Phase II clinical study of neoadjuvant chemotherapy with CDDP/CPT-11 regimen in combination with radical hysterectomy for cervical cancer with a bulky mass.

BACKGROUND: We examined the efficacy and safety of neoadjuvant chemotherapy (NAC) with the CPT-11 + CDDP regimen in combination with radical hysterectomy. SUBJECTS AND METHODS: The subjects were 42 patients with stages IB2 to IIIB squamous cell carcinoma of the uterine cervix with a bulky mass. CDDP at 70 mg/m2 was intravenously administered on day 1 and CPT-11 at 70 mg/m2 was intravenously administered on days 1 and 8 of a 21-day cycle. In principle, two cycles were administered followed by radical hysterectomy. We examined antitumor efficacy, adverse events, completion rate of radical hysterectomy, operative time, surgical blood loss, progression-free survival (PFS), and overall survival (OS). RESULTS: The antitumor effect was complete response in 7 patients, partial response in 28, stable disease in 6, and progressive disease in 1; the response rate was 83.3 % (95 % confidence interval, 68.6-93.0). Grade 3 or more severe neutropenia, anemia, and platelet count decreases were noted in 23 (54.8 %), 4 (9.5 %), and 1 (2.4 %) patient, respectively. Grade 3 nausea occurred in 3 patients (7.1 %), vomiting in 1 (2.4 %), and grade 3 febrile neutropenia in 2 (7.1 %). The completion rate of radical hysterectomy was 88.1 %. The median operative time and surgical blood loss were 260 min (range, 210-334) and 500 ml (range, 393-898), respectively. The 5-year PFS rate was 67.2 %, and the 5-year OS rate was 68.0 %. In multivariate analysis, lymph node metastasis before NAC [hazard ratio (HR), 34.88] and non-response to NAC (HR 30.58) were significant prognostic factors. CONCLUSION: NAC with the CDDP/CPT-11 regimen achieves a high antitumor efficacy with moderate adverse reactions, allowing safe radical hysterectomy, and is thus considered to be a useful therapeutic method that can improve prognosis.

Analysis of prognostic factors for patients with bulky squamous cell carcinoma of the uterine cervix who underwent neoadjuvant chemotherapy followed by radical hysterectomy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is not yet widely recommended for the treatment of stage I/II cervical cancer. However, it may be possible to achieve a favorable outcome by selecting appropriate patients. In the present study, prognostic factors were retrospectively investigated to obtain data for devising individualized NAC. PATIENTS AND METHODS: The subjects were 33 patients with bulky stage Ib2-IIb squamous cell carcinoma (SCC) of the uterine cervix who gave consent and were scheduled to undergo radical hysterectomy. The patients intravenously received irinotecan 70 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 1 of a 21-day course, and two courses were performed in principle. The potential prognostic factors investigated were age, performance status (PS), clinical stage, lymph node metastasis and tumor size before NAC, SCC antigen value, anti-tumor response, histological effect of NAC, lymph node metastasis in resected specimens, and postoperative adjuvant therapy after NAC. The impacts of these factors on overall survival (OS) were calculated with the Cox regression model. RESULTS: According to the univariate analysis, lymph node metastasis before NAC, SCC antigen value after NAC, anti-tumor response, and histological effect of NAC significantly influenced OS. These factors were tested in a multivariate model, and significant prognostic factors were lymph node metastasis before NAC (hazard ratio 0.116, P = 0.027) and anti-tumor response (hazard ratio 0.025, P = 0.003). CONCLUSION: The presence or absence of lymph node metastasis by computed tomography imaging was the only significant prognostic factor identified during the pre-NAC period.

Clinical significance of atypical glandular cells in the Bethesda system 2001: a comparison with the histopathological diagnosis of surgically resected specimens.

Forty-one patients diagnosed with atypical glangular cells (AGC) underwent surgery, and the histopathological diagnosis results for the resected specimens and the clinical features were analyzed. Out of 41 patients, final pathological diagnosis was endometrial cancer in 13 patients, cervical adenocarcinoma in 8, AIS in 7, CIN3 in 6, others in 2, and no lesions in 5. In comparison with previous reports, malignant or premalignant lesions were detected more frequently in patients with AGC who underwent surgery. We believe that conization or hysterectomy aimed at diagnosis and treatment, as well as endometrial histodiagnosis, should be carried out aggressively in patients with AGC.

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy.

