Chemotherapy followed by accelerated fractionated radiation for larynx preservation in patients with advanced laryngeal cancer.

PURPOSE: Larynx preservation in advanced, resectable laryngeal cancer may be achieved using induction chemotherapy (CT) followed in responding patients by definitive radiation (RT). To address potential accelerated repopulation of clonogenic tumor cells during the prolonged total treatment time, we studied the feasibility of accelerated fractionated RT after CT. METHODS: Patients with advanced laryngeal cancer received two cycles of cisplatin 100 mg/m2 and fluorouracil (5-Fu) 1,000 mg/m2/d for 5 days. Responding patients received a third cycle after which those who had complete response or tumor down-staging to T1 proceeded with accelerated RT: 70.4 Gy delivered over 5.5 weeks. Patients who achieved a lesser response to CT underwent total laryngectomy and postoperative RT. RESULTS: Thirty-three patients were accrued. Three died during the course of CT and two declined definitive treatment after CT. Twenty-one patients had a major response to CT, 20 of whom received accelerated RT. Median weight loss during RT was 11%. Late severe morbidity was observed in five patients (25%). All four patients who underwent salvage laryngectomy after accelerated RT experienced major postoperative complications. The locoregional failure rate was 25%. The larynx was preserved in 48% of the total study population and in 80% of the patients irradiated according to the study protocol. CONCLUSION: Accelerated RT after CT as delivered in this study may increase both acute and long-term morbidity rates compared with studies using standard RT after CT. It did not seem to improve local/regional tumor control or survival despite stringent patient selection criteria.

Intensive induction chemotherapy and radiation for organ preservation in patients with advanced resectable head and neck carcinoma.

PURPOSE: We designed a protocol to evaluate the possibility of organ preservation in patients with advanced, resectable carcinoma of the head and neck. The regimen consisted of intensive chemotherapy followed by radiation therapy alone for patients with good response to treatment. The end points of the study were response rate, organ preservation, toxicity, and survival. PATIENTS AND METHODS: Forty-two eligible patients with carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses were enrolled. Induction chemotherapy consisted of three cycles of mitoguazone, fluorouracil (5-FU), and high-dose continuous infusion cisplatin. Patients who had a complete response to chemotherapy, or whose tumor was downstaged to T1N1, were treated with definitive radiation therapy, to a total dose of 66 to 73.8 Gy. Patients with residual disease greater than T1N1 underwent surgery and postoperative radiation. RESULTS: The overall response rate to chemotherapy was 84%, with a 43% complete response rate, and a 68% complete response rate at the primary tumor site. Sixty-nine percent of patients (29 of 42) were initially spared surgery to the primary tumor site, and four of these patients (14%) required neck dissection only, after radiation therapy. These tumor sites included oral cavity, oropharynx, hypopharynx, larynx, and sinuses. Eventually, five of these patients (17%) required salvage surgery and eight patients (28%) had unresectable or metastatic relapses. With a median follow-up duration of 38.5 months, 36% of all patients have had preservation of the primary tumor site and remain disease-free. The median survival duration is 26.8 months. Toxicity was substantial, with a 70% incidence of grade 3 to 4 granulocytopenia and two septic deaths. CONCLUSION: Organ preservation without apparent compromise of survival was achieved in patients with selected nonlaryngeal sites of head and neck carcinoma. Larger site-specific trials with less toxic regimens conducted in randomized fashion are required to extend these data.

Spinal cord astrocytoma: response to PCV chemotherapy.

Information regarding the value of chemotherapy for spinal cord astrocytomas that progress after irradiation is limited. We describe a patient whose conus medullaris astrocytoma responded to PCV (procarbazine, lomustine, and vincristine) chemotherapy after failing radiation and cisplatin-based chemotherapy. PCV should be considered in patients with progressive spinal cord astrocytomas.

A precision cranial immobilization system for conformal stereotactic fractionated radiation therapy.

