Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.

PURPOSE: To assess long-term xerostomia in patients receiving parotid-sparing radiation therapy (RT) for head-and-neck cancer, and to find the patient and therapy-related factors that affect its severity. PATIENTS AND METHODS: From March 1994 through January 2000, 84 patients received comprehensive bilateral neck RT using conformal and multisegmental intensity-modulated RT (IMRT) aiming to spare the major salivary glands. Before RT and periodically through 2 years after the completion of RT, salivary flow rates from each of the major salivary glands were selectively measured. At the same time intervals, each patient completed an 8-item self-reported xerostomia-specific questionnaire (XQ). To gain a relative measure of the effect of RT on the minor salivary glands, whose output could not be measured, the surfaces of the oral cavity (extending to include the surface of the base of tongue) were outlined in the planning CT scans. The mean doses to the new organ ("oral cavity") were recorded. Forty-eight patients receiving unilateral neck RT were similarly studied and served as a benchmark for comparison. Factors predicting the XQ scores were analyzed using a random-effects model. RESULTS: The XQ was found to be reliable and valid in measuring patient-reported xerostomia. The spared salivary glands which had received moderate doses in the bilateral RT group recovered to their baseline salivary flow rates during the second year after RT, and the spared glands in the unilateral RT group, which had received very low doses, demonstrated increased salivary production beyond their pre-RT levels. The increase in the salivary flow rates during the second year after RT paralleled an improvement in xerostomia in both patient groups. The improvement in xerostomia was faster in the unilateral compared with the bilateral RT group, but the difference narrowed at 2 years. The major salivary gland flow rates had only a weak correlation with the xerostomia scores. Factors found to be independently associated with the xerostomia scores were the pre-RT baseline scores, the time since RT, and the mean doses to the major salivary glands (notably to the submandibular glands) and to the oral cavity. CONCLUSION: An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major salivary glands, suggests a long-term clinical benefit from their sparing. The oral cavity mean dose, representing RT effect on the minor salivary glands, was found to be a significant, independent predictor of xerostomia. Thus, in addition to the major salivary glands, sparing the uninvolved oral cavity should be considered as a planning objective to further reduce xerostomia.

Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.

PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.

Optimization and clinical use of multisegment intensity-modulated radiation therapy for high-dose conformal therapy.

Intensity-modulated radiation therapy (IMRT) may be performed with many different treatment delivery techniques. This article summarizes the clinical use and optimization of multisegment IMRT plans that have been used to treat more than 350 patients with IMRT over the last 4.5 years. More than 475 separate clinical IMRT plans are reviewed, including treatments of brain, head and neck, thorax, breast and chest wall, abdomen, pelvis, prostate, and other sites. Clinical planning, plan optimization, and treatment delivery are summarized, including efforts to minimize the number of additional intensity-modulated segments needed for particular planning protocols. Interactive and automated optimization of segmental and full IMRT approaches are illustrated, and automation of the segmental IMRT planning process is discussed.

Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study.

