A phase II study of gemcitabine and cisplatin combination as induction chemotherapy for untreated locally advanced cervical carcinoma.

BACKGROUND: Cisplatin-based chemoradiation for locally advanced cervical carcinoma is now the standard of care for most patients with cervical carcinoma. However, induction chemotherapy followed by surgery, particularly with newer agents or combinations remains to be explored. This study was undertaken to evaluate the antitumor activity and toxicity of gemcitabine in combination with cisplatin for untreated locally advanced cervical carcinoma. PATIENTS AND METHODS: Open-label, single center, phase II, non-randomized study of neoadjuvant gemcitabine plus cisplatin. Forty-one patients with histologic diagnosis of cervical carcinoma, with no previous treatment and staged as IB2 to IIIB, were treated with three 21-day courses of cisplatin 100 mg/m2 day I and gemcitabine 1000 mg/m2 days 1 and 8, followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated before each course and at the end of chemotherapy. RESULTS: All patients were evaluated for toxicity and 40 for response. The overall objective response rate was 95% (95% confidence interval (CI): 88%-100%) being complete in 3 patients (7.5%) and partial in 35 (87.5%). A complete pathological response was found in 6 (26%) of the 23 patients that underwent surgery. Granulocytopenia grades 3-4 occurred in 13.8% and 3.4% of the courses, respectively, whereas non-hematological toxicity was mild. CONCLUSIONS: Induction chemotherapy with the combination of gemcitabine and cisplatin is highly active for untreated cervical cancer patients and has an acceptable toxicity profile.

Cisplatin, radiation, and amifostine in carcinoma of the uterine cervix.

A pilot, open, comparative study was performed on patients with locally advanced cervical cancer to investigate the efficacy and safety of amifostine. Twenty patients with a histologic diagnosis of squamous cervical cancer were treated with radiotherapy and randomized in two groups. Group A received cisplatin at 20 mg/m2 for five days in two cycles during intracavitary radiotherapy and 100 mg/m2 x 2 cycles during external radiotherapy, and amifostine 825 mg/m2 15 min before the cisplatin infusion. Patients in group B received cisplatin in the same doses without amifostine. All patients had complete responses during a median follow-up of 20 months. Grade three neutropenia was present in two patients in group A and in four of the control group, P = 0.31; grade 2 neurologic toxicity was seen in four patients in group B and in one of the patients in group A, P = 0.15. One patient needed temporary interruption of amifostine due to hypotension. Eight of 10 patients in group A developed hypocalcemia during the treatment with amifostine. Our findings indicate that amifostine was well tolerated. In this series a mild neurologic and hematologic protection was found in patients that received amifostine, although this was not statistically significant. No differences in disease-free survival response and overall survival was seen between the two groups.

Human cervical cancer-associated nuclear matrix proteins.

The nuclear matrix is the nonchromatin protein structural component of the nucleus that governs nuclear shape and also exerts regulatory control over higher order gene organization. Recent studies have documented the presence of tumor-associated nuclear matrix proteins in several human cancers. We used high-resolution two-dimensional gel electrophoresis to compare nuclear matrix protein patterns in cervical carcinomas with those from normal cervical tissue. Tumors obtained from 20 patients undergoing hysterectomy for clinically localized cervical cancer were compared with normal cervical tissue. We have identified five polypeptides (CvC-1: Mr = 69,408 Da, pI = 5. 78; CvC-2: Mr = 53,752 Da, pI = 5.54; CvC-3: Mr = 47,887 Da, pI = 5. 60; CvC-4: Mr = 46,006 Da, pI = 5.07; and CvC-5: Mr = 44,864 Da, pI = 6.61) in the nuclear matrix from cervical carcinomas that were present in 20 of 20 cervical tumors but 0 of 10 normal tissues. These data extend similar findings of cancer-associated nuclear matrix proteins in other human cancers and suggest that nuclear matrix proteins may represent a new class of cancer markers that could aid the diagnosis or management of some types of cancer.

HPV prevalence among Mexican women with neoplastic and normal cervixes.

Genital human papillomavirus (HPV) infection is causally linked to cervical cancer, yet little is known regarding HPV prevalence in cancerous and normal women in Mexico, a country with a high cervical cancer incidence. We studied 185 Mexican women among the patients attending gynecological outpatient clinics in four hospitals in Mexico City. Each woman had a Pap smear, a colposcopy, and, when necessary, a biopsy. HPVs were identified by a consensus-primer-based polymerase chain reaction (PCR) assay. HPV was detected in 87% of 69 cancers, 83% of 24 high-grade squamous intraepithelial lesions (HGSILs), 33% of 21 low-grade squamous intraepithelial lesions (LGSILs), and 17% of 71 normals. Twenty-one of the 32 HPV types tested were detected at least once. The ratio of high-risk:low-risk types was 87:6 in HGSILs and cancers, compared to 11:8 for LGSILs and normals. In invasive cancers, HPV types found at the highest frequency were, in descending order: HPV-16, -18, and -45, followed by -39, -59, and -58 with the same frequency. HPV-16 and related types were present in 52% of the cancer cases, as well as in 79% of HGSILs, and HPV-18 and related types were present in 36% of the cancers but in only 12.5% of the HGSILs. HPV-16 was predominant in squamous carcinomas, and HPV-18 and related types were predominant in adenosquamous carcinoma. Both biopsies and scrapes were tested for HPVs in 63 women, all of them with cervical neoplasia. Identical HPV results were obtained in 89% of the samples, but additional types were often identified in scrapes. HPV prevalence and type distribution in cervical cancer in Mexico was similar to the reported worldwide, as well as in other Latin American countries.

