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The Uterus-11 trial was designed to evaluate the role of surgical staging in patients with cervical cancer before primary chemoradiation therapy (CRT). The present report provides the toxicity data stratified by the treatment arm and technique.A total of 255 patients with carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIB-IVA) were randomized to either surgical staging followed by CRT (arm A) or clinical staging followed by CRT (arm B). Patients with para-aortic metastases underwent extended field radiation therapy (RT). Brachytherapy was mandatory. The present report presents the acute therapy-related toxicities stratified by treatment arm and radiation technique.A total of 240 patients were eligible (n=121 in arm A; n=119 in arm B). Of the 240 patients, 236 (98.3%) underwent external beam RT with a median total dose of 50.4 Gy. The mean treatment duration was 53 days. Of the patients, 60% underwent intensity modulated RT (IMRT). A total of 234 patients (97.5%) underwent chemotherapy, and 231 (96.3%) underwent brachytherapy, with a median single dose of 6 Gy covering the tumor to a median nominal total dose of 28 Gy. Treatment was well tolerated, with 0% grade ≥3 genitourinary and gastrointestinal toxicity, 6% grade 3 nausea, 3% grade 3 vomiting, and2% grade 3 diarrhea. More patients after surgical staging experienced grade 2 anemia (54.3% in arm A vs 45.3% in arm B; P=.074) and grade 2 leukocytopenia (41.4% vs 31.6%; P=.56). Of the patients who received IMRT versus a 3-dimensional technique, 65.3% versus 33.7% presented with grade 2 anemia. Grade 3 gastrointestinal and grade 2 bladder toxicity were significantly reduced with the use of IMRT.The incidence and severity of acute therapy-related toxicity compared favorably with those from other randomized trials. Excellent adherence to treatment and treatment quality was achieved compared with patterns of care analyses. Surgical staging led to a doubled number of patients treated with extended field RT. The question of whether surgical staging is beneficial in the context of primary CRT requires further study.

Purpose To assess the efficacy of individual sentinel node (SN)-guided pelvic intensity modulated radiation therapy (IMRT) by determining nodal clearance rate [(n expected nodal involvement − n observed regional recurrences)/n expected nodal involvement] in comparison with surgically staged patients. Methods and Materials Data on 475 high-risk prostate cancer patients were examined. Sixty-one consecutive patients received pelvic SN-based IMRT (5 × 1.8 Gy/wk to 50.4 Gy [pelvic nodes + individual SN] and an integrated boost with 5 × 2.0 Gy/wk to 70.0 Gy to prostate + [base of] seminal vesicles) and neo-/adjuvant long-term androgen deprivation therapy; 414 patients after SN–pelvic lymph node dissection were used to calculate the expected nodal involvement rate for the radiation therapy sample. Biochemical control and overall survival were estimated for the SN-IMRT patients using the Kaplan-Meier method. The expected frequency of nodal involvement in the radiation therapy group was estimated by imputing frequencies of node-positive patients in the surgical sample to the pattern of Gleason, prostate-specific antigen, and T category in the radiation therapy sample. Results After a median follow-up of 61 months, 5-year OS after SN-guided IMRT reached 84.4%. Biochemical control according to the Phoenix definition was 73.8%. The nodal clearance rate of SN-IMRT reached 94%. Retrospective follow-up evaluation is the main limitation. Conclusions Radiation treatment of pelvic nodes individualized by inclusion of SNs is an effective regional treatment modality in high-risk prostate cancer patients. The pattern of relapse indicates that the SN-based target volume concept correctly covers individual pelvic nodes. Thus, this SN-based approach justifies further evaluation, including current dose-escalation strategies to the prostate in a larger prospective series.

