Oxaliplatin combined with infusional 5-fluorouracil and concomitant radiotherapy in inoperable and metastatic rectal cancer: a phase I trial

The aim of this study was to define the recommended dose of oxaliplatin when combined with infusional 5-fluorouracil (5-FU) and concurrent pelvic radiotherapy. Eligible patients had inoperable rectal cancer, or symptomatic primary rectal cancer with metastasis. Oxaliplatin was given on day 1 of weeks 1, 3 and 5 of radiotherapy. Dose level 1 was oxaliplatin 70 mg m(-2) with 5-FU 200 mg m(-2) day(-1) continuous infusion 96 h week(-1). On dose level 2, the oxaliplatin dose was increased to 85 mg m(-2). On dose level 3, the duration of the 5-FU was increased to 168 h per week. Pelvic radiotherapy was 45 Gray (Gy) in 25 fractions over 5 weeks with a boost of 5.4 Gy. Fluorine-18 fluoro deoxyglucose and Fluorine-18 fluoro misonidazole positron emission tomography (FDG-PET and FMISO-PET) were used to assess metabolic tumour response and hypoxia. In all, 16 patients were accrued. Dose-limiting toxicities occurred in one patient at level 2 (grade 3 chest infection), and two patients at level 3 (grade 3 diarrhoea). Dose level 2 was declared the recommended dose level. FDG-PET imaging showed metabolic responses in 11 of the 12 primary tumours assessed. Four of six tumours had detectable hypoxia on FMISO-PET scans. The addition of oxaliplatin to infusional 5-FU chemoradiotherapy was feasible and generally well tolerated. For future trials, oxaliplatin 85 mg m(-2) and 5-FU 200 mg m(-2) day(-1) continuous infusion 96 h week(-1) is the recommended dose when combined with 50.4 Gy of pelvic radiotherapy.     

Anemia in cervical cancers: impact on survival,patterns of relapse,and association with hypoxia and angiogenesis

PURPOSE: The prognostic impact of anemia in cervical cancers is well established. We have investigated the impact of anemia on prognosis and patterns of relapse in cervical cancers. Furthermore, we analyzed the relationship between anemia, tumor hypoxia, and angiogenesis. METHODS AND MATERIALS: Eighty-seven patients (mean age 58 years) with squamous cell cancer of the cervix (Stage IIB: n = 19; Stage IIIB: n = 59; Stage IVA: n = 9) were prospectively enrolled in the study from 1995 through 1999. Patients underwent definitive radiotherapy with a combination of external beam radiotherapy (45-50.4 Gy) and high-dose-rate brachytherapy (5 x 7 Gy). Tumor oxygenation was measured with the Eppendorf pO(2)-histograph before radiotherapy and after 19.8 Gy. Angiogenesis was determined by measuring the microvessel density in pretreatment biopsies in 46 patients. The impact of tumor oxygenation (at 0 Gy and 19.8 Gy), hemoglobin (hb) level (at 0 Gy and 19.8 Gy), angiogenesis and clinical parameters on survival and relapse was investigated. RESULTS: The 3-year overall survival rate (after a median follow-up of 42 months) was 57% for the whole group of patients, 72% for Stage IIB, 60% for Stage IIIB, and 22% for Stage IVA. The presence of pretreatment anemia had a significant impact on the relapse rate. However, the midtherapy hb level (at 19.8 Gy) had the strongest impact on local failure rate and survival: 3-year local failure rate was 6% in 20 patients with a hb > 13 g/dL at 19.8 Gy, 15% in 47 patients with an hb between 11 and 13 g/dL, and 67% in 20 patients with an hb < 11 g/dL, p = 0.0001. This was associated with a significant impact on the 3-year overall survival, 79% vs. 64% vs. 32%. Twenty-three tumors were poorly oxygenated at both measurements (oxygen pressure [median pO(2)] < 15 mm Hg before therapy and at 19.8 Gy). This group had a significantly lower 3-year overall survival as compared with patients with high pO(2) before and/or at 19.8 Gy (38% vs. 68%, p = 0.02), and these poorly oxygenated tumors had also a significantly increased microvessel density. In a multivariate model, the midtherapy hb level maintained an overwhelming impact on local failure rate and survival. CONCLUSION: Hemoglobin level during radiotherapy was the strongest prognostic factor for local control and survival. We could further identify a poor prognostic subgroup with persisting hypoxia during radiotherapy, low hb levels, and increased angiogenesis. According to these findings, an association between anemia, poor tumor oxygenation, and angiogenesis is likely.     

