemotherapy. METHODS: The study was conducted on 50 patients who received their first chemotherapy treatment at St. Marianna University Hospital Obstetrics and Gynecology from July 1, 2021 to December 31, 2022. PRO-CTCAE and NCI-CTCAE were evaluated at each instance of chemotherapy and 2 weeks after. The PRO-CTCAE was additionally collected weekly using e-PRO. RESULTS: The values for "Joint Pain," "Nausea," "Taste Disturbance," "Constipation," "Insomnia," "Fatigue," "Limb Edema," and "Concentration Impairment" were consistently higher in PRO-CTCAE than in NCI-CTCAE, indicating that physicians underestimated the severity of adverse events. In contrast, there was no significant difference in "Peripheral Neuropathy," demonstrating that physicians had a good understanding of this condition in patients. The weekly responses obtained from e-PRO revealed that symptom exacerbations peaked outside of clinic visits. CONCLUSIONS: This study demonstrated physicians tend to underestimate most adverse events. Moreover, the responses using e-PRO revealed peak symptom deterioration occurred outside of outpatient visits. This suggested that e-PRO and actions taken in response to them can improve patients' QOL.

Current state of fertility preservation for adolescent and young adult patients with gynecological cancer.

Although the incidence of the various gynecological cancers has been increasing in recent years, long-term survival is now possible for many patients thanks to advances in multimodality treatment. When treating gynecological cancer in adolescent and young adult (AYA) patients who desire future pregnancy, it is necessary to preserve the reproductive organs and their function to prevent loss of fertility. However, because treatment targets these organs, in the large majority of cases, patients must have these organs removed. In the subfield of oncofertility, treatment of the underlying disease takes priority, and the main principle is preventing delay in treatment. Close cooperation between obstetricians and gynecologists involved in reproductive medicine and oncologists involved in cancer treatment is necessary. In addition, it is important that clinicians work closely not only with other specialists but also with such medical professionals as nurses and counselors so that cancer patients of the AYA generation can be provided the support they need to fight their cancer with hope. Herein, we describe the current status of fertility-sparing therapy for AYA patients with gynecological cancer (cervical cancer, endometrial cancer, or ovarian cancer). In addition, we explain points to keep in mind during a patient's pregnancy after fertility preservation, the latest findings on assisted reproductive technology, and the challenges and prospects of fertility preservation therapy for patients with gynecologic cancer.

Survival and reproductive outcomes after fertility-sparing surgery performed for borderline epithelial ovarian tumor in Japanese adolescents and young adults: Results of a retrospective nationwide study.

OBJECTIVE: Epithelial borderline ovarian tumor (BOT) frequently occurs in young women. Because progression-free survival, overall survival, and reproductive function are important outcomes, BOT is often treated by fertility-sparing surgery (FSS). We conducted a Japan-wide study to understand post-FSS prognosis in relation to clinical characteristics and types of FSS performed. METHODS: We analyzed clinical and outcome data pertaining to 531 adolescent and young adult (AYA) patients (aged 15-39 years) who underwent FSS for BOT between 2009 and 2013. RESULTS: Median (range) age was 30 (15-39) years, and median observation time was 70 (2-120) months. The disease was of FIGO stage I in 492 (93%) patients. Histopathologically, tumors were of the mucinous (n = 372, 70%), serous (n = 120, 23%), seromucinous (n = 23, 4%), and other (n = 16, 3%) types. Five-year overall survival was 99.5% among patients with stage I and 100% among those with stage II-IV. Five-year progression-free survival was 96.7% and 69.3%, respectively. Multivariate analysis in cases of stage I showed a positive peritoneal cytology to be a significant risk factor for recurrence (HR, 5.199; p = 0.0188). The post-FSS pregnancy rate was relatively low for patients aged ≥30 years (OR, 0.868; 95% CI, 1.16-3.00; p = 0.0090). CONCLUSION: Post-FFS outcomes in terms of overall and progression-free survival are favorable, especially for AYA patients with stage I BOT. However, the relapse rate is high for patients with FIGO stage II-IV and for those with stage I but a positive peritoneal cytology. A long-term prospective observation is needed before reproductive outcomes can be fully established.

