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Objective: To determine the recommended dose (RD) of gefitinib when combined with concomitant radiotherapy (RT) in a preoperative setting in patients with locally advanced rectal cancer. Secondary objectives were to evaluate acute toxicities, pathological response rate, progression-free and overall survival (OS). Materials and Methods: 20 patients with cT3-4 or cN+ cM0 tumors were enrolled. The planned RT consisted in 50 Gy given in 2 daily fractions of 1.25 Gy in 4 weeks. During RT, gefitinib was planned to be given orally once daily with 2 successive dose levels: 250 mg and 500 mg. Rectal surgery was scheduled 5 - 6 weeks after completion of RT. The median follow-up for all patients was 57 months. Results: Among the first cohort of 6 patients, 1 patient presented a dose limiting toxicity (DLT) (Grade 3 diarrhea/dehydration). In the second cohort, 2/6 patients presented with the same DLT so that 250 mg was considered as the RD. Main acute toxicities consisted in diarrhea (grade 2 - 3, 63%), and skin reaction (in RT fields grade 2 - 3 in 42%). The 5-year actuarial OS and loco-regional control rates were of 80% and 84% respectively. Conclusion: The concomitant daily administration of 250 mg of gefitinib with 50 Gy preoperative RT is feasible with manageable toxicity. The major pathologic response rate is encouraging, though it needs further confirmation. Distant metastasis still represents a concern and new strategies to overcome this issue are warranted.

Background Due to increased rates of secondary solid organ cancer in patients with severe aplastic anemia who received an irradiation-based conditioning regimen, we decided some years ago to use the combination of cyclophosphamide and antithymocyte globulin. We report the long-term follow up of patients who underwent hematopoietic stem cell transplantation from an HLA-matched sibling donor after this conditioning regimen.Design and Methods We analyzed 61 consecutive patients transplanted from June 1991 to February 2010, following conditioning with cyclophosphamide (200 mg/kg) and antithymocyte globulin (2.5 mg/kg/day × 5 days).Results Median age was 21 years (range 4–43); 41 of the 61 patients were adults. Median duration of the disease before hematopoietic stem cell transplantation was 93 days. All but 2 patients received bone marrow as the source of stem cells and all but 2 engrafted. Cumulative incidence of acute grade II–IV graft-versus-host disease was 23% (95%CI 13–34) and 18 developed chronic graft-versus-host disease (cumulative incidence 32% at 72 months, 95% CI 20–46). In multivariate analysis, a higher number of infused CD3 cells was associated with an increased risk of developing chronic graft-versus-host disease (P=0.017). With a median follow up of 73 months (range 8–233), the estimated 6-year overall survival was 87% (95% CI 78–97). At 72 months, the cumulative incidence of avascular necrosis was 21% and 12 patients presented with endocrine dysfunction (cumulative incidence of 19%). Only one patient developed a secondary malignancy (Hodgkin’s lymphoma) during follow up.Conclusions Cyclophosphamide and antithymocyte globulin is an effective conditioning regimen for patients with severe aplastic anemia and is associated with low treatment-related mortality. Long-term complications include avascular necrosis and endocrine dysfunction.

The aim of this retrospective study was to assess the incidence of late complications occurring ?2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T-cell depletion strategy.

BACKGROUND To assess the feasibility, toxicity, and outcome of prostate hemi-irradiation with a high-dose-rate brachytherapy (HDR-BT) boost for patients presumed to harbor dominant intra-prostatic tumors in a single lobe. METHODS After 3D conformal external radiotherapy (3DCRT) to 64–64.4 Gy, 77 patients with non-metastatic locally aggressive prostate cancer have been treated from 2000 to 2004, with HDR-BT using temporary open MRI-guided 192Ir implants, to escalate the dose in the boost region. Twenty patients (26%) had one lobe involvement (i.e., one sided endorectal MRI, rectal examination, and biopsies) and were boosted to one side of the gland only. A dose of 12, 14, and 16 Gy in two fractions was delivered to 5, 6, and 9 patients, respectively. RESULTS After a median follow-up 69 months, no differences in late rectal toxicity were observed between the unilaterally and bilaterally irradiated cohorts. Although, grade 2 late urinary toxicity was worse in the hemi-irradiated group (P = 0.03), severe grade ≥3 late urinary toxicity at 5 years was not different: 10% versus 8.8% in the unilaterally and bilaterally irradiated cohorts, respectively. Grade 4 late urinary toxicity, however, was exclusively observed in patients boosted to both lobes (5/57, 8.8%). Five-year biochemical relapse-free survival was 79.7% versus 70.5% for the unilateral and bilateral boost groups, respectively (P = 0.99). CONCLUSION Prostate hemi-irradiation with a HDR-BT boost to the dominant tumor region may be considered when rectal examination, MRI, and biopsies suggest one lobe involvement. Nevertheless, strict dosimetric optimization is needed in order to further reduce the risk of late severe toxicity. Prostate 71:1309–1316, 2011. © 2011 Wiley-Liss, Inc.

Purpose To evaluate the feasibility, tolerance, and preliminary outcome of an open MRI-guided prostate partial-volume high-dose-rate brachytherapy (HDR-BT) schedule in a group of selected patients with nonmetastatic, locally aggressive prostatic tumors. Methods and Materials After conventional fractionated three-dimensional conformal external radiotherapy to 64–64.4 Gy, 77 patients with nonmetastatic, locally aggressive ( e.g., perineural invasion and/or Gleason score 8–10) prostate cancer were treated from June 2000 to August 2004, with HDR-BT using temporary open MRI-guided 192 Ir implants, to escalate the dose in the boost region. Nineteen, 21, and 37 patients were sequentially treated with 2 fractions of 6 Gy, 7 Gy, and 8 Gy each, respectively. Neoadjuvant androgen deprivation was given to 62 patients for 6–24 months. Acute and late toxicity were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring system. Results All 77 patients completed treatment as planned. Only 2 patients presented with Grade ≥3 acute urinary toxicity. The 3-year probability of Grade ≥2 late urinary and low gastrointestinal toxicity–free survival was 91.4% ± 3.4% and 94.4% ± 2.7%, respectively. Rates of 3-year biochemical disease-free survival (bDFS) and disease-specific survival were 87.1% ± 4.1% and 100%, respectively. Conclusions Boosting a partial volume of the prostate with hypofractionated HDR-BT for aggressive prostate cancer was feasible and showed limited long-term toxicity, which compared favorably with other dose-escalation methods in the literature. Preliminary bDFS was encouraging if one considers the negatively selected population of high-risk patients in this study.

Das Auftreten klinisch signifikanter Arterienstenosen nach Radiotherapie des Kopf-Hals-Bereichs, des Thoraxbereichs oder groserer Arterien wie z.B. der Aorta oder der Iliakalarterien ist in der Literatur gut dokumentiert und im klinischen Alltag bekannt. Dagegen scheint die Kenntnis bzw. das Bewusstsein bezuglich des Auftretens einer Nierenarterienstenose nach erfolgter Radiotherapie nur marginal zu sein. Das plotzliche Auftreten einer schwer behandelbaren arteriellen Hypertonie bei einem 27-jahrigen komatosen Patienten wird beschrieben, welcher zuvor im Jahre 2001 im Alter von 20 Jahren am Spital Sion, Schweiz, aufgrund eines lumbalen Ewing-Sarkoms mit Chemotherapie und anschliesender Radiotherapie behandelt wurde. Zudem wird dieser Patient mit den zwischen 1965 und 2007 publizierten Fallen einer radiogen induzierten Nierenarterienstenose verglichen, um deren klinische Relevanz als potentielle radiogene Langzeitnebenwirkung zu verdeutlichen. Publizierte Berichte uber die radiogen induzierte Nierenarterienstenose sind relativ selten. Dennoch ist die arterielle Hypertonie infolge einer radiogen induzierten Nierenarterienstenose mit einer sehr variablen Latenz von bis zu 20 Jahren eine ernstzunehmende potentielle Langzeitnebenwirkung der Radiotherapie. Die Ursache des geringeren Bewusstseins bezuglich der radiogen induzierten Nierenarterienstenose und der im Vergleich zu zerebralen oder zervikalen Gefasstenosen selteneren Dokumentation in der klinischen Literatur ist moglicherweise ein diagnostischer Bias. In den Jahrzehnten vor Einfuhrung der CT- und MRT-Diagnostik und deren breitem routinemasigen Einsatz liesen sich retroperitoneale und abdominale Gefasstenosen nur schwer diagnostizieren. Dagegen konnten z.B. signifikante Karotisstenosen bereits sehr fruh sonographisch einfach und zuverlassig diagnostiziert werden. Wie dieser Fallbericht zeigt, muss daher bei Patienten mit schlecht behandelbarer Hypertonie nach lumbaler, abdominaler oder retroperitonealer Radiotherapie eine radiogen induzierte Nierenarterienstenose differentialdiagnostisch berucksichtigt werden.

