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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.

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: 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.

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.

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.