Short duration neoadjuvant chemotherapy followed by radiotherapy for advanced carcinoma of the cervix: results and prognostic variables.

PURPOSE: The value of neoadjuvant chemotherapy in squamous cell carcinomas of the cervix has not been proven. It has been suggested that the potential benefit of this therapy on local and occult metastatic disease could be offset by delaying effective radiation therapy and selection of more aggressive tumor clones. This report examines the potential impact of short duration neoadjuvant chemotherapy on the response and outcome of advanced carcinoma of the cervix. MATERIALS AND METHODS: Between 1993 and 1997, 37 patients with advanced squamous cell carcinoma of the cervix (FIGO Stages IIB to IV) were enrolled in a prospective nonrandomized study using short duration neoadjuvant chemotherapy. Median age was 57 years (range: 34-70). Twenty-one patients (57%) had Stage IIB disease, one (3%) had Stage IIIA, 11 (30%) Stage IIIB, and four (11%) had Stage IV disease. The average tumor diameter at presentation assessed by physical examination and by CT scan measurements was 5.3 + 1.9 cm and 5.3 + 1.4 cm, respectively. Patients received three cycles of chemotherapy consisting of cisplatin 50 mg/m2 and vincristine 1 mg/m2 for 1 dose and bleomycin 25 mg/m2 daily for three days. Cycles were repeated every ten days. All patients started definitive radiotherapy within a week from the end of chemotherapy. Radiation therapy consisted of whole pelvis radiotherapy followed by 1-3 sessions of low dose rate brachytherapy. RESULTS: Response to neoadjuvant chemotherapy was as follows: seven patients (19%) had minor or no response, one patient had progressive disease, and 28 (76%) had more than 50% tumor reduction; 14 of them (38%) had no clinical evidence of residual tumor. Chemotherapy was discontinued in one patient after the second cycle because of significant changes in pulmonary function tests (PFT), and one patient developed a grade 4 urinary complication after radiotherapy. Median follow-up time for the whole group was 24 months (range: 1-67). Five-year actuarial rates of local control and disease-free survival were 47 and 42%, respectively. At three years, 20 patients (54%) were alive or had died without evidence of disease, and 17 (46%) had succumbed to their disease, with a median time to recurrence of 25 months. Stage and response to neoadjuvant chemotherapy had significant impact on survival, while age. tumor size, and menopausal status did not influence survival. CONCLUSIONS: Our data indicate that short duration chemotherapy followed by definitive radiotherapy is well tolerated and feasible. However, despite a high rate of objective response (76%), and improved survival for responders, there was no obvious long-term survival benefit for the entire group.

Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer.

PURPOSE: A multi-institutional, prospective, randomized trial was undertaken in patients with advanced head-and-neck squamous cell carcinoma to address (1) the validity of using pathologic risk features, established from a previous study, to determine the need for, and dose of, postoperative radiotherapy (PORT); (2) the impact of accelerating PORT using a concomitant boost schedule; and (3) the importance of the overall combined treatment duration on the treatment outcome. METHODS AND MATERIALS: Of 288 consecutive patients with advanced disease registered preoperatively, 213 fulfilled the trial criteria and went on to receive therapy predicated on a set of pathologic risk features: no PORT for the low-risk group (n = 31); 57.6 Gy during 6.5 weeks for the intermediate-risk group (n = 31); and, by random assignment, 63 Gy during 5 weeks (n = 76) or 7 weeks (n = 75) for the high-risk group. Patients were irradiated with standard techniques appropriate to the site of disease and likely areas of spread. The study end points were locoregional control (LRC), survival, and morbidity. RESULTS: Patients with low or intermediate risks had significantly higher LRC and survival rates than those with high-risk features (p = 0.003 and p = 0.0001, respectively), despite receiving no PORT or lower dose PORT, respectively. For high-risk patients, a trend toward higher LRC and survival rates was noted when PORT was delivered in 5 rather than 7 weeks. A prolonged interval between surgery and PORT in the 7-week schedule was associated with significantly lower LRC (p = 0.03) and survival (p = 0.01) rates. Consequently, the cumulative duration of combined therapy had a significant impact on the LRC (p = 0.005) and survival (p = 0.03) rates. A 2-week reduction in the PORT duration by using the concomitant boost technique did not increase the late treatment toxicity. CONCLUSIONS: This Phase III trial established the power of risk assessment using pathologic features in determining the need for, and dose of, PORT in patients with advanced head-and-neck squamous cell cancer in a prospective, multi-institutional setting. It also revealed the impact of the overall treatment time in the combination of surgery and PORT on the outcome in high-risk patients and showed that PORT acceleration without a reduction in dose by a concomitant boost regimen did not increase the late complication rate. These findings emphasize the importance of coordinated interdisciplinary care in the delivery of combined surgery and RT.