To evaluate the outcome of patients with carcinoma of anal margin in terms of recurrence, survival, and radiation toxicity. A series of 45 consecutive patients, with anal margin carcinoma treated between 1983 and 2006 with curative intent at two institutions, was retrospectively analyzed. A surgical excision (close or positive surgical margin in 22 out of 29 patients) was realized before radiotherapy (RT). RT consisted of definitive external beam RT (EBRT) in 36 patients, brachytherapy (BT) alone in two patients, and both BT and EBRT in seven patients. The median total radiation dose was 59.4 Gy (range, 30–74 Gy). The 5-year locoregional control (LRC) rate was 78% [95% confidence interval (CI), 64–93%]. The 5-year disease-specific survival (DSS) and overall survival (OS) rates were respectively 86% (95% CI, 72–99%) and 55% (95% CI, 44–66%). The overall anal conservation rate was 80% for the whole series. There was no significant association between local recurrence and patient age, histological grade, tumor size, T stage, overall treatment time, RT dose, or chemotherapy. Long-term side effects were observed in 15 patients (33%). Only three patients developed grade 3–4 late toxicity (CTCAE/NCI v3.0). Significant relationship was found between dose, and complication rate (48% for dose ≥59.4 Gy versus 8% for dose

To assess prospectively the quality of life (QOL) of patients treated by preoperative radiotherapy (RT) and surgery for locally advanced rectal cancer.We studied 53 patients treated with bi-fractionated RT (50 Gy in 40 fractions within 4 weeks) followed at a median interval of 45 days by abdominoperineal resection in 11 patients and low anterior resection in 42 patients. Their QOL was assessed using two self-rating questionnaires developed by the European Organization for Research and Treatment of Cancer (EORTC): one was cancer specific (EORTC QLQ-C30) and one was site specific (EORTC QLQ-C38). The questionnaires were completed before RT and 12-16 months after RT, at which time 17 patients had undergone colostomy. We hypothesized that at least some scores of the various scales would vary between the two analyses.Compared with the pre-RT scores, at 1 year, patients reported statistically significant improvement in their emotional state (median 75 vs. 100, p0.0001), perspective of the future (67 vs. 100, p = 0.0004), and their global QOL (75 vs. 83, p = 0.0008), as well as a decrease in GI symptoms (13 vs. 0, p = 0.002). However, the sexual dysfunction score increased significantly, particularly in men (17 vs. 83, p = 0.0045), and a trend toward a lower body image score was observed (100 vs. 89, p = 0.068). At 1 year, patients with colostomies reported similar or significantly improved symptom scores for fatigue, pain, GI problems, and sleep disturbance, but no such improvements were observed in patients without stomas.One year after combined treatment for locally advanced rectal cancer, patients exhibited statistically significant improvement in some important QOL outcomes, including global QOL, despite a decrease in sexual function and body image. Any additional improvement in QOL outcome may require refinements in the RT and surgical techniques to reduce late sequelae, particularly sexual dysfunction. Our results suggest that QOL considerations do not justify sphincter-conserving approaches if locoregional tumor control would be compromised.

The purpose of this study was to determine the maximum tolerated dose of gemcitabine when it was administered concomitantly with hyperfractionated radiotherapy before surgery in patients with locally advanced rectal cancers and to investigate the midterm efficacy of such a regimen.Thirty-seven patients with stage II-III tumors as assessed by computed tomography/echoendoscopy were enrolled. Radiotherapy consisted of 50 Gy given in two daily fractions of 1.25 Gy over 4 weeks. The starting dose of gemcitabine was 10 mg/m(2)/day (in a 30-minute i.v. perfusion) twice weekly with planned escalation steps of 5 mg/m(2)/day. Surgery was planned at 6 weeks after the end of radiotherapy. Main end-points of the study were complete pathological tumor response, the rate of clear margin resection, and actuarial locoregional control and disease-free survival. The median follow-up for all patients was 32 months (range: 10-51 months).At the level of 45 mg/m(2), two of four patients presented with dose-limiting rectal toxicities (severe acute proctitis requiring hospitalization in the immediate postradiotherapy period). Thus, the gemcitabine biweekly dose of 40 mg/m(2) was considered to be the maximum tolerated dose. Among the 36 patients who underwent surgery, 17 (47%) had a marked pathological response, including six patients (17%) with a microscopically complete response and 11 (30%) with only microscopically residual carcinoma of less than 1 cm. All of them had clear surgical margins. At 3 years, actuarial overall survival rate was 85%, locoregional control was 94.5%, and disease-free survival was 67%.The present study determined the recommended dose of gemcitabine to be 40 mg/m(2) when administered concurrently twice a week with 50 Gy hyperfractionated radiotherapy for the preoperative treatment of locally advanced rectal cancers. The encouraging pathological response rate and the very low locoregional recurrence rate suggest that this innovative approach merits further investigation.

Purpose To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone. Patients and Methods From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity. Results There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease–free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups. Conclusion The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.

Data on early treatment-related morbidity after radiotherapy alone (RT; 217 patients) or combined with chemotherapy (RT + CT; 182 patients) of head and neck squamous cell carcinoma are analyzed.The patients were treated between November 1985 and November 1996 in four Swiss centers that independently introduced combined-modality therapy in selected cases of head and neck cancer. RT schedules varied among the four centers, but within each institution all patients received the same dose-fractionation schedule irrespective of whether they had CT or not. The following early morbidity items were evaluated: skin, mucosa, larynx, salivary glands, dysphagia, weight loss, and toxic death. Toxicity was scored using the EORTC/RTOG scale.Although considerable variation was noted among the treatment schedules/centers, the main findings are as follows: (1) early morbidity was significantly enhanced after all five RT + CT schedules compared with RT alone; (2) typically, a third of the patients lost10% of their body weight during concurrent RT + CT as compared with 10% of the patients receiving RT alone; (3) at 12 weeks, the prevalence of grade 2 morbidity was 25-60% after RT + CT as compared with 4-20% after RT alone.A number of early morbidity items were found to be more prevalent and/or more severe after RT + CT than after RT alone.

Between April 1982 and December 1997 24 patients with carcinoma of the anal margin were treated with radiation therapy (RT) (10 patients) or RT-chemotherapy (CT) (14 patients). External beam RT (EBRT) was delivered in 18 patients, combined with brachytherapy in 5 patients, while one patient was treated with brachytherapy alone. Inguinal nodes were irradiated in 17 patients. Chemotherapy was based on 5-fluorouracil and mitomycin-C. At 5 years, the overall survival rate was 56% and the locoregional rate was 69.5%. Anal sphincter was preserved in 16/24 treated patients. Grade 4 late complications were observed in 3 patients. This study reinforces the notion that radical RT +/- CT provides a high probability of cure and sphincter preservation in patients presenting with this rare condition. Major late toxicity is uncommon; a better adaptation of treatment technique to the individual clinical situation may prevent some of the more severe complications in the future.

This study was conducted to evaluate quality of life (QOL) and functional outcome in patients with carcinomas of the larynx and hypopharynx treated with accelerated radiotherapy (RT).Between January 1991 and September 1996, 21 patients treated with accelerated concomitant boost RT schedule (69.9 Gy in 5. 5 weeks) for laryngeal (n = 10) or hypopharyngeal (n = 11) carcinomas and who remained free of disease at 1-year minimum follow-up were evaluated. The functional outcome was assessed by the subjective Performance Status Scale for Head and Neck cancer (PSSHN) and general QOL by the European Organization for Research and Treatment of Cancer Core QOL questionnaire (EORTC QLQ-C30). The median length of follow-up was 37 months (range, 13 to 75).The PSSHN scores were 89, 84, and 86, respectively, for eating in public, understandability of speech and normalcy of diet (100 = normal function). Significantly lower scores for understandability of speech were observed in patients with advanced and laryngeal carcinomas. Normalcy of diet was affected negatively by the severity of xerostomia. All mean functional scale scores of the EORTC QLQ-C30 module were 20% to 25% below the higher score. Most of these scale scores were significantly affected by the severity of xerostomia.Patients treated with concomitant boost RT for laryngeal and hypopharyngeal carcinomas appear to have similar QOL and functional outcome to those reported for patients treated with conventional or hyperfractionated RT. As expected, many QOL scales were affected by the severity of xero- stomia.