Generation of memory CD4+, CD8+, CD45RO+ and CD16- lymphocytes activated with IL-2, INF-gamma, and TNF-alpha with specific cytotoxicity against autologous cervical cancer cells in a mixed leukocyte-tumour cell culture.

Cytotoxic T lymphocytes (CTL) specific against autologous human cervical cancer cells were generated in vitro from peripheral blood leukocytes (PBL) from four patients with non-keratinized epidermoid carcinoma. For this purpose, these patients' PBL were co-cultured for 28 days either with IL-2 or a mixture of IL-2, IFN-gamma and TNF-alpha in the presence of autologous tumour cells (ATC). Our results showed that these CTL were highly cytotoxic for ATC, weakly cytotoxic for heterologous cervical cancer tumour cells, and not cytotoxic for carcinoma cell lines, normal cervix cells nor autologous PBL. Proliferation and cytotoxicity against ATC were greater when the PBL were activated with the three cytokines. These CTL had a CD4:CD8 ratio of 1:1, were CD16- and CD45RO+ and their killing activity was inhibited by antibodies against CD3, CD8 and MHC-class I but not by antibodies against CD4, CD16 or HLA-class II. The possibility of generating specific CTL in long term cultures for cervical cancer therapy is also discussed.

Simposio. Avances recientes con ifosfamida/mesna en el tratamiento de tumores sólidos malignos: estudio fase II con ifosfamida, mesna y carboplatino en el tratamiento del cáncer cervicouterino etapa IIB / Symposium. Recent Advances with ifosfamide/Mesna in the treatment of malignant solid tumors: Phase II study in carcinoma of the uterine cervix clinical stage IIB with ifosfamide, mesna and carboplatin

Los casos de carcinoma cervicouterino se diagnostican en la mayoría de las pacientes en etapas localmente avanzadas. Esto evita el abordaje quirúrgico. La quimioterapia combinada neoadyuvante ha demostrado reducción tumoral en más de la mitad de los casos tratados. En el Instituto Nacional de Cancerología, elaboramos un estudio fase II con objeto de determinar la eficacia y la toxicidad de la combinación de ifosfamida+mesna+carboplatino. También se evaluó la posibilidad de intervenir quirúrgicamente a las enfermas con carcinoma cervicouterino etapa IIB. Se incluyeron 20 pacientes sin tratamiento previo y con edad promedio de 42 años. Todas recibieron tres ciclos de quimioterapia cada cuatro semanas con carboplatino 300 mg/m² el día 1+ifosfamida 3g/m²/día por dos días en infusión contínua de 24 horas; mesna 600mg por vía intravenosa (bolo) directo antes de ifosfamida; 3,000 mg en la solución de la ifosfamida en infusión de 24 horas por dos días. Al término de ésta se administró 1,500 mg de mesna en 1,00 ml de solución glucosada en infusión de 12 horas. Se obtuvieron cuatro respuestas completas y nueve parciales; tres pacientes cursaron con enfermedad estable y cuatro progresaron. En dos enfermas sometidas a cirugía, los especímenes mostraron: carcinoma in situ residual en una mujer y en la otra no hubo actividad tumoral. De 18 pacientes que recibieron radioterapia posterior a la quimioterapia, 13 tuvieron respuesta completa, una mostró respuesta parcial y cuatro progresaron. La toxicidad para 54 ciclos de quimioterapia fue predominantemente medular; neutropenia grado 1-2 (6 por ciento), grado 3-4 (62 por ciento); plaquetopenia grado 0 (90 por ciento), grado 1-2 (44 por ciento) y grado 3 (4 por ciento). No se observó ningún proceso séptico asociado a la neutropenia. Se presentó emesis grado 2-3 en el 42 por ciento y alopecia grado 3 en el 75 por ciento. El seguimiento promedio para todas la pacientes fue de 12 meses. El intervalo libre de progresión en 14 casos con respuesta completa (13 con quimioterapia+radioterapia y uno con quimioterapia+cirugía) fue de 14.3 meses promedio (extremos 6-19 meses). Los resultados obtenidos con esta combinación confirman un alto índice de respuestas objetivas (65 por ciento) y completas (20 por ciento) con toxicidad moderada. La quimioterapia neoadyuvante puede reducir suficientemente el volumen tumoral; esto permite la cirugía en pacientes tradicionalmente consideradas con enfermedad irresecable