Combination of ifosfamide,paclitaxel, and cisplatin for the treatment of metastatic and recurrent carcinoma of the uterine cervix: a phase II study of the Hellenic Cooperative Oncology Group

OBJECTIVE: Ifosfamide, paclitaxel, and cisplatin have moderate single-agent activity in patients with metastatic or recurrent cancer of the uterine cervix. We administered a combination of these three agents to a large number of patients with metastatic or recurrent cervical cancer to evaluate its activity. METHODS: Sixty patients were treated on an outpatient basis with Ifosfamide (I) 1500 mg/m(2) intravenously over 1 h on Days 1-3, paclitaxel (T) 175 mg/m(2) as a 3-h intravenous infusion on Day 1, and cisplatin (P) 75 mg/m(2) intravenously over 2 h on Day 2 with granulocyte colony-stimulating factor (G-CSF) support. The chemotherapy was repeated every 4 weeks for a maximum of six courses. RESULTS: Fifty-seven patients received at least two courses of treatment and are evaluable for response. Twenty-six patients (46%) achieved an objective response, including 19% complete and 27% partial responses. The median duration of response was 11.5 months and the median time to progression and survival for all patients were 8.3 and 18.6 months, respectively. Patients with excellent performance status, with disease recurrence outside the radiation field, and with nonsquamous tumors had the highest response rate and best survival. Some degree of neurotoxicity occurred in 44% of patients. Grade 3 or 4 toxicity included granulocytopenia in 26% of patients, anemia in 13%, thrombocytopenia in 7%, and neurotoxicity in 3%. CONCLUSION: The ITP regimen is relatively well tolerated and moderately active in patients with metastatic carcinoma of the uterine cervix. Patients more likely to benefit are those with nonsquamous histology, with excellent performance status, and with disease recurrence outside the radiation field.     

Adjuvant radiotherapy in carcinomas of the uterine cervix: the prognostic value of hemoglobin levels

Anemia has been associated with a poorer treatment response and reduced survival in women undergoing primary radiotherapy (RT) or radiochemotherapy for advanced cervical carcinoma. This study aimed to determine the influence of anemia on outcome in patients with cervical carcinoma undergoing adjuvant RT. Medical records were reviewed for 183 cervical cancer patients who had received adjuvant RT because of risk factors after radical surgery (n= 109) or inadequate primary surgery (simple hysterectomy; n= 74). Kaplan-Meier and Cox regression analyses were used to study hemoglobin levels before and during adjuvant RT in relation to recurrence-free and overall survival. Hemoglobin values > or =11 g/dL were considered normal, while those <11 g/dL indicated anemia. Hemoglobin levels before RT influenced significantly overall survival and recurrence-free survival across the whole group (overall survival--log rank(all patients)= 7.5; df = 1; P= 0.006). However, subgroup analysis showed that the observed difference was mainly due to the group of women who had undergone inadequate primary surgery (overall survival--log rank(inadequate surgery)= 10.8; df = 1; P= 0.001). Multifactorial regression analyses comparing hemoglobin before RT with grading and tumor stage confirmed the prognostic value of hemoglobin values. Maintaining normal hemoglobin values before and during adjuvant RT seems to be important, especially in patients who have had inappropriate simple hysterectomy, which may resemble a therapeutic situation.     

Scalp metastasis in carcinoma of the uterine cervix--a rare entity

BACKGROUND: Distant metastasis in carcinoma of uterine cervix is a rare manifestation and bone metastasis is uncommon. CASE: A 60-year-old woman treated by radical radiotherapy for moderately differentiated cervical carcinoma FIGO stage IIIB presented 4 months later with swelling over right side of the scalp. Fine needle aspiration cytology from swelling showed poorly differentiated metastatic carcinoma. X-ray of the skull was suggestive of osteolytic metastasis of calvaria. CONCLUSION: Bone metastasis in cervical carcinoma is a late manifestation of advanced malignancy and heralds poor prognosis. Scalp metastasis is a very rarely reported phenomenon.     

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.     

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.     

