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We investigate the utility of principal component analysis as a tool for obtaining dose-volume combinations related to rectal bleeding after radiotherapy for prostate cancer. A direct implementation of principal component analysis reduces the number of degrees of freedom from the patient's dose-volume histograms that are associated with bleeding. However, when low-variance principal components are strongly correlated to outcome, their interpretation is problematic. A Varimax rotation is employed to aid in interpretability of the low-variance principal components. This procedure brings us closer to finding unique dose-volume combinations related to outcome but reintroduces correlation, requiring analysis of the overlap of information contained in such modes. Finally, we present examples of cost-benefit analyses for candidate dose-volume constraints for use in treatment planning.

Purpose: To review the University of Iowa experience with intensity-modulated radiotherapy (IMRT) in the treatment of head-and-neck squamous cell carcinoma., Methods and Materials: From October 1999 to April 2004, 151 patients with head-and-neck squamous cell carcinoma were treated with IMRT for curative intent. One patient was lost to follow-up 2 months after treatment and therefore excluded from analysis. Of the remaining 150 patients, 99 were treated with definitive IMRT, and 51 received postoperative IMRT. Sites included were nasopharynx, 5; oropharynx, 56; larynx, 33; oral cavity, 29; hypopharynx, 8; nasal cavity/paranasal sinus, 8; and unknown primary, 11. None of the patients treated with postoperative IMRT received chemotherapy. Of 99 patients who had definitive IMRT, 68 patients received concurrent cisplatin-based chemotherapy. One patient received induction cisplatin-based chemotherapy, but no concurrent chemotherapy was given. Three clinical target volumes (CTV1, CTV2, and CTV3) were defined. The prescribed doses to CTV1, CTV2, and CTV3 in the definitive cohort were 70-74 Gy, 60 Gy, and 54 Gy, respectively. For high-risk postoperative IMRT, the prescribed doses to CTV1, CTV2, and CTV3 were 64-66 Gy, 60 Gy, and 54 Gy, respectively. For intermediate-risk postoperative IMRT, the prescribed doses to CTV1, CTV2, and CTV3 were 60 Gy, 60 Gy, and 54 Gy., Results: The median follow-up was 18 months (range, 2-60 months). All living patients were followed for at least 6 months. There were 11 local-regional failures: 7 local failures, 3 regional failures, and 1 failure both in the primary tumor and regional lymph node. There were 16 patients who failed distantly, either with distant metastasis or new lung primaries. The 2-year overall survival, local progression-free survival, locoregional progression-free survival, and distant disease-free survival rates were 85%, 94%, 92%, and 87%, respectively. The median time from treatment completion to local-regional recurrence was 4.7 months (range, 1.8 to 15.6 months). Only one marginal failure was noted in a patient who had extensive tonsil cancer with tumor extension into the orbit and cavernous sinus. Patients with oropharyngeal cancer did significantly better than patients with oral cavity and laryngeal cancer, with a 2-year local-regional control rate of 98%, compared with 78% for oral cavity cancer and 85% for laryngeal cancer (p = 0.005). There was no significant difference in local-regional control for patients who received postoperative radiation or definitive radiation (p = 0.339) and for patients who had chemotherapy or not (p = 0.402). Neither T stage nor N stage had a significant effect on local-regional control (p = 0.722 and 0.712, respectively)., Conclusions: Our results have confirmed the effectiveness of IMRT in head-and-neck cancer. It offers excellent outcomes in local-regional control and overall survival. More studies are necessary to further improve the outcomes of laryngeal cancer as well as oral cavity cancer.