A model of reoxygenation dynamics of head-and-neck tumors based on serial 18F-fluoromisonidazole positron emission tomography investigations

PURPOSE: To develop a model for reoxygenation dynamic and its relationship to local control after radiotherapy (RT), based on repeated dynamic [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) examinations in head-and-neck cancer patients. METHODS AND MATERIALS: Ten head-and-neck cancer patients were examined with dynamic FMISO PET before RT with 70 Gy and after approximately 20 Gy. Two of these patients had two additional dynamic FMISO scans during treatment. Local recurrence was assessed by computed tomography-based follow-up 8-24 months after RT. Tumor-specific values for the level of FMISO retention R and the vascular perfusion efficiency P were determined with a kinetic compartment model. RESULTS: Individual R-P scattergrams before and during therapy were analyzed, and significant therapy-induced changes in the characteristic R-P patterns were observed. A tumor control probability model was derived that involves the tissue parameters R and P and estimates the time to reoxygenation. On the basis of this model, a malignancy value M was introduced and calibrated by a fit to the observed outcome data. Reoxygenation is reflected by the model as a progression to less-malignant tumor types (i.e., smaller values of M). In 4 of 6 patients with severe hypoxia, M had decreased after 20 Gy, whereas 2 patients showed increasing M. Four patients showed no hypoxia in the pretreatment scan. CONCLUSION: A tumor control probability model was developed based on repeated FMISO PET scans during RT. The model combines the local perfusion efficiency and the degree of hypoxia to estimate reoxygenation time. It constitutes a key for hypoxia image-guided dose escalation in RT.     

Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer.

PURPOSE: Advanced head and neck cancer shows hypoxia that results in biological changes to make the tumor cells more aggressive and less responsive to treatment resulting in poor survival. [F-18] fluoromisonidazole (FMISO) positron emission tomography (PET) has the ability to noninvasively quantify regional hypoxia. We investigated the prognostic effect of pretherapy FMISO-PET on survival in head and neck cancer. EXPERIMENTAL DESIGN: Seventy-three patients with head and neck cancer had pretherapy FMISO-PET and 53 also had fluorodeoxyglucose (FDG) PET under a research protocol from April 1994 to April 2004. RESULTS: Significant hypoxia was identified in 58 patients (79%). The mean FMISO tumor/bloodmax (T/Bmax) was 1.6 and the mean hypoxic volume (HV) was 40.2 mL. There were 28 deaths in the follow-up period. Mean FDG standard uptake value (SUV)max was 10.8. The median time for follow-up was 72 weeks. In a univariate analysis, T/Bmax (P=0.002), HV (P=0.04), and the presence of nodes (P=0.01) were strong independent predictors. In a multivariate analysis, including FDG SUVmax, no variable was predictive at P<0.05. When FDG SUVmax was removed from the model (resulting in n=73 with 28 events), nodal status and T/Bmax (or HV) were both highly predictive (P=0.02, 0.006 for node and T/Bmax, respectively; P=0.02 and 0.001 for node and HV, respectively). CONCLUSIONS: Pretherapy FMISO uptake shows a strong trend to be an independent prognostic measure in head and neck cancer.     

Evaluation of early response to radiotherapy in head and neck cancer measured with [11C]methionine-positron emission tomography.