Transrectal ultrasound for staging prostate carcinoma prior to radiation therapy: an evaluation based on disease outcome.

BACKGROUND: Despite its subjectivity and inaccuracy, digital rectal examination (DRE) has a long history of well-documented prognostic significance in patients with prostate carcinoma. To the authors' knowledge, very few studies have evaluated the relative prognostic merits of transrectal ultrasound (TRUS) versus DRE. This question is addressed in this study. METHODS: The outcome for 558 men with T1-T3, N0, M0 adenocarcinoma of the prostate who underwent both DRE and TRUS and received external beam radiation without androgen ablation was evaluated relative to the prognostic information from DRE, TRUS, or both. The outcome endpoints were no evidence of disease (NED) (no relapse or rising prostate specific antigen level) and freedom from metastases. Prognostic factors were evaluated with univariate and multivariate techniques. The median follow-up was 55 months. RESULTS: Both purely DRE-based and purely TRUS-based T categories correlated significantly with NED status. For DRE T categories, 6-year NED rates for T1/T2 and T3 disease were 64% and 36%, respectively (P < 0.001). For TRUS T categories, the rates for T1/T2 and T3 were 63% and 39%, respectively (P < 0.001). There were significant differences in patient composition between DRE and TRUS T categories. Only 40% of patients were in the same DRE and TRUS category, but the majority of the reclassification based on TRUS was within rather than between major T categories (T1/T2 vs. T3). Changes between the prognostically significant T1/T2 versus T3 categories occurred in < or =25%. This accounted for the similarity in NED outcome for DRE and TRUS T categories. However, TRUS categories did not discriminate significantly for metastatic recurrence between T1/T2 and T3 categories, whereas DRE categories did. Upstaging or downstaging by TRUS relative to DRE did not alter the DRE prognostic groupings substantially. CONCLUSIONS: There was no clinically meaningful superiority of TRUS over DRE in the definition of prognostically useful T categories. Moreover, the addition of TRUS to DRE did not enhance the prognostic value of DRE findings in any meaningful way. Despite its subjectivity and inaccuracy, DRE provides prognostic information at least equivalent to TRUS and is preferable because of its low cost.

Factors influencing the development of lung fibrosis after chemoradiation for small cell carcinoma of the lung: evidence for inherent interindividual variation.

