A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma

To clarify the role of thermoradiotherapy for FIGO Stage IIIB cervical carcinomas, both the clinical response and survival of patients treated with radio- or thermoradiotherapy were investigated. Forty patients with Stage IIIB uterine cervix carcinoma were treated with external beam irradiation to the pelvis, combined with iridium 192 high-dose-rate intracavitary brachytherapy. All patients were divided randomly into the following two groups: the radiotherapy (RT) group of 20 patients, who underwent radiotherapy alone; and the thermoradiotherapy (TRT) group of 20 patients, who underwent three sessions of hyper-thermia in addition to radiotherapy. The primary endpoint of this study was local complete response and survival. A complete response was achieved in 50% (10 of 20) in the RT group versus 80% (16 of 20) in the TRT group (p = 0.048). The 3-year overall survival and disease-free survival of the patients who were treated with TRT (58.2 and 63.6%) were better than those of the patients treated with RT (48.1 and 45%), but these differences were not significant. The 3-year local relapse-free survival of the patients who were treated with TRT (79.7%) was significantly better than that of the patients treated with RT (48.5%) (p = 0.048). TRT, as delivered in this trial, was well tolerated and did not significantly add to either the relevant clinical acute or long-term toxicity over radiation alone. TRT resulted in a better treatment response and 3-year local relapse-free survival rate than RT for patients with FIGO Stage IIIB cervical carcinoma.     

A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma

To clarify the role of thermoradiotherapy for FIGO Stage IIIB cervical carcinomas, both the clinical response and survival of patients treated with radio- or thermoradiotherapy were investigated. Forty patients with Stage IIIB uterine cervix carcinoma were treated with external beam irradiation to the pelvis, combined with iridium 192 high-dose-rate intracavitary brachytherapy. All patients were divided randomly into the following two groups: the radiotherapy (RT) group of 20 patients, who underwent radiotherapy alone; and the thermoradiotherapy (TRT) group of 20 patients, who underwent three sessions of hyperthermia in addition to radiotherapy. The primary endpoint of this study was local complete response and survival. A complete response was achieved in 50% (10 of 20) in the RT group versus 80% (16 of 20) in the TRT group (p = 0.048). The 3-year overall survival and disease-free survival of the patients who were treated with TRT (58.2 and 63.6%) were better than those of the patients treated with RT (48.1 and 45%), but these differences were not significant. The 3-year local relapse-free survival of the patients who were treated with TRT (79.7%) was significantly better than that of the patients treated with RT (48.5%) (p = 0.048). TRT, as delivered in this trial, was well tolerated and did not significantly add to either the relevant clinical acute or long-term toxicity over radiation alone. TRT resulted in a better treatment response and 3-year local relapse-free survival rate than RT for patients with FIGO Stage IIIB cervical carcinoma.     

Bax and Bcl-2 protein expression following radiation therapy versus radiation plus thermoradiotherapy in stage IIIB cervical carcinoma

