Weekly dose-volume parameters of mucosa and constrictor muscles predict the use of percutaneous endoscopic gastrostomy during exclusive intensity-modulated radiotherapy for oropharyngeal cancer.

PURPOSE: To define predictors of percutaneous endoscopic gastrostomy (PEG) use during intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer. METHODS AND MATERIALS: Data for 59 consecutive patients treated with exclusive IMRT at a single institution were recovered. Of 59 patients, 25 were treated with hyperfractionation (78 Gy, 1.3 Gy per fraction, twice daily; "HYPER"); and 34 of 59 were treated with a once-daily fractionation schedule (66 Gy, 2.2 Gy per fraction, or 70 Gy, 2 Gy per fraction; "no-HYPER"). On the basis of symptoms during treatment, a PEG tube could have been placed as appropriate. A number of clinical/dosimetric factors, including the weekly dose-volume histogram of oral mucosa (OM DVHw) and weekly mean dose to constrictors and larynx, were considered. The OM DVHw of patients with and without PEG were compared to assess the most predictive dose-volume combinations. RESULTS: Of 59 patients, 22 needed a PEG tube during treatment (for 15 of 22, ≥3 months). The best cutoff values for OM DVHw were V9.5 Gy/week <64 cm(3) and V10 Gy/week <54 cm(3). At univariate analysis, fractionation, mean weekly dose to OM and superior and middle constrictors, and OM DVHw were strongly correlated with the risk of PEG use. In a stepwise multivariate logistic analysis, OM V9.5 Gy/week (≥64 vs. <64 cm(3)) was the most predictive parameter (odds ratio 30.8, 95% confidence interval 3.7-254.2, p = 0.0015), confirmed even in the no-HYPER subgroup (odds ratio 21, 95% CI 2.1 confidence interval 210.1, p = 0.01). CONCLUSIONS: The risk of PEG use is drastically reduced when OM V9.5-V10 Gy/week is <50-60 cm(3). These data warrant prospective validation.

A phase I/II study of altered fractionated IMRT alone for intermediate T-stage oropharyngeal carcinoma.

BACKGROUND AND PURPOSE: To prospectively assess the feasibility and efficacy of an accelerated and hyperfractionated intensity- modulated radiation therapy (IMRT) schedule for intermediate T-stage oropharyngeal cancer. PATIENTS AND METHODS: Patients with T3 or unfavorable T2 oropharyngeal squamous cell carcinoma were eligible; a three-dose level simultaneous integrated boost IMRT strategy was used, delivering 78, 69, and 60 Gy to gross disease, high-risk and low-risk target areas, respectively, in 60 twice daily fractions over 6 weeks. No sequential/concomitant systemic treatment or up-front radical surgery was allowed. Median follow-up is 41.7 months (range: 3.5-80.8 months). RESULTS: 25 patients were treated from 11/2002 to 11/2005. 92% of the individual fractions were delivered as scheduled. Grade 3 mucosal and skin toxicity was 100% and 72%, respectively, none of which persisted beyond 12 weeks; a percutaneous endoscopic gastrostomy tube was temporarily placed in 60% of patients. The estimated locoregional progression-free, distant metastases-free, and overall survival rates at 3 years were 86.3% ± 7.4%, 76.4% ± 9.6%, and 70.0% ± 9.6%, respectively. At the same time interval, the actuarial prevalence of grade 3+ CTCAE v3.0 toxicity was 26.1%. CONCLUSION: While the routine clinical use of this exploratory schedule is discouraged, it may represent the basis for future developments.

Dosimetric predictors of diarrhea during radiotherapy for prostate cancer.

PURPOSE: To investigate dosimetric predictors of diarrhea during radiotherapy (RT) for prostate cancer. PATIENTS AND METHODS: All patients who underwent external-beam radiotherapy as part of treatment for localized prostate cancer at the University of Texas Medical Branch, Galveston, TX, USA, from May 2002 to November 2006 were extracted from the own database. From the cumulative dose-volume histogram (DVH), the absolute volumes (V-value) of intestinal cavity (IC) receiving 15, 30, and 45 Gy were extracted for each patient. Acute gastrointestinal toxicity was prospectively scored at each weekly treatment visit according to CTC (Common Toxicity Criteria) v2.0. The endpoint was the development of peak grade >or= 2 diarrhea during RT. Various patient, tumor, and treatment characteristics were evaluated using logistic regression. RESULTS: 149 patients were included in the analysis, 112 (75.2%) treated with whole-pelvis intensity-modulated radiotherapy (WP-IMRT) and 37 (24.8%) with prostate-only RT, including or not including, the seminal vesicles (PORT +/- SV). 45 patients (30.2%) developed peak grade >or= 2 diarrhea during treatment. At univariate analysis, IC-V(15) and IC-V(30), but not IC-V(45), were correlated to the endpoint; at multivariate analysis, only IC-V(15) (p = 0.047) along with peak acute proctitis (p = 0.041) was independently correlated with the endpoint. CONCLUSION: These data provide a novel and prostate treatment-specific "upper limit" DVH for IC.

