Radiotherapy with or without misonidazole for patients with stage IIIB or stage IVA squamous cell carcinoma of the uterine cervix: preliminary report of a Radiation Therapy Oncology Group randomized trial

Between August 1980 and November 1984, 119 patients with FIGO Stage IIIB or IVA squamous cell carcinoma of the uterine cervix were randomized to receive radiation therapy (4600 cGy pelvis plus 1000 cGy parametrial boost) followed by intracavitary or external boost to the primary with or without misonidazole (MISO) (400 mg/m2 daily 2 to 4 hours prior to radiation therapy). Patients in the two treatment groups were evenly distributed with respect to stratification variables including stage, Karnofsky Performance score, and positivity of para-aortic nodes. Eighty-nine percent of patients had Stage IIIB disease and 88% had a Karnofsky score of 80 or better. Seventy-five percent of patients treated with radiation therapy alone and 79% of patients treated with radiation therapy plus MISO received a boost via intracavitary application. Life threatening (Grade 4) complications occurred in 5 patients receiving radiation therapy alone and one patient receiving radiation therapy plus MISO. MISO toxicity (Grade 3) was limited to severe nausea and vomiting in two patients. With 119 evaluable patients and a median follow-up of 33 months, 64% of patients receiving radiation therapy alone are alive at 18 months compared with 54% for patients assigned to radiation therapy plus MISO. The median survival for patients treated with radiation therapy alone and radiation therapy plus MISO was 1.9 years and 1.6 respectively. At this point in the study the difference in survival is inconsistent with the hypothesis of an improvement associated with MISO. There have been 23 deaths among the 49 patients treated with radiation therapy plus MISO who have been followed for at least 18 months compared with 17 deaths in 48 patients treated with radiation therapy alone. The chance of observing this number of deaths with radiation therapy plus MISO if the addition of MISO improves survival by 10 to 20% is 0.003 and less than 0.001, respectively. The addition of MISO to radiation failed to improve survival for these patients. The results cannot be explained by an uncharacteristically high survival on the radiation therapy alone arm or by an imbalance in the distribution of prognostic factors. Local-regional control remains a problem in the management of patients with advanced cervical carcinoma. More effective and less toxic radiosensitizing agents are needed.     

Plasma proteomic analysis of patients with squamous cell carcinoma of the uterine cervix

Objective

To compare plasma protein expression between patients with squamous cell carcinoma (SCC) of the cervix and normal controls.

Methods

Plasma samples from patients with benign gynecological disease (normal cervix, n=6) and cervical cancer (SCC, n=6) were subjected to plasma proteomic analysis using two dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS). Western blotting and immunoturbidimetric assay were performed to validate the results of 2-DE.

Results

Eight proteins showed differential expression between controls and SCC patients; six (ceruloplasmin, complement C3, afamin precursor, alpha-1-B-glycoprotein, transferrin, alpha-fibrinogen precursor) were up-regulated, while two (chain A, crystal structure of antithrombin and apolipoprotein A-IV precursor) were down-regulated in the plasma of SCC patients. Western blotting analysis revealed significant elevation of ceruloplasmin, complement C3, afamin, and alpha-1-B-glycoprotein in the plasma of SCC patients in comparison to controls. Immunoturbidimetric assay of a larger group confirmed the results of 2-DE and Western blotting, and showed that ceruloplasmin and complement C3 were significantly elevated in the plasma of SCC patients in comparison with controls and patients with carcinoma in situ (CIS) of the uterine cervix.

Conclusion

Plasma protein expression determined using 2-DE and MALDI-MS will give a chance to identify tumor-specific biomarkers for SCC of the cervix.     