Purpose: [(18)F] fluorodeoxyglucose positron emission tomography (FDG PET) imaging has been shown to be valuable in early detection of persistent and recurrent head-and-neck cancer after treatment. Previous studies have reported its use in patients treated with conventional radiation. Many patients are now treated with intensity-modulated radiation treatment (IMRT). We evaluated the value of FDG PET in the assessment of treatment response and surveillance in head-and-neck cancer patients treated with IMRT., Methods and Materials: We performed a retrospective review of 85 head-and-neck cancer patients treated with IMRT at our institution between December 2000 and September 2003 who had FDG PET in their follow-up. Of these, 58 were treated with primary IMRT with or without chemotherapy, and 27 were treated with postoperative IMRT., Results: Sixty-four patients had negative initial FDG PET after treatment. Forty of them, who had 6 to 24 months of follow-up after the imaging study, had no evidence of local or regional recurrence, although three of them developed distant disease. Twenty-one patients had a positive initial FDG PET after treatment, with 11 positive at the primary site, 9 positive in the neck, and 3 positive distantly. Six of 11 patients with a positive FDG PET at the primary site were true positive, and 3 had salvage surgery. Eight of 9 patients positive in the neck had a salvage neck dissection. One had fine needle aspiration of the lymph node with positive cytology but refused surgery later. For patients with follow-up of 6 months and longer, only 1 of 45 patients with a negative initial FDG PET at the primary site developed a local recurrence. None of 49 patients with a negative initial FDG PET in the neck developed a regional recurrence. Two cases are presented in which abnormal FDG PET preceded laryngoscopy or computed tomography in detection of tumor recurrences., Conclusions: FDG PET is useful in the posttreatment management of head-and-neck cancer patients treated with IMRT. It is highly accurate in the detection of persistent and recurrent disease after treatment and allows salvage treatment to be initiated in a timely manner. It also provides prognostic information concerning the risk of recurrence after curative therapy.

Purpose: The role of neck dissection after radiation therapy ([RT] with or without chemotherapy) for regionally advanced head and neck cancer is controversial. As much as 50% of residual lymphadenopathy after radiation has no viable tumor cells present on histopathologic analysis. [(18)F] fluorodeoxyglucose positron emission tomography (FDG PET) imaging can detect metabolically active cancer. This study examines the ability of post-RT FDG PET imaging to predict the tumor status of residual lymphadenopathy after nonsurgical management of regionally advanced neck disease., Methods and Material: From February 2000 to October 2002, 41 patients were treated definitively by radiation (with or without chemotherapy) and underwent FDG PET and computed tomography (CT) imaging after treatment to assess response. Patients with negative CT and FDG PET scans were observed and did not undergo neck dissection. Patients with radiographically persistent lymphadenopathy underwent either neck dissection or fine-needle aspiration of the lymph nodes using ultrasound guidance. The results of the FDG PET scans were correlated with the pathologic findings., Results: Twelve patients with persistent lymphadenopathy underwent either neck dissection or fine-needle aspiration. Four of the 12 were found to have viable residual tumor in the cervical lymph nodes. The pathology did not correlate with the size of the lymph nodes in the pre-RT or post-RT CT studies. However, the pathology correlated strongly with the post-RT FDG PET studies. All patients with a negative post-RT FDG PET or those with a maximum standardized uptake value (SUV(max)) of less than 3.0 in the post-RT FDG PET were found to be free of residual viable tumor. Using an SUV(max) of less than 3.0 as the criterion for a negative FDG PET study, the negative predictive value was 100% and the positive predictive value was 80%., Conclusions: A negative post-RT FDG PET scan is very predictive of negative pathology in neck dissection or fine-needle aspiration even with large residual lymphadenopathy. Therefore, if the post-RT FDG PET scan is negative, neck dissection might not be required for regional control. A prospective study with longer follow-up and greater patient numbers is needed to determine whether a policy of deferring neck dissection based on a negative FDG PET is supported.

Intensity-modulated radiation therapy (IMRT) is a relatively new method of conformal radiotherapy delivery that is rapidly being incorporated in clinical practice. Of all patients treated with conformal techniques, children are the most likely to benefit as normal, developing structures can be minimized in the radiation field. The advantages of IMRT, including increased conformality and possible dose escalation, are discussed in this review. Possible disadvantages of IMRT in children are also discussed, such as lack of dose homogeneity in the target volume, increased dose to nontarget tissues, reliability of treatment setup, increased anesthesia time in younger children, and prolonged treatment planning. The issue of increased risk of second malignancy in this very young population is important, as many of these children will be long-term survivors with current multimodality therapy.