PURPOSE: Clinical observations often reveal individual differences in the severity of lung fibrosis after definitive radiation therapy for lung cancer. Recent experimental studies suggest that the risk of developing lung fibrosis may be genetically controlled. The present study was undertaken to examine the magnitude of individual variation in the incidence and severity of lung fibrosis in a well-defined patient population treated by concurrent chemoradiation for limited small-cell lung carcinomas (LSCLC). MATERIALS AND METHODS: Between 1989 and 1994, 56 patients with LSCLC were enrolled in one of two controlled prospective studies of concurrent chemotherapy and concomitant conventional (45 Gy in 25 fractions q.d. over 5 weeks) or accelerated (45 Gy in 30 fractions b.i.d. over 3 weeks) radiotherapy. Chemotherapy consisted of cisplatin and etoposide (PE) or PE plus ifosfamide and mesna (PIE). Of the 56, a group of 25 patients who had serial computerized tomography (CT) examinations of the chest and were deemed to have unequivocal radiographic complete responses were selected for this study. The severity of lung fibrosis was recorded for each patient from the CT images using an arbitrary scale (0 to 3) at 1 year after treatment. Radiographic fibrosis scores were recorded on 1-3 CT slices in 3 different dose-areas (20-30 Gy; 30-40 Gy; and >40 Gy) that were defined using the corresponding CT slices from the patient's CT treatment plan. Of these patients, 23 (92%) had at least 2 slices scored; 11 patients had all 3 slices scored. RESULTS: Among the clinical and treatment parameters investigated (including type of chemotherapy), only total dose and fractionation schedule were identified as significant and independent determinants of lung fibrosis. Radiographic fibrosis scores were higher in high-dose areas and among patients treated with the accelerated schedule. Using a fit of the proportional odds (PO) model based on the total dose and fractionation schedule, fibrosis score residuals were calculated for each patient. The residual for each score is defined as the difference between the observed and expected score based on the dose and treatment schedule received. Average residuals varied significantly among patients (p = 0.005, Kruskal-Willis test). Using a modified version of the PO model, the coefficient of variation in patient heterogeneity was estimated to be 10.1% (95% confidence interval: 6.2-14.9%). Inclusion of the heterogeneity factor, in addition to total dose and fractionation schedule, improved the fit of the PO model to an extremely high level of significance (p < 10(-7)). CONCLUSIONS: Our data indicate that the risk and severity of lung fibrosis analyzed radiographically on CT images increases with total dose and with the use of an accelerated radiation schedule, for patients treated with chemoradiation for small-cell lung cancer. There was also demonstrable patient-to-patient heterogeneity, suggesting that the risk of lung fibrosis is strongly affected by inherent factors that vary among individuals.

Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival.

PURPOSE: This retrospective study was conducted to identify the prognostic factors for distant metastasis and survival in a population of 378 patients with nasopharyngeal carcinomas treated by radiation therapy alone. MATERIALS AND METHODS: All patients were treated at the University of Texas M.D. Anderson Cancer Center between 1954 and 1992, following a consistent dose and volume prescription policy. There were 286 males and 92 females. The median age was 52 years (range: 16-86 years). The majority of the patients were white Caucasians (282 patients,75%). Tumors were classified as squamous cell carcinomas (193; 51%), lymphoepitheliomas (154; 41%), or unclassified carcinomas (31, 8%). Three fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). The treatment techniques included opposed lateral fields with or without an anteroposterior or an anterior oblique pairs for dose supplementation to the primary site. Average total doses per T-stage ranged between 60.2 and 72.0 Gy. Median follow-up time was 10 years (range 0.3 to 28.6 years). RESULTS: A total of 103 patients (27%) developed distant metastases at a median time of 8 months (range: 1-90 months). Actuarial rates for distant metastasis were 30%, 32%, 32% at 5, 10, and 20 years, respectively. Actuarial rates for disease specific survival at the same time points were 53%, 45%, and 39% with 184 patients (49%) dying of their nasopharyngeal cancer. Advanced T-stage, N-stage, and non-lymphoepithelioma histology were independent adverse prognostic factors for disease specific survival. Advanced N-stage and low neck disease were independent adverse prognostic factors for distant metastasis with a very high rate of distant metastases for those patients who presented with both adverse factors (relative risk 7.86). On average, patients with distant metastasis lived 5 months after they were diagnosed with metastatic disease (range: 0-172 months), although four patients (4%) survived more than 5 years after diagnosis. CONCLUSIONS: This study demonstrates good long term survival rates after definitive radiotherapy for patients with nasopharyngeal carcinomas. Patients with advanced and lower neck disease have the highest risk of developing distant failures. Such patients can be considered the reference risk group to test the value of adjunctive chemotherapy.