The present study assesses the choice of surgical procedure, oncologic results and quality of life (QOL) outcomes in a retrospective cohort of 53 patients with low-lying rectal cancers (within 6 cm of the anal verge) treated surgically following preoperative radiotherapy (RT, median dose 45 Gy) with or without concomitant 5-fluorouracil. QOL was assessed in 23 patients by using two questionnaires developed by the QOL Study Group of the European Organization for Research and Treatment of Cancer: EORTC QLQ-C30 and EORTC QLQ-CR38. After a median interval of 29 days from completion of RT, abdominoperineal resection (APR) was performed in 29 patients (55%), low anterior resection in 23 patients (20 with coloanal anastomosis) and transrectal excision in one patient. The 3-year actuarial overall survival and locoregional control rates were 71.4% and 77.5% respectively, with no differences observed between patients operated by APR or restorative procedures. For all scales of EORTC QLQ-C30 and EORTC QLQ-CR38, no significant differences in median scores were observed between the two surgical groups. Although patients having had APR tended to report a lower body image score (P = 0.12) and more sexual dysfunction in male patients, all APR patients tended to report better physical function, future perspective and global QOL. In conclusion, sphincter-sparing surgery after preoperative RT seems to be feasible, in routine practice, in a significant proportion of low rectal cancers without compromising the oncologic results. However, prospective studies are mandatory to confirm this finding and to clarify the putative QOL advantages of sphincter-conserving approaches. © 2000 Cancer Research Campaign

PURPOSE: Erectile dysfunction is a common late complication patients may experience after external-beam radiotherapy for prostate cancer. The efficacy and safety of oral sildenafil to correct sexual dysfunction caused by external-beam radiotherapy was studied in patients participating in our prospective trial. PATIENTS AND METHODS: Thirty-five assessable patients participated in this prospective pilot study. Using a 25-point scale based on the International Index of Sexual Function, erectile dysfunction was assessed weekly, during which time patients received sildenafil 100 mg orally once a week for 6 consecutive weeks. Response was defined as a score of 18 or more, corresponding to at least one successful attempt at sexual intercourse per week. RESULTS: Thirty patients (86%) completed the 6-week study. Seventy-seven percent of these patients had significantly improved erectile function, allowing recovery of full capacity for sexual intercourse. Of 27 patients not receiving concomitant hormone treatment, failure to respond was observed in only four patients (15%) compared with four (50%) of eight patients receiving hormonal treatment during the study. The time course of response was gradual, with 40%, 57%, 66%, 69%, and 74% responding at weeks 1 through 5, respectively. Therapy was generally well tolerated. The most frequently reported side effects in patients were flushing (37%), transient headache (17%), and dyspepsia (9%). No patient reported priapism, and no cardiovascular event or death was observed. After response, 12 patients (34%) reported the ability to achieve and maintain an erection sufficient for intercourse in the absence of sildenafil (ie, 24 hours to 6 days after taking the medication). CONCLUSION: This study suggests that oral sildenafil is well tolerated and can reverse erectile dysfunction after radiotherapy in a substantial proportion of prostate cancer patients.

To evaluate the influence of different shielding conditions and field geometry on the scatter dose to the remaining testicle during postoperative radiotherapy (RT) in seminoma.Testicular dose measurements were made with LiF thermoluminescent dosimeters (TLD) in 29 patients with stage I and IIA seminoma. The target volume consisted of para-aortic (PA) and para-aortic and homolateral iliac (PAI) lymph nodes in 14 and 15 patients, respectively. All patients had a scrotal shield as well as an additional block extending 7 cm inferiorly from the caudal field edge to shield the testicle from external scatter and collimator leakage. Doses with and without testicular blocks were measured for all patients. In seven patients treated exclusively to the PA region the gonadal dose was assessed according to four different shielding conditions: without any protection, with a gonadal shield alone, with the addition of an inferior field border block to the gonadal shield, and with the field border block alone.For patients treated with PAI fields the mean testicular doses per fraction were 3.89 cGy (S.D. +/- 1.44) and 1.48 cGy (S.D. +/- 0.51) without and with gonadal shielding, respectively (P-value0.001); the corresponding values for PA fields were 1.86 cGy (S.D. +/- 0.86) and 0.65 cGy (S.D. +/- 0.35). For the patients treated to the PA region and assessed according to the four different shielding conditions, the additional external block to the testicular shield did not reduce significantly the measured dose on the testis.These results suggest a benefit of gonadal shielding even in seminoma patients undergoing radiotherapy limited to the para-aortic region.

Primary mediastinal large-B cell lymphomas (PMLCL) are considered to be a distinct clinicopathologic entity among the diffuse large B-cell lymphomas. This study evaluated the prognostic factors and therapeutic outcome of PMLCL in a single-institution series. Twenty seven patients were reviewed. Nineteen of the 27 had Stage I-II and 8 had Stage III-IV disease. B-symptoms were found in 11 (41%) patients and bulky disease in 10 (37%). All patients were initially given combination chemotherapy (CT): doxorubicin-containing regimens to 23 patients (11 patients had CHOP, 12 more intensive third-generation regimens) and 4 elderly (70 years) patients received CVP. Eleven responders were consolidated with irradiation (RT) as part of their initial treatment, with a median total dose of 39 Gy. Nineteen patients (70%) achieved clinical remission (15 CR and 4 PR) with their initial therapy. Forty-four percent of patients remained progression-free and 59% are alive at 3 years. The actuarial 10-year TTP and OS were 44% and 50%, respectively. Age60 years, performance status1 and IPI intermediate-high to high risk were significantly associated with poorer OS and TTP by univariate analysis (log-rank test). A better outcome was associated with the use of more aggressive chemotherapy regimens or with the inclusion of RT in the first-line treatment. In conclusion our analyses suggest that the application of radiotherapy in combination regimens and the use of more aggressive chemotherapy in the treatment of this particular lymphoma entity should be evaluated in prospective randomized trials.

Primary mediastinal large-B cell lymphomas (PMLCL) are considered to be a distinct clinicopathologic entity among the diffuse large B-cell lymphomas. This study evaluated the prognostic factors and therapeutic outcome of PMLCL in a single-institution series. Twenty seven patients were reviewed. Nineteen of the 27 had Stage I-II and 8 had Stage III-IV disease. B-symptoms were found in 11 (41%) and bulky disease in 10 (37%) patients. All were initially given combination chemotherapy (CT): doxorubicin-containing regimens to 23 patients (11 patients had CHOP, 12 received more intensive third-generation regimens) and 4 elderly (>70 years) patients received CVP. Eleven responders were consolidated with irradiation (RT) as part of their initial treatment, with a median total dose of 39 Gy. Nineteen patients (70%) achieved clinical remission (15 CR and 4 PR) with their initial therapy. Forty-four percent of patients remained progression-free and 59% are alive at 3 years. The actuarial 10-year time to progression (TTP) and overall survival (OS) were 44% and 50%, respectively. Age >60 years, performance status >1 and IPI intermediate-high to high risk were significantly associated with poorer OS and TTP by univariate analysis (log-rank test). A better outcome was associated with the use of more aggressive chemotherapy regimens or with the inclusion of RT in the first-line treatment. Our analyses suggest that the application of radiotherapy in combination regimens and the use of more aggressive chemotherapy in the treatment of this particular type of lymphoma should now be evaluated in prospective randomized trials.

The aim of this study was to retrospectively assess the prognostic value of p53 and bcl-2 protein expression, cell proliferation index (Mib-1 index), and tumor microvessel density (factor VIII-related antigen) in pediatric medulloblastoma patients. Tumor specimens of 55 patients (age 2–18 years) with medulloblastoma treated with a curative intent between 1972 and 1991 were studied. Slides of paraffin embedded tissue were stained with monoclonal antibodies (mAb) and examined under high power light microscopy for the presence of immunoreactivity. Microvessel density was scored both in the area of most intense staining (‘Angio-max’) and in 3 additional randomly selected areas. The sum of these 4 scores was termed ‘Angio-total’. ‘Angio-max’ and ‘Angio-total’ were evaluated separately by two independent investigators to assess reproducibility. None of the parameters studied, i.e. p53 or bcl-2 expression, Mib-1 index or microvessel density scores were associated with patient survival. Microvessel scores between observers were significantly but weakly correlated, with correlation coefficients (r)