PURPOSE: To analyze the failure patterns for patients with high-grade astrocytomas treated with high-dose conformal radiotherapy (CRT) using a quantitative technique to calculate the dose received by the CT- or MR-defined recurrence volume and to assess whether the final target volume margin used in the present dose escalation study requires redefinition before further escalation. METHODS AND MATERIALS: Between 4/89 and 10/95, 71 patients with high-grade supratentorial astrocytomas were entered in a phase I/II dose escalation study using 3-D treatment planning and conformal radiotherapy. All patients were treated to either 70 or 80 Gy in conventional daily fractions of 1.8-2.0 Gy. The clinical and planning target volumes (CTV, PTV) consisted of successively smaller volumes with the final PTV defined as the enhancing lesion plus 0.5 cm margin. As of 10/95, 47 patients have CT or MR evidence of disease recurrence/progression. Of the 47 patients, 36 scans obtained at the time of recurrence were entered into the 3-D radiation therapy treatment planning system. After definition of the recurrent tumor volumes, the recurrence scan dataset was registered with the pretreatment CT dataset so that the actual dose received by the recurrent tumor volumes during treatment could be accurately calculated and then analyzed dosimetrically using dose-volume histograms. Recurrences were divided into several categories: 1) "central," in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) "in-field," in which 80% or more of Vrecur was within the D95 isodose surface; 3) "marginal," when between 20 and 80% of Vrecur was inside the D95 surface; 4) "outside," in which less than 20% of Vrecur was inside the D95 surface. RESULTS: In 29 of 36 patients, a solitary lesion was seen on recurrence scans. Of the 29 solitary recurrences, 26 were central, 3 were marginal, and none were outside. Multiple recurrent lesions were seen in seven patients: three patients had multiple central and/or in-field lesions only, three patients had central and/or in-field lesions with additional small marginal or outside lesions, and one patent had 6 outside and one central lesion. Since total recurrence volume was used in the final analysis, 6 of the 7 patients with multiple recurrent lesions were classified into centra/in-field category. CONCLUSION: Analysis of the 36 evaluable patients has shown that 32 of 36 patients (89%) failed with central or in-field recurrences, 3/36 (8%) had a significant marginal component to the recurrence, whereas only 1/36 (3%) could be clearly labeled as failing mainly outside the high-dose region. Seven patients had multiple recurrences, but only 1 of 7 had large-volume recurrences outside the high-dose region. This study shows that the great majority of patient recurrences that occur after high-dose (70 or 80 Gy) conformal irradiation are centrally located: only 1/36 patients (with 7 recurrent lesions) had more than 50% of the recurrence volume outside the region previously treated to high dose. Further dose escalation to 90 Gy (and beyond) thus seems reasonable, based on the same target volume definition criteria

Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life.

PURPOSE: To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). PATIENTS AND METHODS: Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. RESULTS: Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. CONCLUSIONS: Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

A brain tumor dose escalation protocol based on effective dose equivalence to prior experience.

PURPOSE: The current study describes the design of a dose escalation protocol for conformal irradiation of primary brain tumors that preserves the safe experience of a previous, sequential dose escalation scheme while enabling the delivery of substantially higher effective doses to a central target volume. METHODS AND MATERIALS: Normalized isoeffective composite dose distributions were formed for 20 patients treated on the original protocol (which specified three progressively smaller planning target volumes [PTVs]) using the linear quadratic model (here corrected to equivalent 2 Gy fractions using alpha/beta=10 Gy). These distributions were investigated and a new protocol was designed to preserve a similar level of efficacy and lack of toxicity for the outer volumes, but allowing a higher dose to the inner PTV. Treatment plans were then investigated to determine if the objectives of the new protocol were achievable. In particular, plans that simultaneously achieved all biological treatment planning objectives (all fields treated each day) were investigated. Finally, the success of the protocol design was demonstrated by analysis of the effective dose distributions of 10 patients treated using the new protocol. RESULTS: The composite normalized isoeffective minimum doses to the outer PTVs (PTV3 and PTV2) in the original protocol were close to 60 Gy and 75 Gy, respectively, and these values are specified as the minimum doses to those volumes for the new protocol. Homogeneity requirements to maintain equivalence for the outer target volume domains are: not more than 25% of [PTV3 exclusive of PTV2] >75 Gy; and not more than 50% of [PTV2 exclusive of PTV1] >85 Gy. Treatment plans using multiple noncoplanar arrangements of beams and static intensity modulation treat all volumes at each session. DVHs of the normalized isoeffective dose distributions reveal the equivalence of the new protocol plans to the sequential plans in the previous protocol as well as the ability to achieve a higher dose of 90 Gy to the isocenter of PTV1 (+/-5% homogeneity required). CONCLUSION: The ability to incorporate past experience through use of the linear quadratic model in the design of a new dose escalation protocol is demonstrated.

Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: assessment of target coverage and noninvolved tissue sparing.

