Longitudinal study of intestinal symptoms and fecal continence in patients with conformal radiotherapy for prostate cancer.

PURPOSE: To prospectively assess the intestinal symptoms and fecal continence in patients who had undergone conformal radiotherapy (CRT) for prostate cancer. METHODS AND MATERIALS: A total of 78 men who had undergone definitive CRT for prostate cancer were evaluated. The patients were assessed before, during (treatment Weeks 4 and 6), and 2, 12, and 24 months after CRT completion. The intestinal symptoms and fecal continence were evaluated with comprehensive standardized questionnaires. RESULTS: The intestinal symptoms were mostly intermittent, with only a small minority of patients affected daily. Defecation pain, fecal urge, and rectal mucous discharge increased significantly during therapy. Defecation pain and rectal mucous discharge had returned to baseline levels within 8 weeks and 1 year after CRT, respectively. However, fecal urge remained significantly elevated for ≤1 year and then returned toward the pretreatment values. The prevalence of rectal bleeding was significantly elevated 2 years after CRT. Fecal continence deteriorated during CRT and remained impaired at 1 year after treatment. Incontinence was mostly minor, occurring less than once per week and predominantly affecting incontinence for gas. CONCLUSION: Intestinal symptoms and fecal incontinence increased during prostate CRT. Except for rectal bleeding, the intestinal symptoms, including fecal incontinence, returned to baseline levels within 1-2 years after CRT. Thus, the rate of long-term late radiation-related intestinal toxicity was low.

Impact of body mass index on outcomes after conformal radiotherapy in patients with prostate cancer.

PURPOSE: Several retrospective analyses have suggested that obese men with prostate cancer treated with external beam radiotherapy (EBRT) have outcomes inferior to those of normal-weight men. However, a recently presented analysis for the first time challenged this association between body mass index (BMI) and treatment failure. It is therefore important to provide further data on this issue. METHODS AND MATERIALS: This was a retrospective analysis of 564 men treated with risk-adapted conformal EBRT at a single institution. Low-risk patients received EBRT alone, and the other patients received EBRT plus endocrine treatment. In addition, high-risk patients were treated to higher EBRT doses (74 Gy). A rectal balloon catheter for internal immobilization, which can be identified on portal images, was used in 261 patients (46%). Thus, localization did not rely on bony landmarks alone in these cases. RESULTS: The median BMI was 26, and 15% of patients had BMI≥30. Neither univariate nor multivariate analyses detected any significant impact of BMI on biochemical relapse, prostate cancer-specific survival, or overall survival. The 5-year biochemical relapse rate was 21% and prostate cancer-specific survival 96%. CONCLUSIONS: The present analysis of a large cohort of consecutively treated patients suggests that efforts to reduce prostate movement and geographic miss might result in comparable outcomes in obese and normal-weight patients.

Longitudinal analysis of quality of life in patients receiving conformal radiation therapy for prostate cancer.

PURPOSE: To prospectively assess quality of life (QoL) in patients receiving conformal radiation therapy (CRT) for prostate cancer. PATIENTS AND METHODS: 78 men with definitive CRT for prostate cancer were entered into the study. Patients were assessed before CRT, at 40 and 60 Gy, and 2, 12 and 24 months after the end of treatment. QoL was assessed using the EORTC Quality of Life Questionnaire C30 and the prostate module PR25. Changes in mean QoL scores with time of >or= 10 points were considered clinically relevant. RESULTS: Global QoL did not change statistically significant during CRT and was slightly above baseline levels during follow-up. CRT had a statistically significant negative short-term impact on role functioning, fatigue, and PR25 urinary symptoms. The scores recovered within 2 months to 1 year after CRT. Emotional functioning and social functioning scores slightly increased during and after CRT. Role functioning decreased by > 10 points at 60 Gy and urinary symptoms decreased by > 10 points at 40 and 60 Gy. All other differences were < 10 points. A high number of concomitant diseases and having no children were negative pretreatment predictors for long-term global QoL. CONCLUSION: Definitive CRT for prostate cancer does not compromise global QoL during therapy and up to 2 years after treatment. It has a limited negative effect on role functioning, urinary symptoms and, to a lesser extent, on fatigue with restitution within 2 months to 1 year after treatment.

Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) non-small-cell lung cancer (NSCLC).

Stereotactic Radiotherapy has the potential to produce high local control rates with low risk of severe lung toxicity. From December 2000 to January 2006, 68 inoperable patients (median age 76 years) with stage I NSCLC received definitive hSRT. A mean total dose of 37.5 Gy (24-40 Gy; 60%-isodose) in 3-5 fractions was applied. Immobilisation was carried out by means of a vacuum couch and low pressure foil (Medical Intelligence, Schwab München, Germany). Staging procedures were thoracic and abdominal CT-scan, FDG-PET and CT or MRI of the brain in all patients. Clinical target volume was the tumor as seen in lung windowing of CT and in FDG-PET. Organ movements (6-22 mm) and patient positioning in the couch (3-12 mm) were added as safety margin for the definition of the planning target volume (PTV), that was enclosed by the 60%-isodose. We observed four (6%) local tumor recurrences, resulting in an actuarial local tumor control rate of 96%, 88% and 88% after 1, 2 and 3 year follow-up. Nineteen patients died, with eight patients due to cancer (12%), two to local tumor progression alone. Cancer-specific survival is 96%, 82% and 73% at 1, 2 and 3 years. Eleven patients died from comorbidities, making a 53% overall 3-year survival. Fifty five percent of the patients were affected by mild acute and subacute side effects, with only 3% experiencing pneumonitis III degrees . Late effects were pneumonitis III degrees in 1%, rib fractures in 3%, and benign pleural effusion in 2 patients. Hypofractionated SRT is safe even in elderly patients with stage I NSCLC and significantly reduced lung capacity. It leads to high local control rates and should be offered to patients not amenable for curative resection.

High-precision radiation therapy with integrated biological imaging and tumor monitoring: evolution of the Munich concept and future research options.

PURPOSE: To describe an emerging concept of high-precision radiotherapy, a modality characterized by adaptation to patient and organ movements, which might occur between fractions or even during radiation delivery. METHODS AND RESULTS: Today's unprecedented technical capabilities to visualize the target volume and create conformal dose distributions allow for avoidance of critical structures or targeted treatment intensification within a conventionally imaged, anatomically defined tumor. The success of selective dose escalation depends on (1) correct staging and target volume identification, which can be improved by biological imaging, and (2) identification of biologically relevant subvolumes, which determine tumor control. Current efforts are directed at different methods, such as positron emission tomography and magnetic resonance spectroscopy, and integrating them into treatment planning. CONCLUSION: Early clinical trials assessing the safety and efficacy of image- and biology-guided radiotherapy are ongoing. The same modalities might be used to determine the individual tumor response during treatment and to adapt therapy. Temporal changes in tumor biology, which might represent both a challenge and a chance with regard to adaptation of treatment, need to be addressed in greater detail.

Late rectal symptoms and quality of life after conformal radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE: This study was carried out in order to analyze the prevalence of late rectal and anal symptoms after conformal radiation therapy for prostate cancer and to assess their association with quality of life. PATIENTS AND METHODS: Two-hundred and forty nine patients were interviewed at 24-111 months after definitive conformal radiation therapy of localized prostate cancer with a median dose of 70 Gy. Rectal symptoms and fecal incontinence were evaluated with standardized questionnaires. Quality of life was assessed with the EORTC Quality of Life Questionnaire-C30 and the prostate cancer module PR25. RESULTS: Rectal symptoms were mostly intermittent. Daily symptoms occurred in < or =5% of the patients. Incontinence was mostly mild with only 3% of the patients reporting daily incontinence episodes. Quality of life was comparable to that of the male German general population except that cognitive functioning and diarrhea were worse in the study population and pain was worse in the reference population. Global quality of life was associated with fecal incontinence, fecal urge, tenesmus, therapy for rectal symptoms and hormonal therapy for biochemical/clinical recurrence. CONCLUSIONS: Rectal symptoms and fecal incontinence after conformal radiation therapy for prostate cancer are mostly intermittent. Fecal incontinence, fecal urge and tenesmus are associated with lower global quality of life levels.