There have been no case reports of the risk of serious adverse events associated with the administration of irinotecan hydrochloride (CPT-11) in patients with gynecologic cancer who are compound heterozygous for UGT1A1*6 and UGT1A1*28. A 71-year-old patient presented with recurrent stage IIIb cervical cancer. Combined chemotherapy was initiated with CPT-11 (60 mg/m² on days 1 and 8) plus nedaplatin (NDP; 80 mg/m² on day 1), with each cycle lasting for 28 days. The patient was a compound heterozygote for UGT1A1*6 and UGT1A1*28. Hematotoxic adverse events observed during the chemotherapy were grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia, and the non-hematotoxic adverse events were grade 3 diarrhea and grade 3 fatigue. The findings in this patient indicate that CPT-11 should be administered with great care, even at a dose of 60 mg/m², in patients receiving combined therapy with CPT-11 and NDP who are compound heterozygous for UGT1A1*6 and UGT1A1*28.

Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: A multicenter collaborative study.

Paclitaxel/carboplatin chemotherapy for cancer (TC therapy) exhibits neurotoxicity and causes peripheral neuropathy at a high frequency, which is difficult to cope with. In this study, we investigated the efficacy of Goshajinkigan, a traditional Japanese herbal medicine, for TC therapy-induced peripheral neuropathy. The subjects included in our study were patients with ovarian or endometrial cancer who underwent TC therapy and developed peripheral neuropathy. The patients were randomly divided into Group A, comprising of 14 patients (vitamin B12 treatment), and Group B, comprising of 15 patients (vitamin B12 + Goshajinkigan treatment). The observation period was 6 weeks following treatment initiation, and the evaluation items were as follows: i) the current perception threshold (CPT value) of the peripheral nerve, ii) visual analogue scale for numbness, iii) National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade of neurotoxicity, and iv) a questionnaire on the subjective symptoms of peripheral neuropathy (functional assessment of cancer therapy-taxane). These were compared between the groups and no significant differences were noted in any item. However, CTCAE grade 3 neurotoxicity developed in 2 patients (14.3%) after 6 weeks of administration in Group A, whereas no neurotoxicity was observed in Group B. When the change in the frequency of abnormal CPT ratio at 6 weeks of administration from that before treatment was compared between the groups, the frequency of abnormal value was significantly lower in Group B than in Group A (p<0.05). This suggests that Goshajinkigan inhibits the progression of peripheral neuropathy.

Tako-Tsubo cardiomyopathy caused immediately following cesarean section delivery of triplets: a case report.

The name 'tako-tsubo' cardiomyopathy was initially used to describe a unique 'short-neck round-flask'-shaped form of left ventricular apical ballooning, resembling a Japanese tako-tsubo, a jar (tsubo) used for capturing octopus (tako). Tako-tsubo cardiomyopathy exhibits acute onset, transient left ventricular apical wall motion abnormalities with chest symptoms and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without angiographic stenosis on coronary angiography. There have been few case reports on tako-tsubo cardiomyopathy, and this disorder is especially rare in pregnant women. A 30-year-old woman who was pregnant with triplets, and had been treated with ritodrine hydrochloride for 12 weeks for threatened premature delivery, underwent cesarean section with spinal anesthesia at 30 weeks' gestation. Three hours later, she complained of acute chest pain, dyspnea and episodes of unconsciousness. She was transferred to the intensive care unit and intubated for ventilatory support. We diagnosed heart failure due to tako-tsubo cardiomyopathy based on heart ultrasonography, blood tests, chest X-ray, electrocardiogram and myocardial scintigraphy. She was extubated from the ventilator after 3 days of catecholamine, furosemide and carperitide administration. She was discharged from the hospital on day 53 without symptoms.

Case of peptide-YY-producing strumal carcinoid of the ovary: a case report and review.

Ovarian carcinoid is a rare tumor accounting for approximately 0.1% of all ovarian malignancies. We describe a case of peptide-YY-producing strumal carcinoid of the ovary associated with severe constipation. A 48-year-old woman was found to have a pelvic mass on ultrasonography when she visited her primary doctor for a health check-up. She was thus referred to our department. Magnetic resonance imaging revealed a solid right ovarian tumor 60 × 50 mm in size. The patient underwent a right adnexectomy and was histopathologically diagnosed as having strumal carcinoid of the ovary. On immunohistochemical examination, the tumor cells were positive for peptide YY. The patient's constipation resolved rapidly after surgery. Based on her clinical course, her constipation was considered to have been caused by the strumal carcinoid of the ovary. The clinical course of this case supports the previously recognized correlation between peptide-YY-producing ovarian carcinoid and constipation.

Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study).

OBJECTIVE: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. PATIENTS AND METHODS: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). RESULTS: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). CONCLUSIONS: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

[Results of neoadjuvant chemotherapy using tri-weekly CDDP/CPT-11 for locally advanced cervical cancer].

OBJECTIVE: We assessed the antitumor response and safety of neoadjuvant chemotherapy (NAC) using cisplatin (CDDP) and irinotecan(CPT-11)given every three weeks for locally advanced cervical cancer with a bulky mass. SUBJECTS AND METHODS: Nineteen patients with cervical squamous cell cancer in FIGO stage of Ib2 to IIb were enrolled in this study. The FIGO stages were Ib2 in 5 patients, IIa in 2 patients, and IIb in 12 patients. One course of the chemotherapy regimen consisted of intravenous administrations of CDDP at a dose of 70 mg/m 2(day 1)and CPT-11 at 70 mg/m 2 (days 1 and 8) for 21 days, and two courses were administered. This chemotherapy was assessed for antitumor response, adverse events, complete surgical removal rate, progression-free survival time, and overall survival time. RECIST and NCI-CTCAE were used to determine antitumor response and adverse events, respectively. RESULTS: The results of assessment of the antitumor response showed CR in 3 patients(15. 8%), PR in 14(73. 7%), SD in 1 (5. 3%), and PD in 1(5. 3%). Neutropenia of grade 3 or higher occurred in 13 patients(68. 4%). Anemia occurred in 2 patients(10. 5%), and thrombocytopenia in 1 patient(5. 3%). Nausea and vomiting were observed in 2 patients(10. 5%). All patients underwent a chemotherapy regimen consisting of two courses, and the rate of complete surgical removal was 94. 7%. The median observation period was 27 months; the progression-free survival time was 18 months, and survival time was 27 months. CONCLUSION: Adverse drug reactions to NAC with the CDDP/CPT-11 combination administered every three weeks were controllable. The antitumor response rate for this chemotherapy was high. These assessment results indicate that NAC with a CDDP/CPT-11 combination was useful for local advanced cervical cancer.

Usefulness of desensitization protocol for a carboplatin hypersensitivity reaction during docetaxel-carboplatin therapy for recurrent ovarian cancer: Case report.

We report a case of recurrent ovarian cancer in which desensitization for a carboplatin hypersensitivity reaction proved useful. The patient was a 65-year-old woman who presented with a recurrence of stage IIIc ovarian cancer. The initial chemotherapy consisted of 6 courses of paclitaxel and carboplatin. Recurrence in the pelvis, splenic hilum and para-aortic lymph nodes was detected 19 months after the final day of treatment. The patient was treated with docetaxel-carboplatin therapy for the recurrence, but a Grade 3 hypersensitivity reaction to carboplatin was observed during the second course. Carboplatin desensitization was commenced with the third course and 6 courses were completed with no evidence of hypersensitivity reaction. The antitumor effect showed a complete response and the patient has had a disease-free survival thus far. Desensitization for patients diagnosed with a carboplatin hypersensitivity reaction appeared to be a key method of treatment for prolonging the survival time of patients with recurrent ovarian cancer.

Phase II study of tri-weekly cisplatin and irinotecan as neoadjuvant chemotherapy for locally advanced cervical cancer.

The present study aimed to assess the antitumor response and safety of a tri-weekly neoadjuvant chemotherapy regimen consisting of cisplatin and irinotecan for the treatment of locally advanced cervical cancer with a bulky mass. Between June 2002 and March 2008, 20 patients with locally advanced squamous cell carcinoma of the uterine cervix at clinical stage Ib2-IIIb were studied. Two 21-day cycles consisting of intravenous administration of cisplatin at 70 mg/m(2) (Day 1) and irinotecan at 70 mg/m(2) (Days 1 and 8) were performed. Antitumor responses, adverse events and the surgery completion rate were investigated. The response rate of the 15 stage I-II patients was 86.7%, while that of the 5 stage III patients was 20%. Grade 3 or 4 neutropenia was noted in 12 patients, and 4 patients had grade 3 or 4 anemia. Queasiness and vomiting, as grade 3 or 4 non-hematotoxic events, occurred in 1 patient, but none of the patients had diarrhea. The surgery completion rate was 75%. The present data indicate that the tri-weekly cisplatin and irinotecan combination neoadjuvant chemotherapy involves only controllable toxicity and yields a high response rate, suggesting that this combination is a useful therapy regimen.

