Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy in the treatment of locally advanced adenocarcinoma or adenosquamous carcinoma of the cervix uteri

The optimal treatment of women with locally advanced adenocarcinoma or adenosquamous carcinoma of the cervix uteri is still undefined. We report a series of four consecutive patients with locally advanced adeno- or adenosquamous carcinomas of the uterine cervix (FIGO Stages IB-IIIB) treated by concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by one to four cycles of consolidation chemotherapy with the same drug combination. After completion of this treatment all patients showed complete clinical remission. Now, after a median follow-up of 40 (range: 13.5-61) months all patients still present with no evidence of disease. Despite the low number of patients in this series we may conclude that concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy with the same drug combination is an efficacious treatment of patients with locally advanced adeno- or adenosquamous carcinomas of the cervix uteri.     

Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in Gynecologic Oncology Group trials of cisplatin-based chemoradiation

Objective

Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer.

Methods

Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation.

Results

Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB₂ (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p = 0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p = 0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies.

Conclusion

Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.     

Optimal dose for stage IIIB adenocarcinoma of the uterine cervix on the basis of biological effective dose

PURPOSE: Prognosis of uterine cervical adenocarcinoma in locally advanced stage treated with radiation therapy has been considered to be much worse than that of squamous cell carcinoma because the optimal dose for the former one has not been determined. Thus, the current study was performed to investigate the optimal dose for Stage IIIB, locally advanced stage, adenocarcinoma of the uterine cervix on the basis of the biological effective dose (BED). METHODS: One-hundred and seventy-nine patients with Stage IIIB carcinoma of the uterine cervix were treated with curative intended therapy at Kitasato University Hospital between 1976 and 2000. Out of them, 13 patients had an adenocarcinoma component in pathological findings. Nine patients were diagnosed with adenocarcinoma and four patients were diagnosed with adenosquamous cell carcinoma. All patients were treated with external radiation therapy combined with intracavitary radiation therapy. The total BED10 (T-BED10) was caluculated from the BED of the external beam radiation therapy (E-BED10) plus the BED of the intra-cavitary radiation therapy (A-BED). RESULTS: Overall survival rate was 51%. Stratified by T-BED10 overall survival rate of the T-BED10 > or = 100 Gy group was 57% and that of the T-BED10 < 100 Gy group was 30%. There was a trend toward a better survival rate of the T-BED10 > or = 100 Gy group than the T-BED10 < 100 Gy group. CONCLUSION: The current study suggested that the optimal dose for Stage IIIB adenocarcinoma of the uterine cervix might be T-BED10 > or = 100 Gy.     

Long-lasting complete remission of a patient with cervical cancer FIGO IVB treated by concomitant chemobrachyradiotherapy with ifosfamide and cisplatin and consolidation chemotherapy--a case report

The treatment of women with already metastasized cervical cancer at initial diagnosis represents a challenge to gynecologic oncologists. We report on a 63-year-old patient with locally advanced squamous cell carcinoma of the cervix uteri with an isolated metastasis to the left ovary. Following treatment with concomitant chemoradiotherapy with ifosfamide and cisplatin and three cycles of consolidation chemotherapy with the same drug combination a complete clinical remission could be documented. At present, 35 months after her disease was diagnosed, she is still without any evidence of disease. The very promising outcome of this patient might suggest that combined chemoradiation which is the standard treatment of locally advanced cervical cancer is justified as well in the metastatic setting, provided the metastatic lesion is covered within the usual radiation field.     

Small cell carcinoma of the endometrium associated with adenosquamous carcinoma: A light and electron microscopic study

This report describes a 64-year-old woman with a primary small cell carcinoma of the endometrium associated with adenosquamous carcinoma. The light microscopic features resembled those of small cell carcinoma of the lung and those of the uterine cervix, and foci of adenosquamous carcinoma lay scattered sparsely in the small cell carcinoma. Electron microscopy revealed cytoplasmic neurosecretory type granules. The neoplasm behaved in a very aggressive manner such that at 3 months after surgery a metastatic neoplasm appeared in the vagina. This case is a rare example of an endometrial carcinoma with differentiation toward endocrine as well as adeno and squamous cell carcinoma.     