The role of pentoxifylline as a modifier of radiation therapy.

Pentoxifylline (Ptx), a hemorrheologic methylxanthine derivative, is of interest in radiation oncology for several reasons. First, improvement of tumor perfusion might result in better oxygenation and thus radiosensitivity. In addition, the drug also influences cytokine-mediated inflammation. The role of cytokines in the progression of radiation reactions in both tumor and normal tissues therefore provides further opportunities to combine Ptx with ionising radiation in order to improve the therapeutic ratio. This review summarizes preclinical and clinical data in both tumor and normal tissues. Regarding radiosensitization of tumors, a large body of evidence suggests that Ptx improves tumor oxygenation and sensitizes p53 mutant tumors. However, these findings have not translated into positive clinical studies to date. None of three published clinical trials attempting to enhance the effectiveness of radiotherapy with Ptx had a satisfactory design. There is also little evidence to prove that Ptx reduces acute side effects of radiotherapy. The only possible exception is a small randomized trial of lung radiotherapy. Regarding established late sequelae, numerous non-randomized clinical trials described healing of soft tissue necrosis and improvement of trismus and fibrosis after several weeks of Ptx or Ptx plus vitamin E. However, is not unequivocally clear that the combination with vitamin E indeed is superior. The literature data suggest that radiation necrosis can be treated more effectively than fibrosis and that certain improvements might be functional and transient, with less influence on the chronic structural damage induced by ionising radiation. The ultimate individual outcome might depend, for example, on the stage of fibrosis progression, the size of the lesion and comorbid conditions such as diabetes and arteriosclerosis. Some of these factors will influence the actual amount of drug available in the targeted region. It is therefore necessary to evaluate Ptx in larger clinical trials with less baseline variation and to improve the recording of long-term results.

Positron emission tomography for radiation treatment planning.

PURPOSE: To evaluate the impact of positron emission tomography (PET) on target volume delineation for radiation treatment planning. MATERIAL AND METHODS: The data of the literature concerning the use of PET in target volume delineation are summarized. The following points are discussed for each tumor entity: biological background for the PET investigation, sensitivity and specificity of PET (with different tracers) in comparison to computed tomography (CT) and magnetic resonance imaging (MRI) and impact of PET on target volume definition. New PET tracers, which could visualize biological pathways, such as hypoxia, proliferation, angiogenesis, apoptosis and gene expression patterns, will also be discussed. RESULTS: The results of clinical studies on the integration of PET in target volume definition for lung, head-and-neck, genitourinary and brain tumors were analyzed. Fluorodeoxyglucose-(FDG-)PET has a significant impact on GTV (gross tumor volume) and PTV (planning target volume) delineation in lung cancer and can detect lymph node involvement and differentiate malignant tissue from atelectasis. In head-and-neck cancer, the value of FDG-PET for radiation treatment planning is still under investigation. For example, FDG-PET could be superior to CT and MRI in the detection of lymph node metastases and unknown primary cancer and in the differentiation of viable tumor tissue after treatment. Therefore, it might play an important role in GTV definition and sparing of normal tissue. Choline PET and acetate PET are promising tracers in the diagnosis of prostate cancer, but their validity in local tumor demarcation, lymph node diagnosis and detection of recurrence has to be defined in future clinical trials. FDG-PET seems to be particularly valuable in lymph node status definition in cervical cancer. In high-grade gliomas and meningiomas, methionine PET helps to define the GTV and differentiate tumor from normal tissue. For other entities like gastrointestinal cancer, lymphomas, sarcomas, etc., the data of the literature are yet insufficient. The imaging of hypoxia, cell proliferation, angiogenesis, apoptosis and gene expression leads to the identification of different areas of a biologically heterogeneous tumor mass that can individually be targeted using intensity modulated radiotherapy (IMRT). In addition, a biological dose distribution can be generated, the socalled dose painting. However, systematic experimental and clinical trials are necessary to validate this hypothesis. CONCLUSION: Regarding treatment planning in radiotherapy, PET offers advantages in terms of tumor delineation and the description of biological processes. To define the real impact of this investigation in radiation treatment planning, subsequent experimental, clinical and cost-benefit analyses are required.