[Ovarian cancer treatment from the standpoint of the gynecologic oncologist].

Ovarian cancer treatment on the standpoint of the gynecologic oncologist: Ovarian cancer is comprehensively treated with combined surgery and anticancer chemotherapy, which influence each other. In the initial surgery, a cancer stage is decided, and in advanced cancer, primary debulking surgery is conducted. The outcome of postoperative chemotherapy has a correlation with the diameter of the postoperative residual tumor. Recently, a new treatment strategy of interval debulking surgery during chemotherapy has been widely conducted to completely remove tumors. Improved diagnostic imaging such as PET enhances aggressive surgery for recurrent cancer.

Pilot study evaluating the efficacy and toxicity of irinotecan plus oral etoposide for platinum- and taxane-resistant epithelial ovarian cancer.

OBJECTIVES: To evaluate the efficacy and toxicity of combination chemotherapy with intravenous irinotecan and oral etoposide in women with platinum- and taxane-resistant epithelial ovarian cancer. METHODS: Between October 2002 and September 2005, we studied 27 women with platinum- and taxane-resistant epithelial ovarian cancer. Irinotecan was administered in an intravenous dose of 70 mg/m(2) as a 90-min infusion on days 1 and 15 of a 28-day cycle, and etoposide was administered in an oral dose of 50 mg/day on days 1 to 21. For heavily pretreated patients, the initial dose of irinotecan was lowered to 60 mg/m(2). Treatment cycles were repeated until disease progression or unacceptable toxicity. RESULTS: All 27 patients were eligible and assessable. There were 11 partial responses and 1 complete response for an overall response rate of 44.4%. The median durations of overall response and of stable disease were 11 months and 8 months, respectively. The major toxicity was neutropenia (grade 3, 22.2%; grade 4, 37.1%). Diarrhea was infrequent and mild, and gastrointestinal toxicity was moderate and manageable. Acute myeloid leukemia (M5) developed as a secondary malignancy in 1 patient. CONCLUSIONS: The results of our pilot study suggest that a combination of irinotecan and oral etoposide is effective and tolerable in women with platinum- and taxane-resistant epithelial ovarian cancer.

Diagnostic accuracy of FDG PET imaging for the detection of recurrent or metastatic gynecologic cancer.

PURPOSE: This study evaluated the diagnostic role and accuracy of positron emission tomography (PET) using 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) for the detection of tumor foci in patients with suspected recurrent or metastatic lesions of gynecologic cancers. MATERIALS AND METHODS: FDG PET imaging was performed on 51 patients with a previous history of gynecologic cancer who were referred for a clinical suspicion of recurrent disease. PET acquisition was started 50-60 min after the intravenous injection of 5-6 MBq/kg FDG in all patients. The PET images were interpreted visually, and tracer uptake was quantitated as the standardized uptake value adjusted to body weight (SUV) in the lesions showing FDG uptake. The accuracy of the PET results was assessed by a consensual verdict based on histology, cytology, other imaging and clinical follow-up. RESULTS: FDG PET correctly diagnosed 33 of 36 patients with recurrent disease and 12 of 15 patients without recurrence. On patient-based analysis, the sensitivity, specificity and accuracy of FDG PET were 91.7%, 80.0% and 88.2%, respectively, depending on the selected scheme for visual scoring of the lesions. The area index in receiver-operating characteristic analysis was 0.95 for patient detection. Malignant lesions accumulated significantly more FDG than the benign ones (the mean SUVs were 3.7 +/- 1.9 and 1.6 +/- 1.1, respectively, p = 0.004). The sensitivity and specificity in correct identification of tumor recurrence or metastases using a threshold SUV 1.9 were 88.8% and 66.7% in contrast to the visual analysis (sensitivity 96.4%, specificity 50%) on a lesion-based analysis. The partial volume effect of SUV in a few small lesions and the presence of bone lesions in which FDG uptake was relatively low might be the reason for the lower sensitivity in SUV analysis. FDG PET was valuable when CT/MRI was negative or inconclusive, and in patients with elevated tumor marker levels as well as with normal tumor marker levels when recurrence was suspected clinically. However, PET failed to visualize some small metastatic lesions in lung and bone, and showed falsely high FDG uptake in some benign lesions. CONCLUSION: The results indicated that FDG PET is a reliable and accurate diagnostic method for detecting recurrent or metastatic gynecologic cancer particularly lymph node metastases. Although the sensitivity of PET for detecting small metastases was relatively limited, the overall sensitivity of FDG PET was significantly higher than morphologic imaging.