Purpose: The goal of tumor control probability (TCP) models is to predict local control for inhomogeneous dose distributions. All existing fits of TCP models to clinical data have utilized summaries of dose distributions (e.g., prescription dose). Ideally, model fits should be based on dose distributions in the tumor, but usually only dose-volume histograms (DVH) of the planning target volume (PTV) are available. We fit TCP models to biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer using either a dose distribution summary or the full DVH in the PTV. We discuss differences in the radiobiologic parameters and dose-response curves and demonstrate pitfalls in interpreting the results., Methods and Material: Two mechanistic TCP models were fit with a maximum likelihood technique to biopsy outcome from 103 prostate patients treated at Memorial Sloan-Kettering Cancer Center. Fits were performed separately for different patient subgroups defined by tumor-related prognostic factors. Fits were based both on full DVHs, denoted TCP(DVH(calc)), and, alternatively, assuming a homogeneous PTV dose given by the mean dose (Dmean) of each DVH, denoted TCP(Dmean(calc)). Dose distributions for these patients were very homogeneous with any cold spots located on the periphery of the PTV. These cold spots were uncorrelated with biopsy outcome, likely because the low-dose regions may not contain tumor cells. Therefore, fits of TCP models that are potentially sensitive to cold spots (e.g., TCP(DVH(calc))) likely give biologic parameters that diminish this sensitivity. In light of this, we examined differences in fitted clonogenic cell number, N(C), or density, rho(C), surviving fraction after 2 Gy, SF(2), or radiosensitivity, alpha, and their standard deviations in the population, sigma(SF(2)) and sigma(alpha), resulting from fits based on TCP(DVH(calc)) and TCP(Dmean(calc)). Dose-response curves for homogeneous irradiation (characterized by TCD(50), the dose for a TCP of 50%) and differences in TCP predictions calculated from the DVH using alternatively derived parameters were evaluated., Results: Fits of TCP(Dmean(calc)) are better (i.e., have larger likelihood) than fits of TCP(DVH(calc)). For TCP(Dmean(calc)) fits, matching values of SF(2) and sigma(SF(2)) (or alpha and sigma(alpha)) exist for all N(C) (rho(C)) above a threshold that give fits of equal quality, with no maximum in likelihood. In contrast, TCP(DVH(calc)) fits have maximum likelihood for high SF(2) (low alpha) values that minimize effects of cold spots. Consequently, small N(C) (rho(C)) values are obtained to match the observed control rate. For example, for patients in low-, intermediate-, and high-risk groups, optimum values of SF(2) and N(C) are 0.771 and 3.3 x 10(3), 0.736 and 2.2 x 10(4), and 0.776 and 1.0 x 10(4), respectively. The TCD(50) of dose-response curves for intermediate-risk patients is 2.6 Gy lower using TCP(DVH(calc)) parameters (TCD(50) = 67.8 Gy) than for TCP(Dmean(calc)) parameters (TCD(50) = 70.4 Gy). TCP predictions calculated from the DVH using risk group-dependent TCP(Dmean(calc)) parameters are up to 53% lower than corresponding calculations with TCP(DVH(calc)) parameters., Conclusion: For our data, TCP parameters derived from DVHs likely do not reflect true radiobiologic parameters in the tumor, but are a consequence of the reduced importance of low-dose regions at the periphery of the PTV. Deriving radiobiologic parameters from TCP(Dmean(calc)) fits is not possible unless one parameter is already known. TCP predictions using TCP(DVH(calc)) and TCP(Dmean(calc)) parameters may differ substantially, requiring consistency in the derivation and application of model parameters. The proper derivation of radiobiologic parameters from clinical data requires both substantial dose inhomogeneities and understanding of how these coincide with tumor location.

Purpose: To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT)., Materials and Methods: Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale., Results: Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001)., Conclusions: The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.

The use of three-dimensional treatment planning and volume-reduction techniques in radiotherapy has prompted the development of a number of mathematical models to describe the effect of changing treatment volume on the probability of associated complications in normal tissues. However, limited data are available to test or support these models. One prediction of the Probability model and analogous models, which describe the volume-effect relationship for late end points in tissues with a series-type arrangement of functional subunits, is that there is no threshold volume in the development of the end point. This hypothesis was tested in mouse colorectum, a normal tissue with functional subunits suggested to be arranged in series, using the incidence of obstructions due to consequential fibrosis as the end point of damage. Various lengths of the colorectum of C3Hf/Kam mice were irradiated with single doses of 250 kVp X rays. A threshold length between 10 and 15 mm was observed after 32 Gy. The Probability model could not describe the data adequately, but a modified version that included a threshold volume term (the Threshold Probability model) provided an excellent fit. In a separate experiment, epithelial regeneration (migration, extracryptal proliferation and formation of new crypts) was examined as a possible mechanism for the threshold length. Re-epithelialization was complete after 32 Gy was delivered to lengths below (5 or 10 mm) but not above (20 mm) the threshold for consequential obstruction. Proliferation of epithelial cells outside the crypt on the mucosal surface (i.e. extracryptal proliferation) may contribute to the regeneration process. The data indicate that regeneration of the epithelium after irradiation results in a threshold length of the colorectum in the development of consequential fibrosis, in contradiction to predictions of the Probability model.

