Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. METHODS: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. RESULTS: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. CONCLUSION: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

A Case of Systemic Chemotherapy With Paclitaxel/Cisplatin Followed by Wide Local Vulvectomy in Pelvic Lymph Nodes-Related Stage IVB Vulvar Cancer.

Multimodality treatments, including chemotherapy, radiation, and surgery, have been evaluated to reduce the extent of resection and morbidity in patients with advanced vulvar cancer. Here, we report the case of a 55-year-old woman diagnosed with advanced vulvar cancer with inguinal and pelvic lymph node metastasis. She exhibited cancerous labia, which were entirely covered with ulcerated and exophytic lesions of squamous cell carcinoma, and underwent systemic chemotherapy consisting of combined paclitaxel-cisplatin. After eight cycles of this regimen, the tumors had nearly regressed, and we performed a wide local vulvectomy with a plastic musculocutaneous flap. Pathological examination revealed no residual carcinoma in the excised labia, indicating that the chemotherapy elicited a pathological complete response. The paclitaxel-cisplatin regimen may provide sufficient efficacy for selected patients with stage IVB vulvar cancer. In addition, surgical strategies should be tailored to avoid complications associated with extensive surgery and more emphasis should be placed on the patient's expected quality of life.

Establishment and characterization of multiple patient-derived organoids from a case of advanced endometrial cancer.

Patient-derived organoids (PDOs) retain the original tumor's characteristics to a large degree and allow direct evaluation of the drug sensitivity, thereby emerging as a valuable resource for both basic and preclinical researches. Whereas most past studies stereotypically adopted a single PDO as an avatar of the patient, it remains to be investigated whether this assumption can be justified even for the tumor with spatial diversity. To address this issue, we established and characterized multiple PDOs originating from various sites of a patient with advanced uterine carcinosarcoma (UCS). Specifically, cancer cells were separately sampled from three sites; resected UCS tumor tissue, the peritoneal lavage fluid, and an intra-uterine brushing of the tumor. The three derived PDOs were morphologically undistinguishable, displaying typical carcinoma organoids-like appearance, but two of them proliferated at a faster rate. The primary tumor harbored mutations in TP53 and STK11 along with amplifications in CCNE1, ERBB2, and KRAS. These two mutations and the CCNE1 amplification were detected in all PDOs, while either KRAS or ERBB2 amplification was selectively observed in each PDO in a mutually exclusive manner. Observed intra-tumor heterogeneity in HER2 expression was differentially reproduced in the PDOs, which mirrored each PDO's sensitivity to HER2 inhibitors. Inter-PDO heterogeneity was also evident in sensitivity to standard cytotoxic agents. Lastly, a drug screening identified four candidate reagents commonly effective to all PDOs. Collectively, we showed that multiple PDOs could help reproduce the spatial diversity of a tumor and serve as a valuable resource in UCS research in many respects.

Multidisciplinary management for primary uterine osteosarcoma, including gene panel testing: case report and literature review.

Primary osteosarcoma of the uterus (uOS) is rare, and its standard treatment has not yet been established. Herein, we present the case of a 50-year-old woman with uOS who demonstrated an improved prognosis after multiple surgeries to the metastatic sites. After the initial diagnosis of uOS, the patient showed recurrence and distant metastasis and hence expected to exhibit a poor prognosis. The patient underwent multiple surgical resections of the metastatic as well as primary tumors, which enabled the patient to survive for 24 months after the initial surgery. Considering that the median survival time of patients with uOS is approximately 6 months, the survival rate of our patient is noteworthy. Based on our observations, it is suggested that the resection of the primary and metastatic tumors might contribute to the extension of the survival period of the patient with chemo-resistant uOS.

Probing the tumorigenic potential of genetic interactions reconstituted in murine fallopian tube organoids.