Background : The EORTC has initiated studies to combine nicotinamide with carbogen in accelerated fractionation schedules (ARCON), since for some tumour types, acute and chronic hypoxia as well as treatment protraction may prejudice the outcome of radiotherapy. The tolerable dose of nicotinamide and the optimal interval for administration need to be ascertained. Aim : Full pharmacokinetic profiles of nicotinamide concentrations in plasma were analyzed repeatedly in 15 patients to determine the inter- and intra-patient variability in peak plasma concentrations and the optimum times for administering nicotinamide as a radiosensitizer. Methods : Nicotinamide (Nicobion ® ) was administered in tablet form to patients with advanced head and neck and non-small cell lung carcinomas. A standard 6 g dose was given regardless of body weight after an overnight fast and at least 30 min before breakfast. In 15 patients, blood samples were taken prior to and 1, 2, 4, 6, 8, 12 and 24 h after administration of the drug. This full profile was determined on two to four occasions for the head and neck cancer patients and on two occasions for the lung cancer patients. For each profile, the maximum concentration of nicotinamide ( C max ), time to peak plasma concentration ( T max ), elimination half-lives ( t 1/2 ) and area under the curve (AUC) were determined. Compliance was recorded and nausea and vomiting were graded on a 0–3 scale. Complete profiles of the five major metabolites were also obtained. Results : In the 48 complete sets of blood samples, peak plasma concentrations ranged from 787 to 2312 nmol/ml with a median value of 1166 nmol/ml. The peak plasma concentration was achieved at 1 h in only 54% of the pharmacokinetic profiles, but at this time 92% of the profiles had already exceeded the target concentration of 700 nmol/ml, the level required in the mouse for tumour radiosensitization. The median t 1/2 for all 15 cases was 9.3 h, with minimum and maximum values of 4.2 and 26.8 h. The highest concentrations of nicotinamide metabolites were found to be the N -oxide, 2-pyridone and 1-methylnicotinamide. The toxicity (nausea and vomiting) was scored and found not to be correlated with any of the pharmacokinetic parameters. Conclusions : The plasma concentrations considered necessary to radiosensitize can easily be exceeded with a dose of 6 g taken as 12×500 mg in tablet form; 700 nmol/ml was achieved in all patients and apparently would have been achieved in most even with a considerable reduction in dose. An adequate time between administration and radiotherapy appeared to be 1 h with this drug formulation for 92% of the profiles.

Fifty-five patients with resectable and unresectable oropharynx carcinomas were treated with concomitant boost radiotherapy. Forty-two of the patients (76%) had stages III-IV disease. Although none of the patients had undergone major surgery to the primary tumor, 11 had neck dissections prior to radiotherapy, and 19 (35%) received chemotherapy. The planned total tumor dose was 69.9 Gy, delivered over 5.5 weeks. During the last 3.5 weeks, a boost to the initial gross disease was delivered in 13 fractions of 1.5 Gy each, as a second daily fraction in a progressively accelerated schedule; the prescribed dose outside the boost volume thus was 50.4 Gy. Median follow-up for surviving patients was 31.5 months (range: 16-65 months). All patients but one completed the planned radiotherapy schedule. According to the RTOG scoring system, 48 patients (88%) presented with grades 3-4 acute toxicity. The rate of grades 3-4 late complications was 12%. At three years the actuarial locoregional control rate was 69.5% and overall survival was 60%. We conclude that this concomitant boost schedule is feasible and does not seem to be associated with an excess risk of late complications. Acute toxicity was higher in association with chemotherapy, but remained manageable. Although the oncological results appear encouraging, evaluation of the efficacy of concomitant boost schedules compared with conventionally fractionated irradiation with or without concomitant chemotherapy requires prospective randomized trials.

Background Alteration of radiation therapy (RT) fractionation and the combination of chemotherapy (CT) with RT represent two predominant fields of current research in the treatment of head and neck carcinomas. To assess the potential integration of these two fields, a retrospective comparison of toxicity and treatment outcome was carried out in stage III-IV patients treated with a concomitant boost RT schedule with or without CT. Patients and methods Fifty-two patients were treated by RT alone and 35 by RT and CT. In the RT group, there were significantly fewer T3-4 tumors (56% vs. 88%, P=0.002) and higher proportion of planned neck dissections (35% vs. 14%, P=0.047). The planned total dose was 69.9 Gy delivered over 5.5 weeks. In 10 cases CT was given before RT and in 25 concomitantly with RT, either alone or with neoadjuvant and/or adjuvant CT. All patients but two had cisplatin-based (CDDP, 100 mg/m2) CT, associated in 28 patients with 5-fluorouracil (5-FU, 1000 mg/m2/24 h × 5). The median follow-up for the surviving patients was 21 and 31 months for the RT and RT-CT groups respectively. Results Grade 3-4 acute toxicity (RTOG) was observed in 73% and 86% of patients, and grade 3 dysphagia in 31% and 57% (P=0.02) respectively in the RT and RT-CT groups. The rates of grade 3-4 late complications were similar in the two groups (5% vs. 12%). At three years, actuarial loco-regional control (LRC) was 57% and 66% (P%0.66) and overall survival was 56% and 47% (P=0.99) in the RT and RT-CT groups respectively. Conclusion While acute toxicity was higher compared with RT alone, this accelerated RT schedule was feasible in association with 5-FU/CDDP, even administered concomitantly. Despite the significant proportion of more advanced disease in the RT-CT group, LRC was similar to that obtained by RT alone. Combinations of concomitant boost RT and chemotherapy merit further investigation in prospective trials

Purpose: There is increasing interest in potential long-term effects of radiotherapy (RT) in patients treated for breast cancer, particularly those in whom long-term survival can be expected. The purpose of the present study was to determine the effects of treatment techniques, including patient positioning (supine vs. prone) on the absorbed dose in organs at a distance from the treatment volume in breast RT. Methods and Materials: Dose distribution was studied in a Rando-Alderson phantom, modified with a simulated left breast of tissue-equivalent material. RT delivery was studied using 60 Co and 6 MV x-ray beams, as well as electrons and a 192 Ir source for tumor bed boost RT. Doses were measured in several organs and tissues of interest using LiF thermoluminescent dosimeters. Tangential breast RT was simulated using both supine and prone positioning. Results: Peripheral doses generally decreased approximately exponentially with distance from the edge of the treatment field. Peripheral doses in various target organs were significantly higher for supine than for prone tangential breast RT (for 50 Gy prescribed dose): 0.50 Gy vs. 0.25 Gy for the upper abdomen, 0.05 Gy vs. 0.02 Gy for pelvic organs, 0.17 Gy vs. 0.08 Gy for active bone marrow, and 0.47 Gy vs. 0.12 Gy for ipsilateral lung (discounting lung in primary beam). Conclusions: The present study suggests that peripheral doses in several organs and tissues of interest can be reduced by 40 to 75% by prone tangential breast RT. These results may have implications for future strategies in the treatment of screen-detected breast cancer.

The reproducibility of 3-dimensional (3D) conformal therapy in localized prostate cancer was studied in 14 patients, based on retrospective analysis of 196 anteroposterior-posteroanterior (AP/PA) and lateral portal images. The patients were treated supine without rigid immobilization using six isocentric coplanar conformal fields. Three different observers independently compared the portal and simulation images, determining the deviation of each portal film from the corresponding simulation film. No significant deviations were observed in the cephalo-caudal or lateral axes (0 mm median values). However, a systematic median shift of 5 mm (0 to +10, range) was observed in the anteroposterior direction, presumably as a consequence of a sagging in the treatment couch under the patient's weight. After modification of the treatment couch, no further systematic anteroposterior shifts have been observed. These results demonstrate that the daily setup of conformal prostate irradiation fields can be performed with acceptable reproducibility without the use of special immobilization devices.

Summary In patients with nodenegative stage T2 anal cancer, inguinal relapse rates remain low. The omission of elective coverage of inguinal nodes remains a controversial issue, especially in patients with favorable T2N0 disease. The role of inguinal node radiation therapy in the treatment of early-stage anal carcinoma needs to be investigated in future prospective trials. Purpose: To evaluate the influence of elective inguinal node radiation therapy (INRT) on locoregional control (LRC) in patients with early-stage T2N0 anal cancer treated conservatively with primary RT. Methods and Materials: Between 1976 and 2008, 116 patients with T2 node-negative anal cancer were treated curatively with RT alone (nZ48) or by combined chemoradiation therapy (CRT) (nZ68) incorporating mitomycin C and 5-fluorouracil. Sixty-four percent of the patients (nZ74) received elective INRT. Results: Over a median follow-up of 69 months (range, 4-243 months), 97 (84%) and 95 patients (82%) were locally and locoregionally controlled, respectively. Rates for 5-year actuarial local control, LRC, cancer-specific, and overall survival for the entire population were 81.7% � 3.8%, 79.2% � 4.1%, 91.1% � 3.0%, and 72.1% � 4.5%, respectively. The overall 5-year inguinal relapse-free survival was 92.3% � 2.9%. Isolated inguinal recurrence occurred in 2 patients (4.7%) treated without INRT, whereas no groin relapse was observed in those treated with INRT. The 5-year LRC rates for patients treated with and without INRT and with RT alone versus combined CRT were 80.1% � 5.0% versus 77.8% � 7.0% (PZ.967) and 71.0% � 7.2% versus 85.4% � 4.5% (PZ.147), respectively. A trend toward ah igher rate of grade� 3 acute toxicity was observed in patients treated with INRT (53% vs 31%, PZ.076). Conclusions: In cases of node-negative T2 anal cancer, the inguinal relapse rate remains relatively low with or without INRT. The role of INRT in the treatment of early-stage anal carcinoma needs to be investigated in future prospective trials. 2013 Elsevier Inc.