3D conformal radiation therapy for prostate cancer in elderly patients.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate if conformal radiation therapy for localized prostate cancer with doses of 70 Gy is well tolerated in patients aged 75 years or older, and if the side effects and the biochemical recurrence free (bNED) survival are comparable to younger patients. PATIENTS AND METHODS: Eighty patients>or=75 years received definitive conformal radiotherapy for prostate cancer. Acute and late side effects as well as bNED survival (ASTRO criteria) were compared to 221 patients younger than 75 years who were treated during the same period of time. RESULTS: Median dose to the prostate was 70 Gy in both groups. There were no significant differences in acute or late side effects between age groups. The frequency of grade III late symptoms was low and ranged between 0 and 4% for the evaluated symptoms irrespective of age group. Older patients had a better bNED survival than younger patients (bNED survival at 4 years: 76 vs. 61%, P=0.042). CONCLUSIONS: High-dose conformal radiation therapy for prostate cancer is well tolerated in patients aged 75 years or older. In terms of bNED survival radiation treatment is at least as effective as it is for younger patients.

Dose escalation of concurrent hypofractionated radiotherapy and continuous infusion 5-FU-chemotherapy in advanced adenocarcinoma of the pancreas.

BACKGROUND/AIMS: To investigate the advantages and palliative effectiveness of concurrent hypofractionated radiotherapy (RT) and chemotherapy (5-FU) in patients with locally advanced and metastatic adenocarcinoma of the pancreas. METHODOLOGY: A total of 26 patients were enrolled in this study. Twenty patients had locally advanced (M0) and 6 patients had metastatic (M1) disease. They were treated with hypofractionated radiation therapy (RT) (4x3 Gy per week) and concurrent continuous infusion (300mg/sqm/24h) of 5-fluorouracil. The RT doses were escalated in 6-Gy increments starting from 24 Gy in 8 fractions in 2 weeks to 30 Gy in 10 fractions in 2.5 weeks and finally to 36 Gy in 12 fractions in 3 weeks. RESULTS: Only 1 (4%) patient experienced grade 3 mucositis, while 12 (46%) patients experienced grade 2 nausea and 1 (4%) patient experienced grade 2 weakness. No patient experienced treatment interruption or dose reduction. Late high-grade (>3) toxicity was not observed, but few patients experienced prolonged hematological toxicity, due to administration of chemotherapy after radiochemotherapy. Pain improved in 70% of the patients. The median survival time for all 26 patients is 8 months, 9 months for locally advanced cancer patients and 5 months for metastatic cancer patients. CONCLUSIONS: Dose escalation to 36 Gy in a hypofractionated manner proved to be feasible with low toxicity in patients with locally advanced and metastatic adenocarcinoma of the pancreas and warrants further investigation aiming at optimal tailoring in these two subgroups of patients.

Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer.