The impact of the delivery of radiotherapy (RT) on treatment results in rectal cancer patients is unknown.The data from 788 patients with rectal cancer treated within the German CAO/AIO/ARO-94 phase III trial were analyzed concerning the impact of the delivery of RT (adequate RT: minimal radiation RT dose delivered, 4300 cGy for neoadjuvant RT or 4700 cGy for adjuvant RT; completion of RT in44 days for neoadjuvant RT or49 days for adjuvant RT) in different centers on the locoregional recurrence rate (LRR) and disease-free survival (DFS) at 5 years. The LRR, DFS, and delivery of RT were analyzed as endpoints in multivariate analysis.A significant difference was found between the centers and the delivery of RT. The overall delivery of RT was a prognostic factor for the LRR (no RT, 29.6% +/- 7.8%; inadequate RT, 21.2% +/- 5.6%; adequate RT, 6.8% +/- 1.4%; p = 0.0001) and DFS (no RT, 55.1% +/- 9.1%; inadequate RT, 57.4% +/- 6.3%; adequate RT, 69.1% +/- 2.3%; p = 0.02). Postoperatively, delivery of RT was a prognostic factor for LRR on multivariate analysis (together with pathologic stage) but not for DFS (independent parameters, pathologic stage and age). Preoperatively, on multivariate analysis, pathologic stage, but not delivery of RT, was an independent prognostic parameter for LRR and DFS (together with adequate chemotherapy). On multivariate analysis, the treatment center, treatment schedule (neoadjuvant vs. adjuvant RT), and gender were prognostic parameters for adequate RT.Delivery of RT should be regarded as a prognostic factor for LRR in rectal cancer and is influenced by the treatment center, treatment schedule, and patient gender.

Purpose: Several groups have reported the value of bladder preservation by a combined treatment protocol, including transurethral resection (TUR-B) and radiochemotherapy (RCT). As more experience is acquired with organ-sparing treatment, patient selection should be optimized. The purpose of this study was to investigate the role of several biologic markers that may predict response to RCT in muscle-invasive bladder carcinoma. Methods and Materials: The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 70 patients treated for invasive bladder cancer by TUR-B and RCT. Expression of each marker was correlated with initial response, local control, and cancer-specific survival with preserved bladder. An exploratory multivariate analysis was also performed that included clinical and immunohistochemical variables. Results: A high AI (> median = 1.6%) and a high Ki-67 index (> median = 8.8%), but not the p53- and bcl-2 expression, were significantly related to initial complete response (CR) and local control with preserved bladder after 5 years. When the AI and Ki-67 expression were considered simultaneously, the association with initial CR (p < 0.001), local control (p = 0.0002), and cancer-specific survival with preserved bladder (p = 0.008) was highly significant. In an exploratory multivariate analysis (final model), only AI, Ki-67, and the combined AI/Ki-67 variable retained significance for local control with preserved bladder at 5 years. Conclusion: Patients with a high spontaneous AI and a high pretreatment Ki-67 index should be considered preferentially for treatment with RCT, whereas tumors with low proliferation and low levels of apoptosis are less likely to respond to RCT.