A comparison of ovarian metastasis between squamous cell carcinoma and adenocarcinoma of the uterine cervix

OBJECTIVE: The purpose of our study was to investigate a possible difference in ovarian metastasis between squamous cell carcinoma and adenocarcinoma of the uterine cervix and to confirm clinicopathological variables associated with the metastases. METHODS: Clinical and pathological variables of 1064 patients with invasive squamous cell carcinoma and 240 with adenocarcinoma were studied. RESULTS: Ovarian metastasis was found in 14 patients (1.3%) with squamous cell carcinoma and 15 (6.3%) with adenocarcinoma. The mean age of patients with ovarian metastasis of squamous cell carcinoma was 57.4 years, compared to 50.2 years for adenocarcinoma. Ovarian metastasis of adenocarcinoma was more likely to be visible (40.0%) and present in both ovaries (66.7%), while these two characteristics occurred in only 21.4 and 36.7% of patients with squamous cell carcinoma. A logistic regression analysis with clinical variables indicated that clinical stage beyond IIb was a significant variable of squamous cell carcinoma, and more than 30-mm tumor size was significant in adenocarcinoma. CONCLUSION: The incidence of ovarian metastasis of adenocarcinoma of the uterine cervix was significantly higher than that of squamous cell carcinoma. The incidence of adenocarcinoma was associated more closely with tumor size than clinical stage, whereas it was more associated with clinical stage in squamous cell carcinoma. The results thus suggested that the differences in ovarian metastases were caused by the different characteristics of the two types of carcinoma.     

Combination of radiation therapy and interferon α-2b in patients with advanced cervical carcinoma: a pilot study

Abstract. Verastegui-Aviles E, Mohar A, Guadarrama A, de la Garza-Salazar J. Combination of radiation therapy and interferon α-2b in patients with advanced cervical carcinoma: a pilot study.
Carcinoma of the uterine cervix is the most frequent malignancy in women in developing countries. Based on the possible synergistic effect of the combination of interferon and radiotherapy, a clinical trial was conducted in patients with advanced cervical cancer. The objective was to evaluate the efficacy and security of such a therapeutic approach. This prospective phase II trial was done at the Instituto Nacional de Cancerología in Mexico City. The study included 17 consecutive patients with previously untreated squamous cell cervical cancer, clinical stages III and IV, and tumor mean size of 9.7 cm. The patients received radiotherapy and interferon α-2b at a dose of 5 × 106 IU/m² 3 times a week for 6 weeks. Eleven (64%) complete responses were obtained among these patients. Long-term survival was observed in 4 patients (24%) who achieved complete response and are alive after 10 years of follow-up. Immediate toxicity was mild. Late toxicity included the development of proctitis in 13 patients, colostomy was performed in 3 (23%) of them. Our results indicate that the combination of radiotherapy and this cytokine is an active therapy for squamous cell carcinoma of the uterine cervix.     

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.     

Hemostatic radiotherapy in carcinoma of the uterine cervix

Objective: To evaluate the treatment of hemorrhagic carcinoma of the uterine cervix with hemostatic radiotherapy (external and intracavitary radiotherapy). Method: Twenty cases of refractory hemorrhagic carcinoma of the uterine cervix receiving hemostatic radiotherapy between April 1987 and May 1992 were analyzed. The age of the patients ranged between 30 and 60 years with a median of 42 years. Results: The mean tumor volume was 130 mm³; all cases were classified as FIGO stage IIb (n = 8), IIIb (n = 11) or IVa (n = 1). Radiotherapy was carried out either by the external or intracavitary technique. The control of hemorrhage was 100% within 12–48 h after radiotherapy. However 85% of patients failed locally in the form of residual, recurrent pelvic or metastatic disease, within 24 months of follow-up. Conclusion:Hemorrhagic cervical cancer has a poor prognosis.     

Extended radical hysterectomy in early-stage carcinoma of the uterine cervix: tailoring the radicality

The question of whether surgical treatment in early-stage cervical cancer should be aggressive or restricted to less radical techniques is still controversial. To answer this question it was thought useful to investigate the correlation of parametrial lymph node metastases with extension and stage of disease. Two-hundred and sixty-three consecutive primary radical surgical procedures were performed in our institute in clinical stage IB or stage IIA cervical cancer. Positive parametrial nodes were found in 6.9% of cases: 5% in stage IB (3% in the proximal part of the parametrium and 2% in the distal part, near the pelvic wall) and 16.3% in stage IIA (7% proximal and 9.3% distal) ( P = 0.0193). During a median follow-up period of 92 months, disease recurred in 17.1% and 17.6% of cases, in negative and positive parametria, respectively. The 5-year overall and disease-free survival rates were 80.4% and 81.6% for patients with negative and positive parametria, respectively. From this experience it is concluded that the extent of radical hysterectomy should be related to the extent of the disease on the basis of modern knowledge of the pattern of spread. The principal key to prognosis remains pelvic and paracavoaortic nodal status.     