PURPOSE: Conformal radiotherapy has been shown to benefit from precision alignment of patient target to therapy beam (1, 6, 13). This work describes an optimized immobilization system for the fractionated treatment of intracranial targets. A study of patient motion demonstrates the high degree of immobilization which is available. METHODS AND MATERIALS: A system using dental fixation and a thermoplastic mask that relocates on a rigid frame is described. The design permits scanning studies using computed tomography (CT) and magnetic resonance imaging (MR), conventional photon radiotherapy, and high precision stereotactic proton radiotherapy to be performed with minimal repositioning variation. Studies of both intratreatment motion and daily setup reliability are performed on patients under treatment for paranasal sinus carcinoma. Multiple radiographs taken during single treatments provide the basis for a three-dimensional (3D) motion analysis. Additionally, studies of orthogonal radiographs used to setup for proton treatments and verification port films from photon treatments are used to establish day to day patient position variation in routine use. RESULTS: Net 3D patient motion during any treatment is measured to be 0.9 +/- 0.4 mm [mean +/- standard deviation (SD)] and rotation about any body axis is 0.14 +/- 0.67 degrees (mean +/- SD). Day-to-day setup accuracy to laser marks is limited to 2.3 mm (mean) systematic error and 1.6 mm (mean) random error. CONCLUSION: We conclude that the most stringent immobilization requirements of 3D conformal radiotherapy adjacent to critical normal structures can be met with a high precision system such as the one described here. Without the use of pretreatment verification, additional developments in machine and couch design are needed to assure that patient repositioning accuracy is comparable to the best level of patient immobility achievable.

Benign meningioma: partially resected, biopsied, and recurrent intracranial tumors treated with combined proton and photon radiotherapy.

PURPOSE/OBJECTIVE: To evaluate the recurrence-free survival and complications of combined proton and photon radiotherapy of patients with incompletely resected or recurrent histologically-confirmed benign meningioma. METHODS AND MATERIALS: Between May 1981 and November 1996, 46 patients with partially resected, biopsied, or recurrent meningiomas (median age of 50 years; range 11-74 years) were treated with combined photon and 160-MeV proton beam therapy at the Massachusetts General Hospital (MGH) and the Harvard Cyclotron Laboratory, using computed tomography-based conformal 3D treatment planning. Nine patients were treated after incomplete tumor resection, 8 patients after tumor biopsy only, and 29 patients after tumor recurrence following gross total (10/29 patients) or progression after subtotal (19/29 patients) resection. All patients were classified as benign meningioma on review slides at MGH. The median dose to the macroscopic gross tumor volume was 59.0 CGE (range 53.1-74.1 CGE, CGE = proton Gy x 1.1 RBE). The median follow-up was 53 months (range 12-207). RESULTS: Overall survival at 5 and 10 years was 93 and 77%, respectively, and the recurrence-free rate at 5 and 10 years was 100% and 88%, respectively. Survival without severe toxicity was 80% at 5 and 10 years. Three patients presented with local tumor recurrence at 61, 95, and 125 months. One patient developed distant intradural metastasis at 21 and 88 months. No patient died from recurrent meningioma; however, 4 patients died of other causes. A fifth patient died from a brainstem necrosis after 22 months. Eight patients developed severe long-term toxicity from radiotherapy, including ophthalmologic (4 patients), neurologic (4 patients), and otologic (2 patients) complications. All patients with ophthalmologic toxicity received doses higher than those allowed for the optic nerve structures in the current protocol. CONCLUSION: Combined proton and photon radiotherapy is an effective treatment for patients with recurrent or incompletely resected benign intracranial menigiomas. Observed toxicity appears to be dose-related; with currently employed dose constraints, toxicity should not exceed that seen in patients treated with conformal fractionated supervoltage photon radiotherapy.

Three-dimensional treatment planning of astrocytomas: a dosimetric study of cerebral irradiation.

To demonstrate that 3-dimensional planning is both practical and applicable to the treatment of high-grade astrocytomas, 50 patients over a 2-year period have received cerebral irradiation delivered in focussed, non-axial techniques employing from 2 to 5 beams. Astrocytomas have been planned using rapid, practical incorporation of CT data to define appropriate tumor volumes. Tumor + 3.0 cm and tumor + 1.5 cm volumes have been treated to conventional doses of 4500 cGy and 5940 cGy, respectively, using beam orientations that maximally spared normal remaining parenchyma. Analyses of 3-dimensionally calculated plans have been performed using integral dose-volume histograms (DVH) to help select treatment techniques. Using identical CT-based volumetric data as input for generation of Beam's Eye View (BEV) designed blocks, DVH curves demonstrate dosimetric advantages of non-axial techniques over conventional parallel-opposed orientations. Assessment of the non-axial techniques in selected cases indicates that uniform target volume coverage could be maintained with a typical reduction of 30% in the total amount of brain tissue treated to high dose (95% isodose line).

The clinical utility of magnetic resonance imaging in 3-dimensional treatment planning of brain neoplasms.