We reviewed our initial institutional experience with the use of stereotactic hypofractionated radiation therapy (SFRT) in patients with stage I non-small cell lung cancer (NSCLC). Thirty patients with inoperable stage I non-small cell lung cancer due to a severe chronic obstructive pulmonary disease (COPD) and/or chronic heart disease (Eastern Cooperative Oncology Group (ECOG) performance status of 0-2) were treated between December 2000 and October 2003 with SFRT in curative intent. Infiltration of locoregional lymph nodes and distant metastases were ruled out by computerized tomography (CT) scan of the brain, thorax, and abdomen, and by whole body FDG-positron emission tomography scan in all patients. Total RT doses ranged from 24.0 to 37.5 Gy, given in 3-5 fractions to the 60% isodose encompassing the planning target volume. Immobilization was carried out by a vacuum couch and a low-pressure foil. The clinical target volume was the tumor as it appeared in lung windowing on lung CT scan. Organ movements (caused by breathing; range, 6-22 mm) and reproducibility of patient positioning in the couch (range, 3-12 mm) were calculated by sequential CT and orthogonal films. The individual values were taken into account as a safety margin for the definition of the planning target volume (PTV). The median follow-up of living patients is 18 months (range, 6-38 months). As maximum response, there were 10 (33%) complete responses (CRs) and 14 (47%) partial responses (PRs), resulting in a total response rate of 80%. Stable disease was observed in 6 (20%) patients, while no patient experienced progressive disease. During follow-up, 2 (7%) local recurrences were observed (after 17 and 18 months, respectively). Of 5 (17%) patients who developed distant metastasis, 1 patient developed it in liver (3 months), another one in brain (6 months), and another one in the lung (36 months), while 2 patients developed it in mediastinal lymph nodes (after 8, and 11 months, respectively) only. Of 9 (30%) patients who have died, only 3 (10%) died of cancer, while 6 (20%) died of cancer-unrelated or unknown causes. Acute side effects were mild and affected 9 (33%) patients during the RT course (fatigue being the most frequent one in 6 patients). There were 22 acute events occurring in 19 (63%) patients during the first 3 months post-SFRT, the most frequent one being pneumonitis observed in 14 (46%) patients. However, there was only one (3%) grade 3 acute toxicity and no patient experienced greater than grade 3 toxicity during this study. One (3%) patient experienced rib fracture as the late event. SFRT is a feasible and safe treatment method in inoperable patients with stage I NSCLC having reduced lung capacity. Longer follow-up is necessary to get robust data on late toxicity as well as survival.

Sequential and/or concurrent hypofractionated radiotherapy and concurrent chemotherapy in neoadjuvant treatment of advanced adenocarcinoma of the pancreas. Outcome and patterns of failure.

BACKGROUND/AIMS: To investigate treatment outcome and patterns of failure of sequential chemotherapy (CHT) and/or concurrent hypofractionated radiotherapy (RT) and CHT followed by surgery in locally advanced non-metastatic pancreatic adenocarcinoma. METHODOLOGY: Seven patients with locally advanced but marginal resectable tumors (close contact but no signs of infiltration of the mesenteric vessels and/or vena portae) were treated with hypofractionated RT (5x3 Gy per week) and concurrent continuous infusion (300 mg/sqm/24 h, 7 days per week) of 5-fluorouracil (FU). Ten patients with locally advanced disease with radiologically suspected infiltration of the mesenteric vessels and/or v. portae were treated with 2 cycles of Cisplatin (75 mg/sqm) and Gemcitabine (2x1250 mg/sqm), and patients without tumor progression received the same concurrent RT/CHT as group 1. Four weeks after RT/CHT radical pancreatectomy was planned for patients with stable disease or remission. RESULTS: Toxicity was low in both groups, with no CTC grade 4 toxicity. In group 1, RT/CHT was completed in all patients. There was no radiological remission, but stable disease in 5 out of 7 patients. All 5 patients underwent resection of the primary tumor with a R0-resection in 3 patients. In group 2, 8 patients completed CHT and RT/CHT treatment as planned. There were 3 with partial remission. Operation was done in 4 patients, but only one R0 resection was achieved. The median survival time for all 17 patients is 13 months, with 1- and 2-year survival being 53% and 18%, respectively. Local progression was observed in 9, peritoneal seeding in 7 and distant metastasis (mostly liver and lung) in 8 patients. CONCLUSIONS: The neoadjuvant therapy could be administered with low toxicity. Results of this study warrant further investigation aiming at optimal tailoring in of this treatment approach in these two subgroups of patients.