In earlier studies using asynchronously growing Chinese hamster cells, we observed substructure in the survival response at low doses. The substructure appeared to result from subpopulations of cells having different, cell cycle phase-dependent radiosensitivity. We have now applied the same flow cytometry and cell sorting technique to accurately measure the responses of cells of eight different asynchronously growing human tumor cell lines, representing a wide range in radiosensitivity. When the data were fitted with a linear-quadratic (LQ) function, most of these lines showed substructure similar to that observed in Chinese hamster cells, with the result that values of alpha and beta were dependent on the dose range used for fitting. Values of alpha describing the low-dose response were typically smaller (by as much as 2.2 times) than the alpha describing the high-dose response, while values of beta were larger at low doses. Values of alpha/beta from our measurements are in reasonable agreement with other values published recently if we fit the data for the high-dose range (excluding, for example, 0-4 Gy), which corresponds to a conventional survival response measurement. However, the values of alpha/beta describing the low-dose range were, on average, 2.8-fold smaller. The results show that the usual laboratory measurement of cell survival over 2 or 3 logs of cell killing, if fitted with a single LQ function, will yield alpha and beta values which may give a rather poor description of cell inactivation at low dose in asynchronous cells, no matter how carefully those measurements are done, unless the low-dose range is fitted separately. The contribution of killing represented by the beta coefficient at low doses was found to be surprisingly large, accounting for 40-70% of cell inactivation at 2 Gy in these cell lines. A two-population LQ model provides excellent fits to the data for most of the cell lines though, as one might expect with a five-parameter model, the best-fitting value of the various parameters is far from unique, and the values are probably not reliable indicators of the size and radiosensitivity of the different cell subpopulations. At very low dose, below 0.5-1 Gy, another order of substructure is observed: the hypersensitive response; this is described in the accompanying paper (Wouters et al., Radiat. Res. 146, 399-413, 1996).

Purpose: Radiochromic film was used to measure and compare the dose distributions parallel to a high dose rate (HDR) 192Iridium (192Ir) brachytherapy afterloading catheter that resulted from optimized treatment plans using various combinations of prescribed dose magnitude and location as well as source spacing., Methods and Materials: Differences exist among clinical investigators for specification of the magnitude and location of prescribed treatment dose for brachytherapy irradiations using HDR 192Ir afterloading. Typical prescriptions for endobronchial irradiation include 5 to 10 Gy at 10 mm or 15 Gy at 6 mm measured from the center of the afterloading catheter. The dose distributions that result from these irradiations are very difficult to quantify by conventional dosimetry methods. This study used radiochromic film to measure the dose distributions resulting from optimized treatment plans for source dwell position separations of 2.5 or 5.0 mm and for a prescribed treatment dose of either 15 Gy at 6 mm or 5 Gy at 10 mm, conditions that have been used at M. D. Anderson Cancer Center for the treatment of endobronchial lesions. An acrylic phantom was designed to allow for measurement of the dose distributions at 0.95 mm (catheter surface), 6 mm, and 10 mm from and parallel to the catheter for sources positioned along either 20 or 80 mm of the catheter., Results: Radiochromic film is shown to be a suitable quality assurance and dosimetry modality for the measurement of the dose distribution along an afterloading catheter resulting from an HDR I92Ir source. Each of the treatment plans was about equally effective in being able to produce a uniform dose distribution at their respective planned target distances. Differences were more apparent when comparing the dose distributions at nontargeted distances. On the catheter surface the dose was very nonuniform and in the case of 2.5 mm source spacing along 20 mm of catheter with target dose planned to 10 mm, the central minimum dose was only 13 to 24% of the dose opposite to the most proximal and distal sources. The absolute doses measured at equivalent distances for the 15 Gy planned to 6 mm treatments are about 1.3 to 1.5 times higher than those measured for the 5 Gy planned to 10 mm treatments. It was also observed that the lateral positioning of the encapsulated source within the afterloading catheter can contribute to dose differences about the catheter that are greatest for measurements made in contact with the catheter surface (24 to 40%) but may also be large at the treatment planning distances of 6 (0 to 15%) and 10 mm (0 to 9%)., Conclusion: At their respective treatment planning distances of 6 or 10 mm, each of the treatment plans produced dose distributions of comparable uniformity. Against the catheter, relatively more uniform dose distributions with higher minimum doses were obtained for (a) dose prescription at 6 mm, rather than at 10 mm; (b) source separation of 2.5 mm, rather than 5.0 mm (except for a 20 mm active catheter length with dose planned to 10 mm); and (c) longer active length of the catheter of 80 mm, rather than 20 mm.