BACKGROUND: The relative amounts of Bcl-2 and Bax proteins determine cell survival or death following an apoptotic stimulus. To clarify the molecular mechanism of cell death after radiotherapy or thermoradiotherapy and its relation to the response of AJCC/UICC Stage IIIB cervical carcinomas, the expression of Bax and Bcl-2 proteins was investigated both before and in the course of treatment given during this study. METHODS: Thirty-seven patients with Stage IIIB carcinoma of the uterine cervix were treated with external beam irradiation to the pelvis combined with iridium-192 high-dose-rate intracavitary brachytherapy. All patients were randomized to one of the following two groups: the radiotherapy (RT) group of 19 patients who were given radiotherapy alone, and the thermoradiotherapy (TRT) group of 18 patients who were given 3 sessions of hyperthermia in addition to RT. Specimens of the cervical tumors were obtained by punch biopsy both before and in the course of the treatment (after a total dose of 10.8 grays ?Gy for the RT group or after 10.8 Gy plus 1 session of hyperthermia for the TRT group). The tumor sections were stained with anti-Bax and anti-Bcl-2 monoclonal antibody. On the basis of the percentage of immunopositive cells, both pretreatment and posttreatment samples were scored. Furthermore, relative changes in protein expression were determined by comparing the pretreatment scores with those in the course of treatment. In addition, treatment response was evaluated. RESULTS: A complete response was achieved in 52.6% (10 of 19) of the RT group versus 83. 3% (15 of 18) of the TRT group (P = 0.049). Better tumor control was accompanied by increased Bax expression, i.e., 10.5% (2 of 19) of the RT group versus 44.4% (8 of 18) of the TRT group (P = 0.02). The respective number of patients who partially responded (PR) or did not respond to treatment (NC) was 26.3% (5 of 19) and 21.1% (4 of 19) of the RT group versus 11.1% (2 of 18) and 5.6% (1 of 18) of the TRT group (P = 0.2 for both the PR and NC subgroups). CONCLUSIONS: TRT was found to result in better treatment responses than RT for patients with Stage IIIB cervical carcinoma. An additive or synergistic antitumor effect of TRT is likely to occur through induction of apoptosis involving one of the bax pathways.     

A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix.

Because of the poor results in stage III B carcinoma of the cervix with standard treatment using radiotherapy alone, we designed a randomized trial to determine whether administration of chemotherapy before pelvic irradiation would improve survival. Between May 1984 and August 1986, 107 patients with previously untreated squamous cell carcinoma were randomly assigned, after stratification by age (less than 50 v greater than 50 years), extent of parametrial involvement (unilateral v bilateral), and lymphangiographic findings (negative v positive) to pelvic radiotherapy (RT; arm A) or three cycles of chemotherapy (CT; bleomycin, vincristine, mitomycin, and cisplatin [BOMP]), followed by the same radiotherapy regimen (CT + RT; arm B). The groups were balanced by age, performance status, extent of parametrial involvement, bulkiness of cervical disease, nodal involvement, and presence of hydronephrosis. Minimal follow-up is 34 months. A complete local response was observed in 32.5% of the patients in arm A and in 47% of the patients in arm B (P = .19). Overall 5-year survival rates were 39% for the RT arm and 23% for the CT + RT approach (P = .02). Toxicity was severe in arm B and included fatal pulmonary toxicity in four patients. Locoregional and distant failures were similar in both groups. We conclude that, despite a satisfactory response rate, neoadjuvant BOMP chemotherapy adversely affects survival in stage III B cervical cancer and is associated with unacceptable toxicity.     

A randomized trial comparing radiation therapy versus concomitant radiation therapy and chemotherapy in carcinoma of the thoracic esophagus.

From September 1982 to December 1985, 59 previously untreated patients with Stage II squamous cell carcinoma of the thoracic esophagus were randomly assigned to receive radiation therapy (RT) alone versus the concomitant use of RT and chemotherapy (CT) with 5-fluorouracil (5-FU), mitomycin C, and bleomycin (RT + CT). Thirty-one patients were randomized to the RT regimen and 28 to the RT + CT regimen. The complete local response rate was 58% for the RT group and 75% for the RT + CT group (P = 0.77). The median duration of response was 8 months for both groups. The overall 5-year survival rates were 6% and 16% (P = 0.16) for the RT and RT + CT groups, respectively. Acute toxicities were more pronounced in the RT + CT group. This clinical trial did not detect a difference in outcome with combined-technique therapy. This result must be interpreted with caution because of the small number of patients entered in this trial. Confirmation of the value or lack of value for combined therapy will require additional larger clinical trials.     

