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.

Purpose. - To assess the value of treatment-planning related parameters namely, the breast volume: the distance of the inferior field border to diaphragm; and the cardiothoracic ratio for left-tangential breast irradiation.Patients and methods. - Treatment plans of 27 consecutively left-sided breast cancer patients after breast conserving surgery were evaluated for several parameters concerning heart-irradiation. We measured the heart distance respective to the cardiothoracic ratio and the distance of the inferior field border to diaphragm, as well as the breast volume in correlation with the irradiated heart volume.Results. - The mean heart and left breast volumes were 504 cm(3) and 672.8 cm(3), respectively. The mean heart diameter was 13.4 cm; the mean cardiothoracic ratio 0.51 and the mean distance of the inferior field border to diaphragm was 1.4 cm. Cardiothoracic ratio (p = 0.01), breast volume (p = 0.0002), distance of the inferior field border to diaphragm (p = 0.02) and central lung distance (p = 0.02) were significantly correlated with the measured heart distance. A significant correlation was also found between cardiothoracic ratio, breast volume and distance of the inferior field border to diaphragm with the irradiated heart volume measured by VI 0, V20 and V40.Conclusion. - The verification of parameters like cardiothoracic ratio, distance of the inferior field border to diaphragm and breast volume in left-sided breast cancer patients may help in determining which patients could benefit from more complex planning techniques such as intensity-modulated radiotherapy to reduced risk of late cardiac injury. (C) 2011 Published by Elsevier Masson SAS on behalf of the Societe francaise de radiotherapie oncologique (SFRO).

Approximately one in five men with prostate cancer has unilateral tumors amenable to hemi-irradiation or hemi-ablation. We aimed to evaluate the feasibility, toxicity and outcome of a brachytherapy (BT) boost to a single lobe of the prostate for patients with unilateral cancers. Seventy-seven patients with locally advanced prostate cancer were treated in Geneva from 2000 to 2004 with a protocol including a high-dose rate (HDR) BT boost using open MRI-guided 192 Ir implants after conventional fractionated 3D-conformal external radiotherapy to 64-64.4 Gy, with or without androgen deprivation. Twenty (26%) of these patients presented with unilateral tumors (based on endorectal MRI with T2 weighted images, on rectal examination, and on unilateral positive biopsies only) and were boosted to a partial volume. A dose of 12, 14, and 16 Gy in 2 fractions was delivered to 5, 6, and 9 patients, respectively. After a median follow-up of 68 months (range 4-109), 5-year biochemical relapse-free survival was 79.7% vs. 70.5% for the unilateral and bilateral boost groups, respectively (p = 0.99). There was no significant difference in late grade ≥ 2 rectal toxicity between the two groups (5-year grade ≥ 2 rectal toxicity free survival of 84.4 vs. 90.6 % for unilateral and bilateral irradiation, respectively, p = 0.72). Surprisingly, late grade ≥ 2 urinary toxicity-free survival was significantly worse in the partial volume boost group (5-year risk-free survival of 70 vs. 86%, p = 0.03). However, grade ≥ 3 urinary toxicity at 5 years was similar in the unilateral and bilateral boost groups (i.e., 10% vs. 8.7%, respectively), and no patients in the unilateral boost group developed grade 4 late toxicity, while 5 (9%) patients in the bilateral group did. Urinary toxicity was not correlated with dose-volume parameters for the urethra. Partial volume HDR-BT boost to a unilateral lobe of the prostate is feasible with biochemical control similar to patients undergoing a boost to the whole prostatic gland. While grade ≥ 2 rectal and grade 2-3 urinary toxicity were similar with a unilateral and bilateral boost, unilateral treatment significantly reduced grade 4 urinary toxicity.