PURPOSE: To evaluate whether positron emission tomography (PET) with carbon-11-methionine (MET) can be used for detection of early response to external beam radiotherapy (RT) in untreated head and neck cancer using locoregional control and survival as study endpoints. MATERIALS: Fifteen patients with head and neck cancer underwent a MET PET study before RT and after a median dose of 24 Gy. Fractionation was standard (n = 6) or hyperfractionated (n = 9), and 13 out of 15 patients had planned surgery after RT. SUV was calculated for primary tumor (n = 13) or largest lymph node metastasis in two patients of whom one had his primary excised before study enrollment and one presented with unknown primary tumor syndrome. METHODS: Attenuation corrected PET scans acquired 20-40 min from tracer injection were used for evaluation of MET uptake in tumors. A quantitative MET uptake index was expressed as standardized uptake value (SUV) or SUV(lean) (corrected for lean body mass). The PET results were correlated with clinical follow-up data. The median follow-up time is currently 28 months (range 22-34). RESULTS: A total of 13 primary tumors and 12 metastatic lymph nodes were visually identified in MET PET. In the first PET study the median SUV in tumor was 8.6 (range, 5.5-14.0). In the second PET study performed during RT the median SUV decreased to 5.7 (range, 3.1-8.2, P = 0.001). Two out of 15 patients showed no radiation-induced decrease in SUV. The median tumor SUV ratio of patients remaining in local control (CR) after RT was 0.7 (range 0.6-0.8, n = 6), and that of relapsing patients similarly 0.7 (range 0.5-1.0, n = 9, NS). The SUV ratio was not associated with survival time. The MET uptake of submandibular salivary glands decreased in all patients during the first two or three weeks of RT (P = 0.03). CONCLUSIONS: MET uptake in tumor shows a significant decrease during the first two to three weeks of RT of head and neck cancer. It appears that the rate of decrease in tracer uptake is comparable in relapsing patients and those who remain locally controlled and thus the use of MET PET for prediction of response to RT is limited.     

A phase III randomized study of misonidazole plus radiation vs. radiation alone for cervix cancer

BACKGROUND AND PURPOSE: A randomized-controlled study of radical radiotherapy for cervical cancer with or without the hypoxic sensitizer, misonidazole was conducted from 1981 to 1984 to investigate its therapeutic benefit. PATIENTS AND METHODS: Seventy-three patients were accrued from the Princess Margaret Hospital, and St John Regional Cancer Centre and randomized to either misonidazole (MISO, n = 39) or placebo (P, n = 34) in addition to radiotherapy. MISO was given orally each day 4 h prior to external beam radiation treatment (45Gy to midplane in 20 daily fractions) at a dose of 0.45 g/m(2), as well as during intra-uterine brachytherapy (40Gy). RESULTS: The 10-year overall survival (OS) for the entire group was 46%, and the disease-free survival (DFS) was 39%. The 10-year OS for patients in the MISO arm was 45%, compared to 49% for the P arm (P = 0.89). The corresponding DFS figures were 36 and 43%, respectively, (P = 0.6). Ten patients (14%) developed severe late complications (grade 3 or 4). The 10-year serious late complication rate was 14% for MISO and 12% for P (P = 0.51). CONCLUSIONS: Misonidazole failed to improve the outcome of patients with cervix cancer treated with radiotherapy.     

Short-course radiotherapy is not optimal for spinal cord compression due to myeloma

PURPOSE: To investigate the suitability of short-course radiotherapy (RT) for spinal cord compression (SCC) in myeloma patients. METHODS AND MATERIALS: Data for 172 myeloma patients irradiated between January 1994 and December 2004 for SCC were retrospectively evaluated. Short-course RT (1 x 8 Gy, 5 x 4 Gy, n = 61) and long-course RT (10 x 3 Gy, 15 x 2.5 Gy, 20 x 2 Gy, n = 111) were compared for functional outcome up to 24 months after RT. In addition, 10 potential prognostic factors were investigated. RESULTS: Improvement of motor function occurred in 90 patients (52%). Forty-seven percent of nonambulatory patients regained the ability to walk. Functional outcome was significantly influenced by the time of developing motor deficits before RT. Improvement of motor function was more frequent after long-course RT than after short-course RT: 59% vs. 39% (p = 0.10) at 1 month, 67% vs. 43% (p = 0.043) at 6 months, 76% vs. 40% (p = 0.003) at 12 months, 78% vs. 43% (p = 0.07) at 18 months, and 83% v 54% (p = 0.33) at 24 months. A subgroup analysis of the long-course RT group demonstrated a similar functional outcome for 10 x 3 Gy when compared with 15 x 2.5 Gy and 20 x 2 Gy. CONCLUSIONS: Long-course RT is preferable for SCC in myeloma patients because it resulted in better functional outcome than short-course RT. Treatment with 10 x 3 Gy can be considered appropriate.     