PURPOSE: Conformal treatment using static multisegmental intensity modulation was developed for patients requiring comprehensive irradiation for head and neck cancer. The major aim is sparing major salivary gland function while adequately treating the targets. To assess the adequacy of the conformal plans regarding target coverage and dose homogeneity, they were compared with standard irradiation plans. METHODS AND MATERIALS: Fifteen patients with stage III/IV head and neck cancer requiring comprehensive, bilateral neck irradiation participated in this study. CT-based treatment plans included five to six nonopposed fields, each having two to four in-field segments. Fields and segments were devised using beam's eye views of the planning target volumes (PTVs), noninvolved organs, and isodose surfaces, to achieve homogeneous dose distribution that encompassed the targets and spared major salivary gland tissue. For comparison, standard three-field radiation plans were devised retrospectively for each patient, with the same CT-derived targets used for the clinical (conformal) plans. Saliva flow rates from each major salivary gland were measured before and periodically after treatment. RESULTS: On average, the minimal dose to the primary PTVs in the conformal plans [95.2% of the prescribed dose, standard deviation (SD) 4%] was higher than in the standard plans (91%, SD 7%; p = 0.02), and target volumes receiving <95% or <90% of the prescribed dose were smaller in the conformal plans (p = 0.004 and 0.02, respectively). Similar advantages of the conformal plans compared to standard plans were found in ipsilateral jugular nodes PTV coverage. The reason for underdosing in the standard treatment plans was primarily failure of electron beams to fully encompass targets. No significant differences were found in contralateral jugular or posterior neck nodes coverage. The minimal dose to the retropharyngeal nodes was higher in the standard plans. However, all conformal plans achieved the planning goal of delivering 50 Gy to these nodes. In the conformal plans, the magnitude and volumes of high doses in noninvolved tissue were significantly reduced. The main reasons for hot spots in the standard plans (whose dose calculations included missing tissue compensators) were photon/electron match line inhomogeneities, which were avoided in the conformal plans. The mean doses to all the major salivary glands, notably the contralateral parotid (receiving on average 32% of the prescribed dose, SD 7%) were significantly lower in the conformal plans compared with standard radiation plans. The mean dose to the noninvolved oral cavity tended to be lower in the conformal plans (p = 0.07). One to 3 months after radiation, on average 60% (SD 49%) of the preradiation saliva flow rate was retained in the contralateral parotid glands and 10% (SD 16%) was retained in the submandibular/sublingual glands. CONCLUSIONS: Planning and delivery of comprehensive irradiation for head and neck cancer using static, multisegmental intensity modulation are feasible. Target coverage has not been compromised and dose distributions in noninvolved tissue are favorable compared with standard radiation. Substantial major salivary gland function can be retained.

Customized gynecologic interstitial implants: CT-based planning, dose evaluation, and optimization aided by laparotomy.

PURPOSE: Interstitial perineal implants may be utilized to deliver a high local radiation dose in the treatment of advanced gynecologic malignancies. Lack of knowledge of the precise anatomic relationships between the implant and the target and critical organs may limit efficacy and increase complication risks. Computed tomography (CT)-based planning, dose evaluation, and optimization of customized interstitial implants, aided by laparotomy, have been developed to overcome these limitations. METHODS AND MATERIALS: Twenty patients with locally advanced gynecologic malignancies treated between May 1990 to October 1996 with external irradiation and one or two implants. Interstitial implants were performed when intracavitary brachytherapy was judged to be inadequate or when the response to external radiation and an intracavitary implant was not satisfactory. Customized interstitial implants were planned using preimplantation CT to determine catheter angles and paths that best implanted the target while avoiding pelvic bones and organs. Laparotomy aimed at lysing bowel adhesions, placement of omental carpet, and refining needle placement. Postimplantation CT was used for loading optimization and dose evaluation. RESULTS: Catheter angles 15-25 degrees were found to adequately implant anteriorly laying targets while avoiding pubic bones and bladder. Adhesiolysis of bowel loops from the vaginal apex was required in patients with prior hysterectomy. Small modifications in catheter placements were made during laparotomy in all implants. Postimplantation CTs showed deviations of the catheter positions compared with the planning CTs and were essential in determining target and organ doses and loading optimization. At a median follow-up of 42 months (range: 9-80 months), local control rate is 55% and disease-free survival 40%. Late complications occurred in 2 of 11 of patients without local recurrence. CONCLUSIONS: CT-based planning, loading optimization, and dose evaluation of customized implants improve radiation dose delivery. Laparotomy enhances implant accuracy and safety. Local tumor control rate is still unsatisfactory. It reflects the shortcomings of technical advances alone in poor prognosis tumors like those selected for this series.

Potential benefits of eliminating planning target volume expansions for patient breathing in the treatment of liver tumors.