Purpose: Experimental and clinical data support effectiveness of perioperative radiotherapy to prevent heterotopic ossification after hip surgery or trauma. Since 1987, two prospectively randomized trials were performed in patients with high-risk factors to develop heterotopic ossification: the first (HOP 1) to assess the prophylactic efficacy of postoperative how vs. medium dose radiotherapy, and the second (HOP 2) to assess the prophylactic efficacy of pre vs. postoperative radiotherapy. Methods and Material: 410 patients with high risk to develop heterotopic ossifications about the hip following hip surgery were recruited. Between June 1987 and June 1992, 249 patients were randomized in HOP 1 to postoperative “low dose” (5 × 2 Gy; total: 10 Gy) or “medium dose” (5 × 3.5 Gy; total: 17.5 Gy) radiotherapy. Between July 1992 and December 1995,161 patients were randomized in HOP 2 to either 1 × 7 Gy preoperatively (⩽4 h before surgery) or 5 × 3.5 Gy (total: 17.5 Gy) postoperatively (⩽96 h after surgery). With exception of age and type of implant (cemented vs. uncemented prosthesis) all confounding patient variables (gender, prior surgery) and predisposing risk factors were similarly distributed between both trials and treatment arms. Portals encompassed the periacetabular and intertrochanteric soft tissues. Radiographs were obtained prior and immediately after surgery and at least 6 months after surgery to assess the extent of ectopic bone formation about the hip. Modified Brooker grading was used to score the extent of heterotopic ossification. Harris scoring was applied to evaluate the functional hip status. If the scores decreased from immediate post or preoperative status, respectively, to the last follow-up, radiological or functional failures were assumed. Results: Effective prophylaxis was achieved in 227 (91%) hips of HOP 1 and in 142 (88%) of HOP 2. In HOP 1, 15 (11%) radiological failures were observed in the low-dose group compared to 7 (6%) in the medium dose group (p > 0.05). In HOP 2, 4 (5%) radiological failures were observed in the postoperative and 11 (19%) in the preoperative group (p < 0.05). Subgroup analysis of the preoperative group revealed that the highest failure rate occurred in patients with prophylactic radiotherapy prior to removal of ipsilateral Brooker Grade III and IV ossification (39%) (p < 0.001), while all other patients in the preoperative group had a failure rate that was comparable to postoperative treatment groups. In multivariate logistic regression analysis the number of high-risk factors for development of heterotopic ossification (p = 0.03) and the time to RT initiation (p = 0.05) were independent prognostic factors in the HOP 1 study. For the HOP 2 study, the multivariate logistic regression analysis revealed the number of high-risk factors for development of heterotopic ossification (p = 0.003), the preoperative HO grade (p = 0.001) and the RT dose concept (p = 0.05) as independent prognostic factors. Other factors including type of implant (cemented vs. uncemented) did not affect the prophylactic efficacy of radiotherapy. There were no increased intra- and postoperative complications seen in the preoperative group, and no long-term complications were observed in both HOP studies. For functional failures (decrease of Harris score) no statistically prognostic factors were found. There were less functional failures in HOP 1 (18 = 7%) than in HOP 2 (23 = 14%. but this difference was not statistically significant. Only patients with high Brooker Grade III and IV at last FU achieved a lower Harris score than those with how Brooker Grade 0, I and II (p < 0.05). Conclusion: With the exception of a small subgroup of patients with ipsilateral high Brooker Grade III and IV, pre- and postoperative radiotherapy are equally effective to prevent heterotopic ossification about the hip after hip surgery and total hip arthroplasty. Fractionated medium dose radiotherapy resulted in the lowest failure rate.

From January 1986 to October 1991, 90 patients with localized tumors were treated in a Phase I/II trial using low-dose 192Ir brachytherapy (IRT) plus interstitial 915 MHz microwave (MW) hyperthermia (IHT) and external beam radiotherapy (ERT). Tumors were classified as locally advanced primary (class 1: 27), recurrent (class 2: 40), metastatic (class 3: 10) and persistent (class 4: 13) lesions. The treatment sites included tumors of the head and neck (62), pelvis (26), and others (2). The mean cuboidal tumor volume was 63 cm3 (range: 8-288 cm3). Most recurrent and metastatic lesions (48) had received prior treatment including ERT.The treatment protocol prescribed two heating sessions (each 60 min) at 41-44 degrees C before and after IRT. One hundred sixty-one IHT sessions were evaluated. Invasive thermal data were recorded at an average of 18 sites throughout the implant volume. Several thermal variables were analyzed (e.g., averaged parameters: Tmaxav, Tmean, Tminav; index parameters: T10, T50, T90). The study was evaluated with a minimum follow up (FU) of one year. Median follow-up was 19 months.At 3 months FU, a complete response (CR) was observed in 59 of 90 (66%) patients. At 12 months FU, local control (LC) was achieved in 54 of 84 (64%) evaluable patients. Ten patients developed a local and 14 a regional recurrence (REC) after achieving a CR and/or LC. At last FU, a total of 31 (34%) patients were still alive and 28 (31%) patients had relapse-free survival. For all 90 patients, the median overall survival was 20 months and the median relapse-free survival was 17 months. Overall and relapse-free survival was significantly longer for primary and persistent lesions as compared to recurrent and metastatic lesions (p = 0.002; p0.001). Totally 22 (24%) patients experienced acute or subacute side-effects (Grade 1: 12 patients; Grade 2: eight patients; Grade 3: two patients).Univariate logistic regression analysis revealed significant dependencies of CR, LC and REC upon tumor parameters as well as radiation and thermal parameters. The overall and relapse free survival was associated with tumor and radiation parameters. The multivariate analysis revealed two independent predictors of CR: tumor volume and minimum tumor temperature variables. We conclude, that IHT-IRT is a safe and effective treatment. The results provide important implications for planning HT-RT studies and for defining quality assurance (QA) criteria and thermal performance standards in HT studies.

