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.

Low dose rate brachytherapy in the treatment of cervical carcinoma.

The use of ICRT is a critical component in the successful treatment of cervical carcinoma with radiation therapy. Low dose rate ICRT allows optimization of the therapeutic ratio by utilizing physical and radiobiological principles. An optimal geometric relationship among the intracavitary applicators, the tumor, and other pelvic tissues is critically important in maximizing tumor control rates while simultaneously minimizing normal tissue complication rates. Treatment policies that have judiciously combined EBRT and LDR ICRT have achieved very high tumor control rates while maintaining acceptable complication rates. The use of HDR ICRT forfeits some of the radiobiological advantage of LDR ICRT. It remains to be determined whether this difference will have significant clinical consequences.

Apoptosis and the Bcl-2 gene family -- patterns of expression and prognostic value in stage I and II follicular center lymphoma.

PURPOSE: The prognostic significance of spontaneous levels of apoptosis and Bcl-2, Bax, and Bcl-x protein expression in follicular center lymphoma (FCL) is unknown. The objectives of this retrospective study were (1) to investigate the relationship between pretreatment apoptosis levels and long-term treatment outcome in patients with Stage I and II FCL; (2) to define the incidence and patterns of Bax and Bcl-x protein expression in human FC; and (3) to determine the relationship of Bcl-2, Bax, and Bcl-x expression with spontaneous apoptosis levels and clinical outcome in localized FCL. METHODS AND MATERIALS: Between 1974 and 1988, 144 patients with Stage I or II FCL were treated. Hematoxylin and eosin (H & E) stained tissue sections of pretreatment specimens were retrieved for 96 patients. Treatment consisted of regional radiation therapy (XRT) for 25 patients, combined modality therapy (CMT) consisting of combination chemotherapy and XRT for 57 patients, and other treatments for 14 patients. Median follow-up for living patients was nearly 12 years. The apoptotic index (AI) was calculated by dividing the number of apoptotic cells by the total number of cells counted and multiplying by 100. Expression of Bcl-2, Bax, and Bcl-x proteins was assessed using immunohistochemistry. RESULTS: The mean and median AI values for the entire group were 0.53 and 0.4, respectively (range: 0-5.2). The AI strongly correlated with cytologic grade, with mean AI values of 0.25 for grade 1, 0.56 for grade 2, and 0.84 for grade 3 (p < 0.0005; Kendall correlation). A positive correlation was present between grouped AI and grouped mitotic index (MI) (p = 0.014). For patients treated with CMT, an AI < 0.4 correlated with improved freedom from relapse (FFR) p = 0.0145) and overall survival (OS) (p = 0.0081). An AI < 0.4 did not correlate with clinical outcome for the entire cohort or for patients receiving XRT only. Staining of tumor follicles for the Bcl-2 protein was positive, variable, and negative in 73%, 15%, and 12% of cases, respectively. Positive staining of tumor follicles was observed in 96% of cases for both the Bax and Bcl-x proteins. Expression of Bcl-2, Bax, or Bcl-x did not correlate with AI or clinical outcome. CONCLUSION: The level of spontaneous apoptosis in pretreatment specimens correlates with cytologic grade of FCL and is a significant predictor of FFR and OS for patients with localized FCL receiving CMT.

Figo IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy.

PURPOSE: To define patient, tumor, and treatment factors that influence the outcome of patients with FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix. METHODS AND MATERIALS: The records of 1,096 patients treated with radiation therapy between 1960 and 1993 for FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix were reviewed retrospectively. Of these, 983 (90%) were treated with curative intent and 113 were treated only to achieve palliation of symptoms. Of 907 patients who completed the intended curative treatment, 641 (71%) were treated with a combination of external beam irradiation (EBRT) and intracavitary irradiation (ICRT) and 266 (29%) were treated with EBRT only. The median duration of treatment for these 907 patients was 51 days. Between 1966 and 1980, only 52% of patients who completed treatment with curative intent received ICRT, compared with 92% of patients treated during 1981-1993, an increase that reflects an evolution in the philosophy of treatment for advanced tumors. In general, the intensity of ICRT correlated inversely with the dose of EBRT to the,central pelvis. Median follow-up of surviving patients was 134 months. RESULTS: For 983 patients treated with initial curative intent, disease-specific survival (DSS) was significantly worse for those who were < 40 years old, had experienced more than a 10% weight loss, or had a hemoglobin level < 10 g/dl before or during radiation therapy. Tumor factors that correlated with a relatively poor DSS were bilateral pelvic wall involvement, clinical tumor diameter > or = 8 cm, hydronephrosis, lower vaginal involvement, and evidence of lymph node metastases on lymphangiogram (p < 0.01 in all cases). For the 907 patients who completed treatment with curative intent, 641 who had ICRT had a DSS of 45% at 5 years, compared with 24% for those treated with EBRT alone (p < 0.0001). Those who received > 52 Gy of EBRT to the central pelvis had DSS rates of 27-34%, compared with 53% for patients treated with lower doses of EBRT to the central pelvis and more intensive ICRT (p < 0.0001). At 5 years, the actuarial risk of major complications was also greater for patients treated with > 52 Gy of EBRT to the central pelvis (57-68%), compared with those who had 48-52 Gy (28%) and those who had < or = 47 Gy of EBRT to the central pelvis (15%) (p < 0.0001). Outcome was also compared for four time periods during which different treatment policies were in place for patients with Stage IIIB disease. The highest DSS (51%) and lowest actuarial complication rate (17%) were achieved during the most recent period (1981-1993) when modest doses of EBRT were combined with relatively intensive ICRT (p < 0.01 for both comparisons). CONCLUSION: Aggressive use of ICRT, carefully balanced with pelvic EBRT, is necessary to achieve the best ratio between tumor control and complications for patients with FIGO Stage IIIB carcinoma of the cervix. In our experience, the highest DSS rates and the lowest complication rates were achieved with a combination of 40-45 Gy of EBRT combined with ICRT.