宫颈鳞状细胞癌患者血清鳞状细胞癌抗原变化的临床意义

目的　研究子宫颈鳞状细胞癌患者血清中鳞状细胞癌抗原水平与病理分级、临床分期及对治疗反应之间的关系。方法　利用雅培公司提供的 IMX全自动快速粒子酶免疫分析系统 ,对 2 5例正常献血员和 83例经病理学诊断的宫颈鳞状细胞癌患者 ,进行了血清中鳞状细胞癌抗原血清检测并分析其与病理分级、临床分期之间关系。其中 80例患者放射治疗前后血清鳞状细胞癌抗原水平变化情况进行了自身比较。结果　中晚期宫颈鳞状细胞癌患者血清鳞状细胞癌抗原水平与病理分级、临床分期之间无相关性。放射治疗前后患者血清鳞状细胞癌抗原水平有明显变化。结论　对子宫颈鳞状细胞癌患者 ,在治疗前后检测血清鳞状细胞癌抗原水平 ,可以作为对放射治疗疗效判断的参考指标之一。     

Age as a prognostic factor in patients with squamous cell carcinoma of the uterine cervix

Correlations between age and several prognostic factors, such as histologic cell type, depth of invasion, intravascular invasion, and lymph node metastases (LNM), were analyzed in squamous cell carcinoma of the cervix (SCC). A total of 380 patients with Stage IB or more advanced SCC underwent radical hysterectomy at the authors' institution from 1971 to 1987. The cases were divided into four age groups: 30 to 39 years, 40 to 49 years, 50 to 59 years, and 60 to 69 years. The depth of invasion was classified in four categories according to pathologic examination of surgical specimens. The only significant factor was the frequency of LNM with deeper invasion, which was less in the 60-to-69-year age group than in the younger age groups. The 5-year survival rates of the patients with LNM also were higher in the 60-to-69-year group. Thus, age 60 or older can be considered a prognostic factor correlating to LNM in squamous cell carcinoma of the cervix.     

A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79-04)

A randomized prospective trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer, misonidazole (MISO), used as an adjunct to high fractional dose radiotherapy in the management of unresectable Stage III and IV squamous cell carcinomas of the oral cavity, oropharynx and hypopharynx. From June 1979 to February 1983, 42 patients were randomized with 40 patients available for analysis. In the radiotherapy (RT) only group, 19 patients received a short course of high fractional dose radiotherapy with 400 rad per day, 5 days per week, to a total of 4400 to 5200 rad. In the radiotherapy plus misonidazole group (RT + MISO) 21 patients received the same radiotherapy plus 1.5 gm/m2 of misonidazole 3 times a week for a total of 7 doses. The observed side effects associated with misonidazole were: persistent numbness and paresthesia (1 patient), transient peripheral nerve paresis and persistent paresthesia (1 patient), and nausea and vomiting (2 patients). The treatment related morbidities were similar in both groups. Acute mucositis was seen in 4 of 19 patients in the RT group and 3 of 21 patients in the RT + MISO group. Acute airway obstruction requiring tracheotomy was seen in 2 patients with massive tumor in the base of tongue (1 in each group). Severe dysphagia requiring NG tube feeding was seen in 3 patients in the RT + MISO group and 3 patients in the RT group. The initial complete response rate in the RT group was 53%, versus 48% in the RT + MISO group. The estimated 2-year loco-regional control rates were 10% for RT alone and 17% for RT + MISO (no significancy). These results indicate that the addition of misonidazole does not improve the efficacy of high fractional dose radiotherapy for management of unresectable head and neck carcinomas. However, high fractional dose radiotherapy can be administered for the management of advanced head and neck carcinomas with acceptable morbidity and thus, is a useful regimen for future clinical trials of hyperbaric oxygen or new hypoxic cell sensitizers.     