Patterns of locoregional failure after exclusive IMRT for oropharyngeal carcinoma.

PURPOSE: To assess the patterns of failure after intensity-modulated radiotherapy (IMRT) for oropharyngeal squamous cell carcinoma (SCC). METHODS AND MATERIALS: We analyzed patients treated at the University of Texas Medical Branch between May 2002 and February 2006 who met the following criteria: (1) definitive IMRT without chemotherapy for oropharyngeal SCC; (2) no pretreatment radical surgery; (3) minimal follow-up of 1 year. The location of each nodal/primary failure was co-registered to the pretreatment planning computed tomography scan and then expanded by 5 mm to a planning target volume (PTV) of the failure (PTV-f). We then investigated whether the prescription dose to the PTV-f had been appropriate for the amount of disease present before treatment and whether the PTV-f had been adequately covered. RESULTS: A total of 50 patients were eligible. With a median follow-up of 32.6 months (range, 12.1-58.6), three local and six regional failures were observed in 8 patients. All but one failure, that had been neglected, were recorded within 14 months of the treatment end. Of the nine failures, four developed in the neck treated electively to the lowest dose level; in all of them, we could retrospectively identify initial positive lymph nodes that might have justified the subsequent failure. The remaining five failures developed in proximity of the high-dose volume. In all but one, the volume of region of interest receiving >/=95% of the dose of the PTV-f was >95%, suggesting adequate coverage. In 1 patient, about 20% of PTV-f was outside the 95% isodose, so that marginal underdosing could not be ruled out. CONCLUSIONS: A potential cause could be identified in all the failures in the lowest dose level. The implications and possible remedies are discussed. Most failures around the high-dose region were "true failures" with no apparent technical cause.

Comparison of three strategies to delineate the bowel for whole pelvis IMRT of prostate cancer.

PURPOSE: To compare three different contouring approaches of the bowel before and during whole pelvis IMRT of localized prostate cancer. MATERIALS: Nine patients were randomly selected among those treated for localized prostate cancer at UTMB from March 2004 to August 2006. On the planning CT, besides the usual organs at risk (OAR), for each patient we contoured the bowel according to three different definitions: each bowel segment ('BS'); 'BS+1', BS uniformly expanded by 1cm; intestinal cavity ('IC') or the 'container' of the bowel loops up to the pelvic/abdominal walls. For each patient we generated three rival plans each considering a different bowel definition, otherwise identical. Provided that the same target coverage and other OAR spare had been achieved, plans were compared for their ability to minimize bowel dose at planning. Furthermore, after co-registering 6 weekly CT to the initial planning CT for each patient, we investigated which of the three definitions would allow the best bowel protection also during treatment. RESULTS: All definitions provided a very similar average bowel DVH at planning. During treatment BS allowed an average approximately 20 cc more of bowel to receive at least 45 Gy over BS+1 and IC (p=0.008 and 0.029, respectively); on the contrary bowel V45 between IC and BS+1 were not significantly different (p=0.65). CONCLUSION: A definition that takes into account internal organ motion is warranted to maximize bowel protection during treatment.

Acute toxicity of whole-pelvis IMRT in 87 patients with localized prostate cancer.