Role of radiotherapy in the treatment of motor dysfunction due to metastatic spinal cord compression: comparison of three different fractionation schedules

PURPOSE: The optimum fractionation schedule for radiotherapy (RT) of metastatic spinal cord compression (MSCC) is still debated in the literature. Several reports have compared different fractionation schedules for pain relief. To our knowledge, this retrospective analysis is the first to compare three different schedules for functional outcome. METHODS AND MATERIALS: For posttreatment functional and ambulatory outcome, three schedules, 30 Gy in 10 fractions (n = 93), 37.5 Gy in 15 fractions (n = 80), and 40 Gy in 20 fractions (n = 74), were compared. Motor function was evaluated by a 6-point scale before and at the end of RT and 3, 6, and 12 months later. A multivariate analysis was performed for functional outcome, including fractionation schedule and the three relevant prognostic factors (primary tumor type, time of developing motor deficits before RT, and ambulatory status). RESULTS: No significant difference was observed for posttreatment motor function or ambulatory rates among the three schedules. According to the multivariate analysis, the radiation schedule had no significant impact on functional outcome (p = 0.223) in contrast to the three prognostic factors (p <0.001, p <0.001, and p = 0.012). CONCLUSION: The three fractionation schedules were comparable for functional outcome. The least time-consuming schedule (30 Gy in 10 fractions) should be considered for patients with a markedly reduced life expectancy.     

18 F-FLT PET/CT对食管鳞癌放化疗效果预测研究

背景与目的： ¹⁸ F-FLT是一种细胞增殖的示踪剂。探索 ¹⁸ F-FLT PET/CT对食管鳞癌根治性放（化）疗效果的预测价值。方法：对根治性放（化）疗的初治食管鳞癌患者,放疗前及放疗第4周行 ¹⁸ F-FLT PET/CT扫描,记录原发灶的SUV _max-T 、转移淋巴结的SUV _max-N 等参数。随访患者总生存期（overall survival,OS）及无进展生存期（progression-free survival,PFS）,分析PET/CT参数与患者预后的关系。结果：共入组39例患者,25例完成2次PET/CT扫描。 ¹⁸ F-FLT的SUV _max-T 由基线6.63下降到1.22,淋巴结SUV _max-N 由3.69下降到1.84,但下比例与生存率无关。 ¹⁸ F-FLT PET/CT的基线SUV _max-N ＜5.00的患者,其OS明显高于SUV _max-N ≥5.00的患者（P=0.002）。结论：对根治性放（化）疗食管鳞癌,治疗前的基线 ¹⁸ F-FLT PET/CT的淋巴结SUV _max-N 是一个较好的预测预后参数。放疗4周时,病灶在 ¹⁸ F-FLT PET/CT扫描中的SUV值明显下降,但不能预测预后。     

Predictors of acute esophagitis in patients with non-small-cell lung carcinoma treated with concurrent chemotherapy and hyperfractionated radiotherapy followed by surgery

PURPOSE: To evaluate possible clinical and dosimetric predictors of acute esophagitis in patients with locally advanced non-small-cell lung carcinoma treated in a prospective Phase I-II trimodality protocol. METHODS AND MATERIALS: The data from 36 patients with Stage III non-small-cell lung carcinoma treated in a Phase I-II high-dose concurrent chemoradiotherapy protocol were analyzed for possible predictors of acute esophagitis. The median age was 58 years (range, 38-77 years). Patients included in this study had either Stage IIIA (n = 24) or IIIB (n = 12) disease. All patients were treated with induction concurrent carboplatin (area under the plasma concentration-time curve 1), vinorelbine (5-15 mg/m(2)), and hyperfractionated radiotherapy (69.6 Gy) followed by consolidation chemotherapy (carboplatin area under the plasma concentration-time curve 6, vinorelbine 25 mg/m(2), docetaxel 75 mg/m(2)) or surgery (n = 19) plus consolidation chemotherapy. Acute toxicities were graded using the Radiation Therapy Oncology Group criteria. The following clinical and dosimetric parameters were analyzed: age, gender, race, T stage, N stage, pretreatment body mass index, percentage of weight lost during therapy, pretherapy serum albumin, tumor location, length of esophagus in treatment field, percentage of esophagus volume treated to >40, >45, >50, >55, >60, and >65 Gy. These parameters were coded and analyzed against Grade 2 and worse esophagitis using univariate and multivariate regression analyses. RESULTS: Of the 36 patients, Grade 1, 2, and 3 acute esophagitis was observed in 16 (44%), 12 (33%), and 2 (5.5%) patients, respectively. Grade 4 or 5 toxicity was not observed in this patient cohort. Only the pretreatment body mass index (rho = -0.431, p = 0.004) and percentage of esophagus volume treated to >50 Gy (rho = 0.297, p = 0.040) demonstrated a statistically significant correlation with the incidence of Grade 2 or worse esophagitis on univariate analysis. These parameters retained their statistical significance on multivariate regression analysis (p = 0.029 and 0.049, respectively). CONCLUSION: In patients undergoing concurrent high-dose chemotherapy and hyperfractionated radiotherapy, a low pretherapy body mass index and percentage of esophagus volume treated to >50 Gy were significantly associated with acute Grade 2 or worse esophagitis.     