Genetically engineered mice have been the gold standard in modeling tumor development. Recent studies have demonstrated that genetically engineered organoids can develop subcutaneous tumors in immunocompromised mice, at least for organs that prefer predominant driver mutations for tumorigenesis. To further substantiate this concept, the fallopian tube (FT), a major cell of origin of ovarian high-grade serous carcinoma (HGSC), which almost invariably carries TP53 mutations, was investigated for p53 inactivation-driven tumorigenesis. Murine FT organoids subjected to lentiviral Cre-mediated Trp53 deletion did not develop tumors. However, subsequent suppression of Pten and simultaneous induction of mutant Pik3ca led to the development of carcinoma in situ and HGSC-like tumors, respectively, whereas concurrent deletion of Apc resulted in the development of benign cysts, mirroring frequent activation of the PI3K/AKT axis and the marginal impact of Wnt pathway activation in HGSC. Consistent with the frequent activation of the RAS pathway in HGSC, mutant Kras cooperated with Trp53 deletion for the development of tumors, which unexpectedly contained sarcoma cells in addition to carcinoma cells, despite the epithelial origin of the inoculated organoids. This finding is in sharp contrast with the exclusive adenocarcinoma development from gastrointestinal organoids with the same genotype reported in previous studies, suggesting a tissue-specific epithelial-mesenchymal transition program. In tumor-derived organoids, the Cre-mediated recombination rate reached 100% for Trp53 but not for the other genes, highlighting the advantage of p53 inactivation in FT tumorigenesis. The Trp53 wildtype FT organoids expressing the mutant Kras developed sarcoma and carcinoma upon Cdkn2a suppression and Tgfbr2 deletion, respectively, revealing novel pro-tumorigenic genetic cooperation and critical roles of TGF-ß signaling for epithelial-mesenchymal transition in FT-derived tumorigenesis. Collectively, the organoid-based approach represents a shortcut to tumorigenesis and provides novel insights into the relationships among genotype, cell type, and tumor phenotype underlying tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Kras activation in endometrial organoids drives cellular transformation and epithelial-mesenchymal transition.

KRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for KrasG12D. Collectively, we showed that the oncogenic potential of KrasG12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.

A case of cervical clear cell carcinoma with serous component.

Cervical clear cell carcinoma (CCCC) is rare. This report describes the case of CCCC with a serous component. A 22-year-old woman presented with vaginal bleeding. A cervical tumor was discovered: pelvic magnetic resonance imaging revealed a tumor measuring 46 mm. Radical hysterectomy was performed based on the diagnosis of stage IB2 cervical cancer. After histological examination of the specimen revealed a coexisting invasive clear cell carcinoma (95%) and serous carcinoma (5%), five cycles of nedaplatin and irinotecan therapy were administered as postoperative adjuvant chemotherapy. Local recurrence in the vaginal vault was observed at 7 months after surgery. Radiation therapy and chemotherapy were administered. The patient is alive without evidence of recurrence at 26 months after surgery.

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer.

OBJECTIVE: The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting. METHODS: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs). RESULTS: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8-79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease). CONCLUSION: The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

Establishment and characterization of patient-derived organoids from a young patient with cervical clear cell carcinoma.

Cervical clear cell carcinoma (cCCC) constitutes an extremely rare subtype of cervical cancer. Consequently, its pathogenesis remains largely unknown, with no cell lines established from primary tumors. Here, we report the first establishment of cCCC organoids, from biopsy samples of a 23-year-old patient diagnosed with cCCC. By applying a protocol that we recently optimized for gynecological tumors, we were able to propagate a patient-derived cell line (PDC) for more than 6 months as organoids. This PDC tolerated cryopreservation and proliferated either as spheroids or adherent cells, and developed xenografts in immunodeficient mice, ensuring robust utility as a cell line. Intriguingly, the resected tumor focally contained serous carcinoma (SC) in a tiny protruding lesion. Both organoids and derivative xenografts resembled the CCC component of the original tumor in histology, immunostaining profile, and genome-wide copy number changes, including focal gain of MET. Genomic analysis revealed that both organoids and the CCC component harbored only a few mutations, of which 2 mutations were shared in common. In contrast, the SC component showed a mutator-phenotype and prominent genome instability along with biallelic inactivation of TP53, but none of them were found in organoids or the CCC component. The PDC proved sensitive to major chemotherapeutic agents and MET inhibitors. These observations clearly indicated that the PDC, designated as YMC7, can be used as a novel cCCC cell line and provide novel insights into the pathogenesis of mixed cervical adenocarcinoma. As a valuable resource for rare cancer, it will likely contribute to investigations in many fields.

Efficient use of patient-derived organoids as a preclinical model for gynecologic tumors.