Radiation therapy alone or combined with misonidazole in the treatment of locally advanced non-oat cell lung cancer: report of an RTOG prospective randomized trial

From September 1979 to February 1983, 268 patients with unresectable, locally advanced (RTOG Stage III), non-small cell lung cancer were randomized to receive radiation therapy alone (RT) (50 Gy large field and 10 Gy boost), or combined with misonidazole (400 mg/m2 2-4 hr prior to RT daily for 5-6 weeks to a maximum dose of 12 g/m2 or until tumor progression). One hundred twenty-three patients who received irradiation alone and 116 given RT + misonidazole were evaluable for toxicity, time to tumor progression, and survival as of April 1987. The distribution of patient characteristics was similar in both treatment groups; 59% of the patients had a Karnofsky score of 90 or better, 53% had adenocarcinoma or large cell tumors, and 47% had Stage T3 tumors. Complete tumor regression was reported for 33 (27%) patients treated with radiation therapy alone and 24 (21%) who received misonidazole + RT. Median survival was 8 months with RT alone and 7.4 months with misonidazole + RT. Ninety-five percent of the patients have died. Seventy percent of the patients treated with radiation alone and 77% of those treated with misonidazole + RT died of progressive disease. Three patients treated with radiation alone and two with RT + misonidazole died subsequent to radiotherapy-related pneumonitis or pulmonary fibrosis. There was no significant improvement in response rates, local control, or survival for patients who received daily misonidazole along with irradiation compared with patients treated by irradiation alone.     

Muscle metastasis of squamous cell carcinoma of the uterine cervix]

Muscular metatasis are rare, their number is probably underestimate. The authors report a case of a patient treated, in 1993, for a squamous cell carcinoma of the uterine cervix. Five years later, the patient developed a metatasis to muscular psoas. She underwent combined surgical excision and adjuvant radiation therapy. The patient is alive and well 30 months after diagnosis of the metastasis.     

Hyperfractionated radiotherapy with or without misonidazole: results of a prospective randomized study in stage III-IV squamous cell carcinoma of the head and neck

From 1979 to 1980, 52 patients with Stage III-IV squamous cell carcinoma of the head and neck were included in a prospective randomized study on hyperfractionated radiotherapy with or without misonidazole. The radiotherapeutic schedule consisted of two weeks of treatment split by a rest-period of one month, 6 X 1.1 Gy fractions per day for 5 consecutive days (total dose: 2 X 33 Gy/30 f/5 d). Total dose of misonidazole was 12 g/m2 administered daily in 1.2 g/m2 fractions. The overall tolerance of misonidazole was good, with a neuropathy rate of 5.7%. Local control, recurrence and 3 year survival rates did not statistically differ between the two groups. The randomized trials published at the present time, including our own, suggest that misonidazole has no beneficial effect with classical, concentrated or multiple fractions per day radiotherapy.     

Mature results of a pilot study of pelvic radiotherapy with concurrent continuous infusion intra-arterial 5-FU for stage IIIB-IVA squamous cell carcinoma of the cervix.

PURPOSE: To evaluate the long-term results of continuous infusion intra-arterial 5-fluorouracil (CI IA 5-FU) given with concurrent pelvic radiotherapy (RT) for FIGO stage IIIB-IVA carcinoma of the cervix. METHODS AND MATERIALS: Between 1965 and 1974, 27 patients with extensive FIGO Stage IIIB (22 patients) or Stage IVA (5 patients) squamous cell carcinoma of the cervix were treated with CI IA 5-FU and RT. Twenty-one patients (78%) had bilateral pelvic wall involvement, 25 (93%) had massive tumors (> or =8 cm in diameter), 7 (27%) had involvement of the lower one-third of the vagina, and 15 (56%) presented with hydronephrosis. All patients underwent routine clinical staging, transperitoneal para-aortic lymph node dissection, and bilateral hypogastric artery catheter placement. 5-FU was continuously infused at a dose rate of 10 mg/kg/day on Days 1-15 of RT. The median dose of 5-FU was 376 mg/m2/day (range 270-692). All patients received concurrent pelvic RT to a median dose of 50 Gy at 2.0 Gy per fraction. Only 4 patients received intracavitary RT. The median follow-up of surviving patients was 190 months. RESULTS: The overall 5-year survival rate was 37%. For the 22 patients with FIGO Stage IIIB disease, the 5-year survival rate was 41%. The survival rate for 18 patients treated with only external beam radiation and chemotherapy for Stage IIIB disease was 33%. Four of 10 patients treated with only 50 Gy of external beam radiation and CI IA 5-FU were long-term survivors. Acute complications, including hematologic toxicity and skin reactions, were severe, with 1 death from neutropenic sepsis. Severe late complications were only observed in patients treated with > or =60 Gy of external beam radiation. CONCLUSIONS: While this series is small, the fact that 4 patients with massive Stage IIIB tumors survived after a total radiation dose of only 50 Gy suggests that RT with CI IA 5-FU deserves further study. Modifications in dose, technique, and route of administration should reduce toxicity, and the addition of intracavitary RT should improve the local effectiveness of combined treatment.     