Induction chemotherapy followed by radiotherapy versus radiotherapy alone in patients with advanced nasopharyngeal carcinoma: results of a matched cohort study.

BACKGROUND: Prospective randomized and retrospective studies on adjunctive chemotherapy in patients with advanced locoregional nasopharyngeal carcinoma have yielded conflicting results and the role of chemotherapy in this disease had not been clearly defined. The authors report the results of a single institution, matched cohort study comparing a group of 61 patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy followed by radiation therapy with a matched group treated with radiotherapy alone. METHODS: Between 1985 and 1992, 61 patients with advanced locoregional nasopharyngeal carcinoma received induction chemotherapy (cisplatin, 100 mg/m2 on Day 1 and 5-fluorouracil [5-FU], 1000 mg/m2, on Days 1-5) for 3 cycles followed by definitive radiation therapy (CT/RT group). This group was matched with a group of 61 patients from a population of 378 patients who received radiation therapy alone (RT group). Matching characteristics were T classification, N classification, histology, and level of cervical lymph node metastases. These characteristics were found to be significant determinants of distant metastasis (DM) and/or survival in a multivariate analysis that was performed in the entire radiotherapy group. Radiation therapy consisted of 66-72 gray in 6.5 to 7 weeks in both groups. Fifty-nine patients (97%) in both groups had Stage IV disease. Fifteen patients (25%) in both groups had lower cervical lymph node metastases. The tumor histologic types also had similar distribution in both groups. Median follow-up time among surviving patients of the CT/RT group was 4.9 years (range, 1.3-9.8 years). RESULTS: The 5-year cumulative incidence of DM was 19 +/- 5% for the CT/RT group and 34 +/- 6% for the RT alone group (P = 0.019; log rank test). This reduction in distant failure was more prominent in patients with intermediate (N2-N3 disease; upper or midcervical lymph nodes), or high risk (N2-N3 disease; lower cervical lymph nodes) of DM. This reduction in DM translated into improvement in disease free survival (DFS) and overall survival (OS). The 5-year actuarial DFS rates were 64 +/- 6% for the CT/RT group compared with 42 +/- 7% for the RT group (P = 0.015). The 5-year actuarial OS rates were 69 +/- 6% (CT/RT group) and 48 +/- 7% (RT group), respectively (P = 0.012). The incidence of locoregional failure was slightly lower in the CT/RT group, but this difference did not reach statistical significance. There was no significant difference in the incidence and severity of acute mucositis between the two groups during radiotherapy. The 5-year cumulative incidence of Grade 3 or higher late complications was also similar in both groups (5 +/- 3% in the CT/RT group and 8 +/- 3% in the RT group; P = 0.721). CONCLUSIONS: This matched cohort study provides additional evidence that induction cisplatin-5-FU chemotherapy prior to definitive radiation improves freedom from distant metastasis, DFS, and OS for patients with locoregional Stage IV nasopharyngeal carcinoma without increasing treatment-related morbidity.

Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control.

