Hyperfractionated Treatment Research Articles

Extra lethal damage due to residual incompletely repaired sublethal damage in hyperfractionated and continuous radiation treatment

In the conventional linear-quadratic model of single-dose response, the alpha and beta terms reflect lethal damage created during the delivery of a dose, from two different presumed molecular processes, one linear with dose, the other quadratic. With the conventional one-fraction-per-day (or less) regimens, the sublethal damage (SLD), presumably repairing exponentially over time, is essentially completely fixed by the time of the next dose of radiation. If this assumption is true, the effects of subsequent fractions of radiation should be independent, that is, there should be little, if any, reversible damage left from previous fractions, at the time of the next dose. For multiple daily fractions, or for the limiting case, continuous radiation, this simplification may overlook damaged cells that have had insufficient time for repair. A generalized method is presented for accounting for extra lethal damage (ELD) arising from such residual SLD for hyperfractionation and continuous irradiation schemes. It may help to predict differences in toxicity and tumor control, if any, obtained with "unconventional" treatment regimens. A key element in the present model is the finite size and the dynamic character of the pool of sublethal damage. Besides creating the usual linear and quadratic components of lethal damage, each new fraction converts a certain fraction of the existing SLD into ELD, and creates some new SLD. The expressions developed by Thames [Int. J. Radiat. Biol. 47, 319-339 (1987)] for fractionated treatment (the IR model) and by Dale [Br. J. Radiol. 58, 515-528 (1985); 59, 919-927 (1986)] for protracted and fractionated treatment are found to be similar to our results in the limiting case where the pool of SLD is very large (infinite).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic factors in unresectable hepatocellular cancer: Radiation therapy oncology group study 83-01

The Radiation Therapy Oncology Group (RTOG) conducted a Phase I/11 study in hepatocellular cancer that closed on September 9, 1987 and some results presented previously. Here, 17 patient characteristics are evaluated to identify any of prognostic significance. Two hundred sixteen patients were entered and 198 (74% with metastases and/or previous chemotherapy) were evaluable. Treatment began with an induction regimen of external beam radiotherapy to the liver (21.0 Gy, 3.0 Gy/Fx, 10 MV photons, 4 days per week) with low-dose chemotherapy (5Fluorouracil (FU), 500 mg, i.v.; Doxorubicin, 15 mg, i.v.) on treatment Days 1, 3, 5 and 7. In the later stages of these studies, 56 patients received external beam radiotherapy as hyperfractionated treatment (1.2 Gy twice daily, 4 hours separation, 5 days per week, 24.0 Gy total) with similar chemotherapy. One month following induction therapy, cycles of radiolabeled antibody therapy were given every 2 months. Each cycle was derived from a different species of animal and consisted of 30 mCi I-131 antiferritin, Day 0, and 20 mCi, Day 5. On Day -1, 5-FU, 500 mg, and Adriamycin,15 mg, were administered. The overall median survival for the entire group, including previously treated patients, was 4.9 months. The median survival for alpha-fetoprotein (AFP)- patients not previously treated was 10.5 months. Median survival for all AFP- patients was 8.5 months and for all AFP+ patients was 4.6 months ( p = 0.006). Of the 17 pretreatment characteristics investigated for prognostic value Karnofsky Performance Score (KPS) (80–100 vs. <80) ( p = 0.0001), presence/absence of ascites ( p = 0.0002), bilirubin level (<1.5 vs. ≥1.5) ( p = 0.018), SCOT (≤35 vs. >35) ( p = 0.001); alkaline phosphatase (≤95 vs. >95) ( p = 0.008) were found to be significant independently using a multivariant regression model. The relative risk of dying for the unfavorable component of each of these characteristics was 2.2, 2.0, 1.5, 1.9 and 1.7, respectively. Good and poor prognostic groups were then defined and compared to a similar patient population (RTOG Study 83-19) with confirmation of the validity of the model. When stratification for these overpowering clinical factors was incorporated, AFP status was again significant with a relative death rate 1.80 times higher for AFP+ patients. Our recommendations for structuring future prospective randomized trials are discussed and include stratification by AFP status.

Radiotherapy of the rhabdomyosarcoma R1H of the rat: Hyperfractionation—126 fractions applied within 6 weeks

The effect of a hyperfractionated irradiation treatment on the response of the rhabdomyosarcoma R1H of the rat was studied. Tumors were irradiated under ambient conditions with 126 fractions of X rays, applied in 3 fractions per day with a time interval of 8 ± 1 hr between fractions on 7 days per week during 6 weeks. The total dose ranged from 54 to 90 Gy, that is the dose per fraction ranged from 0.43 to 0.71 Gy. Tumor response was assessed by tumor control probability and tumor net growth delay. The tumor response to the hyperfractionated treatment was found to be slightly more effective compared to the results obtained in a previous study where treatments with 6, 18, 30, and 42 fractions were applied. Since normal tissues are considerably spared with increased numbers of fractions, clinical studies with hyperfractionation seem to be very promising.

Radiation studies on multicellular tumour spheroids derived from human neuroblastoma: Absence of sparing effect of dose fractionation

In vitro experiments were carried out to compare the effects of single-dose and split-dose irradiation on a cell line (NB1-G) derived from human neuroblastoma and grown as multicellular tumour spheroids (MTS). The radiation response was evaluated in terms of regrowth delay; estimates of in situ cell survival were made by back-extrapolation of regrowth curves. These studies showed no significant difference in the effectiveness of single as compared to split dose irradiation i.e. no sparing effect of fractionation. If MTS constitute a realistic model for micrometastases in vivo, these results provide a radiobiological rationale for hyperfractionated treatment regimes in the adjuvant radiotherapy of neuroblastoma.