Detection of squamous cell carcinoma antigen in normal squamous epithelia and in squamous cell carcinomas of the uterine cervix

Squamous cell carcinoma (SCC) antigen is a subfraction of tumor antigen TA-4 isolated from a cervical squamous cell carcinoma. The specificity of SCC antigen and the factors influencing its release into serum were evaluated. Antigen concentrations were measured in 157 tissue extracts and in 188 sera of patients with nonmalignant or malignant gynecologic diseases. A commercial radioimmunoassay based on polyclonal antibodies (Abbott Laboratories, North Chicago) was used. Cytosol concentrations were significantly higher (P less than 0.005) in normal squamous epithelia (means = 6040 ng/mg cell protein [CP]) and in squamous cell carcinomas (means = 2483 ng/mg CP) of the exocervix than those in normal columnar epithelia and in adenocarcinomas of the endocervix, endometrium, ovary, and breast (means = 1-508 ng/mg CP). Despite the high antigen concentrations in normal squamous epithelia, elevated serum levels (greater than 2.5 ng/ml) were almost exclusively found in patients with cervical squamous cell carcinomas. The sensitivity of SCC antigen as a marker for primary carcinomas was 61%, increasing from 29% in Stage I to 89% in Stage IV. The positivity rate was higher in women with well-differentiated (78%) and moderately differentiated carcinomas (67%) than in those with poorly differentiated tumors (38%). The results show that SCC antigen is not tumor specific. The release into serum is independent of local tissue content, but is apparently influenced by the infiltrative growth, the mass, and the degree of histologic differentiation of the tumor.     

Serum alpha-N-acetylgalactosaminidase is associated with diagnosis/prognosis of patients with squamous cell carcinoma of the uterine cervix

Serum alpha-N-acetylgalactosaminidase (NaGalase) is responsible for the deglycosylation of vitamin D(3)-binding protein (Gc protein). The deglycosylated Gc protein cannot be converted into major macrophage-activating factor (MAF), leading to immunosuppression. NaGalase is universally detected in a variety of cancer patients, but not in healthy individuals (Cancer Res. 56 (1997) 2827-2831). However, the diagnostic/prognostic utility of NaGalase in squamous cell carcinoma (SCC) of the uterine cervix is not known. To address this issue, the serum NaGalase was quantitatively determined in 210 patients with different stages of SCC of the uterine cervix. NaGalase levels were increased with the progression of the cancer. After radiotherapy, the increased levels returned toward or to normal levels in early stages (FIGO stage I-IIB) but not in advanced stages (FIGO stage III-IV). The present study revealed that the amount of NaGalase in the patient's bloodstream reflects the tumor burden and aggressiveness of the disease. We conclude that NaGalase is an independent predictor of diagnosis/prognosis in SCC of the uterine cervix, and therefore suggest that quantitative NaGalase alteration may reflect important differences in the immunological functions of these neoplasms.     

A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study

A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin.     