Results of the clinical experience gained since 1986 in the treatment planning of patients with brain neoplasms through integration of magnetic resonance imaging (MRI) into computerized tomography (CT)-based, three-dimensional treatment planning are presented. Data from MRI can now be fully registered with CT data using appropriate three-dimensional coordinate transformations allowing: (a) display of MRI defined structures on CT images; (b) treatment planning of composite CT-MRI volumes; (c) dose display on either CT or MRI images. Treatment planning with non-coplanar beam arrangements is also facilitated by MRI because of direct acquisition of information in multiple, orthogonal planes. The advantages of this integration of information are especially evident in certain situations, for example, low grade astrocytomas with indistinct CT margins, tumors with margins obscured by bone artifact on CT scan. Target definitions have repeatedly been altered based on MRI detected abnormalities not visualized on CT scans. Regions of gadolinium enhancement on MRI T1-weighted scans can be compared to the contrast-enhancing CT tumor volumes, while abnormalities detected on MRI T2-weighted scans are the counterpart of CT-defined edema. Generally, MRI markedly increased the apparent macroscopic tumor volume from that seen on contrast-CT alone. However, CT tumor information was also necessary as it defined abnormalities not always perceptible with MRI (on average, 19% of composite CT-MRI volume seen on CT only). In all, the integration of MRI data with CT information has been found to be practical, and often necessary, for the three-dimensional treatment of brain neoplasms.

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.

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas.

In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

Results of primary and adjuvant CT-based 3-dimensional radiotherapy for malignant tumors of the paranasal sinuses.

PURPOSE: This study reports our clinical experience supporting the normal tissue-sparing capability of 3-dimensional (3-D) treatment planning when applied to advanced neoplasms of the paranasal sinuses. METHODS AND MATERIALS: Between 1986 and 1992, computed tomography (CT)-based 3-D radiotherapy was used to treat 39 patients with advanced stage malignant tumors of the paranasal sinuses as all or part of initial treatment. Fifteen unresectable patients were treated with primary radiotherapy to a median prescribed total dose of 68.4 Gy. Twenty-four patients were treated with postoperative adjuvant radiotherapy for close margins (< 5 mm), microscopic or gross residual disease. The median prescribed total doses were 55.8 Gy, 59.4 Gy and 67.8 Gy, respectively. Globe-sparing fields were used in the primary treatment plans of 37 patients (95%). The median follow-up is 4.5 years (range, 19-86 months). RESULTS: For the unresectable patients who were treated with radiotherapy alone, the local control rate at 3 years is 32%. The actuarial overall survivals at 3 and 4 years are 32%. For the patients who received postoperative adjuvant radiotherapy, none of the five patients irradiated for close surgical margins recurred locally. Three of the 14 with microscopic residual (21%) recurred locally at 26, 63, and 74 months from the start of irradiation. Four of the five with gross residual (80%) recurred locally with a median time to recurrence of 2 years. The local control rates at 3 and 5 years for the adjuvant group are 75% and 65%, respectively. The actuarial overall survival at 3 and 5 years are 65% and 60%, respectively. None of the first sites of local disease progression were judged to have occurred outside the high-dose region. There was one case of mild osteoradionecrosis successfully treated with conservative treatment, one case of limited optic neuropathy and one case of possible radiation-induced cataract. There was no blindness related to irradiation. CONCLUSION: This study indicates that computed tomography-based 3-D radiotherapy can preserve critical structures unaffected by tumor invasion and achieve the generally expected local control rates when it is used as all or part of initial treatment for extensive malignant tumors of the paranasal sinus. The presence of gross disease was a major adverse prognostic factor in this study. Additional therapeutic maneuvers are essential to improve the local control and survival rate in patients with advanced paranasal sinus carcinomas.

FDG hypermetabolism associated with inflammatory necrotic changes following radiation of meningioma.

PET with 18F-fluoro-2-deoxy-D-glucose (FDG) is currently the noninvasive gold standard for distinguishing brain tumor recurrence from radiation necrosis. We present a case report that appears to contradict this doctrine. The patient had a history of atypical meningioma and was treated with surgical resection and postoperative proton-beam radiation therapy. Approximately 16 mo after completion of therapy, MRI demonstrated two new regions of enhancement, and an FDG-PET study was performed to further characterize these lesions. FDG-PET demonstrated an area of intense hypermetabolism, and wide surgical resection was performed. Histological examination of the surgical specimen revealed reactive changes and areas of necrosis. There was no evidence of either recurrent or radiation-induced tumor.