Purpose: To assess the prognostic value of biologic (p53, Ki-67) and clinical factors in squamous cell carcinoma of the oropharynx after radical surgery and postoperative radiotherapy (RT). Methods and Materials: Between 1985 and 1995, a total of 102 patients with 104 tumor sites were entered onto the study. Fifty-five primary tumors (53%) involved the tonsils, 26 (25%) the soft palate, and 23 (22%) the base of the tongue. Median age was 53 years (range 36–80 years). The clinical T- and N-categories (UICC 1997) were: T1 (30), T2 (47), T3 (22), T4 (5), N0 (33), N1 (28), N2 (42), and N3 (1). Histologically-clear margins were achieved in all patients by initial surgery. Postoperative RT to the primary and regional lymphatics was given, to a total of 60 Gy in 6 weeks, and single daily fractions of 2 Gy. The expression of the nuclear p53- and Ki-67-labeling index (LI) was investigated by immunostaining using the monoclonal antibodies DO-7 and MIB 1. The nuclear p53-intensity (p53-I) was graded into 4 categories (0/+/++/+++) by densitometry. Median follow-up was 43 months (range 14–132 months). Results: Cancer-specific survival, disease-free survival, and locoregional tumor control rates were 74%, 69%, and 75%, respectively, at 5 years. Significant prognostic factors for disease-free survival were: T-category (T1/2: 77% vs. T3/4: 53%, p = 0.02), tumor site (tonsils: 79% vs. soft palate: 70% vs. base of tongue: 45%, p = 0.05), duration of RT (≤ 46 days: 80% vs. > 46 days: 60%, p = 0.04), Ki-67 LI (≤ 20%: 84% vs. > 20%: 49%, p = 0.006) and p53-I (0/+: 56% vs. ++/+++: 79%, p = 0.008). A significant prognostic impact on locoregional control was noted for the duration of RT (≤ 46 days: 86% vs. > 46 days: 68%, p = 0.01), tumor site (tonsils: 88% vs. soft palate: 67% vs. base of tongue: 51%, p = 0.02), Ki-67 LI (≤ 20% LI: 87% vs. > 20% LI: 56%, p = 0.018), and the p53-I (0/+: 58% vs. ++/+++: 88%, p = 0.0006). On multivariate analysis, the p53 nuclear intensity ( p = 0.002) and the Ki-67 index ( p = 0.01) remained the only significant factors for locoregional control. Conclusion: Ki-67 labeling index above 20% and a weak p53 nuclear intensity (0/+) are both able to identify patients with squamous cell carcinoma of the oropharynx being at high risk for local recurrence after surgery and postoperative RT. Consequently, in this subgroup an intensification of treatment may be contemplated in prospective trials.

Purpose: Presently, for muscle-invasive bladder cancer, radical cystectomy is considered to be the standard treatment. Bladder preservation, in the interest of quality of life, is secondary to the primary treatment goal of curing the patient. We present a 14-year multivariate analysis of prognostic factors influencing survival and bladder preservation after transurethral resection of the bladder (TURB) and radiotherapy (RT) +/− chemotherapy. Methods and Materials: From May 1982 to May 1996, sequential cohorts of 333 patients with bladder cancer (mean age: 66 years) were treated by either RT alone (128 patients), or with platin-based concomitant radiochemotherapy (RCT, 205 patients) after TURB. Patients (282) with muscle-invasive or T1 high-risk cancers (Grade III, residual tumor after TURB, multifocality, tumor diameter > 5 cm, associated Tis or Ta, multiple recurrences or lymph node metastases), who received a minimal target dose of 45 Gy were selected for analysis (med. follow-up = 7.5 years): after October 1985, 115 patients received cisplatin (25 mg/m2) and 69 patients carboplatin (65 mg/m2) before every treatment fraction (1.8 Gy) on Days 1–5 and 29–33 of conventional fractionated RT. Results: Complete remission rate was 20% (55 of 282 patients) after radical TURB, 57% (56 of 98) after TURB plus postoperative RT, and 80% (145 of 181 patients) after TURB plus RCT (85% after concomitant cisplatin and 70% after RCT plus carboplatin). These differences were significant in multivariate analysis (p = 0.003–0.05). The strongest impact on initial response had T-category (p < 0.0001) and R-status after TURB (p < 0.0003). Cause-specific survival (CSS) was 59 and 43% after 5 and 10 years; 79% of patients survived with preserved bladder. Five-year CSS after RT, RCT-Cis, and RCT-Carbo was 40, 64, and 54%, 10-year CSS 31, 48, and 27%, respectively (p = 0.04–0.045, univariate). R-status after TURB was the only independent prognostic factor for survival and bladder preservation. For relapsed patients after cystectomy, the 5- and 10-year CSS were 40 and 33%. Conclusions: TURB followed by RT/RCT is an alternative treatment option to primary cystectomy for patients with muscle-invading bladder cancer. Compared to historic controls, the addition of cisplatin or carboplatin leads to significantly more complete remissions and better survival. Survival rates are similar to those achieved by primary cystectomy and possibly even better for selected subjects, such as patients with T3b and T4 tumors. Cystectomy should be restricted to only those patients who fail after RCT.