Post-operative intensity-modulated radiotherapy for malignancies of the nasal cavity and paranasal sinuses.

PURPOSE: To evaluate the clinical outcome and toxicity of post-operative intensity-modulated radiotherapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS: Twenty-five patients with histological proven cancer of the paranasal sinuses (n=21) or nasal cavity (n=4) were post-operatively treated with IMRT at the Leuven department to a total dose of 60 Gy (n=15) or 66 Gy (n=10). Both acute and chronic toxicity were prospectively scored in all patients. RESULTS: Median follow-up was 27 months (range: 12-47 months) among surviving patients. The actuarial 2-year local control (LC), overall survival (OS) and disease-free survival (DFS) rates were 81%, 88% and 77%, respectively. One patient developed isolated distant metastasis, while none of the patients developed regional failure. No grade 3 or 4 toxicity was reported, either acute or chronic. No radiation-induced blindness or brain necrosis was reported to date, although longer follow-up has to be awaited for definitive results. CONCLUSION: Post-operative IMRT for sinonasal cancer resulted in similar local control and survival rates as conventional or 3D-conformal radiotherapy techniques, and was associated with little acute toxicity. Longer follow-up is necessary to confirm the lack of late complications.     

加味养阴清肺汤联合营养干预对鼻咽癌放疗患者营养状态及疗效的影响

 目的 探讨加味养阴清肺汤联合营养干预对鼻咽癌放疗患者营养状态及疗效的影响。方法 将120例接受放射治疗的鼻咽癌初治患者，随机分为加味养阴清肺汤联合营养干预组（A组）、加味养阴清肺汤组（B组）、营养干预组（C组）和单纯放疗组（D组），每组各30例，各组患者均观察11~13周，（1）检测四组患者放疗前、中、后的生化指标；（2）观察四组患者放疗前、中、后期营养不良发生率和程度；（3）评价四组患者放疗结束时和放疗结束后1月的疗效。结果 （1）治疗中及治疗后四组患者的ALB、PAB、TRF、LC平均水平差异均有统计学意义（P<0.05）；（2）放疗中（DT=40 Gy）和放疗后（DT=70 Gy）四组患者的Ⅰ、Ⅱ、Ⅲ和Ⅳ度营养不良发生率差异均有统计学意义（均P<0.05）；（3）四组患者疾病缓解率的差异在放疗结束后1月时差异有统计学意义（96.67% vs. 93.33% vs. 93.33% vs. 89.66%, 均P<0.05）。结论 加味养阴清肺汤联合营养干预能更好的改善患者营养状况和生化指标，保证放疗进度和疗效。     

Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression

PURPOSE: In many centers worldwide, radiotherapy for metastatic spinal cord compression (MSCC) is performed with 30 Gy in 10 fractions. This study investigated the potential benefit of dose escalation. METHODS AND MATERIALS: Data from 922 patients with carcinomas causing MSCC were retrospectively evaluated. The outcome of 345 patients treated with 10 fractions of 3 Gy in 2 weeks was compared with the outcomes of 577 patients treated with 37.5 Gy in 15 fractions within 3 weeks or 40 Gy in 20 fractions within 4 weeks. Additionally, 10 potential prognostic factors were investigated: age, gender, performance status, tumor type, interval between cancer diagnosis and MSCC, number of involved vertebrae, other bone and visceral metastases, ambulatory status, and the interval to the development of motor deficits before radiotherapy. RESULTS: Motor function improved in 19% of patients after 30 Gy in 10 fractions and in 22% after greater doses (p = 0.31). The local control (p = 0.28) and survival (p = 0.85) rates were not significantly different with doses >30 Gy. Better functional outcome was associated with the absence of visceral metastases, an interval between tumor diagnosis and MSCC of >12 months, ambulatory status, and an interval to the development of motor deficits of >7 days. Improved local control was significantly associated with no visceral metastases, improved survival with favorable histologic features (breast or prostate cancer), no visceral metastases, ambulatory status, an interval between cancer diagnosis and MSCC of >12 months, and an interval to the development of motor deficits of >7days. CONCLUSION: Escalation of the radiation dose to >30 Gy in 10 fractions did not improve the outcomes in terms of motor function, local control, or survival but did increase the treatment time for these frequently debilitated patients. Therefore, doses >30 Gy in 10 fractions are not recommended.     

Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91.

PURPOSE: To evaluate the outcome of children with supratentorial primitive neuroectodermal tumors after surgery, irradiation, and chemotherapy and to identify factors predictive for survival. PATIENTS AND METHODS: Sixty-three children in the prospective trials HIT 88/89 and HIT 91 were eligible. Complete resection was performed in 21 patients. Patients were randomized for preirradiation chemotherapy, consisting of two cycles of ifosfamide, etoposide, methotrexate, cisplatin, and cytarabine (n = 40), or chemotherapy after irradiation, consisting of eight cycles with cisplatin, vincristine, and lomustine (n = 23). Irradiation volume was recommended to encompass the neuraxis with 35.2-Gy total dose followed by a boost (20.0 Gy) to the primary tumor site (n = 54). Seven patients were irradiated to the tumor region only with a total dose of 54.0 Gy. RESULTS: Overall survival at 3 years was 48.4%. Progression occurred in 38 children, with local recurrences in 27 patients. The only significant prognostic factor was dose and volume of radiotherapy (progression-free survival after 3 years was 49.3% with correct treatment compared with 6.7% for 15 children with major violations of radiotherapy). Ten early progressions occurred during adjuvant therapy (eight before and two during radiotherapy), nine of them treated with preirradiation chemotherapy. There was a positive trend in outcome for nonmetastatic and pineal tumors. CONCLUSION: Significant predictive factors were dose and volume of radiotherapy. Volume of irradiation should encompass the whole CNS with additional boost to the tumor region. Local doses of at least 54 Gy and a craniospinal dose of 35 Gy are necessary. Preirradiation chemotherapy seems to increase risk of early progression.     

Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas

BACKGROUND: To assess the impact on survival of consolidation radiotherapy to bulky or semibulky lesions in patients with advanced diffuse large B cell lymphoma (DLCL) in complete remission after primary chemotherapy. PATIENTS AND METHODS: Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty-eight patients were irradiated to the involved field and 12 to the extended field with a dose of 30-46 Gy. RESULTS: In patients with bulky disease, consolidation radiotherapy prevented relapses involving exclusively the bulky area, prolonged time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p = 0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with semibulky lesions. Multivariate analyses confirmed the independent association between consolidation radiotherapy and survival, and showed that a dose > or =36 Gy was related to a longer OS, while the extension of the radiotherapy field did not modify outcome. No treatment-related deaths were observed. Four patients developed a second malignancy, none of whom had undergone consolidation radiotherapy. CONCLUSIONS: Consolidation radiotherapy to bulky or semibulky lesions significantly improved the outcome in patients with advanced DLCL in complete remission after primary chemotherapy. Involved-field irradiation with 36-45 Gy made a prolonged disease control possible without either lethal toxicity or a higher incidence of second malignancies.     