Hydroxyurea plus pelvic radiation versus placebo plus pelvic radiation in surgically staged stage IIIB cervical cancer

Forty-five evaluable patients with stage IIIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties of hydroxyurea. All patients were documented to be without para-aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. The original plan of therapy was for continuous therapy (200 rads/day) of 6,000 rads of pelvic radiation for 6 weeks plus intrauterine radium. However, 16 patients received 6,000 rads in 8 weeks by split-course therapy (2-week rest after 3,000 rads) plus radium. Twenty-nine patients received the planned continuous therapy. The median dose of pelvic radiation for patients who received continuous therapy or split-course radiation was 6,000 rads. Leukopenia (WBC less than 2,500/mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than .001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation skin reaction, diarrhea, or radiation-induced complications requiring surgical correction. The estimated 5-year progression-free survival rate for the combined, continuous, and split-course radiation therapy hydroxyurea patients was 60%, and its was 52% for the corresponding placebo patients (P = .49). However, the estimated 5-year progression free survival rate for the correctly treated patients (continuous therapy) was 91% for the hydroxyurea group and 60% for the placebo group (P less than .06).     

ICRF 159 plus radiation versus radiation therapy alone in cervical carcinoma. A double-blind study

In a double-blind trial the effect of ICRF 159 or placebo associated with radiotherapy was compared in 70 patients with cervical carcinoma. No significant differences were found on histopathological examination of surgical specimens obtained 6 weeks after the end of the treatment. Clinical evaluation after a follow-up of 46 +/- 5 months, also showed no significant effect of ICRF 159 with radiotherapy.     

Expression of hypoxic-inducible factor 1alpha predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma

PURPOSE: Hypoxia-inducible factor-1alpha (HIF-1alpha) is an intrinsic marker of tumor hypoxia. It has been considered that the hypoxic status reduces radiosensitivity, but the role of HIF-1alpha in advanced cervical carcinoma is still unclear. The objective of this study was to clarify the impact of HIF-1alpha, human papillomavirus (HPV), and other molecular factors, such as p53, bax, bcl-2, and their correlations on the outcome of patients with Stage IIIB cervical carcinoma in radiation therapy. METHODS AND MATERIALS: We analyzed 38 patients with FIGO Stage IIIB squamous cell carcinoma of the cervix treated with radiation therapy alone. All patients received the combination therapy of external beam irradiation and low-dose-rate intracavity brachytherapy. The tumor expressions of HIF-1alpha, p53, bax, and bcl-2 were examined by immunohistochemical staining of the pretreatment paraffin embedded specimens. HPV infection was also detected by polymerase chain reaction. The effects of these parameters on clinical outcomes were analyzed by univariate analysis. RESULTS: Of 38 patients, high expression of HIF-1alpha, p53, bax, and bcl-2 were seen in 17 (45%), 22 (58%), 15 (39%), and 15 (39%) patients, respectively, and 28 patients (74%) showed positive infection with HPV. There was a significant positive correlation between high HIF-1alpha expression and disease recurrence (p < 0.05). Furthermore, HIF-1alpha had a significant correlation with the recurrence-free survival rate (p = 0.04). No statistical correlation was noted between high HIF-1alpha expression and the local control rate (p = 0.17), whereas the HIF-1alpha status predicted distant metastasis with strong significance (p = 0.03). Conversely, other factors demonstrated no impact on the clinical outcome. CONCLUSIONS: The present results suggest that HIF-1alpha is an important prognostic factor, especially for predicting future metastasis after radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix.     

Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial

To assess the efficacy and safety of Adriamycin (Adria Laboratories, Columbus, OH) in inoperable hepatocellular carcinoma (HCC), 60 patients were randomized to receive Adriamycin 60 to 75 mg/m2 at 3-week intervals and 46 patients to receive no antitumor therapy. The median survival rate of the Adriamycin group was 10.6 weeks; that of the group receiving no antitumor therapy was 7.5 weeks (P = 0.036). Adriamycin induced tumor regression of 25% to 50% in 5% of patients and of over 50% in only 3.3% of patients. It caused fatal complications (septicemia and cardiotoxicity) in 25% of patients. The severity of neutropenia leading to septicemia for a particular dose was unpredictable. Four of eight patients who developed cardiotoxicity received less than 500 mg/m2 of Adriamycin. We conclude that Adriamycin is not an ideal drug for the treatment of inoperable HCC.     

