Standard or hypofractionated radiotherapy in the postoperative treatment of breast cancer: a retrospective analysis of acute skin toxicity and dose inhomogeneities.

BACKGROUND: To identify predictive factors of radiation-induced skin toxicity in breast cancer patients by the analysis of dosimetric and clinical factors. METHODS: 339 patients treated between January 2007 and December 2010 are included in the present analysis. Whole breast irradiation was delivered with Conventional Fractionation (CF) (50 Gy, 2.0/day, 25 fractions) and moderate Hypofractionated Schedule (HS) (44 Gy, 2.75 Gy/day, 16 fractions) followed by tumour bed boost. The impact of patient clinical features, systemic treatments and, in particular, dose inhomogeneities on the occurrence of different levels of skin reaction has been retrospectively evaluated. RESULTS: G2 and G3 acute skin toxicity were 42% and 13% in CF patients and 30% and 7.5% in HS patients respectively. The retrieval and revaluation of 200 treatment plans showed a strong correlation between areas close to the skin surface, with inhomogeneities >107% of the prescribed dose, and the desquamation areas as described in the clinical records. CONCLUSIONS: In our experience dose inhomogeneity underneath G2 - G3 skin reactions seems to be the most important predictor for acute skin damage and in these patients more complex treatment techniques should be considered to avoid skin damage. Genetic polymorphisms too have to be investigated as possible promising candidates for predicting acute skin reactions.

Is the in vivo dosimetry with the OneDosePlusTM system able to detect intra-fraction motion? A retrospective analysis of in vivo data from breast and prostate patients.

BACKGROUND: The OneDosePlusTM system, based on MOSFET solid-state radiation detectors and a handheld dosimetry reader, has been used to evaluate intra-fraction movements of patients with breast and prostate cancer. METHODS: An Action Threshold (AT), defined as the maximum acceptable discrepancy between measured dose and dose calculated with the Treatment Planning System (TPS) (for each field) has been determined from phantom data. To investigate the sensitivity of the system to direction of the patient movements, fixed displacements have been simulated in phantom. The AT has been used as an indicator to establish if patients move during a treatment session, after having verified the set-up with 2D and/or 3D images. Phantom tests have been performed matching different linear accelerators and two TPSs (TPS1 and TPS2). RESULTS: The ATs have been found to be very similar (5.0% for TPS1 and 4.5% for TPS2). From statistical data analysis, the system has been found not sensitive enough to reveal displacements smaller than 1 cm (within two standard deviations). The ATs applied to in vivo treatments showed that among the twenty five patients treated for breast cancer, only four of them moved during each measurement session. Splitting data into medial and lateral field, two patients have been found to move during all these sessions; the others, instead, moved only in the second part of the treatment. Patients with prostate cancer have behaved better than patients with breast cancer. Only two out of twenty five moved in each measurement session. CONCLUSIONS: The method described in the paper, easily implemented in the clinical practice, combines all the advantages of in vivo procedures using the OneDosePlusTM system with the possibility of detecting intra-fraction patient movements.

Image-guided-radiotherapy retreatment of spine metastasis: a case report and radiobiological evaluation.

AIMS AND BACKGROUND: The present case report describes vertebral metastasis retreatment using kilovoltage cone-beam computed tomography (CBCT) for setup error correction, in order to improve target irradiation and prevent spinal cord toxicity. We evaluated the feasibility of the second radiation therapy course on the overlapping treatment volume. METHODS AND STUDY DESIGN: A patient with metastatic kidney cancer, previously treated to the tenth dorsal vertebra with conventional radiation planning (21 Gy; 3 x 7 Gy), underwent retreatment. In order to deliver 30 Gy (15 x 2 Gy) to the target volume with the second irradiation, we evaluated the residual dose that could be received by the spinal cord. We calculated the biologically effective dose according to the linear-quadratic model, using an alpha/beta ratio of 2 Gy. A 3-dimensional conformal plan was generated; CBCT imaging was used to ensure accurate repositioning. RESULTS: A total of 15 CBCT scans were performed; the mean setup corrections in the lateral, longitudinal and vertical directions were 3.38 mm (SD 2.09; range, -0.2 mm division by 7.6 mm), 2.13 mm (SD 3.38; range, -5.9 mm divison by 6 mm), and -1.28 mm (SD 2.02; range, -7.1 mm division by 0.3 mm), respectively. CONCLUSION: Image-guided radiotherapy is an alternative approach for the retreatment of spine tumors; it ensures accurate patient setup correction and high-precision treatment delivery, which are required for target volumes very close to critical structures.

Triazene compounds: mechanism of action and related DNA repair systems.