In the present in vitro studies we examined the effect of hypoxia and acidic pH, two important consequences of reduced blood flow in vivo, on the cytotoxicity of melphalan treatment in Chinese hamster V79-WNRE and SiHa human tumor cells. Cells were exposed to various concentrations of melphalan for 1 hr at 37 degrees C under oxic or hypoxic conditions; pH 6.6 or 7.4, and cell survival was measured. The cytotoxicity of melphalan was potentiated by both low pH and hypoxia, in both cell lines. The overall potentiation, expressed as an enhancement ratio (ER), from both hypoxia and low pH was 3.5 in V79-WNRE and 2.9 in SiHa cells. The potentiation of cell killing produced by hypoxia alone (ERHyp) ranged from 1.4 to 1.9, and was greater in V79-WNRE than in SiHa cells. The potentiation from low pH (ERpH) was approximately 2 in both cell lines. HPLC analysis showed substantial intracellular accumulation of melphalan in both cell lines. Hypoxia and reduced pH further enhanced uptake of melphalan but this was not sufficient by itself to account for the increased potentiation of cytotoxicity observed under those conditions.

Purpose: We examined the effect of acidic pH and hypoxia on the cytotoxicity of SR4233 and mitomycin C in vitro., Methods and Materials: The importance of tumor microenvironment to the response of solid tumors to cytotoxic treatment is well established. The bioreductive drug SR4233 has a very substantial selective toxicity for hypoxic cells. We have used both Chinese hamster and human tumor cells to investigate the influence of low pH and hypoxia on the response of cultured cells to treatment with SR4233 or mitomycin C., Results: We found that low pH (6.6) had little effect on the hypoxic toxicity of SR4233; under aerobic conditions, however, low pH substantially increased the cytotoxic effects of 1 h exposure to SR4233, with drug dose enhancement ratios (ER) of 3.9 and 2.5 in V79 and HT-29 cells, respectively. In similar studies with mitomycin C, hypoxia had little effect on the cytotoxicity of mitomycin C in V79 cells, though a low pH of 6.6 enhanced the cytotoxicity under both aerobic and hypoxic conditions (ER approximately 2). In HT-29 cells, neither low pH nor hypoxia had any significant effect on mitomycin C toxicity., Conclusion: Low pH, like hypoxia, is a common feature of solid tumors and can be an important determinant of the cytotoxic effect of bioreductive drugs such as SR4233 and mitomycin C.

We have observed that low pH can substantially potentiate the cytotoxic effect of the bioreductive drug SR4233 in aerobic HT-29 human tumour cells. No such potentiation was observed under hypoxic conditions. This pH effect might be relevant both to the therapeutic effectiveness and to the normal tissue toxicity of this new agent.

Studies with mouse tumors have shown that the effectiveness of certain chemotherapeutic agents can be enhanced if they are used in appropriate combination with an anti-hypertensive drug such as hydralazine. This results in reduced tumor blood flow with, among other things, a consequent decrease in oxygenation and increase in acidity in the tumor tissue. The purpose of the present work was to determine to what extent hypoxia and low pH are involved in the mechanism of this effect for chlorambucil. V79-WNRE cells were exposed to various drug concentrations under aerobic or hypoxic conditions, pH 6.4 or 7.4. Measurements of cell survival following 1 hr exposure at 37 degrees C showed that pH 6.4 produced a large potentiation of cell killing by chlorambucil (ER = 4 approx.); hypoxia, on the other hand, had little effect. The potentiation was shown to be greatest for pH values below 7.0. HPLC measurements of drug uptake were made since it was anticipated that chlorambucil, a weak acid, might tend to accumulate in cells under conditions of low extracellular pH. It was found that at an extracellular pH of 6.4 the ratio of the intracellular (Ci) and extracellular (Ce) drug concentrations was increased 4.5 and 3.6 fold for aerobic and hypoxic conditions, respectively. This probably explains most, if not all, of the cell killing potentiation observed at low pH.