Pulsed reduced dose-rate radiotherapy: a novel locoregional retreatment strategy for breast cancer recurrence in the previously irradiated chest wall, axilla, or supraclavicular region.

PURPOSE: Reirradiation of breast cancer locoregional recurrence (LRR) in the setting of prior post-mastectomy radiation poses a significant clinical challenge due to the high risk for severe toxicity. In an attempt to reduce these toxicities, we have developed pulsed reduced dose-rate radiotherapy (PRDR), a reirradiation technique in which a series of 0.2 Gy pulses separated by 3-min time intervals is delivered, creating an apparent dose rate of 0.0667 Gy/min. Here we describe our early experience with PRDR. PATIENTS AND METHODS: We reirradiated 17 patients with LRR breast cancer to the chest wall, axilla, or supraclavicular region using PRDR. The median prior radiation dose was 60 Gy. We delivered a median PRDR dose of 54 Gy (range 40-66 Gy) in 1.8-2.0 Gy per fraction. Eight patients received concomitant low dose capecitabine for radiosensitization. The median treatment volume was 2,084 cm(3) (range 843-7,881 cm(3)). RESULTS: At a median follow-up of 18 months (range 4-75 months) only 2 patients have had tumor failure in the treatment region. Estimated 2-year local control rate is 92%. Treatment was well tolerated with 4 patients experiencing grade 3 acute skin toxicity. Despite a median cumulative dose of 110 Gy (range 80-236 Gy), there has been only one grade 3 and one grade 4 late toxicity. CONCLUSIONS: With a median follow-up of 18 months, PRDR appears to be an effective method to reirradiate large volumes of previously irradiated tissue in selected patients with locoregional chest wall, axilla, and supraclavicular recurrences.

Therapeutic management of metastatic brain tumors.

Whole brain radiation therapy (WBRT) for patients with brain metastases provides increased local control, locoregional control, and median survival over supportive care or steroids alone. In addition, effective palliative relief is realized in the majority of patients. Despite this, median survival with WBRT alone remains fixed at a relatively unfortunate 4-6 months as demonstrated in prospective randomized controlled trials. Key issues in the therapeutic management of brain metastases include techniques to optimize the multimodal application of WBRT in conjunction with surgery, radiosurgery, chemotherapy, and radiosensitizers. Efforts to incorporate these approaches to improve survival are currently under active investigation.

Are we influencing outcome in oropharynx cancer with intensity-modulated radiotherapy? An inter-era comparison.

PURPOSE: To analyze the outcome in all oropharynx cancer patients treated at the University of Wisconsin during 1995-2005 and highlight the methodologic challenge in comparing outcome after intensity-modulated radiotherapy (IMRT) with that of historical controls. METHODS AND MATERIALS: Outcomes were compared in 195 oropharynx cancer patients after definitive radiotherapy with curative intent in the pre-IMRT era (pre-IMRT, n = 105), after IMRT (IMRT+, n = 52) or after non-IMRT techniques during the IMRT era (IMRT-, n = 38). RESULTS: With a median follow-up of 30.4 months, the 3-year overall survival rate in IMRT+, IMRT-, and pre-IMRT patients was 88.2%, 81.1%, and 67.7%, respectively; and for locoregional control was 96.1%, 78.1%, and 81.1%. Patients from the IMRT era more frequently received concurrent chemotherapy (67% vs. 6%, p < 0.001) and underwent adjuvant neck dissection (52% vs. 29%, p = 0.002). Patients with T3-4 disease and bilateral neck disease were significantly less likely to receive IMRT. Cox regression analysis identified IMRT as a significant prognostic factor (p = 0.04); however, after including T stage in the model, IMRT lost independent significance (p = 0.2). Analysis of a potential effect of IMRT on Grade 3+ mucositis or skin reaction was also hampered by the change in other treatment characteristics. CONCLUSIONS: Outcomes in oropharynx cancer have improved at our institution since the introduction of IMRT. However, multiple factors have contributed to this improvement, and presentation of IMRT outcomes without the full context of historical and contemporary controls may yield data that overstate outcome after IMRT.

Planned postradiotherapy neck dissection: Rationale and clinical outcomes.