PURPOSE: This retrospective study was conducted to review the results of treatment and to identify prognostic factors for local and regional control in a population of 378 patients with nasopharyngeal carcinomas treated in a single institution by radiation therapy alone. METHODS AND MATERIAL: All patients were treated at The University of Texas M. D. Anderson Cancer Center between 1954 and 1992 following a consistent treatment philosophy but with evolving technique. There were 286 males and 92 females with a median age of 52 years (range: 16-86 years). The majority of the patients were Caucasian (282 patients, 75%). Thirty-two patients (8%) had one or more cranial nerve deficits. Three-fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). Histologically, 193 tumors (51%) were squamous cell carcinomas, 154 (41%) lymphoepitheliomas, and 31 (8%) unclassified carcinomas. Average total dose varied with T-stage and ranged from 60.2 to 72.0 Gy. Median follow-up time was 10 years. RESULTS: For the entire population the 5-, 10-, and 20-year actuarial survival rates were 48, 34, and 18%, respectively, with 184 patients (49%) dying of nasopharyngeal cancer. Actuarial control rates at 5, 10, and 20 years were 71, 66, and 66% for the primary site and 84, 83, and 83% for the neck. A total of 100 patients (26%) had local failures and 51 patients (13%) had regional failures with a median time to recurrence of 8.2 months and 13 months, respectively. Advanced T-stage, squamous histology, and presence of cranial nerve deficits were poor prognostic factors for local control in both univariate and multivariate analyses. N-stage and tumor histology were significant factors for neck control. Treatment year, total dose within the ranges used, and duration of treatment did not have any significant effect on local or regional control. The actuarial incidence of Grade 3-5 late complications was 16, 19, and 29% at 5, 10, and 20 years, respectively. Twelve patients (3%) died of treatment-related complications; all but one fatal complication occurred before 1971 and the other in 1976. CONCLUSIONS: This study shows very good long-term local and regional control rates for nasopharyngeal carcinomas after definitive radiotherapy and establishes a benchmark for newer treatment strategies. Improvements in treatment technique over the years have dramatically reduced the frequency of severe late complications. Patients with advanced stage tumors and differentiated squamous histology have a relatively poor prognosis when treated with conventional radiotherapy and are candidates for dose escalation or combined modality studies.

Radiation therapy for malignant melanoma.

Sufficient biologic and clinical evidence now exists to refute the longstanding dogma that melanomas are uniformly radiation resistant and hence radiation therapy has little role in the management of this disease. Although surgery remains the treatment of choice for the vast majority of localized melanomas, available data indicate that radiation therapy is a viable alternative for a few subsets of patients in whom surgery would result in cosmetic or functional deformity, such as patients with large facial lentigo maligna melanomas or small or intermediate-sized uveal melanomas. Retrospective and Phase II prospective studies have revealed that elective/adjunctive radiation therapy improves the local-regional control rate in patients with thick primary lesions, nodal involvement, or mucosal melanomas. However, the impact of elective/adjunctive radiation therapy on the survival rate has yet to be determined. Radiation therapy has been established as a simple and cost-effective treatment modality for palliation of patients with symptomatic metastatic spread. The response of metastatic deposits to radiation varies with the tumor volume, total dose, and dose per fraction. The choice of optimal fractionation depends on tumor site and the patient's survival expectation. New data indicate that hyperthermia enhances the response of metastatic lesions to radiation. Ongoing research with a variety of experimental strategies may offer the possibility of further increasing the utility of radiation therapy in the management of this disease.

Comparison between normal tissue reactions and local tumor control in head and neck cancer patients treated by definitive radiotherapy.