Value of adjuvant chemotherapy and informed microscopic examination for occult gynecologic cancer detected upon risk-reducing salpingo-oophorectomy after chemotherapy for BRCA1/2-associated breast cancer: a case report.

BRCA1/2 mutation carriers are at high risk for type II ovarian, fallopian tube or peritoneal cancer. Although risk-reducing salpingo-oophorectomy plays an important role in the prevention of these BRCA1/2-associated gynecological cancers, occult ovarian, fallopian tube, or peritoneal cancer is discovered upon risk-reducing salpingo-oophorectomy in 1-4% of BRCA1/2 mutation carriers. Notably, around 30% of BRCA1/2 mutation carriers who undergo risk-reducing salpingo-oophorectomy have undergone adjuvant chemotherapy for breast cancer. We describe the discovery and treatment of occult cancer at the edge of the left fimbria in a BRCA1 mutation carrier who had, just a short time previously, undergone neoadjuvant paclitaxel plus carboplatin (TC) chemotherapy for triple-negative breast cancer. During subsequent risk-reducing salpingo-oophorectomy, a 5.5-mm nodule was observed at the edge of the left fimbria. Microscopic examination of the tumour tissue revealed high-grade serous carcinoma with degenerate tumour cells and fibrosis. Peritoneal fluid was negative for cancer cells. Two months later, hysterectomy, omentectomy and retroperitoneal lymphadenectomy were performed. The final diagnosis was stage FIGO IA fallopian tube cancer. Adjuvant chemotherapy (TC administered every 3 weeks) was applied, and there has been no evidence of recurrence for 5 years. In applying gynecologic surgery and adjuvant chemotherapy, we followed the general recommendation for stage IA fallopian tube cancer. There is no standard strategy for the treatment of occult fallopian tube cancer detected after chemotherapy for BRCA1-associated triple-negative breast cancer. According to our experience in this case, we believe the clinical value of staging laparotomy in cases of a small occult BRCA1/2-associated gynecological cancer should be further investigated.

A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases.

OBJECTIVE: High-grade neuroendocrine carcinoma of uterine cervix (HGNCUC) has been recognized as a highly malignant tumor. Therapeutic strategy specific to neuroendocrine (NE) tumors needs to be considered, but some cases wouldn't allow simple final diagnoses. Insulinoma-associated protein 1 (INSM1), which is a zinc-finger transcription factor related to NE differentiation, is frequently expressed in NE tumors. We investigated the association between INSM1 and HGNCUC, and the possibility of INSM1 as a useful NE marker. METHODS: Thirty-seven cases of formalin-fixed and paraffin-embedded HGNCUCs were evaluated immunohistochemically for conventional NE markers and INSM1. We also surveyed polymerase chain reactions and examined the frequency and the genotype of human papillomavirus (HPV) infections. RESULTS: In HGNCUC, chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) were expressed in 86%, 86% and 68%, respectively. In addition, INSM1 was detected in 95%. Positivity for INSM1 was clearly evaluated histologically, because the intensity of nuclear staining on positive cells was high and nonspecific reactions were minimal. In uni- and multivariate analyses of prognostic factors on stage I and II surgical cases, the association between INSM1 expression and prognosis was insignificant. We confirmed 72% of 29 examined cases had high risk HPV infections (type 16, 14%; type 18, 86%). CONCLUSIONS: This study has clarified that INSM1 is closely related to the development of HGNCUC, and a useful new NE marker in conducting its correct and rapid diagnosis.

The issues regarding postoperative adjuvant therapy and prognostic risk factors for patients with stage I-II cervical cancer: A review.