Lymphoma of the nasal cavity and paranasal sinuses: improved outcome and altered prognostic factors with combined modality therapy.

BACKGROUND: Lymphoma of the nasal cavity and paranasal sinuses is a rare presentation of extranodal lymphoma with a natural history that is not well characterized in this era of combination chemotherapy. The goals of this retrospective study were 1) to define the natural history of sinonasal lymphomas; 2) to compare the results of radiation therapy (XRT) alone with those of combined modality therapy (CMT) in the treatment of patients with lymphoma of the nasal cavity and paranasal sinuses; and 3) to define prognostic factors for each treatment. METHODS: Between 1947 and 1993, 70 patients with newly diagnosed lymphoma of the nasal cavity and paranasal sinuses were treated. The Ann Arbor stages were: Stage IE: 42 patients; Stage IIE: 14 patients; Stage IIIE: 2 patients; and Stage IV: 12 patients. The distribution of T classifications of the primary tumors was as follows: T1: 2 patients; T2: 16; T3: 18; and T4: 34. Greater than 90% of the patients had intermediate grade lymphoma (Working Formulation), and none had follicular lymphoma. Twenty-eight patients received XRT alone, and 42 received CMT. RESULTS: The actuarial 5-year freedom from progression (FFP) and overall survival (OS) rates for the entire group were 57% and 52%, respectively. For patients with localized disease (Stages IE and IIE) receiving CMT, the actuarial 5-year FFP and OS were 83% and 67%, respectively. In multivariate analysis, treatment with CMT (P = 0.0005) and stage (IE vs. IIIE-IV) (P = 0.0001) were associated with improved FFP. In the group of patients receiving XRT, extent of disease (Stage IE, T1-3 vs. Stage IE, T4 vs. Stage IIE-IV) (P = 0.0001) was the only clinical characteristic associated with improved FFP in multivariate analysis. For patients receiving CMT, International Index (0 vs. 1-3 vs. 4, 5) (P = 0.0001) was the only significant factor predictive of improved FFP in multivariate analysis. One patient failed in the central nervous system (CNS) after initial therapy as a result of a radiation therapy marginal miss. CONCLUSIONS: In a Western population, patients with localized lymphoma of the nasal cavity and paranasal sinuses have a favorable prognosis when treated with CMT. FFP is significantly improved by treatment with CMT. For patients treated with XRT, extent of disease is the strongest predictor of outcome. International Index is the most significant prognostic factor for patients receiving CMT. Failure in the CNS is rare after initial therapy and is associated with local failure.

Technical and tumor-related factors affecting outcome of definitive irradiation for localized carcinoma of the prostate.

PURPOSE: The influence of some tumor-related and technical factors on therapeutic outcome is analyzed in 738 patients with histologically confirmed carcinoma of the prostate treated with definitive irradiation. METHODS AND MATERIALS: This is a retrospective study of the records of the Radiation Oncology Center. The information was coded on computer-compatible forms and analyzed with multiple cross-reference checks to ensure data reliability. Detailed analysis of portal films and dose distribution isodose curves was carried out in 310 patients on whom this information was readily available. All patients were followed-up for a minimum of 3 years (median observation, 6.5 years). RESULTS: Disease-free survival rates in Stages A2 (T1b) and B (T2) were 76% at 5 years and 62% at 10 years; in Stage C (T3) it was 57% at 5 years and 38% at 10 years. Overall, prostate recurrence rates were: 8% for Stage A2, 17% for Stage B, 28% for Stage C, and 46% for Stage D1 (T4). The 10-year actuarial local failure rate by stage was 20% in Stage A2 (T1b), 24% in Stage B (T2), 40% in Stage C (T3), and 70% in Stage D1 (T4) tumors. When the inferior margin of the portals was at or caudal to the ischial tuberosity, the actuarial 5-year pelvic failure rate was 0% for Stage A2 (T1b), 18% for Stage B (T2), and 20% for Stage C (T3), in contrast to 60% for Stage A2 (T1b), 27% for Stage B (T2), and 38% for Stage C (T3) when the inferior margin was cephalad to the ischial tuberosity (p = 0.05 in Stage C). Local tumor control was comparable in Stages A2 (T1b) and B (T2) when either small fields limited to the prostate and periprostatic tissues were used or, in addition, the pelvic lymph nodes were irradiated (85% and 80%, respectively). In Stage C (T3) there was significantly better pelvic tumor control (80% of 274 patients) when all of the pelvic (including common iliac) lymph nodes were treated compared with 65% in a group of 137 patients on whom the lymph nodes were irradiated with smaller fields (14 x 14 cm) (p = 0.01). In Stage C (T3), 30 patients treated with doses less than 6000 cGy had a 50% overall pelvic failure rate compared with 35% in 20 patients receiving 6500 cGy and 24% in 362 patients treated with 7000 cGy (p = 0.01). Pelvic tumor control or failure was closely associated with development of distant metastasis. In patients with pelvic tumor control, the distant metastasis rate was 18% for stages A2 (T1b) and B (T2) and 30% for stage C (T3), in contrast to 30% (p = 0.02) and 65% (p < 0.01), respectively, when prostate/pelvic failure was detected. CONCLUSION: Volume treated and dose of irradiation are important factors influencing local/pelvic recurrence rate in carcinoma of the prostate, particularly in stage C tumors. With recent advances in three-dimensional treatment planning and conformal radiation therapy techniques, it is imperative to determine optimal volumes and doses of irradiation to be delivered to these patients while minimizing morbidity to enhance the role of irradiation in the management of localized carcinoma of the prostate.