Large fraction irradiation with or without misonidazole in advanced non-oat cell carcinoma of the lung: a phase III randomized trial of the RTOG. Radiation Therapy Oncology Group

The Radiation Therapy Oncology Group (RTOG) investigated the use of misonidazole as an hypoxic cell sensitizer in a Phase III prospective randomized trial employing radiotherapy, 600 cGy twice weekly to a total of 3600 cGy with and without misonidazole in the treatment of locally advanced non-metastatic squamous cell, adeno, or large cell carcinoma of the lung. Between January 1980 and July 1983, 117 patients from 21 institutions were enrolled. One-hundred eight patients were evaluable; 53 in the combined treatment arm and 55 in the radiation alone arm. Grade 3 or worse complications associated with radiation occurred in 17% of patients. Esophageal toxicity accounted for the majority of complications. Two (4%) patients in the radiotherapy plus misonidazole group experienced grade 3 peripheral neurotoxicity. Complete or partial responses were produced in 58% of the patients with radiotherapy alone and 36% of those treated with radiotherapy plus misonidazole (p = 0.08). At the time of first progression, over 50% of the patients had persistent local disease. Median survival was 7 months regardless of treatment. Misonidazole in the dose and schedule employed did not enhance the effect of radiotherapy on either local tumor control or overall survival in patients with advanced lung cancer.     

Prognosis of patients with stage IIIb-IVa squamous cell carcinoma of the cervix following intra-arterial neoadjuvant chemotherapy.

Our purpose was to determine the long-term prognosis in patients with stage IIIb-IVa squamous cell carcinoma of the cervix who were treated with intra-arterial neoadjuvant chemotherapy (NAC), and to analyze factors related to prognostic value. We assessed the disease-free survival of 21 patients with FIGO stage IIIb-IVa squamous cell carcinoma of the cervix treated with intra-arterial NAC (cisplatin 70 mg/m2 and peplomycin sulfate 30 mg/m2) followed by irradiation therapy. Before chemotherapy, five factors (age, clinical stage, histologic type, parametrial involvement and serum level of SCC) were evaluated for their correlation with disease-free survival. The absolute 5-year disease-free survival rate for the entire group was 52%, with a median follow-up time in disease-free survivors of 87 months. Among the prognostic factors, age was the only one to be significantly correlated with disease-free survival; older (> 60 years) patients showed a significantly better disease-free survival rate than did younger (< 60 years) patients (p < 0.05, log-rank test). The absolute 5-year disease-free survival rate was 69% for older patients and 25% for younger patients. Univariate Cox's proportional hazard model also demonstrated that age was a significant prognostic factor as a continuous variable (p < 0.01). Intra-arterial NAC thus appeared to be effective in treating older patients with stage IIIb-IVa squamous cell carcinoma of the cervix.     

High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial

BACKGROUND: This was a prospective randomized clinical trial undertaken at our institution to compare low-dose-rate (LDR) intracavitary radiation therapy versus high-dose-rate (HDR) intracavitary radiation therapy for the treatment of cervical carcinoma. METHODS: From January 1984 to December 1997, a total of 132 patients with Stage II or IIIB of invasive carcinoma of the uterine cervix were entered into this randomized study. Treatment arm by HDR or LDR was allocated according to the month of each patient's birth. External irradiation consisted of whole pelvis irradiation and pelvic irradiation. Doses of external irradiation for both groups were identical. The authors used 0.588 as the conversion factor of total intracavitary dose from LDR to HDR. RESULTS: The 5-year disease specific survival rates of Stage II and III patients treated with HDR were 69% and 51% whereas those with LDR were 87% and 60%, respectively. The 5-year pelvic recurrence free survival rates of Stage II and III patients treated with HDR were 89% and 73% whereas those with LDR were 100% and 70%, respectively. There was no significant difference in disease specific survival or pelvic recurrence free survival rates between HDR and LDR. The actuarial complication rate (Radiation Therapy Oncology Group Grade 3, 4, or 5) at 5 years was 10% in the HDR group and 13% in the LDR group, and the difference between the HDR and LDR groups was not statistically significant. CONCLUSIONS: The pelvic control or actuarial complication rates were comparable between HDR and LDR treatment. The difference between the disease specific survival rates for HDR and LDR was not statistically significant for Stage II or III, although in Stage II, patients treated with LDR appeared to have a better survival rate than those treated with HDR.