The treatment for most patients with early-stage cervical cancer involves radical hysterectomy and pelvic lymph node dissection, and indications for postoperative adjuvant therapy have been determined by evaluating the prognostic risk factors for recurrence in each case. The aim of this review is to raise and discuss the various issues that have not yet been resolved regarding the prognostic risk factors and postoperative adjuvant therapy. Several clinicopathological factors, such as tumor size, lymphovascular space involvement, deep stromal invasion, parametrial involvement and lymph node metastasis, have been identified to have prognostic significance in early-stage cervical cancer. However, this remains controversial because there is suggested to be substantial heterogeneity among patients after radical hysterectomy and lymphadenectomy and it would be difficult to define the risk groups clearly. This indicates the need to develop more convenient and accurate criteria to define risk groups. According to the currently available evidence, patients in the high-risk group should receive adjuvant concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) and fluolouracil. However, CCRT with CDDP administered weekly (CCRT-P) has instead been applied in a clinical context worldwide. Whether CCRT-P has a survival benefit compared with radiotherapy (RT) alone is unknown because no randomized phase III trials have been performed for patients in the high-risk group after radical surgery. Patients with high-risk factors have a high incidence of distant metastasis, for whom systemic chemotherapy might be a key to improving overall survival. The pivotal study that investigated the role of RT alone for patients with intermediate-risk factors after hysterectomy is the GOG092 trial. This trial showed a 47% reduction in the risk of recurrence after RT compared with no further treatment (NFT). However, the improvement in overall survival with RT did not reach statistical significance, while patients allocated to the RT group did experience an increase in severe toxicities compared with the NFT group. This could be why many physicians are reluctant to treat patients with this approach, although guidelines recommend RT for patients with intermediate-risk factors. With regard to toxicities, postoperative RT would be problematic because the organs in the pelvis targeted by RT have already been damaged by radical surgery. To reduce the toxicities, intensity-modulated radiotherapy would best be used worldwide. Further improvement in adjuvant therapy will come from enhanced definition of prognostic risk factors, better patient selection, and refinements in both local and systematic therapies.

Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial.

PURPOSE: Olanzapine is effective in chemotherapy-induced nausea and vomiting (CINV). In patients receiving highly emetogenic chemotherapy (HEC), its efficacy was reported as rescue therapy for breakthrough emesis refractory to triplet therapy (palonosetron, aprepitant, and dexamethasone). However, its preventive effects with triplet therapy for CINV are unknown. This study aimed to investigate efficacy and safety of preventive use of olanzapine with triplet therapy for CINV of HEC. METHODS: This study is a prospective multicenter study conducted by Kansai Clinical Oncology Group. Forty chemo-naïve gynecological cancer patients receiving HEC with cisplatin (≥50 mg/m(2)) were enrolled. Oral olanzapine (5 mg) was administered with triplet therapy a day prior to cisplatin administration and on days 1-5. The primary endpoint was complete response (no vomiting and no rescue) rate for the overall phase (0-120 h post-chemotherapy). Secondary endpoints were complete response rate for acute phase (0-24 h post-chemotherapy) and delayed phase (24-120 h post-chemotherapy) and complete control (no vomiting, no rescue, and no significant nausea) rate and total control (no vomiting, no rescue, and no nausea) rate for each phase. These endpoints were evaluated during the first cycle of chemotherapy. RESULTS: Complete response rates for acute, delayed, and overall phases were 97.5, 95.0, and 92.5 %, respectively. Complete control rates were 92.5, 87.5, and 82.5 %, respectively. Total control rates were 87.5, 67.5, and 67.5 %, respectively. There were no grade 3 or 4 adverse events. CONCLUSIONS: Preventive use of olanzapine combined with triplet therapy gives better results than those from previously reported studies of triplet therapy.

Adjuvant chemotherapy versus concurrent chemoradiotherapy for high-risk cervical cancer after radical hysterectomy and systematic lymphadenectomy.