PURPOSE: This study was conducted to test for the relationship between tumor and normal tissue radiosensitivity, by comparing local tumor control to the severity of acute and late normal tissue reactions in head and neck cancer patients treated by definitive radiotherapy. METHODS AND MATERIALS: Two hundred eighty-six patients with head and neck cancer who were treated at the University of Texas M. D. Anderson Cancer Center between 1983 and 1993 were selected for the study. Of these, 124 (43%) were treated by a concomitant boost regimen and 162 (57%) by hyperfractionation. All patients had at least 1 year of follow-up. The tumor stage distribution according to the 1992 American Joint Committee on Cancer (AJCC) staging system was as follows: T1, 3%; T2, 53%; T3, 40%; T4, 4%. The average doses delivered were 71.2 Gy and 76.2 Gy for the concomitant boost and hyperfractionation regimens, respectively, with no significant variation between patients. Acute and late reactions were recorded using the Radiation Therapy Oncology Group (RTOG)/European Organization for Research on Treatment of Cancer (EORTC) grading system (0 to 4). The median follow-up period was 38 months (range: 12-107 months). The time to local tumor recurrence was analyzed in relation to the severity of acute and late reactions expressed as the maximum recorded grades, and to the time intensity of acute mucositis, expressed as the area under the curve of mucositis grade vs. time. Univariate and multivariate analyses also included T stage, N stage, and site of origin as other prognostic variables, and were carried out using a proportional hazards model. RESULTS: Fifty-four patients (19%) suffered local failure. T stage was found to significantly influence local control (p = 0.009). There was a nonsignificant trend for higher failure rates in patients with maximum Grade 1 or 2 vs. those with Grade 3 or 4 acute mucositis (28 and 18%, respectively; p = 0.17). No correlation was found between the severity of late reactions and local tumor control after radiotherapy. Analysis by time intensity of mucositis revealed a wide variation between individuals with a nonsignificant trend for higher local failure rates in patients with low mucositis time intensity scores. CONCLUSIONS: These clinical results suggest a possible relationship between normal tissue and tumor radiosensitivity. However, additional studies with a larger numbers of patients, and using refined normal tissue endpoints that incorporate a time function are needed to fully elucidate this question.

How much could the radiotherapy dose be altered for individual patients based on a predictive assay of normal-tissue radiosensitivity?

Predictive assays are presently being developed to identify the patients at highest risk for developing severe late normal-tissue complications. If such patients could be identified prior to treatment, then the doses to those patients could be reduced to lower their complication rate. In addition, patients identified as being relatively radioresistant could receive higher doses without an increase in complications. The aim of the present study was to estimate the magnitude of the dose adjustments that could potentially be made if radiotherapy doses were tailored to the individual patient using a predictive assay of normal-tissue radiosensitivity. The dose adjustments were estimated by re-analyzing data from an earlier study [13] to determine the influence of dose and in vitro fibroblast radiosensitivity on the incidence of severe late normal-tissue complications. Although the dose estimates are preliminary and based on limited data, the results of this study support the concept that a significant therapeutic gain could be achieved for a subset of patients from the use of a predictive assay of normal-tissue radiosensitivity.

Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer.

PURPOSE/OBJECTIVE: To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy. METHODS AND MATERIALS: In the 1970s, a series of breast cancer patients was treated at the Department of Oncology in Gothenburg, Sweden with postoperative irradiation to the parasternal region. Patients were treated bilaterally using different fractionation schedules and doses to the right and left fields. Peak acute reactions were scored on a six-point scale, and skin erythema was measured by reflectance spectrophotometry. Telangiectasia was graded over time on a six-point scale. In April 1992, two small skin biopsies were obtained from 22 patients in two treatment groups (i.e., four dose-fractionation schedules) and, using either delayed or immediate plating, fibroblast radiosensitivity was measured in early passage cultures by clonogenic survival, after high and low dose-rate irradiations. Survival at 2.0 Gy (SF2) was calculated from complete survival curves. RESULTS: To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediate plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when averaged high dose-rate SF2 values and telangiectasia scores were compared. There was no significant correlation between average SF2 values and acute responses or between individual SF2 measurements and either the acute or late clinical response. CONCLUSION: The results of this study suggest that the degree of late telangiectasia is at least partially dependent upon the intrinsic cellular radiosensitivity of normal fibroblasts, but the relationship is not clear cut. Multiple replicate assays are necessary to obtain reliable estimates of fibroblast SF2 values using current techniques.

Influence of initial presentation on treatment outcome of clinically localized prostate cancer treated by definitive radiation therapy.