PURPOSE: To assess the acute toxicity profile of whole pelvis IMRT (WP-IMRT) for localized prostate cancer. MATERIALS: Eighty seven patients treated with definitive WP-IMRT at UTMB from May 2002 to November 2006 were retrospectively reviewed. Treatment consisted of two sequential phases, WP-IMRT to 54 Gy at 1.8 Gy per fraction to the pelvic nodes and seminal vesicles and 60 Gy at 2 Gy to the prostate, and a separate external beam boost, 3DCRT or IMRT, to bring the dose to the prostate to 76 Gy. Acute toxicity was prospectively scored weekly during treatment and at 3 month follow-up according to CTC v2.0 for 10 genitourinary (GU) and gastrointestinal (GI) domains. The proportion of patients experiencing a given level of peak acute toxicity at a given point is reported. RESULTS: Treatment was feasible with delivered doses to PTVs not significantly lower than planned ones and with only two patients experiencing treatment gaps longer than 5 days. About 2/3 and 1/10 of the patients experienced peak grade 2 and grade 3 reactions at least once during RT, respectively. Frequency/urgency (Grade 2+: 37.9%) and diarrhea (36.7%) were the most prevalent symptoms followed by proctitis (21.8%) and dysuria (16.1%). GI reactions were generally shorter lasting compared to GU ones which accumulated progressively during treatment. At 3 months, almost half of the patients were asymptomatic and most of observed reactions (89.2%) were mild, with GI ones more likely to be fully resolved (92.5%) than GU ones (68.7%, chi(2), p=0.001). CONCLUSION: Our approach is dosimetrically and clinically feasible with intense, but transient, acute toxicity.

Dosimetric predictors of laryngeal edema.

PURPOSE: To investigate dosimetric predictors of laryngeal edema after radiotherapy (RT). METHODS AND MATERIALS: A total of 66 patients were selected who had squamous cell carcinoma of the head and neck with grossly uninvolved larynx at the time of RT, no prior major surgical operation except for neck dissection and tonsillectomy, treatment planning data available for analysis, and at least one fiberoptic examination of the larynx within 2 years from RT performed by a single observer. Both the biologically equivalent mean dose at 2 Gy per fraction and the cumulative biologic dose-volume histogram of the larynx were extracted for each patient. Laryngeal edema was prospectively scored after treatment. Time to endpoint, moderate or worse laryngeal edema (Radiation Therapy Oncology Group Grade 2+), was calculated with log rank test from the date of treatment end. RESULTS: At a median follow-up of 17.1 months (range, 0.4- 50.0 months), the risk of Grade 2+ edema was 58.9% +/- 7%. Mean dose to the larynx, V30, V40, V50, V60, and V70 were significantly correlated with Grade 2+ edema at univariate analysis. At multivariate analysis, mean laryngeal dose (continuum, hazard ratio, 1.11; 95% confidence interval, 1.06-1.15; p < 0.001), and positive neck stage at RT (N0-x vs. N +, hazard ratio, 3.66; 95% confidence interval, 1.40-9.58; p = 0.008) were the only independent predictors. Further stratification showed that, to minimize the risk of Grade 2+ edema, the mean dose to the larynx has to be kept < or =43.5 Gy at 2 Gy per fraction. CONCLUSION: Laryngeal edema is strictly correlated with various dosimetric parameters; mean dose to the larynx should be kept < or =43.5 Gy.

Is there a "mucosa-sparing" benefit of IMRT for head-and-neck cancer?

PURPOSE: To investigate whether intensity-modulated radiation therapy (IMRT) allows more mucosal sparing than standard three-field technique (3FT) radiotherapy for early oropharyngeal cancer. METHODS AND MATERIALS: Whole-field IMRT plans were generated for 5 patients with early-stage oropharyngeal cancer according to Radiation Therapy Oncology Group 0022 (66 Gy/30 fractions/6 weeks) guidelines with and without a dose objective on the portion of mucosa not overlapping any PTV. 3FT plans were also generated for the same 5 patients with two fractionation schedules: conventional fractionation (CF) to 70 Gy/35 fractions/7 weeks and concomitant boost (CB) to 72 Gy/40 fractions/6 weeks. Cumulative dose volume histograms (DVHs) of the overall mucosal volume (as per in-house definition) from all trials were compared after transformation into the linear quadratic equivalent dose at 2 Gy per fraction with a time factor correction. RESULTS: Compared with IMRT without dose objective on the mucosa, a 30-Gy maximum dose objective on the mucosa allows approximately 20% and approximately 12% mean absolute reduction in the percentage of mucosa volume exposed to a dose equivalent to 30 Gy (p < 0.01) and 70 Gy (p < 0.01) at 2 Gy in 3 and 7 weeks, respectively, without detrimental effect on the coverage of other regions of interest. Without mucosal dose objective, IMRT is associated with a larger amount of mucosa exposed to clinically relevant doses compared with both concomitant boost and conventional fractionation; however, if a dose objective is placed, the reverse is true, with up to approximately 30% reduction in the volume of the mucosa in the high-dose region compared with both concomitant boost and conventional fractionation (p < 0.01). CONCLUSIONS: Intensity-modulated radiation therapy can be potentially provide more mucosal sparing than traditional approaches.