OBJECTIVES: In this study, we examine pathology results and clinical outcome for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) who present with advanced neck disease and undergo planned postradiotherapy neck dissection. STUDY DESIGN: Review of all patients with SCCHN treated with primary radiation (or chemoradiation) and postradiotherapy neck dissection at the University of Wisconsin between 1992 to 2005 was performed. One hundred seven neck dissections were identified in 93 patients, 79 unilateral and 14 bilateral. All major treatment and outcome parameters were examined with particular emphasis on the postradiotherapy neck dissection. RESULTS: Thirty of 107 neck dissection specimens (28%) showed evidence of residual carcinoma on pathologic review. The mean number of lymph nodes identified at neck dissection for the entire cohort was 21 per specimen (range, 1-60) with 1.3 nodes per positive neck dissection demonstrating residual carcinoma. No correlation was found between the type of neck dissection performed and the presence of residual nodal disease. Eighty-two evaluated patients (93%) remain free of regional disease recurrence, whereas six patients have subsequently manifested neck recurrence. Four of the six patients who developed regional recurrence showed residual carcinoma in their neck dissection specimen. Five of these patients underwent comprehensive neck dissection (levels I-V); one underwent selective neck dissection (

Comparison of linac based fractionated stereotactic radiotherapy and tomotherapy treatment plans for skull-base tumors.

BACKGROUND AND PURPOSE: To compare and evaluate helical tomotherapy and linac based fractionated stereotactic radiotherapy (FSRT) techniques in the treatment of skull-base tumors. PATIENTS AND METHODS: Ten patients diagnosed with skull-base tumors, originally planned for optically guided FSRT to prescribed doses of 50.4-54 Gy were replanned for treatment with clinically deliverable helical tomotherapy. All original CT scans, MR-CT fusion defined target and normal structure contours, and PTV margins were used for helical tomotherapy planning. Linac based plans utilized one of the following FSRT planning techniques: non-coplanar or coplanar intensity modulated radiation therapy (IMRT), multiple non-coplanar conformal arcs, and non-coplanar conformal radiation therapy (CRT). These plans were used as the standard to which the subsequent tomotherapy plans were compared, using the following criteria: prescription isodose to target volume (PITV) ratios, an inhomogeneity index (II), equivalent uniform dose (EUD) for PTV volumes, mean normalized total doses (NTDmean) for critical structures, and size of 10, 20, and 30 Gy isodose volumes. RESULTS: Use of both linac based FSRT techniques and helical tomotherapy generated highly conformal treatment plans. Tomotherapy plans, which are predominantly coplanar in nature, compared to non-coplanar linac based plans exhibited increased PITV ratios, variable change in II, similar EUD values, and generally comparable NTD(mean) values for organs at risk. When compared to non-coplanar field arrangements, deliverable (as opposed to idealized) tomotherapy plans also resulted in 13-540% increases in low dose isodose volumes. All criteria except for the II, which was generally improved with tomotherapy, were found to be similar when coplanar linac based plans were compared to helical tomotherapy plans. CONCLUSIONS: Results show a distinct advantage in using non-coplanar beam arrangements for treatment of skull-base tumors. In the case where disease spreads far inferiorly, limiting the ability to use non-coplanar arrangements, helical tomotherapy can be used to generate a comparable treatment plan, with potentially superior homogeneity.

Customized conformal high-dose-rate brachytherapy boost for limited-volume nasopharyngeal cancer.

PURPOSE: To determine the feasibility of and patient outcomes using customized high-dose-rate (HDR) brachytherapy to boost the nasopharynx after external beam radiation therapy (EBRT) in patients with carcinoma of the nasopharynx. METHODS AND MATERIALS: Patients with nonmetastatic squamous cell carcinoma of the nasopharynx were treated using EBRT followed by a HDR brachytherapy boost delivered via customized catheters in a noninvasive, accurate, and reproducible method under direct fiber-optic visualization. Local control (LC), disease-free survival (DFS), and overall survival (OS) were analyzed. We also measured the change in maximum oral aperture as an indication of temporomandibular joint dysfunction. RESULTS: Between March 1996 and July 2003, we treated 38 patients with this customized brachytherapy method. The procedure was well tolerated without any incidents of soft-tissue or bone necrosis and with minimal decrease of oral aperture. Median follow-up time was 47 months (range, 2-84 months); 35 patients had at least 1 year of follow-up. The 5-year actuarial rate of LC, DFS, and OS were 96.0%, 81.4%, and 92.7%, respectively. CONCLUSIONS: The treatment has been well tolerated by all patients. The combination of conformal EBRT with our customized HDR brachytherapy boost has resulted in excellent local control to date, while minimizing temporomandibular joint dysfunction.

Clinical experience using respiratory gated radiation therapy: comparison of free-breathing and breath-hold techniques.