The role of chemotherapy in squamous cell carcinoma of the uterine cervix: a review

A critical review of the potential role of chemotherapy in the management of patients with squamous cell carcinoma of the uterine cervix is presented. Both its role in the management of recurrent and/or metastatic cervical cancer and its usefulness as part of the primary treatment of high-risk patients are discussed. It is emphasized that high-risk patients with cervical cancer should preferably be treated in specialized centers and entered into research protocols.     

Randomized trial with neoadjuvant chemotherapy in stage IIIB squamous carcinoma cervix uteri: an unexpected therapeutic management

A prospective randomized study was carried out in patients with squamous carcinoma of the cervix, stage IIIB. The trial considers the randomization in three different arms: the control group, 53 evaluable patients who were treated with radiotherapy; the neoadjuvant chemotherapy plus radiotherapy group, in which 52 evaluable patients were subjected to the neoadjuvant treatment followed by radiotherapy, and the surgical group which included 50 evaluable patients who were administered neoadjuvant cytostatic treatment followed by surgery and whole pelvis irradiation. The 'quick VBP scheme' was the neoadjuvant scheme used. Overall survival is, after 4 years follow-up, 37% in the control group, 53% in the neoadjuvant radiotherapy group and 63% in the surgical group; this was due to a decrease in pelvic recurrences. Distant metastases were similar in the three groups. In those cases with good response, in the neoadjuvant radiotherapy group, an unexplained unusual incidence of distant metastasis was observed. Surgery is ' a priori ' the best treatment after neoadjuvant chemotherapy because the best cure rates were obtained with it; but the patients with unresectable tumors after neoadjuvant chemotherapy constitute a high risk group. Patients with hydronephrosis, bilateral parametrial involvement or bulky lymph node metastases are another high risk group in which the development of new therapeutic strategies is wholly justified.     

Reducing the burden of glandular carcinomas of the uterine cervix

Widespread use of the Papanicolaou test for the screening of cervical cancers has lead to a significant decline in overall incidence and mortality rates over the past 3 decades. When different histologic types of cervical cancers are considered and trends are reexamined, it becomes apparent that observed declines are reflective of squamous cell carcinomas predominantly; the rates for adenocarcinomas continue to rise. This rise in incidence may be due to the greater difficulty in screening for glandular precursor lesions that often arise high within the endocervical canal. Reducing the incidence and mortality rates that are associated with adenocarcinomas can be accomplished by using improved screening techniques and large-scale implementation of cervical cancer vaccines that target the predominant oncogenic human papillomavirus types that are associated with adenocarcinoma.     

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.     

Time course and outcome of central recurrence after radiation therapy for carcinoma of the cervix

We investigated the time course of central disease recurrence (CDR) in 2997 patients treated with radiation for stage I-II squamous cell carcinoma of the cervix. CDR rates were 6.8%, 7.8%, and 9.6%, at 5, 10, and 20 years, respectively. The risk of CDR was independently correlated with tumor size (P < 0.0001) but not with FIGO stage. The hazard rate peaked in the first year of follow-up and then fell steeply; after 3 years, the hazard rate was approximately constant at 0.2-0.4% per year. Although after 3 years the risk of CDR was low, it continued to be slightly greater for patients with tumors > or =5 cm than for those with smaller tumors (P= 0.001). Patients who had CDR < 36 months after treatment were less likely to be candidates for salvage therapy and had a poorer post-recurrence survival rate than those with recurrence > or =36 months after treatment (4.5% versus 42.1%, P < 0.0001). The higher rate of CDR in the first 3 years and the poor survival after early recurrence suggest that most early CDRs are true relapses. The relatively stable annual actuarial risk between 3 and 25 years and the better survival rate after late CDR suggest that most "recurrences" after 3 years are actually new neoplasms.     