We have studied the molecular effects of a LFD in a murine model in order to better define the biochemical changes associated with folate deficiency. In addition, we have demonstrated the effect of a LFD on the pharmacokinetic profile and therapeutic activity and toxicity of lometrexol. These studies showed increased density of FR in tumors implanted in LFD mice and a decrease in the affinity of these receptors for folic acid. The results suggest that tumors can compensate for low folate bioavailability by up-regulation of a second FR with slightly lower affinity for folic acid. The higher density of this FR would provide greater capacity for garnering serum folate.FPGS activity increased in several tumors and liver and kidney of LFD mice. The increase in this enzyme activity would result in enhanced polyglutamation of folates and classical antifolates and thus increased cellular retention. Consistent with these changes in liver FPGS, mice injected i.v. with a single dose of lometrexol accumulated significantly more drug in liver and tumors of LFD animals compared to SD mice. Also, higher liver concentrations of lometrexol persisted longer in LFD mice. Polyglutamate analysis showed that longer polyglutamate forms appeared earlier in liver of LFD mice. After 7 days, longer polyglutamyl forms were recovered from liver of LFD mice (octa- and hepta-glutamyl lometrexol) compared to those on SD.A comparison of the efficacy and toxicity of lometrexol in C3H mammary tumor-bearing mice showed that in mice on LFD, lometrexol treatment produced a delayed toxicity with an LD50 of 0.1-0.3 mg/kg, a 3000-fold increase in lethality compared to SD mice. Supplementation of mice with folic acid restored anti-tumor activity and increased the therapeutic dose-range over which efficacy could be assessed.These studies support the use of folic acid supplementation for cancer patients treated with antifolate therapy in order to prevent the biochemical changes in FR and FPGS associated with folate deficiency, prevent delayed toxicity to GARFT inhibitors and enhance the therapeutic potential of this class of drugs.

In total, 124 adult patients in remission after allogeneic hematopoietic SCT (HSCT) participated in a cross-sectional study to assess health-related quality of life (HRQL). Assessment of HRQL was carried out using two questionnaires: the (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy ( FACT) with specific modules for BMT (FACT-BMT). Transplanted patients differed from healthy controls in many HRQL-related dimensions in the EORTC QLQ-C30: social functioning 73.4 versus 85.8, P < 0.0001; role functioning 74.6 versus 83.3, P < 0.004; physical functioning 83.9 versus 89.9, P < 0.001; emotional functioning 72.2 versus 82.8, P < 0.0001 but were not significant for global HRQL 71.2 versus 75.3, P < 0.03. In total, 60% of the patients returned to work after HSCT; 31% part time and 29% full time. Age at HSCT and employment status were significantly associated with HRQL. Other factors such as disease and disease stage and especially the occurrence of late complications did not impact the perception of HRQL. This study suggests that the perception of HRQL after HSCT differs from the general population. Issues to increase work-related capabilities and improve social support need to be addressed.

The purpose of this study was to determine factors predictive for severe hematologic toxicity (HT) in cervical cancer patients with para-aortic lymph node metastasis treated with concurrent cisplatin chemoradiation to an extended field (EFCRT).Thirty-eight patients with cervical cancer and para-aortic lymph node metastasis who underwent EFCRT were analyzed. Active bone marrow was defined as the region within irradiated total bone marrow (BMTOT) with a standard uptake value on 18F-fluorodeoxyglucose positron emission tomography/computed tomography greater than the mean standard uptake value for BMTOT. Serial weekly blood counts from the beginning to the end of radiation treatment were evaluated for HT using Common Terminology Criteria for Adverse Events, version 4.0.Nineteen patients had grade 3 or higher hematologic toxicity (HT3+), not including lymphocyte toxicity. Obese patients (n = 12) were less likely to get HT3+ (P = .03) despite getting equivalent doses of chemotherapy. Volumes of BMTOT and active bone marrow receiving doses of 20, 30, and 45 Gy and body mass index significantly predicted HT3+. Patients who had HT3+ had prolonged treatment time (62 vs 53 days, P < .001).For patients receiving EFCRT, bone marrow irradiation parameters and patient body mass index were associated with HT3+. A simplified nomogram has been created to predict HT3+ in these patients, allowing the potential to explore bone marrow–sparing delivery techniques.

Aggressive angiomyxoma (AAM) is a rare tumor that preferentially involves the pelvis and perineal regions and arises from the connective tissue. Its cause and pathogenesis are unknown at present. Treatment typically involves surgery, and despite apparently complete resection, local recurrences are common. We describe a case of a large angiomyxoma of the left pelvis in a 59-year-old woman who underwent two surgical excisions. The first had been done in May 1998. She developed a local recurrence in December 1998. A palliative resection with macroscopic residuals was performed in February 2001, followed by radiation therapy with a total dose of 60 Gy. The diagnosis was revised at the time of the second operation. Initially, the tumor was diagnosed as angiomyofibroblastoma. Follow-up 3 years after the radiation treatment revealed no recurrence. The time of the local control achieved as yet is already longer than the former time to progression between the first two surgical procedures. This is, to our knowledge, the second description of a therapeutic irradiation of a recurrent AAM. Radiation therapy is able to control a recurrent AAM for at least 3 years.