In situ hybridization study on the detection of HPV DNA in adenocarcinoma and adenosquamous carcinoma of the uterine cervix]

Human papillomavirus (HPV) types 16 and 18 have been found closely associated with squamous cell carcinoma and related lesions of the uterine cervix. In order to investigate the relationship between HPV and adenocarcinoma and adenosquamous carcinoma of the uterine cervix, formalin-fixed, paraffinembedded tissues prepared from 38 cases consisting of 30 cases of adenocarcinoma and 8 cases of adenosquamous carcinoma were examined for the presence of HPV DNA by in situ hybridization with digoxigenin labeled HPV 6/11, 16, 18 DNA probes. HPV DNA was localized on the nuclei of the cancer cells in adenocarcinoma and adenosquamous carcinoma. HPV DNA was detected in 13 cases (43.3%) of adenocarcinoma and 4 cases (50.0%) of adenosquamous carcinoma, and HPV type 18 DNA was detected in 13 cases (34.2%) of adenocarcinoma and adenosquamous carcinoma. These findings suggest an association between HPV, especially HPV type 18, and adenocarcinoma and adenosquamous carcinoma of the uterine cervix.     

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.     

Multi-agent chemotherapy in combination with fractioned radiation therapy for advanced carcinoma of the cervix: acute toxicity

Five patients with advanced, previously untreated squamous cell carcinoma of the cervix were treated with combination chemotherapy (cisplatin, mitomycin C, and bleomycin) while undergoing daily fractioned radiation therapy to cover all known disease. All patients exhibited complete clinical responses at the time of the completion of external radiation therapy. Toxicities encountered were mild. This regimen deserves further study in patients with advanced squamous cell carcinoma of the cervix.     

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.     

Hyperfractionated radiation therapy plus chemotherapy in locally advanced cervical cancer: results of two phase I dose-escalation Gynecologic Oncology Group trials

OBJECTIVE: The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix. METHODS: The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions. RESULTS: Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used. CONCLUSIONS: The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare.     

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.     

A short and intensive single-agent cisplatin regimen for recurrent carcinoma of the uterine cervix

Between May 1991 and September 1993, 36 patients with recurrent carcinoma of the uterine cervix were treated with single-agent cisplatin using an intensive regimen of four weekly cycles of 50 mg m⁻² followed in responders by a further four cycles given every fortnight. The response rate was 47% (95% CI: 27–66%), 56% in those with pelvic recurrence, and 38% in those with metastatic disease. All responses but one were seen within 4 weeks of commencing treatment. Three patients (9%) had a complete response, although in two cases this was of short duration. The treatment was moderately well tolerated and the principle toxicities were myelotoxicity and emesis. The median survival was 32 weeks, and the 18-month survival was 13%.
This regimen gives a response rate similar to that seen with more toxic combination chemotherapy regimens such as BIP (bleomycin, ifosfamide and cisplatin). It has the particular advantages of a short duration of treatment and early response, allowing treatment to be stopped after 4 weeks in non-responders. The response rate in pelvic recurrence was better than that seen in most previous chemotherapy trials, particularly as 78% of the evaluable patients with pelvic recurrence had previously received radical radiotherapy to the pelvis.
Weekly, followed by fortnightly cisplatin, is an appropriate palliative treatment for patients with recurrent carcinoma of the uterine cervix for whom chemotherapy is indicated.     

Neoadjuvant chemotherapy followed by extended-field concurrent chemoradiotherapy in squamous cell carcinoma of the cervix with positive paraaortic lymph nodes: two cases

PURPOSE: To report the feasibility of neoadjuvant chemotherapy (NAC) followed by extended-field concurrent chemoradiotherapy (EF-CCRT) for squamous cell carcinoma of the cervix (CC) with paraaortic lymph node (PAN) metastasis. METHODS: Two patients were diagnosed with CC with positive PAN, and received two courses of cisplatin (120 mg/m2) in a neoadjuvant setting. They then received extended-field, external-beam radiotherapy (50.4 Gy) followed by intracavitary brachytherapy concurrently with cisplatin (20 mg/m2 x 5 days) at 21-day intervals. RESULTS: EF-CCRT was interrupted in one patient for five days because of grade 4 neutropenia. No severe late toxicities were observed. The two patients are alive with no evidence of recurrence at present. CONCLUSIONS: NAC followed by EF-CCRT is feasible and may improve the survival outcome of patients with CC with positive PAN.     