PURPOSE: To investigate potential benefits derived from reduction or elimination of planning target volume (PTV) margins associated with patient breathing through examination of hepatic tumors treated with conformal therapy. METHODS AND MATERIALS: We reviewed the treatment plans of 50 patients who had previously received conformal partial organ liver irradiation for treatment of hepatic malignancies. PTVs for these plans included expansions (1-2 cm) for patient breathing. Data consisted of the three-dimensional dose distributions computed for the conformal plans generated for these volumes, and also for plans using identical beam arrangements but smaller block margins to treat planning target volumes that did not include the expansions for breathing. We calculated effective volumes (V(eff)) and normal tissue complication probabilities (NTCP) using dose-volume histograms for normal liver and analyzed changes in: V(eff), NTCP at the prescription dose, doses associated with selected NTCP levels, and tumor control probabilities (TCP) at these new dose levels. RESULTS: Elimination of the patient breathing components of the PTVs for these conformal treatments of liver tumors: (a) decreased the average V(eff) by 5%; (b) decreased the average predicted NTCP at the prescription (isocenter) dose used to treat the patients by 4.5%; (c) increased the average target volume (isocenter) dose associated with low (1-10%) predicted normal liver NTCP by 6-8 Gy, which corresponded to (d) a predicted average 6-7% increase in TCP for aggressive liver tumors. Plans with PTV expansions for breathing that occurred mostly within the liver showed greatest potential benefit. CONCLUSIONS: Elimination of the margin added to hepatic target volumes for patient ventilation could lead to clinically meaningful increases in dose without increasing the predicted frequency of complications.

Dose-volume complication analysis for visual pathway structures of patients with advanced paranasal sinus tumors.

PURPOSE: The purpose of the present work was to relate dose and volume information to complication data for visual pathway structures in patients with advanced paranasal sinus tumors. METHODS AND MATERIALS: Three-dimensional (3D) dose distributions for chiasm, optic nerve, and retina were calculated and analyzed for 20 patients with advanced paranasal sinus malignant tumors. 3D treatment planning with beam's eye view capability was used to design beam and block arrangements, striving to spare the contralateral orbit (to lessen the chance of unilateral blindness) and frequently the ipsilateral orbit (to help prevent bilateral blindness). Point doses, dose-volume histogram analysis, and normal tissue complication probability (NTCP) calculations were performed. Published tolerance doses that indicate significant risk of complications were used as guidelines for analysis of the 3D dose distributions. RESULTS: Point doses, percent volume exceeding a specified published tolerance dose, and NTCP calculations are given in detail for patients with complications versus patients without complications. Two optic nerves receiving maximum doses below the published tolerance dose sustained damage (mild vision loss). Three patients (of 13) without optic nerve sparing and/or chiasm sparing had moderate or severe vision loss. Complication data, including individual patient analysis to estimate overall risk for loss of vision, are given. CONCLUSION: 3D treatment planning techniques were used successfully to provide bilateral sparing of the globe for most patients. It was more difficult to spare the optic nerves, especially on the ipsilateral side, when prescription dose exceeded the normal tissue tolerance doses. NTCP calculations may be useful in assessing complication risk better than point dose tolerance criteria for the chiasm, optic nerve, and retina. It is important to assess the overall risk of blindness for the patient in addition to the risk for individual visual pathway structures.

A single plan approach for differentially dosing sequential target volumes.

An in-house protocol for treatment of malignant astrocytomas requires development of a single treatment plan constructed to deliver different doses to three sequential target volumes. This single plan approach fundamentally differs from a previous protocol in which these sequential volumes were approached with three consecutive treatment plans, each tailored to a separate target, with the final target receiving a cumulative dose of 80 Gy. The intent of the revised protocol is to deliver doses to the two larger targets that are biologically equivalent (using the linear quadratic model) to the cumulative doses received by these targets in the earlier protocol, while escalating the final target dose to 90 Gy. This requires the treatment planner to manipulate the conformation of three different isodose levels simultaneously to produce a treatment plan fulfilling all protocol specifications. This paper will focus on the evolution of design for the current technique used to clinically implement this protocol.

Parotid gland sparing in patients undergoing bilateral head and neck irradiation: techniques and early results.