A prospective trial was performed to better assess the risk of nausea and vomiting and the rescue value of tropisetron (TRO), a 5-HT3 receptor antagonist, in 88 patients undergoing fractionated radiotherapy to the abdomen or to large supradiaphragmatic fields and failing a first anti-emetic trial with metoclopramide (MET). Nausea was graded 0 (absent), 1 (mild), 2 (moderate) and 3 (severe). Nausea requiring anti-emetics (s grade 2) was present in 64% of the patients. MET was able to control nausea (≤ grade 1) in 26 of 58 patients (45%) who developed ≥ grade 2 nausea during radiation treatment (2 patients vomiting without nausea included). 34 patients required TRO, and 31 experienced immediate relief. However, nausea (≥ grade 2) recurred in 7 patients from 1 to 3 weeks after starting TRO. Sex, age, field type and field size (cm2) did not influence the incidence and severity of nausea and vomiting. Only 24 88 patients vomited after starting radiotherapy. MET helped to eliminate emesis in one third of these patients. TRO helped to control vomiting in 73% of the salvaged patients. Constipation was observed in 8 patients on TRO and was a reason to stop the medication in 4 cases.

PURPOSE: Chemotherapy (CT) combined with radiation therapy (RT) is the standard treatment for limited disease small-cell lung cancer (LDSCLC). Many questions including RT dose, fractionation, and sequence of RT/CT administration remain controversial. In this paper, we retrospectively assessed the outcome of patients with LDSCLC treated with radiation of at least 50 Gy.METHODS AND MATERIALS: From December 1997 to January 2006, 69 consecutive patients with LDSCLC were treated at our institutions. Treatment consisted of at least 4 cycles of CT, and 3D conformal thoracic RT. The median age was 61 years (range, 37-78 years). Sequential or concomitant CT/RT was given in 47 (68%) and 22 (32%) of the patients, respectively. The median RT dose was 60 Gy. Prophylactic cranial irradiation (PCI) was administered in 47 (68%) patients.RESULTS: With a median follow-up of 36 months (range, 6-107), 16 patients were alive without disease. The median overall survival time was 24 months, with a 3-year survival rate of 29%. The 3-year disease-free survival (DFS) and loco-regional control (LRC) rates were 23% and 60%, respectively. A better DFS was significantly associated with performance status (PS) 0 (p = 0.004), complete response to treatment (p = 0.03), and PCI group (p = 0.03). A trend towards improved overall survival (OS) was observed for patients who underwent PCI (p = 0.07). Patients treated with sequential CT/RT had a better outcome than those treated with concomitant treatment (3-year DFS rate 27% vs. 13%; p = 0.04). However, PCI was delivered more frequently for the sequential group. No significant dose-response relationship was found in terms of LRC. The multivariate analysis showed that complete response to treatment was the only significant factor for OS.CONCLUSION: Complete response to treatment was the most important factor for OS. A better DFS was significantly associated with the PCI group. We did not find a significant difference in outcome between patients receiving doses of 60 Gy or more and patients receiving 60 Gy or less.

Brachytherapy, the placement of an encapsuled radioactive source (Iridium) in or near a tumor, is a palliative therapeutic modality available for patients suffering of a bronchogenic cancer, especially if they present invalidating symptoms such an incoercible cough, haemoptysis, dyspnea. The treatment modality is indicated if chemotherapy or external irradiation are not possible. It is typically a team work.

The aim of this retrospective study was to assess the incidence of late complications occurring ≥2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T-cell depletion strategy.Between 1984 and 2004, 142 patients were eligible for the study. Total body irradiation (TBI) was carried out in 85% of the patients and T-cell depletion in 84%.Non-relapse mortality (NRM) was 3% (95% CI 0-11) at 10 years, and serious late events affected a substantial number of patients. The cumulative incidence (CI) of chronic graft-versus-host disease (cGvHD) was 30% (95% CI 23-40), and that of infectious complications was 17% (95% CI 11-23). Multivariate analysis showed a higher risk for late complications in patients with cGvHD (HR 1.9, 95% CI 1.2-3.2, P=0.011) and patients receiving methylprednisolone during conditioning (HR 1.9, 95% CI 1.1-3.3, P=0.019 1), patients with cGvHD also having a higher risk for NRM (HR 13.2, 95% CI 1.2-143, P=0.03), as well as those receiving steroids for3 months (HR 40.3, 95% CI 2.3-718, P=0.02) and those receiving antithymocyte globulin (HR 9.6, 95% CI 0.8-68, P=0.024).A significant proportion of long-term survivors of HSCT had late complications. cGvHD remained an important risk factor for late complications despite T-cell depletion resulting in immunosuppression and infectious complications.

To assess the feasibility, toxicity, and outcome of prostate hemi-irradiation with a high-dose-rate brachytherapy (HDR-BT) boost for patients presumed to harbor dominant intra-prostatic tumors in a single lobe.After 3D conformal external radiotherapy (3DCRT) to 64-64.4 Gy, 77 patients with non-metastatic locally aggressive prostate cancer have been treated from 2000 to 2004, with HDR-BT using temporary open MRI-guided (192) Ir implants, to escalate the dose in the boost region. Twenty patients (26%) had one lobe involvement (i.e., one sided endorectal MRI, rectal examination, and biopsies) and were boosted to one side of the gland only. A dose of 12, 14, and 16 Gy in two fractions was delivered to 5, 6, and 9 patients, respectively.After a median follow-up 69 months, no differences in late rectal toxicity were observed between the unilaterally and bilaterally irradiated cohorts. Although, grade 2 late urinary toxicity was worse in the hemi-irradiated group (P = 0.03), severe grade ≥3 late urinary toxicity at 5 years was not different: 10% versus 8.8% in the unilaterally and bilaterally irradiated cohorts, respectively. Grade 4 late urinary toxicity, however, was exclusively observed in patients boosted to both lobes (5/57, 8.8%). Five-year biochemical relapse-free survival was 79.7% versus 70.5% for the unilateral and bilateral boost groups, respectively (P = 0.99).Prostate hemi-irradiation with a HDR-BT boost to the dominant tumor region may be considered when rectal examination, MRI, and biopsies suggest one lobe involvement. Nevertheless, strict dosimetric optimization is needed in order to further reduce the risk of late severe toxicity.

Background To determine the outcome of patients with brain metastasis (BM) from lung cancer treated with an external beam radiotherapy boost (RTB) after whole brain radiotherapy (WBRT). Methods A total of 53 BM patients with lung cancer were treated sequentially with WBRT and RTB between 1996 and 2008 according to our institutional protocol. Mean age was 58.8 years. The median KPS was 90. Median recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) grouping were 2 and 2.5, respectively. Surgery was performed on 38 (71%) patients. The median number of BM was 1 (range, 1-3). Median WBRT and RTB combined dose was 39 Gy (range, 37.5 - 54). Median follow-up was 12.0 months. Results During the period of follow-up, 37 (70%) patients died. The median overall survival (OS) was 14.5 months. Only 13 patients failed in the brain. The majority of patients (n = 29) failed distantly. The 1-year OS, -local control, extracranial failure rates were 61.2%, 75.2% and 60.8%, respectively. On univariate analysis, improved OS was found to be significantly associated with total dose (≤ 39 Gy vs. > 39 Gy; p < 0.01), age < 65 (p < 0.01), absence of extracranial metastasis (p < 0.01), GPA ≥ 2.5 (p = 0.01), KPS ≥ 90 (p = 0.01), and RPA < 2 (p = 0.04). On multivariate analysis, total dose (p < 0.01) and the absence of extracranial metastasis (p = 0.03) retained statistical significance. Conclusions The majority of lung cancer patients treated with WBRT and RTB progressed extracranially. There might be a subgroup of younger patients with good performance status and no extracranial disease who may benefit from dose escalation after WBRT to the metastatic site.