PURPOSE: To investigate the clinical use of a commercially available gating system for minimizing respiratory-induced anatomic motion over a range of treatment sites. METHODS AND MATERIALS: The gating system consists of a reflective marker placed on the patient's anterior surface. The motion of the marker is tracked using a camera interfaced to a computer. Gated intervals were defined that limited the motion of the diaphragm to less than 1 cm during free breathing. Patients underwent a computed tomography virtual simulation using a breath-hold technique. At the time of treatment, verification of patient position and gating interval were performed using electronic portal imaging. RESULTS: Between September 2000 and January 2002, 136 patients were simulated with respiratory gating. Of these, 108 patients were treated to 110 sites for a total of 2301 treatment sessions. Ninety-seven percent of patients completed their entire course of therapy with gated treatment delivery. CONCLUSIONS: Respiratory gating is a practical and achievable solution for minimizing respiratory-induced target motion during both simulation and treatment. With proper patient selection and training, it can be successfully implemented in a clinical radiation therapy department.

Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate radiotherapy.

PURPOSE: Pulsed reduced-dose-rate radiotherapy (PRDR) is a reirradiation technique that reduces the effective dose rate and increases the treatment time, allowing sublethal damage repair during irradiation. PATIENTS AND METHODS: A total of 103 patients with recurrent glioma underwent reirradiation using PRDR (86 considered to have Grade 4 at PRDR). PRDR was delivered using a series of 0.2-Gy pulses at 3-min intervals, creating an apparent dose rate of 0.0667 Gy/min to a median dose of 50 Gy (range, 20-60) delivered in 1.8-2.0-Gy fractions. The mean treatment volume was 403.5±189.4 cm3 according to T2-weighted magnetic resonance imaging and a 2-cm margin. RESULTS: For the initial or upgraded Grade 4 cohort (n=86), the median interval from the first irradiation to PRDR was 14 months. Patients undergoing PRDR within 14 months of the first irradiation (n=43) had a median survival of 21 weeks. Those treated ≥14 months after radiotherapy had a median survival of 28 weeks (n=43; p=0.004 and HR=1.82 with a 95% CI ranging from 1.25 to 3.10). These data compared favorably to historical data sets, because only 16% of the patients were treated at first relapse (with 46% treated at the second relapse, 32% at the third or fourth relapse, and 4% at the fourth or fifth relapse). The median survival since diagnosis and retreatment was 6.3 years and 11.4 months for low-grade, 4.1 years and 5.6 months for Grade 3, and 1.6 years and 5.1 months for Grade 4 tumors, respectively, according to the initial histologic findings. Multivariate analysis revealed age at the initial diagnosis, initial low-grade disease, and Karnofsky performance score of ≥80 to be significant predictors of survival after initiation of PRDR. CONCLUSION: PRDR allowed for safe retreatment of larger volumes to high doses with palliative benefit.

Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: the University of Wisconsin experience.

BACKGROUND: We retrospectively examined the treatment efficacy and toxicity profile of intensity-modulated radiotherapy (IMRT) plus concurrent weekly cisplatin chemotherapy in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 57 patients with stage III or IV HNSCC were treated with IMRT and concurrent weekly cisplatin (dosed at 30 mg/m(2)) between November 2001 and May 2007. The median prescription dose to the gross tumor volume was 70 Gy (using 2.0-2.2 Gy daily fractions). RESULTS: In-field tumor control at 2 years was 89.1%, locoregional control was 85.5%, and overall survival was 86.9%. The median radiation dose delivered was 70 Gy. The mean dose intensity of cisplatin administered was 25.7 mg/m(2)/week. CONCLUSION: Comprehensive head and neck IMRT to 70 Gy delivered with weekly cisplatin chemotherapy (30 mg/m(2)) is feasible and generally well tolerated.

Motexafin gadolinium: a novel radiosensitizer for brain tumors.

For a variety of reasons, the management of brain tumors, both primary and metastatic, remains a considerable challenge. As most systemic therapies do not cross the BBB at therapeutic doses, radiation and surgery have played primary roles in the management of these diseases. Despite significant advances in surgical techniques and radiation delivery, outcomes for most adult brain tumors continue to be poor. In an effort to enhance the effects of radiation in the brain, a variety of radiation sensitizers, including motexafin gadolinium, have been investigated. In the following manuscript, we summarize motexafin gadolinium and its role in brain tumors.

Motexafin gadolinium in the treatment of brain metastases.

