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Volumetric modulated arc therapy (VMAT) has recently been used to improve the dose distribution and efficiency of treatment delivery over the standard intensity-modulated radiotherapy (IMRT) technique. This study compares the dosimetry between RapidArc plan and standard IMRT plan for head and neck cancer. Three head and neck patients treated clinically with sliding window intensity-modulated radiotherapy (IMRT) technique at Grand River Regional Cancer Center were selected randomly and re-planned using RapidArc technique with 6 MV photon beams generated by a Varian 21EX linac with 120-leaf multileaf collimator. Three dose prescriptions were used to deliver 70 Gy, 63 Gy and 58.1 Gy to the regions of the primary tumors, intermediate-risk nodes and low-risk nodal level, respectively, in 35 fractions. Dosimetric comparison based on the dose-volume histogram, target coverage, organ at risk (OAR) dose sparing were studied between the RapidArc plan and IMRT plan. RapidArc technique from Varian Medical Systems showed superior target coverage, better OAR sparing, fewer monitor units per fraction with less treatment time over IMRT technique for head and neck cancers. The average homogeneity index, defined as the difference between the percentage dose covering 5% and 95% of the PTV, is 9.5 for RapidArc plan and 10.5 for IMRT plan. All RapidArc plans met the dose objectives for the primary OAR: spinal cord, brainstem, brain etc. Both parotid mean dose and D50% are lower for RapidArc plan than those of the IMRT plan. The technique is currently being used clinically at our cancer center.

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Tumor response to radiation is dependent not only on the quantity of hemoglobin (Hb) available for oxygen (O2) transport but also on the position of the Hb-O2 dissociation curve (Hb affinity). Previous studies have shown that administering agents which shift the Hb-O2 dissociation curve to the right (decrease Hb affinity) sensitize tumors to radiation by reducing the fraction of radiobiologically hypoxic cells. However, there may be toxicity limitations when agents aimed at altering Hb affinity are administered directly to the host. The present studies evaluated the therapeutic benefit of shifting the Hb-O2 dissociation curve in vitro prior to the transfusion of the biochemically modified RBCs into recipient hosts. Mice were given a hemolysis agent (phenylhydrazine hydrochloride, PH) prior to transfusing RBCs with normal or altered Hb affinity. A 100 mg/kg dose of PH reduced the hematocrit to approximately 60% of control 24 hr after treatment. Tumors irradiated at this time demonstrated an increased fraction of hypoxic cells. If the hematocrit was returned to normal by transfusing mice prior to irradiation, a significant but transient reduction in the hypoxic fraction was seen. Tumor response was reduced if RBCs with elevated Hb affinity, obtained by storing the erythrocytes at 4 degrees C, were used. Alternatively, tumor sensitization was noted when animals were transfused with RBCs having decreased Hb affinities. The latter was achieved by incubating the RBCs in the presence of either clofibrate or the precursors of 2,3 diphosphoglycerate (2,3 DPG). These findings further support the notion that the Hb affinity is an important parameter in determining tumor response to radiation and suggest that this factor ought to be considered when RBCs are used to transfuse anemic patients undergoing radiotherapy.

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The KHT sarcoma is a model system in which metastases can be studied in multiple organs without prior clonal selection. The present series of experiments were designed to evaluate and compare the extent of potentiation of chemotherapeutic agent activity by radiosensitizers when KHT sarcoma cells were grown in different anatomical sites. In these studies the effect of combining misonidazole (MISO) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on KHT lung nodules and ovarian metastases was determined. Ovarian metastases were a consequence of the direct spread of tumor cells growing as lung nodules. Once established, KHT cells in the lungs and ovaries grew with a similar doubling time (1-2 days). Response of tumors at either site to chemotherapy in the presence or absence of a sensitizer was assessed using an in vivo to in vitro excision assay. MISO (1.0 mmol/kg) was administered simultaneously with a range of CCNU doses and survival of clonogenic tumor cells was measured 24 h after treatment. The results demonstrate that the addition of MISO to CCNU treatment potentiated the action of this chemotherapeutic agent at both tumor sites although greater cell kill enhancement occurred in the ovarian metastases. In the lung nodules, when combined with CCNU, a 1.0 mmol/kg dose of MISO was found to yield a dose modifying factor (DMF) of approximately 1.3. The same combination resulted in a DMF of approximately 1.8 in the ovarian metastases. This difference in DMF was not a result of an intrinsic difference in sensitivity to CCNU since cells grown at either site gave rise to the same dose response curve. Rather the difference in dose modification by MISO appears to be a consequence of the larger fraction of radiobiologically hypoxic cells in the ovarian tumors (approximately 50 per cent) than in the lung nodules (approximately 5 per cent) at the time of treatment. These findings suggest the use of drug-sensitizer combinations to treat disseminated disease and provide further evidence for the requirement of hypoxia in chemopotentiation by radiosensitizers.

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Studies were performed to determine whether the radiation sensitizer misonidazole (MISO) could enhance the tumor response of the KHT sarcoma to a treatment combining fractionated radiotherapy and the chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). A single dose of CCNU (20 mg/kg) was given 24 hr prior to the start of a multi-fraction radiation protocol in which 10 fractions were delivered once a day in 12 days overall treatment time. Daily radiation doses ranged from 1.0 to 4.0 Gy. MISO was administered at a dose of 1.0 mmol/kg, either once as a chemopotentiator simultaneously with CCNU, or repeatedly as a radiosensitizer 30-40 min prior to each radiation dose. Tumor response to treatment was assessed using tumor regrowth delay as the end point. The results indicate that, at 1.0 mmol/kg, MISO failed to radiosensitize the tumors in each of the fractionation schedules evaluated; that is, there was no difference between the regrowth delay curves obtained when CCNU treatment was followed by fractionated radiation, administered either alone or with MISO prior to each radiation dose fraction. However, when a single dose of 1.0 mmol/kg MISO was combined with CCNU 24 hr prior to the start of radiotherapy, regrowth delay was increased for all fractionated radiation schedules, particularly, at the larger dose fraction sizes. Comparison of the dose response curves suggests that MISO, used as a chemopotentiator, effectively reduced the proportion of radiobiologically hypoxic cells in the tumors prior to the start of the radiation therapy. These findings indicate that chemopotentiation can be used effectively in a combination with fractionated radiotherapy.

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Previous investigations have shown that combining the radiation sensitizer misonidazole with conventional alkylating chemotherapeutic agents can lead to a therapeutic advantage. More recently, another sensitizer, RSU 1069, has been reported to give an enhancement of antitumor agent efficacy similar to that observed with misonidazole, but at an approximately tenfold lower sensitizer dose. One chemotherapeutic agent whose activity has been modified by sensitizers to a greater extent in tumors than in critical normal tissues is the nitrosourea lomustine (CCNU). The present studies evaluated the therapeutic benefit of combining RSU 1069 and CCNU in KHT sarcoma-bearing C3H/HeJ mice. The drugs were administered ip, and tumor response was assessed by measuring the survival of clonogenic KHT cells 22-24 hours after treatment. Normal tissue toxicity was determined using peripheral wbc counts 3 days after treatment and a 30-day lethality assay. Combining CCNU with a 0.38-mmol/kg dose of RSU 1069 increased tumor cell killing by a factor of approximately 1.9. Wbc toxicity and 30-day animal lethality increased with CCNU dose, but the addition of RSU 1069 enhanced either endpoint only slightly (factor of 1.0-1.2). The addition of RSU 1069 to CCNU treatment, therefore, led to a significant therapeutic benefit.

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