PURPOSE: To minimize xerostomia in patients receiving bilateral head and neck irradiation (RT) by using conformal RT planning to spare a significant volume of one parotid gland from radiation. METHODS AND MATERIALS: The study involved 15 patients with head and neck tumors in whom bilateral neck radiation was indicated. The major salivary glands and the targets (tumor, surgical bed, metastases to lymph nodes, and the locations of lymph nodes at risk for metastases) were outlined on axial computed tomography images. Beam's-eye view (BEV) displays were used to construct conformal beams that delivered the prescribed doses to the targets while sparing from direct radiation most of one parotid gland. The gland that was planned to be spared resided in the neck side that was judged in each patient to be at a lesser risk of metastatic disease. Major salivary gland flow rates and the responses to a subjective xerostomia questionnaire were assessed before, during, and after radiation. RESULTS: Radiation planning for patients with central oropharyngeal tumors required the generation of multiple axial nonopposed beams. The resulting isodoses encompassed the targets, including the retropharyngeal nodes and the jugular nodes up to the base of skull bilaterally, while limiting the dose to the oral cavity, spinal cord, and one parotid gland. For patients with lateralized tumors, the ipsilateral neck side was treated up to the base of the skull; in the contralateral neck side, the treatment included the subdigastric nodes but excluded the jugular nodes at the base of the skull and most of the parotid gland. This was accomplished by a moderate gantry angle that was chosen using the BEV displays. Three months following the completion of radiation, the spared parotid glands retained on average 50% of their unstimulated and stimulated flows. In contrast, no saliva flow was measured from the unspared glands in any of the patients. Subjective xerostomia was absent, mild, or not different from that reported before radiation in 10 of 15 patients (67%). CONCLUSION: Partial parotid gland sparing is feasible by using three-dimensional planning in patients undergoing bilateral head and neck radiation. Approximately 50% of the saliva flow from the spared glands may be retained, and most patients thus treated have no or mild xerostomia in the early period after the completion of radiation. Whether tumor control and late complications are comparable to standard radiation will be assessed as more experience is gained.

Simplified method for three-dimensional evaluation of interstitial brachytherapy applications.

Although three-dimensional (3-D) treatment planning has primarily been used for external beam radiation therapy, the advantages of 3-D treatment planning can be realized for brachytherapy applications. As with teletherapy, the use of 3-D treatment planning for brachytherapy can provide both superior dose distribution as well as detailed evaluations of the relationship of dose and volume in critical structures and target tissues. Conventional 3-D treatment planning uses computed tomography (CT) scans to localize structures; however, localizing individual brachytherapy sources on each CT slice can be impractical for routine clinical use. In the transition from two-dimensional to 3-D localization and dose evaluation of interstitial perineal templates in particular, a practical method of seed localization on a postimplant CT dataset has been developed. This method does not utilize dummy sources and, as such, does not require individual seed locations to be identified. Instead, the position of the afterloading catheter is defined as a reference line by connecting its location as seen on the axial CT slices and seed locations defined along its length. Full volumetric calculations can then be performed, including dose-volume histograms (DVH) for critical organs and tumor volumes. Source localization and normal tissue doses were calculated using both orthogonal films and the 3-D method for a series of perineal template guided implants. Point dose calculations of the rectum and bladder were obtained from orthogonal films and were then compared to the corresponding DVHs for these organs.

A customized non-axial external beam technique for treatment of prostate carcinomas.

A nonaxial four-field technique for primary and boost treatment of prostate carcinoma has been developed in an effort to minimize dose to rectum and bladder. Using a treatment planning CT scan, prostate, rectal and bladder volumes are outlined and corresponding three-dimensional structures are created. An oblique CT image, which bisects the prostate volume and excludes rectum and bladder, is reconstructed. Four beams, consisting of direct laterals and two anterior, inferior obliques, are designed, which lie in the plane of the generated image. Utilizing a beam's-eye-view display and multilevel dose calculations, blocks are designed for each port, which encompass the target volume within a minimum isodose surface. These customized angles result in oblique ports with rectal and bladder sparing that can be comparable to that of direct lateral ports. Dose-volume histogram analysis is used to evaluate the merits of this nonaxial method with other approaches.