High external parametrial dose can increase the probability of radiation proctitis in patients with uterine cervix cancer

OBJECTIVE: The aim of this study was to evaluate the relationship between external parametrial dose and radiation proctitis after external irradiation and high-dose-rate intracavitary (HDR-IC) brachytherapy among patients with cervical cancer. METHODS: From May 1993 through December 1996, 191 patients with stage IB-IVA cervical cancer were managed by curative-intent radiotherapy. External irradiation to the whole pelvis (44-45 Gy/ 22-25 fractions) was delivered to all patients initially. One hundred twenty-seven patients received additional bilateral parametrial and sidewall boost (5.4-14.4 Gy/ 3-8 fractions) with 4-cm midline shielding. HDR-IC brachytherapy, 19.2-24 Gy/ 5 fractions to Point A, was given after external irradiation. Patients receiving an external dose of 44-45, 50-54, and >54 Gy were categorized as no parametrial boost (NPMB), low parametrial boost (LPMB), and high parametrial boost (HPMB) group, respectively. The actuarial proctitis rate was compared among the three groups. RESULTS: Three-year overall and Grade 2-4 proctitis rates were 30 and 15%, respectively. Overall proctitis rates were 12, 34, and 51% in the NPMB, LPMB, and HPMB groups (P < 0.0001), respectively. Grade 2-4 proctitis rates were 5, 17, and 27% in the NPMB, LPMB, and HPMB groups (P = 0.0022), respectively. In multivariate analysis of overall and Grade 2-4 radiation proctitis, external parametrial dose was the only independent prognostic factor (P = 0.0002 and 0.0030, respectively). CONCLUSION: Regardless of central shielding after 44-45 Gy whole pelvis irradiation, more patients with high external parametrial dose developed radiation proctitis. Incomplete midline shielding of the upper rectum may be the cause. Diminishing the external beam doses further may decrease rectal complications.     

Endometrial extension of adenosquamous carcinoma of the uterine cervix

Endometrial in situ extension of cervical cancer is extremely uncommon. Previous reports only present the cases of squamous cell carcinoma or related category. This report presented adenosquamous carcinoma of the uterine cervix that showed a paradoxical extension of each component in a 72-year-old patient. Main tumor in the cervix was revealed to be adenosquamous carcinoma. The glandular component extended to the vagina, while the squamous component grew into the entire uterine cavity and replaced the glandular epithelium. We presented the first case of adenosquamous carcinoma of the uterine cervix with vaginal and endometrial extension. Furthermore, the endometrium was replaced with squamous component, while the vagina was invaded by glandular component. The observed paradoxical extension of the present case was extremely rare.     

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.     

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.     

Radiotherapy in the adjuvant setting of cervical carcinoma: treatment, results, and prognostic factors

To evaluate the efficacy of postoperative radiotherapy and to investigate prognostic factors for early-stage cervical cancer patients. From December 1993 to December 2001, 141 patients with stage I-II cervical cancer without para-aortic lymph node (LN) metastases and treated by surgery and postoperative radiotherapy (RT) were included in this study. Indications for postoperative external RT were based on pathologic findings, including LN metastasis, positive surgical margins, parametrial involvement, pT2 tumor, and presence of any two minor risk factors like lymphvascular space involvement, deep stromal invasion, and tumor diameter between 2-4 cm. Sixty-six (47%) patients received RT alone, whereas 59 (42%) were treated with RT and concomitant chemotherapy (CT), and 16 received neoadjuvant CT. Patients with positive vaginal margins also received 27.5 Gy high-dose rate vaginal cuff brachytherapy in five fractions. Median follow-up time was 55 months. The actuarial 5-year overall (OS), disease-free (DFS), locoregional recurrence-free (LRFS), and distant metastases-free (DMFS) survival rates are 70%, 68%, 77%, and 88%, respectively. Univariate and multivariate analyses revealed that level and number of metastatic LNs and concomitant CT were unique significant prognostic factors for OS, DFS, and LRFS. Endometrial involvement, on the other hand, was proven to be significant for DFS and DMFS. Patients with less than three LN metastases or having only obturator LN involvement showed similar prognosis with their counterparts having no LN metastases. On the other hand, patients with either common iliac LN or more than three LN metastases had significantly worse outcome. Our results indicate that level and number of metastatic LNs are the most important prognostic factors determining the survival rates, and patients with upper lymphatic involvement or more than three metastatic LNs seem to need more effective treatment approaches.