The fact that therapeutic irradiation can induce significant stenosis in the arteries of the head, neck, and chest, as well as in the aorta and the iliac arteries, is familiar in daily practice and well documented in the literature. By contrast, radiation-induced renal artery stenosis seems to be a less widely known complication.The sudden onset of medically refractory arterial hypertension and coma in a 27-year-old man is reported, who had been treated at age 20 with chemotherapy and radiotherapy for Ewing's sarcoma in the lumbar region. This treatment had been performed at the hospital of Sion, Switzerland in 2001. Also, the relevant literature from 1965 to 2007 is reviewed to underscore various aspects of this problem and to demonstrate the clinical relevance of renal artery stenosis as a potential long-term sequela of radiotherapy.Radiation-induced renal artery stenosis has only rarely been described in the literature, but arterial hypertension due to radiation-induced renal artery stenosis is a serious long-term sequela that can appear at a latency of up to 20 years after treatment. The paucity of reports presumably reflects the lesser frequency of radiotherapy for retroperitoneal tumors as compared to head-and-neck cancers, as well as lower awareness of the problem due to diagnostic bias in the era before CT and MRI were in routine use: at that time, carotid artery stenosis was easy to diagnose by ultrasonography, while radiation-induced renal artery stenosis, whose real incidence may well be higher, probably often went undetected. Thus, when a patient with a history of abdominal or retroperitoneal radiotherapy unexpectedly develops intractable hypertension, radiation-induced renal artery stenosis must be included in the differential diagnosis.

Patients with malignant hematologic disorders undergoing bone marrow transplantation (BMT) may develop renal insufficiency. A study was undertaken to assess prospectively the subclinical renal function changes with radioisotopic methods in patients undergoing BMT for hematologic malignancies.We studied 71 patients with normal renal function undergoing BMT for various hematologic malignancies, mostly leukemias. Conditioning included chemotherapy and 12 Gy (45 patients) or 13.5 Gy (26 patients) fractionated total-body irradiation (TBI). In 21 patients receiving 12 Gy TBI, the kidney dose was limited to 10 Gy using partial transmission blocks fabricated after renal opacification with nonionic, hypo-osmolar contrast medium. The glomerular filtration rate (GFR) and effective renal plasmatic flow (ERPF) were determined radioisotopically before conditioning and at 4, 12, and 18 months, using (51)Cr ethylene-diamine-tetra-acetic acid and (131)I ortho-iodo-hippurate, respectively. Renal insufficiency was defined as a decrease of/=30% in GFR or ERPF compared with the baseline values. The potential influence of patient- and treatment-related variables on renal dysfunction was assessed.At 4 (early) and 12-18 (late) months, a/=30% GFR drop was observed in 54% and 49% of patients and a/=30% ERPF drop in 44% and 34% of patients, respectively. After stepwise logistic analysis, a GFR reduction at 4 months correlated significantly with age (40 years old, worse), TBI using kidney blocks (partial kidney shielding to 10 Gy was associated with a higher rate of renal dysfunction at 4 months compared with the full TBI dose), and days of aminoglycoside/vancomycin use. An ERPF drop at 4 months was independently related with the days of amphotericin use and days of prostaglandin E(1) use (prophylaxis against hepatic venoocclusive disease). A GFR and ERPF reduction at 12-18 months correlated with days of amphotericin use and days of prostaglandin E(1) use, respectively.Early post-BMT renal dysfunction is associated with the administration of potentially nephrotoxic drugs. An inverse correlation with the prescribed TBI dose was observed; patients whose kidneys received 10 Gy through the use of partial shielding blocks had significantly greater renal dysfunction at 4 months. The administration of potentially nephrotoxic contrast agents used in radiotherapy treatment planning may be responsible for the latter observation. Prostaglandin E(1) use correlated with a significant reduction in ERPF at both 4 and 12-18 months.

PURPOSE: To assess the outcome and patterns of failure in patients with testicular lymphoma treated by chemotherapy (CT) and/or radiation therapy (RT). METHODS AND MATERIALS: Data from a series of 36 adult patients with Ann Arbor Stage I (n = 21), II (n = 9), III (n = 3), or IV (n = 3) primary testicular lymphoma, consecutively treated between 1980 and 1999, were collected in a retrospective multicenter study by the Rare Cancer Network. Median age was 64 years (range: 21-91 years). Full staging workup (chest X-ray, testicular ultrasound, abdominal ultrasound, and/or thoracoabdominal computer tomography, bone marrow assessment, full blood count, lactate dehydrogenase, and cerebrospinal fluid evaluation) was completed in 18 (50%) patients. All but one patient underwent orchidectomy, and spermatic cord infiltration was found in 9 patients. Most patients (n = 29) had CT, consisting in most cases of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with (n = 17) or without intrathecal CT. External RT was delivered to scrotum alone (n = 12) or testicular, iliac, and para-aortic regions (n = 8). The median RT dose was 31 Gy (range: 20-44 Gy) in a median of 17 fractions (10-24), using a median of 1.8 Gy (range: 1.5-2.5 Gy) per fraction. The median follow-up period was 42 months (range: 6-138 months). RESULTS: After a median period of 11 months (range: 1-76 months), 14 patients presented lymphoma progression, mostly in the central nervous system (CNS) (n = 8). Among the 17 patients who received intrathecal CT, 4 had a CNS relapse (p = NS). No testicular, iliac, or para-aortic relapse was observed in patients receiving RT to these regions. The 5-year overall, lymphoma-specific, and disease-free survival was 47%, 66%, and 43%, respectively. In univariate analyses, statistically significant factors favorably influencing the outcome were early-stage and combined modality treatment. Neither RT technique nor total dose influenced the outcome. Multivariate analysis revealed that the most favorable independent factors predicting the outcome were younger age, early-stage disease, and combined modality treatment. CONCLUSIONS: In this multicenter retrospective study, CNS was found to be the principal site of relapse, and no extra-CNS lymphoma progression was observed in the irradiated volumes. More effective CNS prophylaxis, including combined modalities, should be prospectively explored in this uncommon site of extranodal lymphoma.

Purpose : To assess the toxicity, pathologic response rates, type of surgery, and oncologic results in a prospective Phase I–II trial using pure hyperfractionated radiotherapy (RT) preoperatively in locally advanced rectal cancer. Methods and Materials : Between September 1997 and April 2000, 50 patients with T3-T4 or N1 rectal cancers were treated preoperatively with 50 Gy (45 Gy to the pelvis and a 5-Gy tumor boost) in 40 fractions of 1.25 Gy during 4 weeks. The pretreatment tumor stage as determined by CT and endorectal ultrasonography (80% of patients) included 1 Stage T2 (2%), 45 T3 (90%), and 4 T4 (8%). Nodal involvement (N1) was documented in 26 patients (52%). Surgery was performed at a median interval of 45 days (range 26–114 days) after RT completion. Seventeen patients who presented with pT4 or pN1 and/or pM1 received 5-fluorouracil-based chemotherapy postoperatively. Results : All patients completed the RT schedule as planned. Severe acute toxicities included two Grade 3 skin reactions (4%) that did not require a break. The other acute toxicities were Grade 2 or less (skin, diarrhea, urinary, rectal tenesmus, and fatigue). A complete pathologic response was observed in 7 patients (14%), and microscopic residual cancer was found in 10 (20%). Of the 20 patients presenting with tumor located ≤6 cm from the anal verge, sphincter-saving surgery was performed in 14 (70%). At 3 years, the actuarial locoregional control rate was 90.5%, and the disease-free survival rate was 74.6%. At a median follow-up of 32 months, 4 patients (8%) presented with severe late complications (Grade 3-4) that might have been RT related (one rectovaginal fistula, two chronic perineal fistulas, and one bilateral ureteral stenosis). Conclusion : In locally advanced rectal cancer, preoperative hyperfractionated RT to a total dose of 50 Gy is feasible, with acceptable acute and late toxicity and an objective downstaging effect. In view of these results, this schedule might be used as a basis for additional investigation regarding RT dose escalation or the addition of concomitant chemotherapy.

Purpose: This study was performed to retrospectively assess the potential influence of total-body irradiation (TBI) dose on overall survival in patients undergoing allogeneic bone-marrow transplants (BMT) for hematologic malignancies. Methods and Materials: Between October 1984 and December 1996, 116 patients were conditioned with high-dose chemotherapy and fractionated TBI before allogeneic BMT. The median age was 34 years (range 3–60). The TBI dose was given in 6 fractions, twice-a-day, over 3 days before BMT. The total dose was 10 Gy in 24 patients, 12 Gy in 66 patients, and 13.5 Gy in 26 patients. Results: TBI dose was inversely correlated with overall survival. Five-year survival was 62% for patients conditioned with 10 Gy, 55% for patients conditioned with 12 Gy, and 46% for patients conditioned with 13.5 Gy. Age at BMT was also independently correlated with survival, with the best outcome for patients Conclusion: A TBI dose (fractionated) > 10 Gy may not necessarily be associated with a better outcome in patients undergoing allogeneic bone-marrow transplant for hematologic malignancies.