High radiation dose may reduce the negative effect of large gross tumor volume in patients with medically inoperable early-stage non-small cell lung cancer

PURPOSE: To determine whether the effect of radiation dose varies with gross tumor volume (GTV) in patients with stage I/II non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Included in the study were 114 consecutive patients with medically inoperable stage I/II NSCLC treated with three-dimensional conformal radiotherapy between 1992 and 2004. The median biologic equivalent dose (BED) was 79.2 Gy (range, 58.2-124.5 Gy). The median GTV was 51.8 cm(3) (range, 2.1-727.8 cm(3)). The primary endpoint was overall survival (OS). Kaplan-Meier estimation and Cox regression models were used for survival analyses. RESULTS: Multivariate analysis showed that there was a significant interaction between radiation dose and GTV (p < 0.001). In patients with BED < or = 79.2 Gy (n = 68), the OS medians for patients with GTV >51.8 cm(3) and < or = 51.8 cm(3) were 18.2 and 23.9 months, respectively (p = 0.015). If BED was >79.2 Gy (n = 46), no significant difference was found between GTV groups (p = 0.681). For patients with GTV >51.8 cm(3) (n = 45), the OS medians in those with BED >79.2 Gy and < or = 79.2 Gy were 30.4 and 18.2 months, respectively (p < 0.001). If GTV was < or = 51.8 cm(3) (n = 45), the difference was no longer significant (p = 0.577). CONCLUSION: High-dose radiation is more important for patients with larger tumors and may be effective in reducing the adverse outcome associated with large GTV. Further prospective studies are needed to confirm this finding.     

Cervical cancer regression measured using weekly magnetic resonance imaging during fractionated radiotherapy: radiobiologic modeling and correlation with tumor hypoxia

PURPOSE: To measure regression of cancer of the uterine cervix during external beam radiotherapy using magnetic resonance imaging, derive radiobiologic parameters from a mathematical model of tumor regression, and compare these parameters with the pretreatment measurements of tumor hypoxia. METHODS AND MATERIALS: A total of 27 eligible patients undergoing external beam radiotherapy for cervical cancer underwent weekly magnetic resonance imaging scans. The tumor volume was assessed on each of these scans and the rate of regression plotted. A radiobiologic model was formulated to simulate the effect on tumor regression of the surviving proportion of cells after 2 Gy (SP(2)), the cell clearance constant (clearance of irreparably damaged cells from the tumor [T(c)]), and accelerated repopulation. Nonlinear regression analysis was used to fit the radiobiologic model to the magnetic resonance imaging-derived tumor volumes and to derive the estimates of SP(2) and T(c) for each patient. These were compared to the pretreatment hypoxia measurements. RESULTS: The initial tumor volume was 8-209 cm(3). The relative reduction in volume during treatment was 0.02-0.79. The simulations using representative values of the independent biologic variables derived from published data showed SP(2) and T(c) to strongly influence the shape of the volume-response curves. Nonlinear regression analysis yielded a median SP(2) of 0.71 and median T(c) of 10 days. Tumors with a high SP(2) >0.71 were significantly more hypoxic at diagnosis (p = 0.02). CONCLUSION: The results of our study have shown that cervical cancer regresses during external beam radiotherapy, although marked variability is present among patients and is influenced by underlying biologic processes, including cellular sensitivity to radiotherapy and proliferation. Better understanding of the biologic mechanisms might facilitate novel adaptive treatment strategies in future studies.     

Cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy and radiotherapy for stage I intermediate or high grade non-Hodgkin's lymphomas: results of a strategy that adapts radiotherapy dose to the response after chemotherapy.