The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy alone

BACKGROUND: It has been suggested that the p53 tumor suppressor gene regulates the radiosensitivity in human malignancies after irradiation; however, in cervical carcinoma, the role of the p53 gene is still unclear because of inactivation of functional p53 by infection with human papillomavirus (HPV). The objective of this study was to clarify the effects of p53 status and HPV infection on the clinical outcome of patients with cervical carcinoma after undergoing radiation therapy. METHODS: Fifty-two patients with International Federation of Gynecology and Obstetrics Stage IIIB squamous cell carcinoma of the cervix who received radiation therapy alone were reviewed. The combination of external beam irradiation therapy and three sessions of intracavity brachytherapy irradiation was performed for all patients. Genomic DNA extracted from paraffin embedded tissues was examined for HPV types 16, 18 and 33 by the polymerase chain reaction (PCR) method and for p53 status by PCR-single-strand conformation polymorphism (PCR-SSCP) technique. The effects of HPV infection, p53 status, and other parameters on clinical outcome were investigated by univariate analysis. RESULTS: HPV-DNA was detected in 40 patients (76.9%), and 14 patients (26.9%) had mutations of the p53 gene in the study. There was a significant correlation between the existence of HPV and p53 status (P < 0.001). Mutations of the p53 gene were detected in 6 of 12 patients (50%) who had local recurrent tumors, whereas p53 were wild type in 32 of 40 patients (80%) who achieved local control. The p53 mutation had a significant correlations with local tumor recurrence. Furthermore, p53 status caused statistical significant differences in the curves of the recurrence free survival rate and local control rate as determined by the log rank test (P = 0.02 and P = 0.03, respectively). Conversely, no obvious correlation with any clinical outcome for patients with cervical carcinoma was found concerning HPV infection. CONCLUSIONS: It is possible that the p53 gene may be used as a predictive factor in radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix.     

Cisplatin-ifosfamide as neoadjuvant chemotherapy in stage IIIB cervical uterine squamous-cell carcinoma

Survival in patients with advanced cervical cancer (stage III B) treated by radical radiotherapy is low. In this study we attempted to assess the efficacy of thecis-diamminedichloroplatinum(II) (CDDP)-ifosfamide combination as neoadjuvant chemotherapy in advanced cervical cancer. The treatment schedule was: 20 mg/m² CDDP on days 1–5; 1.5 g/m² ifosfamide on days 1–5; and 900 mg/m² mesna on days 1–5. Courses were given every 28 days. Radiotherapy was given 15 days after the completion of chemotherapy. A total of 26 patients were entered in this trial. Of the 24 patients evaluable for response, 15 (62.5%) achieved at least a 50% reduction in tumor volume, 6 (25%) showed stable disease, and three (12.5%) had progressive disease. At 38 months (mean follow-up) after completion of radiotherapy, 13 of the 24 (54%) evaluable patients were disease-free; 73% of the patients responding to chemotherapy vs 22% of the nonresponders remained free of disease (Fisher's exact test:P<0.02). major=" hematologic=" depression=" occurred=" in=" 2=" of=" the=" 26=" patients=" evaluable=" for=" toxicity.=" no=" cns=" toxicity=" was=" detected.=" these=" results=" are=" superior=" to=" those=" obtained=" by=" radical=" radiotherapy=" alone.=" future=" treatment=" should=" be=" directed=" toward=" improving=" response=" rates=" as=" the=" best=" way=" of=" increasing=" both=" local=" and=" distant=" long-term=" disease=" control=" in=" these=">Presented at the Satellite Symposium Ifosfamide in Gynecological Tumors of the 5th European Conference on Clinical Oncology and Cancer Nursing, London, September 3–7, 1989     