Purpose: A retrospective study of radiation-induced apoptosis in CD4 and CD8 T-lymphocytes, from 12 cancer patients who displayed enhanced toxicity to radiation therapy and 9 ataxia telangiectasia patients, was performed to test for altered response compared to healthy blood-donors and normal cancer patients. Methods and Materials: Three milliliters of heparinized blood from each donor was sent via express post to the Paul Scherrer Institute (PSI) for subsequent examination. The blood was diluted 1:10 in RPMI medium, irradiated with 0-, 2-, or 9-Gy X-rays, and incubated for 48 h. CD4 and CD8 T-lymphocytes were then labeled using FITC-conjugated antibodies, erythrocytes were lysed, and the DNA stained with propidium iodide. Subsequently, cells were analyzed using a Becton Dickinson PACScan flow cytometer. Radiation-induced apoptosis was recognized in leukocytes as reduced DNA content attributed to apoptosis-associated changes in chromatin structure. Apoptosis was confirmed by light microscopy, electron microscopy, and by the use of commercially available apoptosis detection kits (in situ nick translation and Annexin V). Data from hypersensitive individuals were compared to a standard database of 105 healthy blood-donors, and a database of 48 cancer patient blood donors who displayed normal toxicity to radiation therapy. To integrate radiosensitivity results from CD4 and CD8 T-lymphocytes after 2 and 9 Gy, z-score analyses were performed. Results: A cohort of 12 hypersensitive patients was evaluated; 8 showed enhanced early toxicity, 3 showed enhanced late toxicity, and 1 showed both. The cohort displayed less radiation-induced apoptosis (-1.8 sigma) than average age-matched donors. A cohort of 9 ataxia telangiectasia homozygotes displayed even less apoptosis (-3.6 sigma). Conclusion: The leukocyte apoptosis assay appears to be a useful predictor of individuals likely to display increased toxicity to radiation therapy; however, validation of this requires a prospective study. (C) 1999 Elsevier Science Inc.

Purpose: To assess the impact of treatment interruption on the potential gain in locoregional control obtained with accelerated radiotherapy (RT) compared with conventionally fractionated RT in patients with oropharyngeal carcinomas. Methods and Materials: 152 patients treated with radical RT for oropharyngeal carcinomas between 1979 and 1996 were retrospectively analyzed. According to the American Joint Committee on Cancer (AJCC) staging system, there were 6/30/43/73 stages I/II/III/IV. Sixty-one patients were treated with a conventional RT schedule (median dose 70 Gy in 35 fractions), and 91 patients with either of two 5/5.5-week accelerated RT schedules (median dose 69.6–69.9 Gy in 41 fractions). Discounting weekends, RT was interrupted for 2 consecutive days or more in 53 patients (median duration 11 days, range 2–97), including 67% of the patients in the conventional RT group and 13% in the accelerated RT group. Median follow-up for surviving patients was 55 months (range 23–230). The Cox proportional hazards model was used for the multivariate analysis of factors influencing locoregional control. Results: In univariate analysis, factors associated with a significant decrease in locoregional control included WHO performance status ≥1, advanced AJCC stages (III and IV), conventional RT fractionation, overall treatment time ≥44 days (median), and RT interruption. In the multivariate analysis, when introduced into the model individually, the three significant therapeutic factors remained significant after adjustment for the forced clinical variables. However, when the three therapeutic factors were introduced together into the model, beside the AJCC stage ( P = 0.017), only RT interruption remained a significant independent adverse prognostic factor ( P = 0.026). Conclusions: This multivariate analysis highlights the potential negative impact of treatment gaps on locoregional control in oropharyngeal carcinomas. This suggests that treatment interruption may be an even more important parameter than the type of RT schedule per se. Thus, when assessing the relative merit of two RT schedules, inclusion of the other therapeutic factors in a multivariate model is mandatory in order to avoid misinterpretation of the results.

Background. Surgical management of advanced neck disease remains controversial when a conservative approach based on radiotherapy is retained for primary tumors. The objective of this study was to evaluate retrospectively treatment results in pharyngeal cancers presenting with N2-N3 neck disease, using neck dissection followed by radical locoregional radiotherapy (RT) and to compare these results with those obtained in patients treated by radical RT alone. Methods. From August 1991 to November 1996, 41 patients with carcinomas of the oro- or hypopharynx were staged as T1-T3 N2-N3 MO (American Joint Committee on Cancer [AJCC] stage IV). Twenty-four patients were treated with neck dissection followed by RT (group 1) and 17 patients with radical RT (group 2) using a progressively accelerated concomitant boost schedule. Chemotherapy was delivered to 6 patients in group 1 and 8 in group 2 partially concomitantly with RT. Results. Three-year actuarial locoregional control was 73% and 55% for groups 1 and 2, respectively (p =.52). The corresponding 3-year actuarial overall survival rates were 37% and 50% (p=.42). Severe postoperative complications were observed after neck dissection in four patients (16%). Acute toxicity during RT was similar in the two groups. Late toxicities were also similar, except for two patients in group 1 who developed severe laryngeal edema. Conclusions. Neck dissection followed by radical RT to the primary tumor and neck represents a valid treatment option in this subset of patients, allowing good control of advanced neck disease, while at the same time conserving pharyngolaryngeal function. However, for patients who are at high risk of severe postoperative complications, radical RT can be considered a worthy alternative, particularly for oropharyngeal carcinomas.

The incidence of impotence following transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) was investigated, as well as its correlation with the localization of peroperative capsular perforations and the amount of prostate tissue resected. Patients underwent an interview questioning their potency before and after TURP. For each patient, the TURP technique was reviewed: the localization of eventual capsular perforations was noted and the amount of tissue resected was recorded. Of the 100 patients assessed, 83 were anamnestically potent prior to TURP. Of these, 27 (##%) reported complete loss of erections after operation. Peroperative capsular perforations adjacent to the neurovascular bundles and small-size adenomas correlated significantly with postoperative impotence. The results suggest that capsular perforations adjacent to the neurovascular bundles may be a cause of impotence after TURP, and that patients with small-size adenomas bear a higher risk of post-TURP erectile dysfunction.

Purpose: To evaluate toxicity and treatment outcome in patients with head and neck carcinomas treated with a modified bifractionated concomitant boost radiotherapy schedule. Methods and Materials: Eighty-five patients were treated from February 1991 to October 1995. According to clinical TN stage 23 tumors were T1, 33 T2, 20 T3, 9 T4, 44 N0, and 41 N1-N3. The primary tumor was located in the oral cavity in 6 patients, oropharynx in 36, larynx in 19, hypopharynx in 17, and nasopharynx in 7. The basic treatment delivered 50.4 Gy in 28 fractions, once a day, to the primary site and both sides of the neck. During the last 3.5 weeks, a boost to the initial gross disease was delivered in 13 fractions of 1.5 Gy each as a second daily fraction in a progressively accelerated schedule (total dose 69.9 Gy). Eighteen patients had a unior bilateral neck dissection, and 2 an adenectomy before radiotherapy. The median follow-up for the surviving patients was 28 months (range: 3-61 months). Results: All the patients completed the planned radiotherapy schedule. According to the RTOG scoring system, 57 patients (67%) presented with Grade 3-4 acute toxicity. Grade 3 dysphagia was observed in 20 patients (23.5%). Three patients died during the 3 months following the treatment. Among 73 patients evaluable for late effects, five developed Grade 3-4 complications. At 3 years actuarial loco-regional control was 67% and overall survival was 62%. Conclusions: Although longer follow-up is needed to evaluate the definitive results, we conclude that this particular concomitant boost schedule is feasible and appears to be effective. While acute toxicity was greater than in monofractionated schedules, it was manageable, provided that supportive care measures were implemented in a timely fashion.

In this study factors are analyzed that may potentially influence the site of failure in pediatric medulloblastoma. Patient-related, disease-related, and treatment-related variables are analyzed with a special focus on radiotherapy time-dose and technical factors.Eighty-six children and adolescents with a diagnosis of medulloblastoma were treated in Switzerland during the period 1972-1991. Postoperative megavoltage radiotherapy was delivered to all patients. Simulation and portal films of the whole-brain irradiation (WBI) fields were retrospectively reviewed in 77 patients. The distance from the field margin to the cribiform plate and to the floor of the temporal fossa was carefully assessed and correlated with supratentorial failure-free survival. In 19 children the spine was treated with high-energy electron beams, the remainder with megavoltage photons. Simulation and port films of the posterior fossa fields were also reviewed in 72 patients. The field size and the field limits were evaluated and correlated with posterior fossa failure-free survival.In 36 patients (47%) the WBI margins were judged to miss the inferior portion of the frontal and temporal lobes. Twelve patients failed in the supratentorial region and 9 of these patients belonged to the group of 36 children in whom the inferior portion of the brain had been underdosed. On multivariate analysis only field correctness was retained as being significantly correlated with supratentorial failure-free survival (p = 0.049). Neither the total dose to the spinal theca nor the treatment technique (electron vs. photon beams) were significantly correlated with outcome. Posterior fossa failure-free survival was not influenced by total dose, overall treatment time, field size, or field margin correctness. Overall survival was not influenced by any of the radiotherapy-related technical factors.A correlation between WBI field correctness and supratentorial failure-free survival was observed. Treatment protocols should be considered that limit supratentorial irradiation mainly to subsites at highest risk of relapse. Optimized conformal therapy or proton beam therapy may help to reach this goal. Treating the spine with electron beams was not deletereous. A significant correlation between local control and other technical factors was not observed, including those relating to posterior fossa treatment. The use of small conformal tumor bed boost fields may be prefered to the larger posterior fossa fields usually considered as the standard treatment approach.