OBJECTIVE: The relevance of patient-derived cancer cells has been recently increasing, particularly in terms of drug discovery and precision medicine. Whereas Matrigel-based organoid culture is a promising technique that enables infinite proliferation of cells from many types of organs in a physiological condition, its validity in gynecologic tumors remains to be established. To address this issue, we aimed at developing an efficient method for organoid culture of both ovarian and endometrial tumors. METHODS: We conducted 3D culture of 21 gynecologic tumors following our original and modified protocol for Matrigel bilayer organoid culture. We investigated whether propagated organoids retained various features of the original tumors by histopathological examination and targeted genome sequencing. RESULTS: We customized the protocol we previously optimized for murine normal and cancer tissues, so as to circumvent the digestion-resistant nature inherent to gynecologic tumors. Indeed, this modified protocol improved the success rate from 45 to 90%, for robust propagation of organoids from tumors with various stages and subtypes. Finally, 14 patient-derived organoids were established. The recovered organoids were enriched for cancer cells that retained many aspects of the original tumors, including histological features, mutation profiles, and intra-tumoral heterogeneity. A subset of the expanded organoids could develop xenografts in immunodeficient mice, potentially paving the way to drug screening in vivo. Drug response assay in vitro for paclitaxel and cisplatin was feasible using organoid-derived spheroids. CONCLUSIONS: We showed that patient-derived organoids closely resembled the original gynecologic tumors, and thereby would serve as a promising resource for preclinical studies.

Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection.

The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P = 2.4 × 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 × 10-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.

Identification of novel mutations in Japanese ovarian clear cell carcinoma patients using optimized targeted NGS for clinical diagnosis.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is an aggressive ovarian cancer with a higher frequency in Japan and often becomes chemorefractory disease. Reliable genetic diagnosis is essential to affirm the success of precision medicine for OCCC treatment. The aim of this study is, therefore, to identify novel mutations in OCCCs and develop a feasible clinical next generation sequencing (NGS) approach using formalin-fixed paraffin-embedded (FFPE) rather than preferable but not always available fresh frozen (FF) samples. METHODS: We optimized and evaluated exome analyses of 409 cancer-related genes using FFPE and FF DNA and analyzed NGS data to identify somatic mutations in Japanese OCCCs. RESULTS: Sufficient and good quality DNAs from FFPE samples were extracted from 18 (FIGO Stage I: 12) out of 29 pairs of matched normal and OCCC for NGS (63%). The fine quality of extracted DNAs depended on the length of storage period (<2years storage). We also identified 45 somatic mutations in 34 genes including unreported variants from those FFPE DNA, in which somatic mutations in the PIK3CA gene was the most common (28%) as previously reported. Seven genes (PIK3CA, ARID1A, CTNNB1, CSMD3, LPHN3, LRP1B, and TP53) were mutated in at least two independent OCCCs. FF samples from 3 out of those 18 OCCCs were available and 13 out of 14 FFPE somatic mutations were confirmed. CONCLUSIONS: We successfully identified novel genetic alterations in Japanese OCCCs and demonstrated a feasible clinical diagnostic procedure using targeted NGS for OCCC FFPE samples.

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.

Evaluation of oral etoposide in combination with cisplatin for patients with recurrent cervical cancer: long-term follow-up results of a Japanese multicenter study.

AIM: To evaluate the efficacy and toxicities of cisplatin and daily oral etoposide in patients with recurrent cervical cancer. PATIENTS AND METHODS: Treatment was initiated with oral etoposide 25 mg/day for 21 consecutive days, with intravenous cisplatin at 50 mg/m², on day 1, every 4 weeks, then the etoposide dose was increased to 50 mg/day. RESULTS: Thirty patients were enrolled in this study. Twenty-seven (90.0%) patients had a history of prior treatment (cisplatin with concurrent chemoradiotherapy in 15, radiation therapy in 3, chemotherapy in 1, and both radiation therapy and chemotherapy in 9), and 22 (73.3%) patients had a treatment-free interval of less than 6 months. NCI-CTC grade 3/4 hematologic toxicities were leukopenia in 19 (63.3%), neutropenia in 17 (58.6%), anemia in 15 (50.0%) and thrombocytopenia in 6 (20.0%). Four patients developed febrile neutropenia. NCI-CTC grade 3 nonhematologic toxicities consisted of nausea/vomiting in 2 (6.7%), anorexia in 4 (13.3%) and fatigue in 2 (6.7%). The overall response rate was 16.7% including one complete response. The median progression-free survival period and overall survival period were 4.5 and 9.7 months, respectively. CONCLUSION: Combination chemotherapy consisting of oral etoposide and intravenous cisplatin is safe and effective for recurrent cervical cancer.