BACKGROUND: The aims of this study were to evaluate the efficacy and toxicity of chemotherapy (CT) compared with concurrent chemoradiotherapy (CCRT) after radical hysterectomy and lymphadenectomy in high-risk patients with early-stage cervical cancer and to evaluate whether the radicality of the lymphadenectomy would affect the outcome and toxicity of postoperative adjuvant therapy. METHODS: The cases of all patients (n = 393) with FIGO IB1-IIB cervical cancer who were treated by radical surgery at Shizuoka Cancer Center between January 2002 and December 2013 were reviewed. Of these, 111 patients met the inclusion criteria for this retrospective study: (1) high risk for occurrence due to pathologically confirmed parametrial invasion and/or pelvic lymph node metastasis; (2) postoperative treatment with adjuvant CT or CCRT. The clinical data of these patients were reviewed. RESULTS: Of the 111 patients, 37 and 74 patients underwent CT and CCRT, respectively. The 4-year progression-free survival rate [PFS; 71.7 (CT) vs. 68.3 % (CCRT)] and overall survival rate [76.0 (CT) vs. 82.7 % (CCRT)] did not differ significantly between the two groups. The CT group contained significantly more patients with severe neutropenia than the CCRT group (66.7 vs. 23.0 %, respectively; p < 0.001), and the CCRT group contained significantly more patients with diarrhea than the CT group (10.8 vs. 0 %, respectively; p = 0.04). The patients who had ≥40 lymph nodes dissected (≥40 group) had higher PFS than the patients who had <40 lymph nodes dissected (<40 group) (73.2 vs. 64.2 %, respectively), although the difference was not significant. In the CT group, there was no significant association between the number of dissected lymph nodes and severe toxicities. However, in the CCRT group, significantly more vomiting (p = 0.046) and edema (p = 0.046) occurred in the ≥40 group than in the <40 group. CONCLUSIONS: Chemotherapy after surgery for high-risk patients had similar efficacy and a different toxicity profile compared with CCRT, and a more radical surgical procedure would improve the survival outcome. However, CCRT was associated with worse toxicity than CT. We advocate a prospective randomized study to compare CT with CCRT for patients with high-risk factors for recurrence.

[Posterior Reversible Encephalopathy Syndrome Associated with Cancer Therapy].

Posterior reversible encephalopathy syndrome(PRES)is a subacute neurological syndrome typically manifesting with headache, cortical blindness, and seizures. This syndrome is associated with risk factors such as malignant hypertension, eclampsia, and renal failure. Numerous case reports depict its occurrence in cancer patients. The direct causal mechanisms of PRES in cancer patients have not yet been identified. Cytotoxic chemotherapy may cause direct endothelial damage, which would impact the blood brain barrier. Angiogenesis inhibitors also cause elevation in blood pressure;this is significant, because PRES onset may be solely related to hypertension. An increased number of case reports involving new molecular targeted agent suggests that incidence of PRES as an oncological emergency may increase in the future.

Reconsideration of postoperative concurrent chemoradiotherapy with fluorouracil and cisplatin for uterine cervical cancer.

AIM: The aim of this retrospective study was to analyze data for patients with stage IB-IIB uterine cervical cancer who were treated with concurrent chemoradiotherapy with fluorouracil (5-FU) and cisplatin (CCRT-FP) as postoperative adjuvant therapy and to re-examine these issues and further treatment. METHODS: Patients with high risk for recurrence underwent CCRT-FP as postoperative adjuvant therapy. A total of 73 patients who met these criteria were included in this study. Data related to survival, toxicity, and treatment feasibility were analyzed, and the question of whether there were differences in survival and toxicity according to the number of dissected lymph nodes at surgery was evaluated. RESULTS: Median patient age was 45 years (range, 24-67 years). Two-thirds of patients had squamous cell histologic type, 41 patients (56.2%) had parametrial invasion, and 60 patients (82.2%) had lymph node metastases. Estimated 4-year progression-free survival, overall survival, and local control rates were 71.8%, 84.1%, and 88.5%, respectively. Sixteen patients (21.9%) had grade 3-4 neutropenia and one of them died of septic shock. Non-hematological toxicities were also common: 13 (17.8%) experienced grade 3-4 nausea, and nine (12.3%) experienced grade 3-4 diarrhea. Ileus occurred in 17 patients (23.3%), and seven of them (9.6%) were not yet cured. One patient experienced gastrointestinal perforation. CONCLUSIONS: CCRT-FP in the postoperative setting resulted in good survival outcome but toxicity remained problematic. Development of appropriate treatment for patients with high-risk prognostic factors after radical hysterectomy and lymphadenectomy is required.