PURPOSE: The increasing proportion of early stage prostate cancer diagnosed by various early detection methods together with reports espousing watchful waiting as a management option raise the possibility that patients may be selected for surveillance according to their initial presentation. METHODS AND MATERIALS: The outcome for 427 men with clinical stages T1 to T4 localized prostate cancer treated with radiation therapy was evaluated according to their presentation: elevated prostate-specific antigen (PSA) level; abnormal digital rectal examination; or, urologic symptomatology. RESULTS: With a median follow-up of 30 months, there were no significant differences in disease outcome according to initial presentation. The actuarial incidence of relapse at 5 years was: PSA-detected (54 patients), 24%; digital rectal-detected (173 patients) 29%; and, symptom-detected (200 patients) 31% (p = 0.79). Likewise, there were no significant differences in the incidence of postradiation rising PSA profiles among the three groups. The actuarial incidence of relapse and/or rising PSA at 5 years was: PSA-detected 35%; digital rectal-detected 42%; symptom-detected, 48% (p = 0.72). On the other hand, T-stage, Gleason grade, pretreatment PSA, pretreatment acid phosphatase, and transurethral resection in T3/T4 disease were each highly correlated with outcome. In multivariate proportional hazards regression pretreatment PSA (p = 0.0003), Gleason grade (p = 0.045), and transurethral resection in T3/T4 disease (p = 0.0562) correlated with outcome, but initial presentation did not (p = 0.25). CONCLUSION: The absence of a prognostic gradient, good to bad, from PSA-detected through digital rectal-detected to symptom-detected cancer suggests that the initial presentation of patients with localized prostate cancer is not a valid basis for selecting watchful waiting vs. initial treatment.

The T classification of clinically localized prostate cancer. An appraisal based on disease outcome after radiation therapy.

BACKGROUND: This study was performed to evaluate the use of the 1992 International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) T categories for localized prostate cancer treated with radiation therapy and to compare the prognostic power of this system with the Whitmore-Jewett scheme. METHODS: The outcome for 427 men with Stages A2-C or T1a-T4b prostate cancers, followed for a mean of 32 months after treatment, was evaluated for relapse or rising prostate-specific antigen (PSA) levels, disease relapse, metastatic failure, and local recurrence relative to the two staging systems. Univariate and multivariate analysis was used to compare the two staging systems. The T categories were based on digital rectal examination. RESULTS: At 5 years, the actuarial incidence of relapse or rising PSA level was as follows: Stage A2, 29%; Stage B, 41%; Stage C, 62%. The corresponding results according to T category were as follows: T1a, 0%; T1b, 37%; T1c, 23%; T2a, 39%; T2b, 38%; T2c, 42%; T3a, 53%; T3c, 68%; T4b, greater than 75%. Too few patients were in the T3b and T4a categories. The following five-category grouping was significantly superior prognostically to the Whitmore-Jewett system: T1a, T1c, T1b/T2, T3, T4. The actuarial incidences of relapse or rising PSA at 5 years were as follows: T1a, 0%; T1c, 23%; T1b/T2, 41%; T3, 61%; and T4, 75%. No differences were evident within the T2 or T3 categories. CONCLUSIONS: The current UICC/AJCC system appears to be a valid method for categorizing a primary prostate carcinoma. This system defines a greater number of meaningful tumor categories and is prognostically superior to the traditional Whitmore-Jewett scheme.

Prospective comparison of in vitro normal cell radiosensitivity and normal tissue reactions in radiotherapy patients.

