Marc R. Bussière

Analysis of prostate and seminal vesicle motion: Implications for treatment planning

PURPOSE To quantify prostate and seminal vesicle positional changes (target motion) between treatment planning and delivery, and to identify the factors contributing to target motion. METHODS AND MATERIALS Thirty patients with adenocarcinoma of the prostate were prospectively evaluated by analyzing two sequential planning computerized tomography (CT) scans (S1, obtained prior to treatment, and S2, obtained during the fourth week of treatment) for each patient. All anatomical volumes of interest (soft tissue and bony) were reconstructed from transverse CT images and projected onto anterior and lateral beams-eye view projections. Positional changes between S1 and S2 were eliminated by applying a rigid body translation and rotation. Target motion was then measured by recording the positional change between S1 and S2 at the edges (right, left, superior, inferior). Potential correlation of target motion with bladder volume, rectal volume, and rectal diameter changes were evaluated by linear regression analysis. RESULTS Neither the prostate nor seminal vesicles remained fixed with respect to bony anatomy between S1 and S2. The distribution of positional changes were generally small (< 0.5 cm), but maximum displacements of 1.5-2.2 cm did occur, particularly in the lateral view. In this study, bladder volume changes between the scans were small and did not correlate with target motion (P = 0.67). Both rectal volume and rectal diameter changes correlated with target motion for both the prostate (p = 0.004 and 0.005, respectively) and seminal vesicles (p < 0.001 and < 0.001, respectively). However, neither the initial rectal volume nor the initial rectal diameter could be used to predict subsequent target motion when evaluated either singly or as part of a multiple regression model. CONCLUSIONS Target motion occurs during the course of treatment planning and delivery and should be considered when designing conformal radiation fields. Although the target position at the time of planning CT may differ substantially from the mean treatment position, target motion cannot be predicted by evaluating simply measured parameters from a single scan, or double scan sequence.

Management of Atypical and Malignant Meningiomas: Role of High-dose, 3D-conformal Radiation Therapy

AbstractObjective Atypical and malignant meningiomas are at high risk for local failure. The role of radiation therapy (RT) and dose levels required to improve tumor control are poorly defined. This study reviews our experience with RT. Material and methods Thirty-one patients underwent fractionated RT for atypical (AM, 15 patients) or malignant meningioma (MM, 16 patients) of the cranium. Sixteen patients presented with primary and 15 with recurrent disease. Eight patients received RT following total resection, 21 patients after subtotal resection and 2 patient following biopsy only. RT was given using megavoltage photons in 15 patients and combined photons and 160 MeV protons in 16 patients. Total target doses ranged from 50 to 68 (AM, mean 62) and from 40 to 72 (MM, mean 58) Gy or CGE (= cobalt-gray-equivalent). Results With mean observation time of 59 months (range: 7–155 months) actuarial local control rates at 5- and 8-years were similar for both histologies (38% and 19% for AM and 52 and 17% for MM). However, significantly improved local control was observed for proton versus photon RT (80% versus 17% at 5 years, p = 0.003) and target doses ≥60 Gy for both, atypical (p = 0.025) and malignant meningioma (p = 0.0006).At time of analysis, 14/15 patients (93%) with AM and 6/16 (38%) with MM were alive. Three patients (19%) with MM developed distant metastasis. Actuarial 5- and 8-year survival rates for MM were significantly improved by use of proton over photon RT and radiation doses ≥60 CGE. Three patients developed symptomatic radiation damage after 59.3, 68.4 and 72 Gy/CGE. Conclusion Conformal, high dose RT resulted in significant improvement of local control for atypical and malignant meningiomas. Increased local control resulted also in improved rates of survival for patients with malignant meningioma.

Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity.

OBJECTIVEWe sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery. METHODSBetween November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5–35 mm), and the median tumor volume was 1.4 cm3 (range, 0.1–15.9 cm3). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10–18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12–102.6 mo). RESULTSThe actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9–99.9%) and 93.6% (95% CI, 88.3–99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2–98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85–97.6%) and 89.4% (95% CI, 82–96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed. CONCLUSIONProton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.