Treatment of locally advanced and metastatic non-small cell lung cancer in the elderly.

In locally advanced NSCLC, RT/CHT can be used in fit elderly patients. In cases in which CHT is prohibitive, RT can be used alone. Advanced IIIB stage may be treated with palliative RT or CHT, each given alone. In metastatic NSCLC, platinum-containing regimens are feasible when elderly patients have good renal/cardiac function, but a third-generation drug may be a viable option, the choice depending on its toxicity profile. Short-course, palliative RT given in addition to CHT may play an important role in the treatment of symptomatic intra- and extrathoracic disease. Many questions concerning the optimal treatment for elderly patients with NSCLC remain unanswered and more trials designed for the elderly are urgently needed in the future.

Fatigue in patients with adjuvant radiation therapy for breast cancer: long-term follow-up.

PURPOSE: The aim of this study was to evaluate fatigue 2.5 years after adjuvant radiation therapy (RT) in patients with localized breast cancer and to assess its relation to pre- and immediate post-treatment fatigue values. The association of fatigue with psychological distress and functional impairment was analyzed as well as pretreatment predictors for chronic fatigue. METHODS: Of a set of 41 patients whose fatigue was evaluated during adjuvant radiation therapy, 38 patients alive and free of cancer at 2.5 years (t2) after RT were assessed in this study. Patients received the Fatigue Assessment Questionnaire (FAQ), a visual analog scale on fatigue intensity (VAS-F) as well as on cancer-related distress (VAS-D), the Hospital Anxiety and Depression Scale (HADS), and three questions of the Short-Form 36-Item Health Survey (SF-36) per mail. All 38 patients returned their questionnaires. The values were compared to pretreatment (t0) and immediate post-treatment levels (2 months after RT, t1). RESULTS: There was no significant difference between chronic fatigue levels at 2.5 years after RT and pretreatment values. When compared to immediate post-treatment levels the FAQ global score and the HADS anxiety score displayed a significant increase. Cancer-related distress correlated closely with fatigue scores. Patients with functional impairment had slightly higher fatigue values. Age or hormonal therapy were not associated with chronic fatigue levels. Pretreatment fatigue and pretreatment HADS anxiety and depression scores were good predictors of fatigue at 2.5 years after RT explaining 60% (FAQ) and 49% (VAS-F) of its variance. CONCLUSIONS: Fatigue 2.5 years after RT did not increase above baseline levels before RT in conservatively operated breast cancer patients. Chronic fatigue correlated closely with psychological distress. Patients with pretreatment elevated fatigue, anxiety or depression levels are at risk for chronic fatigue.

Limited-disease small-cell lung cancer.

Substantial improvements in treatment outcome for limited-disease small-cell lung cancer (LD SCLC) have been achieved in the last two decades owing to the introduction of chemotherapy (CHT) consisting of cisplatin and etoposide (PE), and the understanding that thoracic radiation therapy (TRT) is an essential component in improving treatment outcome. In addition, a recent metaanalysis confirmed the importance of prophylactic cranial irradiation (PCI) in general treatment plans for patients who show a complete response to treatment. However, numerous questions remain unanswered regarding this disease. While TRT/PE/PCI is considered to be the standard treatment in the majority of centers worldwide, the emergence of new and effective drugs (e.g., topoisomerase I inhibitors and paclitaxel) for the treatment of LD SCLC will likely affect therapy strategies in the near future. Important issues regarding optimal doses and fractionation regimens, as well as the timing of TRT, remain to be resolved. While most centers currently use b.i.d. fractionation as a result of the Intergroup findings, high-dose standard TRT may also be beneficial. TRT volumes are also considered an important issue, since they likely relate to the incidence of both local failure and toxicity. Finally, the optimization of PCI (total dose, fractionation regimen, and timing) is already under way. The value of surgery is limited to peripheral tumors and poorly responding cancer, and to confirm histology or improve local control and survival.