Triazene compounds of clinical interest (i.e. dacarbazine and temozolomide) are a group of alkylating agents with similar chemical, physical, antitumour and mutagenic properties. Their mechanism of action is mainly related to methylation of O(6)-guanine, mediated by methyldiazonium ion, a highly reactive derivative of the two compounds. The cytotoxic/mutagenic effects of these drugs are based on the presence of DNA O(6)-methylguanine adducts that generate base/base mismatches with cytosine and with thymine. These adducts lead to cell death, or if the cell survives, provoke somatic point mutations represented by C:G-->T:A transition in DNA helix. Triazene compounds have excellent pharmacokinetic properties and limited toxicity. Dacarbazine requires hepatic activation whereas temozolomide is spontaneously converted into active metabolite in aqueous solution at physiological pH. Moreover, temozolomide is fully active when administrated orally (100% bioavailability). The biological effects of triazene compounds and cell resistance to them depend on at least three DNA repair systems, (a) O(6)-alkylguanine-DNA-alkyltransferase, called also methyl-guanine methyl-transferase (MGMT); (b) mismatch repair (MMR), and (c) base excision repair (BER). MGMT is a small enzyme-like protein that removes small alkyl adducts from the O(6) position of DNA guanine through a stoichiometric and auto-inactivating reaction. This reaction consists in a covalent transfer of the alkyl group from the alkylated site in DNA to an internal cysteine residue of MGMT protein. High levels of MGMT are responsible for normal and tumour cell resistance to triazenes. Therefore, pre-treatment with MGMT inhibitors - i.e. O(6)-benzylguanine or O(6)-(4-bromotenyl)guanine (Lomeguatrib) - is followed by a great increase in the activity of triazenes against target cells expressing high MGMT levels. MMR is represented by a protein complex dedicated to the repair of biosynthetic errors generated during DNA replication. The MMR system recognizes base mismatches and insertion-deletion loops, cuts the nucleotide sequence containing the lesion, and restores the correct base sequence. Therefore, not only MGMT but also MMR is involved in target cell susceptibility to triazenes. However, the system does not suppress, but instead promotes the cytotoxic effects of triazenes. In fact, MMR is not able to repair the incorrect base pairing determined by treatment with triazenes and, according to a predominant hypothesis, it causes reiterated "futile" attempts of damage repair leading to the activation of cell cycle arrest and apoptosis. BER removes lesions due to cellular metabolism, or to physical or chemical agents. BER is able to repair N(7)-methylguanine and N(3)-methyladenine determined by treatment with triazenes. Therefore, triazene compounds can also kill tumour cells by a N(3)-methyladenine-mediated mechanism if BER activity is inhibited by chemical agents (i.e. PARP inhibitors). In conclusion, in selected cases, triazenes can represent a therapeutic alternative to treatment of neoplastic diseases including haematological malignancies. Moreover, the susceptibility of neoplastic cells to these compounds can be substantially increased through pharmacological modulation of the expression level and functional activity of DNA repair enzymes.

Novel role of triazenes in haematological malignancies: pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia.

Previous studies indicated that dacarbazine and Temozolomide could be highly effective against refractory acute leukaemia. Their activity relies mainly on the generation of methyl adducts at the O(6)-position of guanine in DNA. High levels of O(6)-methylguanine-DNA methyltransferase (MGMT) or a defective mismatch repair (MMR) system, are associated with cellular resistance to triazenes. The MGMT inhibitor, O(6)-(4-bromothenyl)guanine (Lomeguatrib), can restore in vitro sensitivity to Temozolomide in MMR-proficient blasts. In the early 1970s we discovered that, in vivo, triazene compounds induce the appearance of novel transplantation antigens in murine leukaemia ("Chemical Xenogenization", CX). Non-self peptides presented by class I MHC molecules are generated by triazene-induced somatic mutations, affecting retroviral sequences that are detectable in the mouse genome. Moreover, preliminary experiments suggested that human cancer cells can also undergo CX. Therefore, we designed a chemo-immunotherapy strategy in leukaemic patients as follows: (a) cytoreduction and a hypothetical CX phase, i.e. treatment with Lomeguatrib (to suppress MGMT activity) and Temozolomide (to kill sensitive blasts and to presumably induce CX in resistant leukaemic cells); (b) immune response recovery phase using interleukin-2 (to possibly restore an immune response and take advantage of the hypothetical, triazene-induced CX). Here we present the results of pilot study which is in progress in patients with refractory/relapsed acute leukaemia. In all tested cases, Lomeguatrib suppressed MGMT activity in vivo. Six out of eight patients showed partial or complete disappearance of blast cells in peripheral blood or in bone marrow. We observed severe and long-lasting myelosuppression, accompanied by limited non-haematological toxicity. Up to now, two patients are alive (after 9 and 10 months, respectively), four died of opportunistic infections and two of progressive disease. This investigation confirms the potential role of triazenes in leukaemia and highlights the contribution of Lomeguatrib in overcoming drug resistance. Further studies are required to establish whether Temozolomide can induce CX in human leukaemia, and thus offer a new approach to control minimal residual disease.