Feasibility of extended-field irradiation and intracavitary brachytherapy combined with weekly cisplatin chemosensitization for IB2-IIIB cervical cancer with positive paraaortic or high common iliac lymph nodes: a retrospective review.

BACKGROUND: The aim of this retrospective study was to investigate the feasibility of primary treatment with extended-field irradiation and weekly cisplatin (extended-field concurrent chemoradiotherapy, EFCCRT) as initial therapy in patients with International Federation of Gynecology and Obstetrics IB1 to IIIB cervical cancer with paraaortic or high common iliac lymph node metastases. METHODS: Participants comprised patients with confirmed cervical cancer, showing paraaortic or high common iliac lymph node metastases on diagnostic imaging, treated with EFCCRT. Total external radiation doses were 50.4 Gy to the whole pelvis and 45.0 Gy to the lumbar paraaortic region. High-dose-rate intracavitary brachytherapy was performed to deliver a total dose of 18-24 Gy in 6-Gy fractions prescribed at point A. Weekly cisplatin (30-40 mg/m(2)) was given concurrently with radiotherapy. RESULTS: Twenty-four patients were treated. Median follow-up interval was 34 months. The dose of cisplatin was 30 mg/m(2) in 2 cases, 35 mg/m(2) in 8 cases, and 40 mg/m(2) in 14 cases. Twenty-two cases (92 %) received more than 160 mg/m(2) cisplatin. Ten cases (42 %) experienced acute grade 3/4 hematological toxicity, and 9 cases (38 %) experienced acute grade 3 nonhematological toxicity. No case presented late grade 3/4 toxicity. Three-year progression-free and overall survival rates were 54 % and 72 %, respectively. Eleven cases recurred during follow-up. Sites of recurrence were within the irradiation field in 4 cases, outside the field in 6 cases, and in both fields in 1 case. CONCLUSION: EFCCRT and high-dose-rate intracavitary brachytherapy for patients with paraaortic or high common iliac lymph node metastases from cervical cancer is feasible.

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.

Immunosensitivity and specificity of insulinoma-associated protein 1 (INSM1) for neuroendocrine neoplasms of the uterine cervix.

OBJECTIVE: Previously, we reported that insulinoma-associated protein 1 (INSM1) immunohistochemistry (IHC) showed high sensitivity for neuroendocrine carcinoma of the uterine cervix and was an effective method for histopathological diagnosis, but that its specificity remained to be verified. Therefore, the aim was to verify the specificity of INSM1 IHC for a large number of non-neuroendocrine neoplasia (NEN) of the cervix. METHODS: RNA sequences were performed for cell lines of small cell carcinoma (TCYIK), squamous cell carcinoma (SiHa), and adenocarcinoma (HeLa). A total of 104 cases of formalin-fixed and paraffin-embedded specimens, 16 cases of cervical NEN and 88 cases of cervical non-NEN, were evaluated immunohistochemically for conventional neuroendocrine markers and INSM1. All processes without antigen retrieval were performed by an automated IHC system. RESULTS: The transcripts per million levels of INSM1 in RNA sequences were 1505 in TCYIK, 0 in SiHa, and HeLa. INSM1 immunoreactivity was shown only in the TCYIK. Immunohistochemical results showed that 15 cases of cervical NEN showed positive for INSM1; the positivity score of the tumor cell population and the stain strength for INSM1 were high. Two of the 88 cases of cervical non-NENs were positive for INSM1 in one case each of typical adenocarcinoma and squamous cell carcinoma. The sensitivity of INSM1 for cervical NEN was 94%; specificity, 98%; the positive predictive value, 88%; and the negative predictive value, 99%. CONCLUSION: INSM1 is an adjunctive diagnostic method with excellent specificity and sensitivity for diagnosing cervical NEN. Higher specificity can be obtained if morphological evaluation is also performed.