Solitary metastasis of a clear cell ovarian adenocarcinoma to the small bowel mucosa.

Metastasis of ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination is uncommon. A 63-year-old woman underwent surgery for a clear cell adenocarcinoma of the ovary and received adjuvant chemotherapy. Eighteen months after the operation, she presented with recurrent occult bowel hemorrhage without evidence of an abdominal mass. Nine months later, a rapidly growing abdominal mass was detected. Laparoscopy revealed a solitary tumor of the ileum covered with an intact serosal layer. Partial ileectomy was performed for tumor resection. Histological examination revealed cells resembling the primary ovarian tumor in the mucosal surface of the small bowel along with an intact serosa. The tumor cells were positive for cytokeratin 7 and negative for cytokeratin 20, suggesting an ovarian origin. This is the first report of solitary metastasis of an ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination. Metastasis to the small bowel should be considered in ovarian carcinoma patients with occult gastrointestinal hemorrhage.

Up-regulation of CXC chemokines and their receptors: implications for proinflammatory microenvironments of ovarian carcinomas and endometriosis.

Molecular abnormalities in the epithelial cells of endometriosis and their relevance to carcinogenesis of the ovary have been well studied. On the other hand, the differences of proinflammatory microenvironments between endometriosis and ovarian carcinomas have not been well documented yet. In this study, the expression patterns of CXC chemokines (IL-8, ENA-78, GRO-alpha, I-TAC, Mig, and SDF-1) and their receptors (CXCR2, CXCR3, and CXCR4) were compared among 12 ovarian carcinomas, 8 endometriosis, and 6 normal ovaries using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. The CXCR3-mediated signaling in ovarian carcinoma cells in vitro was also investigated. In quantitative reverse transcriptase polymerase chain reaction, ENA-78 was up-regulated both in endometriosis and carcinomas, whereas I-TAC was detected exclusively in carcinomas. CXCR3 was up-regulated both in carcinomas and endometriosis. However, immunohistochemical studies revealed that the localization of CXCR3 in carcinomas was distinctively different from that in endometriosis. In carcinoma-endometriosis coexisting cases, CXCR3-positive lymphocytes in benign lesions decreased in proportion as CXCR3-positive tumor cells replaced the tissues. CXCR3 was also detected in ovarian carcinoma cell lines in vitro. Administration of interferon gamma (IFN-gamma)-inducible chemokines induced extracellular signal-regulated kinase phosphorylation in these carcinoma cells. The results indicated that CXC chemokines might contribute to the progression of ovarian carcinomas and endometriosis in different manners. Aberrant expression of IFN-gamma-inducible chemokines and CXCR3 in carcinoma cells in association with reduced CXCR3-positive immune cells raised the possibility that IFN-gamma-inducible chemokines might not exert effective antitumor immune responses but that they might work in favor of tumor progression.

Relapse rate of patients with low-risk gestational trophoblastic tumor initially treated with single-agent chemotherapy.

OBJECTIVE: To determine the factors for relapse in patients with low-risk gestational trophoblastic tumor (GTT) treated with single-agent chemotherapy. METHODS: Between 1974 and 2000, 272 consecutive patients with low-risk GTT were initially treated with methotrexate (MTX), actinomycin D (Act-D) or etoposide chemotherapy. The primary remission rate, change of chemotherapy because of drug resistance or toxicity, and relapse rate were compared. RESULTS: Overall survival rate and primary remission rate for 272 patients were 100% and 75.7%, respectively. Primary remission rate was significantly higher in patients given etoposide than those given conventional MTX (P < 0.0001) or MTX-folinic acid (MTX-CF) (P = 0.0005). Twenty-four (8.8%) patients required a change of chemotherapy because of drug resistance. The frequency of drug resistance was significantly higher in patients treated with MTX-CF than those treated with etoposide (P = 0.006). Although maternal age, presence of metastasis, high pretreatment hCG titer, and planned hysterectomy did not influence the development of drug resistance, the new FIGO scores were significantly higher in patients who developed drug resistance. Relapse rate increased significantly in patients who had high FIGO scores and who required change of chemotherapy due to drug resistance. CONCLUSIONS: All patients with low-risk GTT eventually attained complete remission, even though some developed drug resistance to the first-line chemotherapy. The relapse rate was significantly higher in patients with drug resistance than those with primary remission. Chemotherapy regimen that induces little drug resistance is desirable from the viewpoint of long-term prognosis.