PURPOSE To evaluate retrospectively the cumulative risk probability and factors correlated with renal dysfunction after allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS From October 1984 to July 1994, 84 patients with malignant hematopoietic diseases received allogeneic BMT after conditioning with high-dose chemotherapy and total-body irradiation (TBI). Seventy-nine patients with normal renal function before conditioning are included in this study. Conditioning included high-dose cyclophosphamide without (n = 46) or with (n = 33) other agents (daunorubicin, busulfan, cytarabine, and thiotepa) followed by TBI. The TBI dose prescribed to the center of the abdomen was 10 Gy for 24 patients, 12 Gy for 32, and 13.5 Gy for 23. In vitro T-cell depletion was undertaken in 48 cases. The post-BMT nephrotoxicity of aminoglycosides, vancomycin, amphotericin, and cyclosporine was assessed. Time to renal dysfunction was defined as the time to a persistent increase of serum creatinine (SCr) level greater than 110 mumol/L. The potential influence of sex, age, diagnosis, chimerism, and graft-versus-host disease (GvHD) on renal dysfunction was also assessed. RESULTS The 18-month probability of renal dysfunction-free survival (RDFS) for the whole group was 77%. Only TBI dose and presence of GvHD were significantly correlated with renal dysfunction by multivariate analysis. The 18-month probabilities of RDFS were 95%, 74%, and 55% for the patients conditioned with 10, 12, and 13.5 Gy, respectively. The 18-month RDFS probabilities were 88% and 61% for patients without and with GvHD, respectively. Combining both variables, we have defined two risk categories: low-risk (ie, 10 Gy TBI with/without GvHD and 12 Gy TBI without GvHD) and high-risk (ie, 12 Gy TBI with GvHD and 13.5 Gy TBI with/without GvHD). The predicted 18-month RDFS rates were 93% and 52% for the low- and high-risk groups, respectively. CONCLUSION Renal dysfunction after allogeneic BMT is strongly related to the delivered TBI dose (and dose per fraction) and to the presence of GvHD. Renal shielding should be recommended if a TBI dose greater than 12 Gy (fractionated twice daily over 3 days) is to be prescribed. Furthermore, in those cases with a high risk of developing GvHD (eg, unrelated allogeneic BMT, absence of T-cell depletion), these data suggest that kidney doses greater than 10 Gy should be avoided.

Total body irradiation (TBI) is frequently a complex and time-consuming technique that significantly overloads Radiation Oncology departments. In an attempt to shorten TBI setup and treatment time we aimed to develop a system where the lung blocks are fixed with optimal precision to the build-up booster lucite screen while the patient is immobilized in a reproducible upright position.Fifteen patients diagnosed with leukemia were conditioned before bone marrow transplant since March 1992. Patients were immobilized in a semistanding position in a special stand with arm bars and hand grips. Treatment was delivered with a 6 MV x-ray horizontal beam. Six fractions of 2.25 Gy (mean instantaneous dose rate of 13.8 +/- 3.8 cGy/min) were delivered twice a day over 3 days (total dose: 13.5 Gy). Each fraction was given in alternating AP (facing the beam) and PA (turning the back) projections. Customized lung blocks (35% transmission) were used to assure a maximum lung dose of 10 +/- 0.5 Gy. The blocks were taped to a 1 cm thick lucite screen interposed between the source and the patient. Lung shields were checked by port films before each fraction. The reproducibility of the patient's positioning (and lung shielding) was evaluated by measuring the horizontal and vertical deviations of the infero-external corners of the lung blocks in the port films in relation to the same point in the simulation films. In vivo dosimetry (thermoluminescence and diodes) was performed by placing dosimeters and probes in the central axis and in several off-axis sites.The mean horizontal and vertical deviations were 3.5 +/- 4.1 mm and 7.5 +/- 5.9 mm for the anterior fields, and 4.1 +/- 4.1 mm and 6.9 +/- 6.4 mm for the posterior fields. An acceptable position of the blocks was considered when deviations were5 mm horizontally and/or10 mm vertically. The mean time per fraction (i.e., interval between the patient's entering and leaving the treatment room) was 35 +/- 5 min.A satisfactory level of reproducibility can be reached with this technique. The reasonably short treatment time contributes to reproducibility and patient comfort.

Abstract 4090 Background: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) from an HLA- identical sibling is the treatment of choice for young patients with acquired severe aplastic anemia (SAA). Due to increased rates of secondary solid cancer in patients with SAA who received an irradiation-based conditioning regimen, we decided 2 decades ago to use the association of Cyclophosphamide (CY) and Antithymocyte globulin (ATG). We report here the long-term follow-up of patients who underwent HSCT from an HLA-identical related donor after this conditioning regimen. Patients and Methods: 61 consecutive patients with SAA who received a first transplantation from June 1991 to February 2010 in our center were included. Patients with Fanconi anemia or other congenital bone marrow failure were excluded. The conditioning regimen consisted in CY (200mg/Kg) and ATG (2.5 mg/kg/day × 5 days). The donors were HLA-identical siblings in 60 cases and family HLA-matched in 1 case. Graft-versus -host disease (GvHD) prophylaxis associated cyclosporine and methotrexate (days 1, 3, 6 and 11). Long-term clinical outcome, immune recovery and quality of life were assessed. Results: The median age was 21 years [range: 4–43], 41 being adults. Median duration of the disease before HSCT was 93 days. Most of the patients had idiopathic aplastic anemia (n=49, 80%). Median time from diagnosis to HSCT was 3 months (range, 1 to 140). All but 2 patients received bone marrow as source of stem cells and all but 2 engrafted (primary graft failure= 3.4%) with a neutrophils count > 0.5 G/L and a platelets count >20 G/L after a median of 23 (range, 19 to 43) and 21 days (range, 10 to 177), respectively. In patients who had achieved neutrophil recovery, no secondary graft failure was observed. Cumulative incidence (CI) of acute grade II-IV GvHD was 23% (95%CI, 13 to 34) and 18 patients developed chronic GvHD (CI: 32%, 95% CI, 20 to 46). In multivariate analysis, a higher number of infused CD3 cells was associated with an increased risk of developing chronic GvHD (p=0.017). With a median follow-up of 73 months (8 to 233), the estimated 6-year overall survival was 87% (95%CI, 78 to 97). At 72 months, the CI of secondary malignancies was 9%, 10 patients developed avascular necrosis (21% CI), 12 patients were diagnosed with endocrine dysfunctions (19% CI) and 5 presented cardiovascular complications (CI of 10%). The CI of bacterial, fungal and viral infections were 25% (95% CI, 15 to 36), 8% (95% CI, 3 to 17) and 61% (95% CI, 46 to 73) at 72 months, respectively. At 2 years post HSCT, the immune reconstitution was normal for CD3, CD8 T-cells, B-cell and NK-cell but still incomplete for CD4 T-cells. A FACT-BMT questionnaire of quality of life (QOL) was sent to all survivors (n= 53) of who 26 accepted to respond to the questionnaire. There was no evidence for a change in QOL perception with time after transplantation. Our data were compared with those obtained from HSCT recipients from a Swiss transplant center (n=125 patients), mainly transplanted for hematological malignancies. The perception of QOL in patients who were transplanted for SAA was similar to the group of patients who were transplanted for other reason than SAA. Conclusions: Our results confirm that HSCT from HLA-identical sibling donors after CY-ATG conditioning regimen is a curative treatment for patients with SAA, with an excellent long-term outcome. We found an increased risk of chronic GvHD associated with the number of infused CD3 cells. Furthermore, we also found non negligible late complications as well as a similar quality of life with patients transplanted for hematological malignancies. Improving long-term health conditions must thus be a priority field for research, exploring the use of new conditioning regimen as well as new GvHD prophylaxis to improve the quality of life post HSCT of such patients. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.