Motexafin gadolinium (MGd) is a novel, MRI-detectable, anticancer agent that enhances the cytotoxic potential of radiation therapy through several mechanisms, including depleting intracellular reducing metabolites that are necessary for repairing the oxidative damage induced by irradiation. It has tumor-specific uptake, normal tissue sparing, and tolerable and reversible toxicities in clinical trials. MGd's use in conjunction with whole-brain radiation therapy (WBRT) has demonstrated an improvement in neurocognitive decline, neurologic progression, and quality of life in patients with brain metastases from NSCLC. Its use in conjunction with radiosurgery and whole brain radiation therapy in the setting of brain metastases is currently being studied, as is MGd with radiation and temozolomide in patients with glioblastoma multiforme. MGd is also being actively investigated as a single agent or in combination with chemotherapy or radiation therapy in other tumors, including pediatric brain tumors, NSCLC, lymphoma, renal cell carcinoma, and pancreatic and biliary tumors.

Motexafin gadolinium: a novel radiosensitizer for brain tumors.

Despite advances in the field of oncology, progress for patients with brain metastases and most primary brain tumors has been slow. New efforts to enhance the therapeutic index of radiation therapy are under way, including the use of radiosensitizers. Motexafin gadolinium (Xcytrin) is one such novel agent with several unique properties that enhance the cytotoxic potential of radiation therapy, as well as several chemotherapeutic agents, and possibly has independent cytotoxicity in certain lymphoid malignancies. Motexafin gadolinium is very well tolerated with tumor specific uptake. The rationale for the use of this drug as well as its current and future role as a radiation enhancer in the management of brain tumors is reviewed.

Linear accelerator radiosurgery for trigeminal neuralgia.

OBJECTIVE: To report the clinical outcomes following treatment of trigeminal neuralgia with linear accelerator-based radiosurgery. METHODS: Twenty-eight patients with medication refractory idiopathic trigeminal neuralgia were treated with a single fraction of 80 Gy to the trigeminal nerve root. For treatment delivery, a 4-mm collimator and a 7-arc technique were delivered using a stereotactic floor stand system with an isocenter stability of 0.2 +/- 0.1 mm to minimize dose to the brainstem. Treatment delivery time was approximately 55 minutes. RESULTS: With a median follow-up of 12 months (range, 1-40 mo), 57% of patients achieved complete pain relief and 75% (exact 95% confidence interval, 55 to 89%) had their pain reduced to 3 or less on a 10-point pain scale. Median time to pain relief was 1 month. Four patients did not respond to treatment. The actuarial mean time to pain recurrence in responders was 14 months, and the actuarial mean response duration in major to complete responders was 16 months. Women had significantly longer mean time to pain recurrence than men (16 versus 7 months; P = 0.05). Three patients reported new mild facial numbness after radiosurgery and one patient developed neurotrophic keratopathy. CONCLUSION: Linear accelerator-based radiosurgery for medication refractory trigeminal neuralgia provides effective pain relief with a low complication rate.

Acute toxicity of high-dose-rate intracavitary brachytherapy with the MammoSite applicator in patients with early-stage breast cancer.

BACKGROUND: Intracavitary brachytherapy with the MammoSite applicator as the sole radiation treatment in breast-conserving therapy is an option for women with early-stage breast cancer; we evaluated the acute toxicities associated with this treatment method. METHODS: Thirty-one patients with 32 stage I or II breast carcinomas underwent breast-conserving therapy, which included lumpectomy with negative margins, sentinel node biopsy, or axillary dissection, followed by brachytherapy with the MammoSite applicator. Acute radiation skin complications were graded on the day of radiotherapy completion and at weeks 2, 4, 6, and 12 after radiation treatment. Cosmesis was graded on the Harvard Scale at all follow-ups. RESULTS: The median follow-up was 11 months (range, 4-15 months). Twenty-seven of the 31 patients were treated with the device as the sole method of radiotherapy. No acute toxicities occurred during the 5 days of treatment. Nineteen patients (68%) had no to mild acute skin reactions, and 25% developed bright erythema and patchy moist desquamation. Two patients (7%) developed confluent moist desquamation within the first 4 weeks (grade 3); this healed by week 12. All skin reactions were localized to the area overlying the balloon. Sixteen percent (5 of 32) of all breasts with implants developed infection. Cosmesis was good to excellent in 86% of cases. CONCLUSIONS: Most acute skin toxicities were mild. Our infection rate was higher than in prior studies that used interstitial brachytherapy. Cosmesis was good to excellent in most patients. Breast brachytherapy with the MammoSite catheter was well tolerated; further investigations of breast brachytherapy with this system are warranted.