Patients with squamous cell versus adeno(squamous) carcinoma of the cervix, what factors determine the prognosis?

Patients with squamous cell carcinoma of the cervix FIGO stages IB to IV ( n = 306) were compared to patients with adeno(squamous) carcinoma ( n = 70). There was no difference between the mean ages of the groups. In the patients who underwent radical surgical treatment, whether or not in combination with radiotherapy ( n = 209), stepwise regression analysis showed that a positive lymph node status was the most unfavorable prognostic factor, followed by the histologic type (adeno(squamous) carcinoma) and the tumor diameter (> 3 cm). Vascular-space invasion had no additional prognostic value. Patient's age did not affect the prognosis. Distant metastases were not found to be more prevalent in the patients with adeno(squamous) carcinoma. In patients with adeno(squamous) carcinoma and positive lymph nodes, it is worth considering more intensive locoregional treatment than is usually prescribed for these patients and/or adjunctive chemotherapy, because there is a high risk of tumor recurrence.     

Polyradiculopathy post-concomitant chemoradiation for carcinoma of the uterine cervix treated with pelvic and para-aortic fields

BACKGROUND: It is becoming more common to include the para-aortic lymph nodes in the radiation fields of patients treated with concomitant weekly cisplatin for node-positive squamous cell carcinoma of the cervix. CASE: We report on two patients who developed unexpected subacute neurological toxicity with lower extremity paresis and paresthesis, beginning 1 and 4 months post-treatment. CONCLUSION: We believe this to be a rare side effect of chemoradiation. As the dose delivered to the spinal nerve roots was less than 37 Gy in 25 fractions, we believe that the extended fields and concomitant cisplatin had a synergistic effect on the nerves.     

Bleomycin, vincristine, and methotrexate with citrovorum factor rescue in the treatment of advanced squamous cell carcinoma of the cervix

Fourteen patients with advanced or locally recurrent squamous cell carcinoma of the uterine cervix were treated with bleomycin, vincristine, and moderately high dose methotrexate with citrovorum rescue. Two patients (14%) had a partial response; no patient had a complete response. Two patients were felt to have significant bleomycin associated pulmonary toxicity. This chemotherapy regimen is not felt to be clinically useful in our patient population.     

宫颈鳞癌与腺癌生物学行为的回顾性对比分析

目的探讨宫颈鳞癌(SCC)和宫颈腺癌(AC)在生物学行为方面存在的差异,为宫颈癌的合理诊治提供更多的临床依据。方法回顾分析山东大学齐鲁医院妇产科1997年1月至2006年3月收治的273例宫颈癌初治患者的临床资料,对比分析SCC和AC在发病相关因素、临床病理特征、5年生存率等生物学行为方面的不同。结果SCC和AC两组病例中有吸烟史者分别占22%和10%、宫颈涂片阳性率分别为80%和46%,体重指数(body mass index,BMI)≥24kg/m2者分别占15%和34%,确诊时FIGOⅠ期、Ⅱ期、Ⅲ期、Ⅳ期患者分别占SCC患者的42%、46%、11%、1%和AC患者的31%、47%、12%、10%,卵巢转移率分别为0.5%和6.7%,5年生存率分别为69.9%和50.6%,以上差异均有统计学意义(P<0.05)。结论SCC和AC在发病相关因素、临床病理特征和预后等方面均有统计学差异,SCC组有吸烟史者的比例及宫颈涂片阳性率更高,AC患者中则体重超重或肥胖者占较高比例,AC患者确诊时晚期患者较多而且更容易发生卵巢转移,预后较SCC差。     