PROTON STEREOTACTIC RADIOSURGERY IN MANAGEMENT OF PERSISTENT ACROMEGALY

OBJECTIVE To evaluate the efficacy and safety of proton stereotactic radiosurgery (PSRS) for acromegaly that is refractory to surgical treatment and medication. METHODS From 1992 to 2003, 22 patients were treated at our institution for persistent acromegaly with use of PSRS. All patients had undergone at least one transsphenoidal surgical procedure without biochemical cure. The median treatment dose delivered during PSRS was 20 (range, 15 to 24) cobalt gray equivalents. RESULTS Follow-up was available for all patients at a median of 6.3 (range, 2.5 to 14.2) years after PSRS. A response to PSRS was observed in 21 of 22 patients (95%). A complete response (CR), defined as sustained (> or =3 months) normalization of insulinlike growth factor-I without medical suppression, was attained in 13 patients (59%). Among patients with CR, the median time to CR was 42 (range, 6 to 62) months. No visual complications, seizures, clinical evidence of brain injury, or secondary tumors were noted on regular magnetic resonance imaging scans. One patient had complete pituitary dysfunction before PSRS and was therefore excluded from evaluation for failure. Of the other 21 patients, 8 (38%) had new pituitary deficits. CONCLUSION These results demonstrate that PSRS is effective for persistent acromegaly, with 59% of patients attaining normal insulinlike growth factor-I levels without use of any medication after a median of 6.3 years. Our findings indicate that radiosurgery results in an expeditious biochemical response with low morbidity.

Visual Outcome and Tumor Control After Conformal Radiotherapy for Patients With Optic Nerve Sheath Meningioma

PURPOSE Optic nerve sheath meningioma (ONSM) is a rare tumor that almost uniformly leads to visual dysfunction and even blindness without intervention. Because surgical extirpation carries a high risk of postoperative blindness, vision-sparing treatment strategies are desirable. METHODS AND MATERIALS We retrospectively reviewed the outcomes of 25 patients (25 optic nerves) with ONSM, treated at a single institution with conformal fractionated radiotherapy by either stereotactic photon or proton radiation. Primary endpoints were local control and visual acuity. RESULTS The patients presented with symptoms of visual loss (21) or orbital pain (3) or were incidentally diagnosed by imaging (3). The mean age was 44 years, and 64% were female patients. The indication for treatment was the development or progression of symptoms. Of the patients, 13 were treated with photons, 9 were treated with protons, and 3 received a combination of photons and protons. The median dose delivered was 50.4 gray equivalents (range, 45-59.4 gray equivalents). Median follow-up after radiotherapy was 30 months (range, 3-168 months), with 3 patients lost to follow-up. At most recent follow-up, 21 of 22 patients (95%) had improved (14) or stable (7) visual acuity. One patient had worsened visual acuity after initial postirradiation improvement. Of the 22 patients, 20 (95%) had no radiographic progression. Three patients had evidence of asymptomatic, limited retinopathy on ophthalmologic examination, and one had recurrent ONSM 11 years after treatment. CONCLUSIONS Highly conformal, fractionated radiation therapy for symptomatic primary ONSM provides tumor control and improvement in visual function in most cases, with minimal treatment-induced morbidity. Longer follow-up is needed to assess the durability of tumor control and treatment-related late effects.

PROTON BEAM STEREOTACTIC RADIOSURGERY OF VESTIBULAR SCHWANNOMAS

PURPOSE The proton beams Bragg peak permits highly conformal radiation of skull base tumors. This study, prompted by reports of transient (30% each) and permanent (10% each) facial and trigeminal neuropathy after stereotactic radiosurgery of vestibular schwannomas with marginal doses of 16-20 Gy, assessed whether proton beam radiosurgery using a marginal dose of only 12 Gy could control vestibular schwannomas while causing less neuropathy. METHODS AND MATERIALS Sixty-eight patients (mean age 67 years) were treated between 1992 and 1998. The mean tumor volume was 2.49 cm(3). The dose to the tumor margin (70% isodose line) was 12 Gy. The prospectively specified follow-up consisted of neurologic evaluation and MRI at 6, 12, 24, and 36 months. RESULTS After a mean clinical follow-up of 44 months and imaging follow-up of 34 months in 64 patients, 35 tumors (54.7%) were smaller and 25 (39.1%) were unchanged (tumor control rate 94%; actuarial control rate 94% at 2 years and 84% at 5 years). Three tumors enlarged: one shrank after repeated radiosurgery, one remained enlarged at the time of unrelated death, and one had not been imaged for 4 years in a patient who remained asymptomatic at last follow-up. Intratumoral hemorrhage into one stable tumor required craniotomy that proved successful. Thus, 97% of tumors required no additional treatment. Three patients (4.7%) underwent shunting for hydrocephalus evident as increased ataxia. Of 6 patients with functional hearing ipsilaterally, 1 improved, 1 was unchanged, and 4 progressively lost hearing. Cranial neuropathies were infrequent: persistent facial hypesthesia (2 new, 1 exacerbated; 4.7%); intermittent facial paresthesias (5 new, 1 exacerbated; 9.4%); persistent facial weakness (2 new, 1 exacerbated; 4.7%) requiring oculoplasty; transient partial facial weakness (5 new, 1 exacerbated; 9.4%), and synkinesis (5 new, 1 exacerbated; 9.4%). CONCLUSION Proton beam stereotactic radiosurgery of vestibular schwannomas at the doses used in this study controls tumor growth with relatively few complications.