Does treatment of the pelvic nodes with IMRT increase late rectal toxicity over conformal prostate-only radiotherapy to 76 Gy?

PURPOSE: To compare late rectal toxicity rates after three-dimensional conformal radiotherapy to the prostate alone (P-3D-CRT) and whole-pelvis intensity-modulated radiotherapy along with a prostate boost (WP-IMRT/PB) to the same nominal total dose to the prostate. PATIENTS AND METHODS: 68 patients treated with conformal radiotherapy to the prostate only to 76 Gy at the National Institute for Cancer Research, Genoa, Italy, represented the first group (P-3D-CRT). The second group consisted of 45 patients treated at the University of Texas Medical Branch (UTMB), Galveston, TX, USA, with IMRT covering the pelvic nodes and seminal vesicles to 54 Gy at 1.8 Gy per fraction and the prostate to 60 Gy in the same 30 fractions. A separate phase boosted the prostate to 76 Gy (WP-IMRT/PB). Major aspects of planning were remarkably similar at both institutions leaving the inclusion or not of pelvic nodes as the main treatment-related difference between the two groups. Late rectal toxicity was prospectively scored according to the RTOG scale. All patients have a 12-month minimum follow-up, and mean follow-up, similar in both groups, is 25.9 months (SD [standard deviation]: 8.4 months). RESULTS: At 2 years, the estimated cumulative incidence of grade 2 late rectal toxicity is 6%+/-4% for WP-IMRT/PB and 21.2%+/-6% for P-3D-CRT (p=0.06). The difference became significant (HR [hazard ratio]=0.1, 95% CI [confidence interval]: 0.0-0.6; p=0.01) at multivariate analysis. None of the patients developed grade 3+ toxicity. CONCLUSION: Despite the larger treated volume, WP-IMRT/PB allows more rectal sparing than P-3D-CRT.

Is IMRT needed to spare the rectum when pelvic lymph nodes are part of the initial treatment volume for prostate cancer?

PURPOSE: To assess whether a 4-field box technique (4FBT), along with its technical refinements, is an adequate approach in terms of rectal sparing and target coverage for patients with localized prostate cancer undergoing whole-pelvic radiotherapy followed by a prostate boost and whether or not intensity-modulated radiotherapy (IMRT) is needed. METHODS AND MATERIALS: For 8 patients, 31 plans were generated, each of them differing in one or more features, including prescription (dose/volume) and/or technical factors. For the latter, several "solutions" to try to reduce the amount of irradiated rectal volume were addressed, including modifications of the 4FBT and the use of sequential IMRT. We constructed a database with 248 plans that were tested for their ability to meet a series of rectal dose-volume constraints at V50, V60, V65, V70, V75, and V75.6. Multivariate logistic regression was used to identify factors independently associated with the end point. Successful solutions were also compared in terms of coverage of both pelvic node and prostate planning target volume (PTV) by isodose 95%. RESULTS: At multivariate logistic regression, both rectal blocking and IMRT were independent predictors of the probability of meeting rectal dose-volume constraints during the pelvic and boost phases of treatment with close relative risks. However, on average, partial rectal blocking on lateral fields of 4FBT during whole-pelvic radiotherapy resulted in about 3% of pelvic node PTV being outside isodose 95%; only 2 of 8 patients had the pelvic nodal PTV covered similarly to what was achieved by whole-pelvis IMRT. Conversely, blocking the rectum during the last 3 fractions of the conformal boost showed a dosimetric coverage of prostate PTV similar to that achieved by IMRT boost. Interestingly, patient anatomic configuration was the strongest predictor of rectal sparing. Finally, the size of prostate margins to generate PTV was also independently associated with the probability of meeting rectal dose-volume constraints. CONCLUSION: In the dose range of 70-76 Gy to the prostate, IMRT and standard techniques are equally effective in meeting rectal dose-volume constraints. However, whole-pelvis IMRT might be preferable to standard techniques for its slightly superior PTV coverage.