Three-dimensional motion analysis of an improved head immobilization system for simulation, CT, MRI, and PET imaging.

A mask/marker immobilization system for the routine radiation therapy treatment of head and neck disease is described, utilizing a commercially available thermoplastic mesh, indexed and mounted to a rigid frame attached to the therapy couch. Designed to permit CT, MRI, and PET diagnostic scans of the patient to be performed in the simulation and treatment position employing the same mask, the system has been tested in order to demonstrate the reproducibility of immobilization throughout a radical course of irradiation. Three-dimensional analysis of patient position over an 8-week course of daily radiation treatment has been performed for nine patients from digitization of anatomic points identified on orthogonal radiographs. Studies employing weekly simulation indicate that patient treatment position movement can be restricted to 2 mm over the course of treatment. This easily constructed system permits rapid mask formation to be performed on the treatment simulator, resulting in an immobilization device comparable to masks produced with vacuum-forming techniques. Details of motion analysis and central axis CT, MRI, and PET markers are offered.

A quantitative assessment of the addition of MRI to CT-based, 3-D treatment planning of brain tumors.

Quantitative 3-D volumetric comparisons were made of composite CT-MRI macroscopic and microscopic tumor and target volumes to their independently defined constituents. Volumetric comparisons were also made between volumes derived from coronal and axial MRI data sets, and between CT and MRI volumes redefined at a repeat session in comparison to their original definitions. The degree of 3-D dose coverage obtained from use of CT data only or MRI data only in terms of coverage of composite CT-MRI volumes was also analyzed. On average, MRI defined larger volumes as well as a greater share of composite CT-MRI volumes. On average, increases in block margin on the order of 0.5 cm would have ensured coverage of volumes derived from use of both imaging modalities had only MRI data been used. However, the degree of inter-observer variation in volume definition is on the order of the magnitude of differences in volume definition seen between the modalities, and the question of which imaging modality best describes tumor volumes remains unanswered until detailed histologic studies are performed. Given that tumor volumes independently apparent on CT and MRI have equal validity, composite CT-MRI input should be considered for planning to ensure precise dose coverage for conformal treatments.

Technical advances in radiotherapy of head and neck tumors.

Future teletherapy in head and neck sites will include treatment of additional aggressive base-of-skull tumors, acoustic neuromas, and external ear canal tumors. In addition, protocols are being developed to take advantage of the enhanced precision of stereotaxic and conformal teletherapy to deliver concomitant boosts to gross or residual disease after surgery. These field-in-field boosts permit accelerated, hyperfractionated radiotherapy to be delivered to tumor, while maintaing or decreasing dose to surrounding normal tissues. The improved results of aggressive, accelerated fractionation schedules may be realized with acceptable morbidities through the use of more focused irradiation.

Automated determination of patient setup errors in radiation therapy using spherical radio-opaque markers.

Patient positioning accuracy can be quantified by the three-dimensional (3-D) translations and rotations required to transform the patient back to the desired position. Results of the current study show that the translations and rotations could be obtained from two projection images obtained radiographically on a linear accelerator when spherical radio-opaque markers were implanted inside or affixed to the surface of a skull phantom. In this study, film used to record the images were converted into digital gray scale images using a laser film digitizer. The marker images were located automatically by the computer using image processing techniques. By combining information from both projections, the 3-D locations of the markers were determined to submillimeter precision. Pairs of films were also analyzed for the phantom displaced from its original location by known amounts. The accuracy of the computed translations and rotations required for realignment of the phantom were found to be better than 1 mm and 0.3 degrees, respectively; comparable to the accuracy of the readout system of the equipment used. The general methodology could be coupled with an electronic portal imaging device for use in computer aided or automated correction of patient position in radiotherapy.

Comparison of proton and x-ray conformal dose distributions for radiosurgery applications.

Highly focused dose distributions for radiosurgery applications are successfully achieved using either multiple static high-energy particle beams or multiple-arc circular x-ray beams from a linac. It has been suggested that conformal x-ray techniques using dynamically shaped beams with a moving radiation source would offer advantages compared to the use of only circular beams. It is also thought that, generally, charged particle beams such as protons offer dose deposition advantages compared to x-ray beams. A comparison of dose distributions was made between a small number of discrete proton beams, multiple-arc circular x-ray beams, and conformal x-ray techniques. Treatment planning of a selection of radiosurgery cases was done for these three techniques. Target volumes ranged from 1.0-25.0 cm3. Dose distributions and dose volume histograms of the target and surrounding normal brain were calculated. The advantages and limitations of each technique were primarily dependent upon the shape and size of the target volume. In general, proton dose distributions were superior to x-ray distributions; both shaped proton and shaped x-ray beams delivered dose distributions which were more conformal than x-ray techniques using circular beams; and the differences between all proton and x-ray distributions were negligible for the smallest target volumes, and greatest for the larger target volumes.

