Tirapazamine plus cisplatin in advanced or recurrent carcinoma of the uterine cervix: a Southwest Oncology Group study

The objective of this study was to determine objective response and overall survival (OS) and progression-free survival (PFS) following cisplatin plus tirapazamine treatment in eligible consenting patients with metastatic or recurrent squamous or adenosquamous carcinoma of the cervix. Treatment consisted of intravenous tirapazamine, 260 mg/m(2), followed by cisplatin, 75 mg/m(2), every 21 days for six cycles. Of 56 registered cases, 52 were evaluable for toxicity. There were six grade 4 toxicities (anemia [three], dyspnea [one], neutropenia/granulocytopenia [one], and dehydration [one]). Fifty-three patients were evaluable for response, OS, and PFS. The 6-month OS rate was 56.6% (95% CI 43.3-69.9%). The objective response rate was 32.1% (4 complete [2 confirmed and 2 unconfirmed] and 13 partial [8 confirmed and 5 unconfirmed]). Higher response rates (16/34 [47.1%] vs 1/19 [5.3%], P= 0.0018) were observed in patients who had not previously received radiation-sensitizing chemotherapy, as were OS and PFS (13.9 vs 4.0 months, P < 0.0001; 5.3 vs 1.8 months, P= 0.01). The OS was considered too low to warrant further testing in this disease setting. Despite this, tirapazamine plus cisplatin was active in patients who had not received cisplatin previously. Prior use of radiosensitizing chemotherapy impacted response and survival significantly and should be considered in future clinical trials.     

Prognostic factors of the uterine cervix adenocarcinoma

Background: Prognosis factors for adenocarcinoma of the uterine cervix after primary treatment are poorly established. Methods: A retrospective study of 45 cases of adenocarcinoma of the cervix with a follow-up of 96 months on average was performed. The primary treatment consisted in combined radical surgery and radiotherapy for stage I-II patients while patients with advanced disease were treated by radiotherapy. In case of poor prognosis factors, they were given chemotherapy. Survival rates were established and prognosis factors influencing survival and recurrences were studied. Results: Fifteen women remained alive without evolutive disease. FIGO stage and pelvic node involvement were the most important parameters influencing overall survival. Local failures (27%, average period of 30 months) were unpredictable and led to a dramatic outcome. Histological grade and pelvic node status were significant predictive factors for metastatic recurrence (40%, average period of 29 months). Conclusions: Local recurrence and metastatic dissemination of cervical adenocarcinoma after primary treatment prove to be rapidly fatal although life expectancy can be prolonged with adjuvant treatment of the recurrence. In the event of aggressive tumors with high histological grade and pelvic node involvement, an attempt to assess adjuvant systemic chemotherapy could be useful.     

Salvage chemotherapy with a combination of paclitaxel, ifosfamide, and cisplatin for the patients with recurrent carcinoma of the uterine cervix

The aim of this study was to assess the efficacy and toxicities of a combination of paclitaxel, ifosfamide, and cisplatin (TIP) for recurrent carcinoma of the uterine cervix. Fifty-three patients with recurrent cervical carcinoma were treated with ifosfamide 1500 mg/m(2) intravenously over 3 h on days 1-3, paclitaxel 135 mg/m(2) as a 3-h intravenous infusion, and cisplatin 50 mg/m(2) intravenously over 30 min on day 1. The chemotherapy was repeated every 3 weeks until there was disease progression or unacceptable toxicity. Forty-five patients received at least three courses of treatment and were evaluable for their response. Twenty-one patients (46.7%) showed objective responses, including 4.4% complete responses and 42.2% partial responses. The median time to progression and the overall survival for all the patients were 8.0 months (95% confidence interval [CI], 7.1-8.9 months) and 19.0 months (95% CI, 11.9-26.1 months), respectively. The median duration of response was 9.0 months. Patients who had previously been treated with another chemotherapy after tumor recurrence showed a moderate response rate (29.4%) but a shorter time to progression (6 vs 8 months, P= 0.0421) and a shorter survival (11 vs 39 months, P= 0.0018). Patients with good performance status showed a higher response rate (63.6% vs 30.4%, P= 0.026) and a longer time to progression (9 vs 7 months, P= 0.0049). Patients with recurrent disease only outside the previous radiotherapy (RT) field exhibited a slightly higher response without statistical significance (60.0% vs 36.0%, P= 0.109). Grade 3 or 4 toxicities included neutropenia in 13% of patients and neurotoxicity in 5%. Three deaths during treatment were observed, but two of them were due to disease progression. We conclude that the combination chemotherapy with TIP yields a high response rate with acceptable toxicity for patients with recurrent cervical carcinoma, including those patients who have failed to respond to prior platinum-based chemotherapy.     