PURPOSE: This pilot study was undertaken to assess the relationship between in vitro radiosensitivity of different normal cell types and the type and severity of normal tissue reactions in individual patients after radiotherapy. METHODS AND MATERIALS: Twenty-one patients with head and neck cancer were studied prospectively; four with head and neck and two with breast cancer were studied retrospectively. The retrospective cases were chosen because they exhibited unusual (severe or minimal) normal tissue reactions after radiotherapy. Small skin biopsies and blood samples were obtained and used to generate in vitro fibroblast and lymphocyte cultures, respectively. Clonogenic assays were used to measure in vitro fibroblast and lymphocyte radiosensitivity after high- and low-dose rate irradiation. Head and neck patients were treated by conventional, hyperfractionated, or concomitant boost regimens, which have been found to yield an equal probability of late normal tissue reactions. The highest dose received by each normal tissue in the target volume was estimated using computed tomography treatment plans. The median patient follow-up time was 19 months (range: 13-25). RESULTS: The distributions of in vitro radiosensitivity parameters and the grade of tissue reaction scores in the patients showed a broad range between individuals. When in vitro parameters were compared to the acute and late tissue reactions, the radiosensitivity of fibroblasts, measured as surviving fraction at 2 Gy after high-dose rate irradiation, showed a highly significant correlation with the maximum grade of late effects (p < 0.0001 for the whole group and p = 0.0013 for the group of patients studied prospectively). No significant correlation was found between fibroblast radiosensitivity and maximum grade of acute effects or between lymphocyte radiosensitivity and either acute or late effects. CONCLUSION: We conclude that individuals vary in normal cell radiosensitivity, and that in vitro measurements of fibroblast radiosensitivity may predict the magnitude of late normal tissue reactions after radiotherapy. These preliminary results, however, need to be validated in a larger group of patients.

Intrinsic radiosensitivity of normal human fibroblasts and lymphocytes after high- and low-dose-rate irradiation.

The existence of heritable radiosensitivity syndromes and clinical observations in radiotherapy patients suggests that human cellular radiosensitivity differs among individuals. We report here an in vitro study of radiosensitivity in 30 fibroblast and 29 lymphocyte cultures obtained from cancer patients and controls. In 25 cases, both fibroblasts and lymphocytes were obtained from the same donors. Fibroblasts were cultured from skin biopsy samples, and peripheral T-cell lymphocytes were cultured from blood. Clonogenic survival assays were performed by using high- and low-dose-rate irradiation; lymphocytes were in G0 phase and fibroblasts in confluent plateau phase. Various end points were calculated and compared (i.e., surviving fraction at 2 Gy, initial slope of the survival curve, and doses resulting in 10 and 1% survival, respectively). Depending on the end point, the coefficient of variation of the survival parameters ranged from 31 to 68% for lymphocytes and 21 to 41% for fibroblasts following high-dose-rate irradiation. Similar ranges were obtained after low-dose-rate irradiation. Variance analysis performed on replicate assays in cultures derived from the same patient showed that variation due to technical or sampling errors was significantly lower than variation between individuals (P = 0.00034 and 0.014 for fibroblasts and lymphocytes, respectively). No correlation was observed between the radiosensitivity of lymphocyte and fibroblast cultures derived from the same donors. We conclude that there is significant variation in normal cell radiosensitivity among individuals. On the other hand, comparisons of lymphocyte and fibroblast radiosensitivities suggest that tissue-specific characteristics, such as differentiation status, may variably modulate radiosensitivity.

Radiosensitivity measurement of keratinocytes and fibroblasts from radiotherapy patients.

Genetic diversity is believed to influence cellular radiosensitivity and individual variability in normal tissue reactions to radiotherapy. To measure normal cell radiosensitivity in vitro, we investigated a culture technique that yields keratinocyte and fibroblast cell cultures from small skin biopsy samples (average weight 32 mg). This technique uses 3T3 NIH cells as feeder cells, culture medium containing dialyzed fetal calf serum, low calcium, and various growth factors for keratinocyte growth. A calcium concentration of 4 x 10(-3) M and the use of lethally irradiated NIH 3T3 feeder cells were critical to the success of this method. Primary keratinocyte cultures were successfully obtained from nine biopsy specimens, and radiosensitivity measurements were obtained in six of the resulting strains. Keratinocytes were, in general, more radioresistant than fibroblasts derived from the same specimen. We conclude that radiosensitivity assessment of keratinocyte and fibroblast cultures derived from small punch biopsy specimens is feasible. Further studies can now be carried out to determine the degree of variability between individuals and the relationship between in vitro keratinocyte and fibroblast radiosensitivity and their value in predicting normal tissue responses to radiotherapy.