A simple technique of vaginal cuff closure to prevent tumor cell spillage in laparoscopic radical hysterectomy for uterine cervical cancer.

INTRODUCTION: The Laparoscopic Approach to Cervical Cancer (LACC) trial, a prospective randomized phase III clinical trial reported in 2018, unexpectedly showed inferior oncologic outcomes in laparoscopic radical hysterectomy (LRH) for cervical cancer compared with those in open surgery. It was proposed that the spillage of tumor cells into the peritoneal cavity might cause the inferiority of LRH. It has been suggested, based on retrospective studies, that transvaginal closure of the vaginal cuff before the colpotomy part of the surgery may prevent this. MATERIALS AND SURGICAL TECHNIQUE: Before starting colpotomy, we closed the vaginal cuff transvaginally. After the assessment of the cutline of the vagina, the vaginal mucosa is pulled at the eight sites using the sutures. The four pairs of sutures on the diagonal line are ligated. A purse string suture is additionally placed on the vaginal mucosa to close the vaginal cuff completely. After that, we start the intracorporeal colpotomy using a vaginal pipe. DISCUSSION: Our technique is simple and quick. The blood loss during the transvaginal procedures is minimal. The use of the vaginal pipe helps keep the vaginal cuff closed during the colpotomy. Our technique may be an alternative to the conventional approach closing the vaginal cuff.

Primary malignant melanoma of uterine cervix treated with pembrolizumab as adjuvant immunotherapy.

This is the case report of primary malignant melanoma (MM) of uterine cervix treated by immune checkpoint inhibitor: the Pembrolizumab. Despite the merge of the novel drugs that has been strikingly improving prognosis of MM, we still struggle treatment of MM of uterine cervix that has aggressive characteristics with unknown etiology. We present our case to contribute its rarity of the disease case report, the primary MM of the uterine cervix that had poor response to pembrolizumab and had OS of 6 months. The treatment ineffectiveness is mainly considered for mucosal MM of low tumor mutation burden and its unusual type of pathology. Accumulation of retrospective studies exclusively on cervical melanoma needs to be proceeded to investigate on characteristics between poor and long survival to establish standardized treatment.

Phase I study on pegylated liposomal doxorubicin in combination with docetaxel for patients with platinum-resistant or partially platinum-sensitive epithelial ovarian cancer: The Kansai Clinical Oncology Group study.

CONTEXT: In platinum-resistant ovarian cancer, single-agent chemotherapy is recommended for the reduction of adverse events. However, in clinical practice, some patients can tolerate drug-specific adverse events. AIMS: We assessed the safety of pegylated liposomal doxorubicin (PEG-LD) and docetaxel regimen in the first cycle of ovarian cancer. SETTINGS AND DESIGN: We performed a phase I study to evaluate the combination therapy of PEG-LD and docetaxel. MATERIALS AND METHODS: We recruited five patients with recurrent ovarian cancer within 12 months of first-line platinum-based chemotherapy. All patients had measurable disease severity. PEG-LD and docetaxel were intravenously administered on day 1 and every 21 days using three dose levels: 25 mg/m2 PEG-LD and 50 mg/m2 docetaxel; 30 mg/m2 PEG-LD and 50 mg/m2 docetaxel; and 30 mg/m2 PEG-LD and 60 mg/m2 docetaxel. STATISTICAL ANALYSIS USED: We defined the maximum tolerated dose of the combination therapy based on the modified Fibonacci method. RESULTS: Five patients were enrolled in this study. The median treatment-free interval was 5.5 months. Two dose-limiting toxicities (Grade 4 neutropenia) were observed in two patients. One complete response, one partial response, one stable disease, and two progressive disease cases were observed. The overall response rate was 2/5, and the disease control rate was 3/5. The median overall survival was 7.4 months. CONCLUSIONS: We determined that 25 mg/m2 of PEG-LD and 50 mg/m2 of docetaxel were safe and effective doses. This preliminary efficacy and safety data should be further investigated in a Phase II trial.