Angiogenesis in the uterine cervix

Abstract. Abulafia O, Sherer DM. Angiogenesis in the uterine cervix.
Our objective was to present current data pertaining to angiogenesis of the uterine cervix. We conducted a computerized search to identify relevant studies published in the English language literature. MEDLINE, Current Contents and Index Medicus were searched utilizing the terms: angiogenesis, uterine cervix, intraepithelial neoplasia, squamous cell carcinoma, and adenocarcinoma, from 1966 through June 1999. In contrast to the cyclic phases of the menstrual cycle of the ovary and endometrium in which angiogenesis plays a significant physiologic role, angiogenesis in the uterine cervix is involved primarily in neoplastic processes. These include intraepithelial disease, human papilloma-related disease, and microinvasive and invasive squamous cell and adenocarcinoma of the cervix. In invasive squamous cell and adenocarcinoma of the uterine cervix, angiogenesis appears to be a prognostic indicator for overall survival and disease-free survival. Initial trial studies with anti-angiogenic (angio-inhibitor) therapy such as TNP-470 have been reported and concurrent antitumor activity observed in a limited number of patients with advanced (inoperable or metastatic) disease.     

Gross omental metastasis of mucoepidermoid carcinoma of the uterine cervix: A case report

Reich O, Tamussino K. Gross omental metastasis of mucoepidermoid carcinoma of the uterine cervix: A case report. Int J Gynecol Cancer 1998; 8 : 349–351.
A 54-year-old female with invasive mucoepidermoid carcinoma (MEC) of the uterine cervix had an uncommon type of spread. On clinical examination the patient had FIGO stage IIB disease; MRI showed a tumor volume of 15 ml and extension to right parametrium. Radical hysterectomy was planned but laparotomy revealed gross extrapelvic metastases in the greater omentum. The unexpected spread of this tumor may suggest that MECs of the cervix are more aggressive than their squamous cell counterparts.     

Small-cell carcinoma of the uterine cervix: a clinicopathologic study of 11 cases

We report the clinical profiles and immunohistochemical features of small-cell carcinoma of the uterine cervix. Eleven cases that we have encountered at the Department of Gynecology, Kitasato University Hospital, between 1971 and 2003 are presented. Of 1370 invasive carcinomas of the uterine cervix, the incidence of small-cell carcinoma was 0.8%. Patient ages ranged between 32 and 65 years, with a mean age of 46.3 years. The clinical stages at diagnosis were Ib in four patients, IIb in three, IIIb in three, and IVb in one. All patients presented with abnormal vaginal bleeding. Two patients who are alive with no evidence of disease for 12 years and 3 years 6 months, while eight patients died of primary carcinoma between 4 and 25 months after treatment. Histopathologic findings showed solid nests with marked peripheral palisading pattern and rosette formation. Small tumor cells with scant cytoplasm demonstrated a very high nuclear/cytoplasm ratio and indistinct cell borders. The nuclei were round to oval and demonstrated increased but fine granular chromatin. Nucleoli were indistinct in all cases. Immunohistochemical findings were positive in 81.8% each for neuron-specific enolase and protein gene product 9.5, 72.7% for synaptophysin, 63.6% for chromogranin A, and 54.5% for neural cell adhesion molecule. All specimens were positive for at least one of the above. In conclusion, small-cell carcinoma of the uterine cervix revealed poor prognosis. Making an accurate diagnosis of small-cell carcinoma before performing treatment is of great significance but often difficult. Immunohistochemical analysis using several kinds of neuroendocrine markers is helpful in establishing the correct diagnosis in addition to focusing on characteristic histo- and cytopathologic features.     

Continuous intra-arterial cisplatin combined with radiotherapy in locally advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group pilot study

The high local failure rate in patients with locally advanced carcinoma of the cervix treated with standard radiation has spurred interest in radiosensitization. Cisplatin is the most active single chemotherapeutic agent in squamous carcinoma of the cervix, and is considered to be a radiosensitizer. Based on a previous single-institution study looking at continuous low-dose intra-arterial cisplatin given throughout planned radiation therapy in patients with advanced carcinoma of the cervix, the Gynecologic Oncology Group initiated a limited access pilot study to assess the feasibility of this treatment method for a group-wide study. Patients with locally advanced squamous carcinoma of the cervix and surgically documented negative periaortic lymph nodes were eligible for the study. During surgical staging, the catheters of a totally implantable pump were placed in the internal iliac arteries. The pump was filled with cisplatin which was delivered at 4.5–6.5 mg day⁻¹ continuously throughout both external radiation and brachytherapy. Drug distribution through the catheters was determined using radiolabelled macro-aggregated albumin particles. Three of nine evaluable patients were free of disease at follow-up. Drug distribution was less than optimal through 4.6% of the pump catheters. Five patients had premature discontinuation of the cisplatin for various reasons. These problems resulted in low accrual and subsequent closure of the study. This treatment method is not feasible for a phase III evaluation on a group-wide basis.     

Chemotherapy rapidly alternating with accelerated radiotherapy for advanced carcinoma of the uterine cervix

The objective of this study was to determine the feasibility of treating patients with advanced cervical carcinoma using a regimen combining chemotherapy with intermittent hyperfractionated teletherapy. Eight patients with advanced cervical carcinoma were treated with bleomycin, ifosfamide and cisplatin, followed by a 5-day course of hyperfractionated external radiation. Three such courses were given at 21-day intervals. Treatment was completed using standard brachytherapy. Seven of the eight patients were evaluable for response; all obtained a complete response. Two patients developed recurrence (one in the pelvis and one distant) and died of disease. One patient died of treatment complications. The remaining four remain alive and free of disease 9–42 months after treatment. The simultaneous use of chemotherapy and intermittent hyperfractionated teletherapy is a promising strategy for the treatment of cervical carcinoma, resulting in a high rate of complete response.     

Primary malignant lymphoma of uterine cervix

Primary malignant lymphoma of the uterine cervix is a rare disease. Malignant lymphoma can be clinically and histopathologically misdiagnosed for the infrequent presentation in this are. A case of 56-year-old woman with uterine cervical tumor with infiltration to both parametria is presented. A biopsy was performed and histopathological studies reported a large cell B lymphoma. After the diagnosis CT abdominal, pelvic and thoracic scan was performed and shows infiltration to posterior bladder without evidence of disease in lymph nodes or another organ. The patient was treated with chemotherapy and radiotherapy. Six month after finish the treatment is well and free of disease.     

Assessment of pelvic lymph node micrometastatic disease in stages IB and IIA of carcinoma of the uterine cervix

The objective of this study was to assess the frequency of micrometastatic disease (MID) in pelvic lymph nodes (PLNs) in carcinoma of the uterine cervix (CUC) and to determine the risk of recurrence. The PLNs from 289 patients with CUC (IB and IIA) were studied. Each PLN was assessed via immunohistochemistry using a single histologic section (AE1/AE3). Metastatic deposits were measured and the disease status was classified into three groups: 1) absence of metastatic disease (MOD); 2) MID, one or more metastatic PLN with only isolated tumor cells and/or micrometastases (up to 2 mm); and 3) macrometastatic disease (MAD), presence of one or more metastatic PLN with macrometastases (more than 2 mm). Eleven patients (3.8%) were classified as having MID and 37 (12.8%) as having MAD. The 5-year disease-free survival (DFS) rates for MOD, MAD, and MID were 88.7%, 80.4%, and 50.0%, respectively (P < 0.001). The Cox proportional hazards model showed that MID was an independent variable for recurrence when adjusted for MAD, depth of tumor invasion, severity of inflammatory reaction, and use of adjuvant radiotherapy. We conclude that the frequency of MID in PLN was low. However, patients with MID presented a high risk of recurrence and reduced DFS.     

The basement membrane in the carcinoma in situ of the cervix: A morphological study

A morphological study of the basement membrane in the carcinoma in situ of the cervix has been carried out.Undifferentiated carcinoma in situ that arises usually from the squamocolumnar junction and which extends into the endocervical canal, always shows a continuous and clearly delineated basement membrane, which runs parallel to the basal layer. It has a homogeneous appearance. The hemidesmosomes attached to the lamina propria are quite normal and there are no slender protrusions from basal cells into the lamina propria.Differentiated carcinoma in situ, that originates in the squamous epithelium of the portio, may extend either in the direction of vagina, or towards the endocervical canal. It is always underlined by a basement membrane loosely constituted of irregular or fragmented reticular fibers; it frequently looses its homogeneous appearance and may be dehiscent or duplicated. Basal cells send down small pseudopods or threadlike extensions into the lamina propria.The authors suggest that in the management of carcinoma in situ of the cervix, one should take into consideration the direction of spread and the stroma-invasion potential of the carcinoma. These histologic patterns carry with them a very important morphologic implication, namely ‘cells differentiation’ of the carcinoma.     

Primary hepatoid adenocarcinoma of the uterine cervix

Hepatoid adenocarcinoma is characterized histologically by neoplastic epithelial cells that resemble hepatocellular carcinoma (HCC) and produce alpha-fetoprotein (AFP). We describe a case of hepatoid adenocarcinoma of the uterus that, unlike any other previously reported case, was strictly confined to the cervix. A cervical biopsy demonstrated poorly differentiated adenocarcinoma, and hysterectomy and bilateral salpingo-oophorectomy were subsequently performed. Histologically, the lesion consisted of solid sheets of hepatoid cells accompanied with areas of endometroid adenocarcinoma. The tumor cells showed strong and diffuse cytoplasmic immunoreactivity with AFP in both medullary and adenocarcinoma components. Metastases to bilateral pelvic lymph nodes were detected 12 months after surgery. Since undergoing total pelvic irradiation, the patient has been alive and in full remission for 22 months. To our knowledge, this is the first report of primary hepatoid adenocarcinoma of the uterine cervix.     