Postoperative pelvic radiotherapy for cervical cancer patients with positive parametrial invasion.

OBJECTIVE: To evaluate patterns of failure in cervical cancer patients with histopathologic parametrial invasion treated with postoperative pelvic radiation therapy. METHODS: Records of 117 stages IB-IIB cervical cancer patients with parametrial invasion treated with postoperative radiation therapy from 1985 to 2002 were retrospectively reviewed. Patients were divided into two groups based on status of pelvic lymph nodes. Patterns of recurrence and prognosis by status of pelvic lymph nodes were statistically analyzed. RESULTS: Status of pelvic lymph nodes had significant impact on both recurrence and survival. Extrapelvic recurrence was observed in 23 of 66 node-positive patients compared with 6 of 51 node-negative patients (P = 0.005). Of 66 patients with a positive pelvic lymph node, 18 developed visceral metastases, whereas only three visceral metastases were noted in the 51 node-negative patients (P = 0.003). Five-year overall survival in node-positive and -negative patients was 52% and 89%, respectively (P = 0.0005). Corresponding rates for recurrence-free survival were 44% and 83%, respectively (P = 0.0002). The correlation between nodal metastasis and prognosis was enhanced when node-positive patients were stratified into two groups based on number of positive nodes (n = 1 and n > or = 2). Five-year recurrence-free survival rates for patients with negative, one positive, and two or more positive nodes were 83%, 61%, and 31%, respectively (P = 0.0001). CONCLUSIONS: Extrapelvic recurrence was uncommon in node-negative patients with parametrial invasion. These findings do not support use of systemic therapy for cervical cancer patients with parametrial invasion if pelvic lymph node metastasis is negative.

Phase I study of daily cisplatin and concurrent radiotherapy in patients with cervical carcinoma.

OBJECTIVE: Chemoradiation based on cisplatin is the standard treatment for locally advanced cervical carcinoma; however, the optimal scheduling and dosing have still not been established. This study was conducted to determine the maximum-tolerated dose (MTD) of cisplatin for daily administration during pelvic radiotherapy (RT). METHODS: Fourteen patients with locally advanced cervical carcinoma and 13 who required postoperative RT were registered. A low dose of cisplatin was given daily concurrently with RT. Cisplatin dosing was started at 6.0 mg/m(2)/day, which was incremented by 0.5 mg/m(2)/day. RT was delivered at 2 Gy/day to a total dose of 50 Gy. The MTD was defined as the dose level immediately below that causing dose-limiting toxicity (DLT) in over one-third of treated patients. RESULTS: Twenty-five patients were treated with a maximum of six escalating dose levels. In 22/25 patients (88%), cisplatin was administered continuously as planned without interruption. The MTD was determined to be 8 mg/m(2) and the DLT was indicated by the onset of neutropenia. CONCLUSION: Daily cisplatin, at 8 mg/m(2)/day, is a well-tolerated radiosensitizer in cervical carcinoma patients.

Early pregnancy outcomes after chemotherapy for gestational trophoblastic tumor.

OBJECTIVE: To analyze the outcome of the first pregnancy following chemotherapy for gestational trophoblastic tumor (GTT). STUDY DESIGN: A total of 393 patients with GTT (87 with high-risk and 306 with low-risk GTT) underwent chemotherapy at Chiba University Hospital between 1974 and 2000. Of them, 137 (19 with high-risk and 118 with low-risk GTT) who achieved primary remission and had at least 1 conception following chemotherapy were included in the study. RESULTS: The overall outcomes of the first subsequent pregnancies in the 137 women treated with chemotherapy were comparable to those in the general Japanese population. However, the incidence of abnormal pregnancies (spontaneous abortion, stillbirth, repeat mole) was significantly higher in women who conceived within 6 months of completing chemotherapy (6 of 16, 37.5%) than in those who conceived after the recommended waiting period, > 12 months (11 of 99, 10.5%) (P=.014). CONCLUSION: Patients who achieved primary remission with various kinds of chemotherapy may anticipate a normal future reproductive outcome. As pregnancies occurring within 6 months following remission are at risk of abnormality, a waiting period of at least 6 months after chemotherapy for GTT is recommended.