Clinicopathologic features, treatment, prognosis and prognostic factors of neuroendocrine carcinoma of the endometrium: a retrospective analysis of 42 cases from the Kansai Clinical Oncology Group/Intergroup study in Japan.

OBJECTIVE: We conducted a retrospective, multi-institutional, collaborative study to accumulate cases of neuroendocrine carcinoma of the endometrium, to clarify its clinicopathologic features, treatment, prognosis and prognostic factors to collate findings to establish future individualized treatment regimens. To our knowledge, this is the largest case study and the first study to statistically analyze the prognosis of this disease. METHODS: At medical institutions participating in the Kansai Clinical Oncology Group/Intergroup, cases diagnosed at a central pathologic review as neuroendocrine carcinoma of the endometrium between 1995 and 2014 were enrolled. We retrospectively analyzed the clinicopathologic features, treatment, prognosis and prognostic factors of this disease. RESULTS: A total of 65 cases were registered from 18 medical institutions in Japan. Of these, 42 (64.6%) cases were diagnosed as neuroendocrine carcinoma of the endometrium based on the central pathological review and thus included in the study. Advanced International Federation of Gynecology and Obstetrics stages (stage III and IV) and pure type small cell neuroendocrine carcinoma cases had a significantly worse prognosis. Upon multivariate analysis, only histologic subtypes and surgery were significant prognostic factors. Pure type cases had a significantly worse prognosis compared to mixed type cases and complete surgery cases had a significantly better prognosis compared to cases with no or incomplete surgery. CONCLUSION: Our findings suggest that complete surgery improves the prognosis of neuroendocrine carcinoma of the endometrium. Even among cases with advanced disease stages, if complete surgery is expected to be achieved, clinicians should consider curative surgery to improve the prognosis of neuroendocrine carcinoma of the endometrium.

Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy.

OBJECTIVE: Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV). But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. METHOD: Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0-120 h after chemotherapy) despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1) with olanzapine. RESULTS: Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0-24 h after chemotherapy) and 2% to 94% in delayed phase (24-120 h after chemotherapy). In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (P < 0.001). CONCLUSION: Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea.

Platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer.

OBJECTIVE: The concept of platinum sensitivity and cross-resistance among platinum agents are widely known in the management of recurrent ovarian cancer. The aim of this study was to evaluate two hypotheses regarding the validity of the concept of platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer. METHODS: In this retrospective study, the clinical data of patients with recurrent cervical cancer, who had a history of receiving cisplatin based chemotherapy (including concurrent chemoradiotherapy [CCRT] with cisplatin) and who received second-line chemotherapy at the time of recurrence between April 2004 and July 2012 were reviewed. RESULTS: In total, 49 patients--34 squamous cell carcinomas (69.4%) and 15 non-squamous cell carcinomas (30.6%)--were enrolled. The median age was 53 years (range, 26 to 79 years). Univariate and multivariate analysis showed that a platinum free interval (PFI) of 12 months has a strong relationship with the response rate to second-line chemotherapy. Upon multivariate analysis of survival after second-line platinum-based chemotherapy, a PFI of 12 months significantly influenced both progression-free survival (hazard ratio [HR], 0.349; 95% confidence interval [CI], 0.140 to 0.871; p=0.024) and overall survival (HR, 0.322; 95% CI, 0.123 to 0.842; p=0.021). In patients with a PFI of less than 6 months, the difference of progression-free survival between patients with re-administration of cisplatin (3.0 months) and administration of cisplatin analogue (7.2 months) as second-line chemotherapy was statistically significant (p=0.049, log-rank test). CONCLUSION: The concept of platinum sensitivity could be applied to recurrent cervical cancer and there is a possibility of noncross-resistance of cisplatin analogue with cisplatin.