子宫颈鳞状细胞癌复发患者血清鳞状细胞癌抗原监测的意义

目的探讨血清鳞状细胞癌抗原（SCCAg）在监测宫颈鳞癌患者复发中的意义。方法对1999-2005年收治的72例宫颈鳞癌复发患者血清SCCAg水平与诊断、预后的关系进行单因素和多因素分析。结果72例复发患者中,术后复发30例、放化疗后复发42例,其中血清SCCAg水平升高者61例（占85％）。此61例患者中,20例在随诊中首先出现血清SCCAg水平升高而临床及影像学检查未发现肿瘤,血清SCCAg水平提前升高的中位时间为3个月,平均4．6个月（1～13个月）。72例复发患者中,45例患者无任何临床症状,仅因血清SCCAg水平升高或常规随诊发现复发;27例患者有症状,其中单侧下肢水肿或疼痛15例,阴道不规则流血7例,出现远处转移相关症状5例。细胞或组织病理学检查诊断复发者33例;临床及影像学检查结合血清SCCAg水平诊断复发者39例,其中29例仅依靠血清SCCAg水平升高及影像学检查即诊断复发。72例复发患者的中位生存时间为11个月,平均生存时间为23个月（2～62个月）,总的3年生存率为25％,5年生存率为19％。单因素分析发现,初治前患者血清SCCAg水平、病理分级、复发部位、复发后治疗方式以及复发时、复发后治疗中、治疗后血清SCCAg水平对患者的3年生存率有明显影响（P〈0．01）;但20例血清SCCAg水平提前出现升高的患者与52例血清SCCAg水平未提前升高的患者相比,3年生存率分别为22％、27％,差异无统计学意义（P=0．5761）。多因素分析发现,复发患者仅病理分级、复发后的治疗方式是独立的预后影响因素（P〈0．05）;而复发部位及各种血清SCCAg状态不是独立的预后影响因素（P〉0．05）。结论血清SCCAg水平监测在宫颈鳞癌复发患者中的诊断及其对预后的判断中有一定的价值。     

Concurrent carboplatin/5-FU and radiotherapy for locally advanced cervical carcinoma

Landoni F, Maneo A, Colombo A, Cormio G, Placa F, Nava S, Rossi R,Mangioni C. Concurrent carboplatin/5-FU and radiotherapy for locally advancedcervical carcinoma. Int J Gynecol Cancer 1997; 7 :471–476.
Despite innovative techniques in radiotherapy delivery no significant improvement in survival rates for cervical carcinoma has been achieved during the last few decades. Concurrent chemoradiation (CR) is one of the several avenues being explored to improve these results.
Forty-seven women with locally advanced (IB2-IVA) squamous cell carcinoma of the uterine cervix were treated with CR, comprising a combination of external and intracavitary radiation along with three cycles of 5-FU and carboplatin.
Treatment was well tolerated with 81% of the patients completing the CR protocol as planned. Acute toxicity was severe but manageable: 16 patients (34%) experienced grade 3–4 acute toxicity. Late morbidity occurred in 15% of the patients. Overall response rate was 88%. At a median follow-up time of 19 months (range 12–59) 62% of the patients are alive without disease and 18% are dead of disease. Actuarial two-year survival rate for the whole group of patients is 64%.
Concomitant carboplatin/5-FU and radiotherapy is a safe and tolerable mean of treatment for locally advanced cervical cancer. The true advantage for survival, however, can be demonstrated only after completion of randomized trials comparing CR with conventional radiation therapy.     

Etoposide (VP-16), ifosfamide/mesna, and cisplatin chemotherapy for advanced and recurrent carcinoma of the cervix.

A Phase II study of VP-16 (etoposide), ifosfamide/mesna, and cisplatin (VIP) in advanced and recurrent carcinoma of the cervix was initiated March 1989. VP-16, 75 mg/m2, ifosfamide, 1.0 g/m2, and cisplatin, 25 mg/m2, were administered intravenously daily for 3 consecutive days, every 28 days to a maximum of six cycles. Fourteen patients were entered on protocol. Eight patients had objective responses, all complete. Response duration ranged from 7+ to 24+ months. The chemotherapy was well-tolerated. Hematologic toxicity was the major toxicity and was manageable. VIP appears to be active in advanced carcinoma of the cervix.