Surgical treatment for neuroendocrine carcinoma of the uterine cervix.

OBJECTIVE: To identify the best operative approach for neuroendocrine cervical carcinoma (NECC). METHODS: The records of surgically treated patients with stages IB to IIB NECC were reviewed. RESULTS: Of 10 patients who met the study criteria for NECC and underwent radical hysterectomy, 4 had pT1bN0, 4 had pT1bN1, 1 had pT2aN0, and 1 had pT2bN1 disease. Those with pT1bN1 or pT2bN1 disease received postoperative adjuvant radiotherapy and/or chemotherapy, and recurrence occurred in 7 patients (70%). Among these 7 patients, 5 (71%) had a primary NECC tumor with deep stromal invasion and 5 (71%) had extrauterine disease (parametrium and/or lymph node). The recurrences in 6 patients (86%) were located outside the pelvis (lung, liver, or brain). Stromal invasion was 6 mm or less in the 3 patients who did not experience disease recurrence. CONCLUSIONS: Pelvic control by radical hysterectomy may not be beneficial for patients with NECC except for those with an early invasive lesion.     

A phase I/II study combining radical radiotherapy with concurrent cisplatin in the treatment of advanced squamous cell carcinoma of the cervix

Sixteen patients with advanced cervix cancer have been treated in a phase I/II study of concurrent radiotherapy and cisplatin chemotherapy. The external beam radiotherapy was given as a 'split course' because of initial concerns about acute toxicity. The treatment was well tolerated with all patients completing the prescribed radiotherapy and all patients received the intended four doses of cisplatin. One of 5 patients with stage IVB disease is alive and disease free 35 months after treatment. Six of the 11 patients with disease confined to the pelvis are alive and disease free between 28 and 53 months after treatment. One patient has required surgery for a recto-sigmoid stricture.     

Radiotherapeutic management in carcinoma of the uterine cervix: current status

Despite refinement in the delivery of external radiation and brachytherapy, there has been little improvement in the survival rate of patients with invasive cancer of the uterine cervix in recent years. With advancing stage disease, there is an increase in both local failure and distant metastases. Although recent efforts to improve local control for late stage disease have been encouraging, research efforts should be directed to the identification of new active drugs for radiation sensitization and systemic therapy. Also, due to early detection, therapeutic investigations should focus on the high-risk subsets of patients with early stage disease.     

A phase I study of concurrent cisplatin chemotherapy in patients with carcinoma of the cervix receiving pelvic radiotherapy

The purpose of this study was to evaluate the maximum tolerated dose (MTD) of weekly cisplatin in a sample population of South African patients with cervical carcinoma, when given in combination with radical pelvic irradiation. Patients with cervical carcinoma stage IB2-IIIB (without hydronephrosis) received up to six cycles of cisplatin at weekly intervals. Groups consisting of three patients each were treated at each of the three predetermined dose levels of cisplatin (20, 25, and 30 mg/m(2)). Eighteen patients were treated and evaluated for toxicity. All the patients who received 20 mg/m(2) (n = 3) and 25 mg/m(2) (n = 3) cisplatin had no dose-limiting toxicity (DLT). Four of the 12 patients who were given cisplatin 30 mg/m(2) experienced DLT with rising serum creatinine and declining creatinine clearance. The minimum creatinine clearance was 22 mL/min. The highest serum creatinine was 174 mumol/L. This study showed that a weekly dose of 25 mg/m(2) of cisplatin was the MTD when used in combination with pelvic irradiation for this sample of patients. This dose is lower than the recommended dose of cisplatin 40 mg/m(2)/week. The patients in this study may have reduced tolerance to higher doses of cisplatin, when compared to patients from Western countries.     

Paclitaxel and carboplatin for large cell neuroendocrine carcinoma of the uterine cervix

The prognosis of large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is generally poor despite multimodality of treatments. We report a case of advanced stage cervical LCNEC that showed definite response to paclitaxel/carboplatin, resulting in years of survival. The patient was referred to our institution after undergoing a simple hysterectomy with bilateral salpingo-oophorectomy in her local hospital because of a ruptured metastatic ovarian mass. She declined pelvic radiation treatment, so adjuvant chemotherapy (six cycles of paclitaxel/carboplatin) was given for the residual pelvic nodal diseases. Clinical complete remission was obtained, with a disease-free period of 19 months. Systemic recurrent diseases also showed partial response to the same drug regimen for months with only minimal toxicity. However, she subsequently had progressive diseases in the liver and brain and finally died at 44 months after primary diagnosis and 19 months after recurrent diseases.