Dose-escalation with proton/photon irradiation for daumas-duport lower-grade glioma : Results of an institutional phase I/II trial

PURPOSE The role of dose escalation with proton/photon radiotherapy in lower-grade gliomas was assessed in a prospective Phase I/II trial. We report the results in terms of local control, toxicity, and survival. MATERIALS AND METHODS Twenty patients with Grade 2/4 (n = 7) and Grade 3/4 (n = 13) gliomas according to the Daumas-Duport classification were treated on a prospective institutional protocol at Massachusetts General Hospital/Harvard Cyclotron Laboratory between 1993 and 1996. Doses prescribed to the target volumes were 68.2 cobalt Gray equivalent (CGE, 1 proton Gray = 1.1 CGE) to gross tumor in Grade 2 lesions and 79.7 CGE in Grade 3 lesions. Fractionation was conventional, with 1.8 to 1.92 CGE once per day. Eligibility criteria included age between 18 and 70 years, biopsy-proven Daumas-Duport Grade 2/4 or 3/4 malignant glioma, Karnofsky performance score of 70 or greater, and supratentorial tumor. Median age of the patient population at diagnosis was 35.9 years (range 19-49). Ten tumors were mixed gliomas, one an oligodendroglioma. RESULTS Five patients underwent biopsy, 12 a subtotal resection, and 3 a gross total resection. Median interval from surgery to first radiation treatment was 2.9 months. Actuarial 5-year survival rate for Grade 2 lesions was 71% as calculated from diagnosis (median survival not yet reached); actuarial 5-year survival for Grade 3 lesions was 23% (median 29 months). Median follow-up is 61 months and 55 months for 4 patients alive with Grade 2 and 3 patients alive with Grade 3 lesions, respectively. Three patients with Grade 2 lesions died from tumor recurrence, whereas 2 of the 4 survivors have evidence of radiation necrosis. Eight of 10 patients who have died with Grade 3 lesions died from tumor recurrence, 1 from pulmonary embolus, and 1 most likely from radiation necrosis. One of 3 survivors in this group has evidence of radiation necrosis. CONCLUSION Tumor recurrence was neither prevented nor noticeably delayed in our patients relative to published series on photon irradiation. Dose escalation using this fractionation scheme and total dose delivered failed to improve outcome for patients with Grade 2 and 3 gliomas.

Treatment Planning for Conformal Proton Radiation Therapy

Clinical results from various trials have demonstrated the viability of protons in radiation therapy and radiosurgery. This has motivated a few large medical centers to design and build expensive hospital based proton facilities based proton facilities (current cost estimates for a proton facility is around

Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma.

100 million). Until this development proton therapy was done using retrofitted equipment originally designed for nuclear experiments. There are presently only three active proton therapy centers in the United States, 22 worldwide. However, more centers are under construction and being proposed in the US and abroad. The important difference between proton and x-ray therapy is in the dose distribution. X-rays deposit most of their dose at shallow depths of a few centimeters with a gradual decay with depth in the patient. Protons deliver most of their dose in the Bragg peak, which can be delivered at most clinically required depths followed by a sharp fall-off. This sharp falloff makes protons sensitive to variations in treatment depths within patients. Treatment planning incorporates all the knowledge of protons into a process, which allows patients to be treated accurately and reliably. This process includes patient immobilization, imaging, targeting, and modeling of planned dose distributions. Although the principles are similar to x-ray therapy some significant differences exist in the planning process, which described in this paper. Target dose conformality has recently taken on much momentum with the advent of intensity modulated radiation therapy (IMRT) with photon beams. Proton treatments provide a viable alternative to IMRT because they are inherently conformal avoiding normal tissue while irradiating the intended targets. Proton therapy will soon bring conformality to a new high with the development of intensity modulated proton therapy (IMPT). Future challenges include keeping the cost down, increasing access to conventional proton therapy as well as the clinical implementation of IMPT. Computing advances are making Monte Carlo techniques more accessible to treatment planning for all modalities including proton therapy. This technique will allow complex delivery configurations to be properly modeled in a clinical setting.

Proton Stereotactic Radiosurgery for the Treatment of Benign Meningiomas

Proton therapy has been a hotly contested issue in both scientific publications and lay media. Proponents cite the modalitys ability to spare healthy tissue, but critics claim the benefit gained from its use does not validate its cost compared with photon therapy. The objective of this study was to evaluate the cost effectiveness of proton therapy versus photon therapy in the management of pediatric medulloblastoma.