Complete resolution of stage IIIB juvenile nasopharyngeal angiofibroma with radiation therapy

Juvenile nasopharyngeal angiofibroma is a benign, locally aggressive, vascular tumour of adolescent males. Extension to intracranial cavity is not uncommon and presents difficulties in management. Here we report a patient who had Radkowsky stage IIIB lesion, with blood supply from internal carotid artery. In view of anticipated problems with surgery, the patient was treated with 30 Gy in 15# external beam radiotherapy. On follow up, tumour was noted to disappear gradually overtime and at 3 years complete disappearance was noted with normal return of vision. Hence we are re-affirming the earlier studies than angiofibroma mass regresses gradually after completion of radiotherapy. Radiotherapy is a useful way of treating angiofibroma with significant intracranial extension.     

Randomized phase II study of immunomodulator Z-100 in patients with stage IIIB cervical cancer with radiation therapy

OBJECTIVE: To find the optimal dose of immunomodulator Z-100 in patients with stage IIIB squamous cell carcinoma of the cervix in combination with radiation therapy. METHODS: The patients were randomly assigned to the dosage levels of 2, 20 or 40 mug of Z-100. Z-100 was subcutaneously injected twice a week during radiotherapy and once in two weeks during the maintenance period. The response rate after radiotherapy was evaluated, and the optimal clinical dosage was then determined. Safety of Z-100 was evaluated during the radiation therapy and maintenance therapy. Survival was also evaluated. RESULTS: A total of 116 patients were entered. The adverse reactions were not dose-dependent and no serious toxicities were observed. The response rates were 72.2% (26/36) in the 2 microg group, 84.6% (33/39) in the 20 microg group and 94.3% (33/35) in the 40 microg group (P = 0.006). However, the survival was not significantly different. CONCLUSIONS: The optimal dose of Z-100 was determined to be 40 mug in combination with radiation therapy for stage IIIB cervical cancer. However, impact of Z-100 on survival must be determined by the placebo controlled randomized trial, because survival benefit was not observed in this small population study.     

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma

BACKGROUND: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.     

早期鼻咽癌单纯外照射与加近距离治疗的远期结果比较

目的随机比较单纯常规外照射与外照射加近距离治疗对早期鼻咽癌原发灶的局部控制疗效和并发症。方法对126例初治的、福州分期为T1期和部分12期(口咽、颈动脉鞘、椎前软组织受侵者除外)鼻咽癌病例进行前瞻性分组。单纯常规外照射组(RT)61例，外照射加^192Ir高剂量率近距离治疗组(RB)65例。26例T1期在疗前经抽签随机接受单纯外照射66～70Gv或外照射56Gv加近距离治疗10～16Gy，1～2次(中位剂量16Gy)；100例12期先采用常规外照射至50Gy后，行CT或MRI检查，对咽旁间隙消退满意的病例入组随机接受单纯外照射(中位剂量72Gv)或外照射(中位剂量66Gy)加近距离治疗8～24Gy，1～3次(中位剂量16Gy)。近距离治疗在外照射结束后1周进行，剂量参考点距施源器中心轴的距离为7～12mm，单次近距离照射剂量为5～8Gy／周。结果外照射结束时RT组鼻咽病灶残留6例，消退55例；RB组残留13例，?肖退46例，未评价6例。RT组鼻咽部失败8例，RB组鼻咽部失败7例(包括单独颅底失败2例)。5年鼻咽(颅底)局部控制率RT组为86％，RB组为88％。5年总生存率RT组为83％，RB组为84％(P=0．84)。放射性脑病RT组为10例(1级4例，2级6例)，RB组为7例(1级4例，2级3例)。张口困难发生率RT组明显高于RB组(26％：10％，P=0．02)。结论对早期鼻咽癌行计划性外照射加腔内近距离治疗，能获得与单纯常规外照射相近的局部控制率及总生存率，并降低外照射剂量和减低张口困难的发生率。