Purpose:In vivo data support the effectiveness of pre- and postoperative radiotherapy in suppressing the development of heterotopic ossification after hip surgery. In June 1992 a prospectively randomized trial was initiated to assess the comparative efficacy of pre- vs. postoperative prophylactic radiotherapy in patients with high risk to develop heterotopic ossification after hip surgery. Methods and Material: Between June 1992 and September 1993 a total of 84 eligible patients with high risk profile for the developement of heterotopic ossification were entered in the study. They were randomized to receive radiotherapy either preoperatively (< 4 h before surgery) or according to a “standard protocol” postoperatively (< 72 h after surgery). A single 7 Gy fraction was administered to the preoperative group, while the postoperative group received a previously tested scheme of five fractions of 3.5 Gy (total dose 17.5 Gy). The treatment portal encompassed the soft tissues between the periacetabular region of the pelvis and the intertrochanteric portion of the femur. Important patient variables (age, sex, prior surgery) and predisposing risk factors were equally distributed between both treatment arms. X rays of the irradiated hips were obtained prior and immediately after surgery as well as at 6 months after surgery. The modified Brooker grading was used to score the extent of heterotopic ossification. The Harris score was applied to judge the overall functional status of the hip. If the Brooker grade and Harris score decreased from the immediate postoperative or preoperative status respectively to the follow-up situation, the case was considered as a “treatment failure.” Results: At a minimum 6 months follow-up after hip surgery 44 patients were available for evaluation. Effective prophylaxis was achieved in 41 (93%) hips. Two “radiological failures” were observed in the preoperative group and one in the postoperative group. Neither the pre- nor the postoperative interval affected the prophylactic efficacy. There were no increased intra- and postoperative complications seen in the preoperative group. The interval of partial strain (50% body weight) to the operated hip was longer in the preoperative group (19 days ± 27) as compared to the postoperative group (8 days ± 13), however the interval to full strain (100% body weight) was equal in both groups. The functional status (Harris Score change) of the operated hip decreased only in two (5%) patients (“functional failures”). The overall change was better in the postoperative group (42.7 ± 17.1) as compared to the preoperative group (34.3 ± 13.7) (p = 0.08, NS) as well as with regard to the criteria “limp” (p = 0.05) and “use of walking support” (p = 0.10, NS). In in all other aspects no differences were observed between both treatment arms. Therefore, the preliminary results for preoperative radiotherapy are similar to historical results obtained with postoperative radiotherapy regimens. Conclusion: Preoperative radiotherapy of the operative site applied within 4 h prior to elective hip surgery and total hip arthroplasty appears to be equally effective to currently accepted postoperative radiotherapy regimens in prevention of clinically significant heterotopic ossification about the hip. Improved patient comfort, ease of treatment management, and avoidance of possible postoperative complications associated with moving and positioning the patient in the immediate postoperative period are the major advantages of the preoperative radiotherapy concept.

Materials & Methods: Between 1987 and 1995,120 patients (pts, 73 with primary tumor, 47 with recurrent disease) received CRT for rectal cancer. RT was given by 3-4 field box technique with 6-10 MV-photons. Daily fraction size was 180 cGy, total dose 5040 cGy including 540 cGy local boost. Dose was specified to the ICRU reference point. During the first and fifth week of RT S-FU (1000 mg/m*/24 h) was administered by continuous intitsion for 120 hours. 56 pts received preoperative CRT, 64 pts were treated postoperatively. Toxicity was recorded following (modified) WHO-criteria.