BACKGROUND: A limited number cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy followed by involved field radiotherapy is the treatment of choice for Ann Arbor stage I intermediate or high grade non-Hodgkin's lymphomas (NHL). The optimal radiotherapy dose in this combined modality setting, resulting in maximal disease control with minimal toxicity is unknown. In this retrospective single-center study we evaluated the results of a combined modality treatment strategy that adapts the radiotherapy dose to the response after chemotherapy, and focus on the influence of radiotherapy dose on local control and survival. PATIENTS AND METHODS: One hundred and forty patients with NHL Ann Arbor stages I/IE of intermediate or high grade malignancy received four cycles of CHOP chemotherapy followed by involved field radiotherapy (IF-RT). The radiotherapy dose for patients in complete response (CR) after CHOP was either 26 or 40 Gy. Patients in partial response (PR) after CHOP always received 40 Gy. The influence of the radiotherapy dose on treatment outcome was evaluated for patients in CR at the end of treatment (n=128). RESULTS: CR rates after chemotherapy and after radiotherapy were 67 and 91%, respectively. Seventy-four of the patients in CR after CHOP received 26 Gy, 20 patients in CR after CHOP 40 Gy. All patients in PR after CHOP (n=34) received 40 Gy. The localization of relapse (within or outside the radiation field) did not differ between patients receiving 26 or 40 Gy. Overall survival (OS) at 5 years for patients in CR after CHOP who received 26 and 40 Gy and for patients in PR after CHOP but CR after 40 Gy IF-RT was 76, 100 and 75%, respectively, (P=0.16), disease free survival (DFS) at 5 years 69, 90 and 75%, respectively, (P=0.52). CONCLUSIONS: No statistically significant differences in patterns of relapse or survival were found between patients receiving 26 or 40 Gy IF-RT, however the number of events in all subgroups was small.     

Prospective evaluation of urinary and intestinal side effects after BeamCath stereotactic dose-escalated radiotherapy of prostate cancer.

BACKGROUND: New data suggest that a higher radiation dose will improve outcome in treatment of localized prostate cancer. External beam radiotherapy (EBRT) may on the other hand induce disturbances in the patient's urinary and intestinal function. Since 1997, 195 patients have been treated with a stereotactic boost of 4-8 Gy added to conventional 70 Gy EBRT. Late side effects were prospectively evaluated 3 years after dose-escalated EBRT. METHODS: Urinary and intestinal problems were prospectively evaluated with a validated self-assessment questionnaire, the Prostate Cancer Symptom Scale (PCSS). Two hundred and eighty-seven patients completed the questionnaire at the 1 year follow-up, and 153 at 3 years after treatment. Pre-treatment mean age was 66 years. One hundred and sixty-eight patients were treated with the conformal technique and 195 were treated with the dose-escalated stereotactic BeamCath technique. Mean total dose in the conformal group (< or =70 Gy) was 66 Gy (60.8-70.4 Gy). The dose-escalated group consists of three dose levels, 74 Gy (n = 68), 76 Gy (n = 74), and 78 Gy (n = 53). RESULTS: Analyzing the whole population 3 years after treatment, urgency and starting problems decreased in comparison to pre-treatment. A minor increase in urinary incontinence was reported 3 years after treatment in comparison to pre-treatment. No increases in other urinary symptoms were reported. Intestinal symptoms were slightly increased during the follow-up period in comparison to pre-treatment. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal or genitourinary late side effects at 1 year or 3 years in comparison to doses < or =70 Gy. CONCLUSIONS: The stereotactic BeamCath EBRT technique facilitates safe dose escalation of patients with prostate cancer.     

Fractionated stereotactic radiotherapy for acoustic neuromas

PURPOSE: When compared with radiosurgery, fractionated stereotactic radiotherapy for acoustic neuroma (AN) offers escalation of the tumor dose and potential sparing of auditory and facial nerve functions. METHODS AND MATERIALS: Between 1996 and 2001, 249 consecutive patients have received fractionated stereotactic radiotherapy for AN. One hundred twenty-five patients had follow-up >1 year and were the subject of this report. A noninvasive, repeat-fixation mask allowed simulation by way of spiral CT. Two distinct schedules for total dose and fractionation were used. For an AN <3.0 cm in diameter (volume 1.4 +/- 0.2 cm(3)), patients received 25 Gy given in 5 consecutive daily fractions of 5 Gy (111 patients), and for ANs >or=3.0 cm (volume 8.1 +/- 1.2 cm(3)), patients received 30 Gy given in 10 fractions of 3 Gy (14 patients). RESULTS: The percentage of decrease in tumor size was 12% +/- 2% (range 0-100%) vs. 13% +/- 3% (range 0-38%) for the 25 Gy vs. 30 Gy regimens, respectively. No patient had growth of the AN or developed facial weakness. Two patients developed transient decreases in facial sensation. The rates of hearing preservation were similar for the larger and smaller tumors. CONCLUSION: Fractionated stereotactic radiotherapy may preserve normal function and control both small and large ANs.