Spinal cord astrocytomas: results of therapy.

Spinal cord astrocytomas are rare lesions, usually of low grade, with a long natural history. Because of this, it is difficult to define the optimum approach to therapy based on available data. To provide more data, a retrospective review was performed. From 1975 through 1989, 21 patients were seen and treated (median age, 21 years), and 15 patients received radiation therapy after undergoing either biopsy or resection. The median time until death or the last follow-up examination was 41 months. The actuarial survival of all patients was 68% at 5 years. Of the five deaths, four were related to local tumor recurrence. The overall survival and recurrence-free survival of irradiated patients at 5 years was 57% and 44%, respectively. The age of the patient was a prognostic factor, with younger patients surviving substantially longer before recurrence. Of the 15 irradiated patients, 7 experienced recurrence of the tumor, which occurred within the irradiated portion of the spinal cord in all 7. Gross total resections were rarely achieved and, also, the extent of resection did not influence the risk for recurrence. In summary, we observed a long natural history for this disease, and although additional local therapy appears needed, it is unclear that either higher doses of radiation or more extensive surgery will decrease the risk of recurrence.

Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy.

Hochberg and Pruitt have reported glioblastomas recurring within 2 cm of the primary site in 90% of patients after whole-brain radiation therapy. They suggested that computerized tomography (CT) scan accuracy would permit smaller radiation fields. A treatment protocol with smaller-field focal brain irradiation following surgical resection is reported. The first 4500 cGy of radiation is focused to within a 3-cm margin around the tumor, with a 1500-cGy boost within a 1.5-cm margin. Forty-two patients with grade III or IV astrocytoma, treated with focal brain radiation therapy were reviewed retrospectively to assess patterns of tumor recurrence. Thirty patients received intra-arterial bromodeoxyuridine (BUdR) radiosensitization with focal brain radiation therapy, and 12 patients underwent conventional focal brain radiation therapy. Tumor margin was defined on preoperative and recurrence CT scans as the contrast-enhanced area; these were traced on acetate templates and compared with each other and with the actual scans. In all 42 patients, the lesion recurred within a 2-cm margin of the original tumor. Four patients had two recurrent areas: the second area was within the 2-cm margin in two, and outside this margin in two. These results are similar to those of Hochberg and Pruitt. It is suggested that focal irradiation is now the optimal treatment for malignant astrocytoma. Since recurrences continue to be within the irradiated volumes, it appears that higher focal doses of radiation are appropriate for clinical treatment trials of malignant astrocytomas.

Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas.

The authors provided procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy to 32 patients whose tumors contained varying mixtures of oligodendroglial and astrocytic cells. Twenty-five patients had oligodendroglioma-astrocytoma (oligoastrocytoma) with a histological Grade of III (19 patients) or IV (six patients); seven had anaplastic oligodendroglioma. The PCV therapy was administered every 6 weeks for a total of at least 124 cycles. The median duration of follow-up review from the start of chemotherapy was 19.3 months. Nineteen patients were treated before receiving radiation therapy and 12 after receiving it (one patient received concurrent radiotherapy and chemotherapy). Grade 3 or 4 hematological toxicity was experienced by nine (31%) of 29 patients. Ten patients had delayed treatment due to treatment-related toxicities (34.5%). Ninety-one percent of the 32 patients responded to the therapy. These included 10 patients with a complete response and 19 with a partial response. The median time to progression was 15.4 months for all patients and 23.2 months for those with Grade III tumors. The median time to progression for patients with Grade III oligoastrocytomas was 13.8 months; for those with Grade IV oligoastrocytoma it was 12.4 months and for those with anaplastic oligodendrogliomas it was 63.4 months (p = 0.0348). These patients survived a median of 49.8 months, 16 months, and 76 or more months, respectively, from the start of chemotherapy (p = 0.0154). The PCV therapy provides durable responses in patients with Grade III or IV oligoastrocytomas.

Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial.

OBJECT: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival. METHODS: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18%, respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p = 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume. CONCLUSIONS: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis.