Khan W. Li

Paclitaxel: a review of adverse toxicities and novel delivery strategies

Better known as Taxol® (Bristol-Myers Squibb), paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. The taxanes exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. The use of paclitaxel as a chemotherapeutic agent has become a broadly accepted option in the treatment of patients with ovarian, breast and non-small cell lung cancers, malignant brain tumors, and a variety of other solid tumors. However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. This review addresses the toxicities associated with paclitaxel treatment and describes existing and future strategies of paclitaxel administration directed at limiting these toxicities.

Meningiomas Invading the Superior Sagittal Sinus: Surgical Experience in 108 Cases

OBJECTIVE:Radical resection of meningiomas invading the superior sagittal sinus (SSS) presents several hazards. Some surgeons consider SSS invasion a contraindication for complete resection, and others advocate total resection with venous reconstruction. There is a lack of published large series to provide definitive guidelines for the surgical treatment of these complex cases. We report our 15-year experience with surgery of parasagittal meningiomas invading the SSS. METHODS:Between 1986 and 2001, 108 patients (73 women, 35 men; age range, 22–83 yr; mean age, 56.2 yr) underwent surgery at the Neurological Institute “C. Besta” of Milan for tumors invading the SSS. Parasagittal meningiomas not invading the SSS were excluded from this series. RESULTS:Simpson Grade I to II removal was achieved in 100 patients. Thirty patients with meningiomas totally occluding the SSS had complete resection of the encased portion of the sinus. Histological examination revealed 86 benign (79.6%), 16 atypical (14.8%), and 4 malignant (3.7%) meningiomas along with 2 hemangiopericytomas. There were two perioperative deaths. Serious complications included brain swelling (nine patients; 8.3%) and postoperative hematoma (two patients; 1.85%). Follow-up ranged from 19 to 223 months (mean, 79.5 mo). One patient was lost to follow-up. Tumors recurred in 15 patients (13.9%). After multivariate analysis, histological type, tumor size, and Simpson grade were confirmed as significant independent prognostic factors for recurrence. CONCLUSION:On the basis of our results, we conclude that if the sinus is partially invaded, it can be opened to obtain as complete a resection as possible and to attempt to preserve the patency of the sinus. If the sinus is obstructed, the portion of the sinus involved can be resected completely. In both situations, extreme care is vital to preservation of cortical veins, which may offer important collateral drainage. With our approach, good results are achieved and it is not necessary to reconstruct the sinus.

Clinical course and pathologic findings after Gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management.

Randomized trials have demonstrated Gliadel® improves survival for appropriately selected patients with newly diagnosed malignant glioma. As only limited information is available to guide the management of patients who have Gliadel® controlled-release BCNU wafers implanted in the cranial resection cavity prior to radiotherapy (RT), this retrospective review was conducted to describe clinical course, toxicity, and pathologic findings after this therapy for newly diagnosed malignant glioma. Forty-six consecutive patients receiving Gliadel® (3.8% BCNU impregnated wafers) followed by radiotherapy for newly diagnosed malignant glioma at Johns Hopkins Hospital from 1990 to August 1999 were identified, although one was lost to follow up and is excluded. Patients were evaluated for postoperative infection, pathology at reoperation, and survival. Twenty-eight patients received radiotherapy at Johns Hopkins and these patients are also evaluable for toxicity experienced during and one month after completion of RT. The median age of all patients is 57 years. Eighty-nine percent had glioblastoma, and median follow-up of surviving glioblastoma patients is 16.8 (12–20) months. Postoperative infection or need for reoperation within 30 days was uncommon after Gliadel® placement. Full-dose radiotherapy was tolerable after Gliadel® implantation. Five patients (19%) developed neurologic symptoms during radiotherapy responding to increased steroids and/or anticonvulsants, whereas an additional 8 of 27 (30%) developed neurologic symptoms during dexamethasone taper that responded to increases in dexamethasone dose. At one month after RT, 58% of patients were still on dexamethasone despite attempted taper. Fifteen of 45 patients, 33% underwent reoperation or biopsy for a new local contrast-enhancing lesion. In five of 15 (33%) the reoperation revealed necrosis or treatment effect without active tumor. Two of five patients with treatment/effect necrosis had a third surgery 2.9 and 3.2 months after the initial reoperation, and treatment effect/necrosis without tumor was demonstrated in both cases. The Kaplan–Meier median survival for all the glioblastoma patients is 12.8 (95% CI 9.6, 15.9) months. For glioblastoma patients under 55 years old, median survival is 15.9 (95% CI 13.5, too few events) months whereas for older patients it is 9.6 (7.7, 14.4) months. We conclude that Gliadel® followed by full-dose standard radiotherapy is acutely well tolerated, although, close supervision should be emphasized during dexamethasone taper. Median survival in excess of one year suggests that there are not complications that result in overall premature death. The finding of necrosis/treatment effect was noted in five of 45 (11%) of all patients and five of 15 (33%) of those undergoing reoperation. Therefore, the possibility of necrosis/treatment effect should be considered for each patient with radiographic findings suspicious for local recurrence.

Maximizing the potential of minimally invasive spine surgery in complex spinal disorders.

Minimally invasive surgery (MIS) in the spine was primarily developed to reduce approach-related morbidity and to improve clinical outcomes compared with those following conventional open spine surgery. Over the past several years, minimally invasive spinal procedures have gained recognition and their utilization has increased. In particular, MIS is now routinely used in the treatment of degenerative spine disorders and has been shown to be as effective as conventional open spine surgeries. Although the procedures are not yet widely recognized in the context of complex spine surgery, the true potential in minimizing approach-related morbidity is far greater in the treatment of complex spinal diseases such as spinal trauma, spinal deformities, and spinal oncology. Conventional open spine surgeries for complex spinal disorders are often associated with significant soft tissue disruption, blood loss, prolonged recovery time, and postsurgical pain. In this article the authors review numerous cases of complex spine disorders managed with MIS techniques and discuss the current and future implications of these approaches for complex spinal pathologies.

Combination of intracranial temozolomide with intracranial carmustine improves survival when compared with either treatment alone in a rodent glioma model.

BACKGROUNDLocal delivery of temozolomide (TMZ) through polymers is superior to oral administration in a rodent glioma model. OBJECTIVEWe hypothesized that the observed clinical synergy of orally administered TMZ and carmustine (BCNU) wafers would translate into even greater effectiveness with the local delivery of BCNU and TMZ and the addition of radiotherapy in animal models of malignant glioma. METHODSTMZ and BCNU were incorporated into biodegradable polymers that were implanted in F344 rats bearing established intracranial tumors. We used 2 different rodent glioma models: the 9L gliosarcoma and the F98 glioma. RESULTSIn the 9L rodent glioma model, groups treated with the combination of local TMZ, local BCNU, and radiation therapy (XRT) had 75% long-term survivors (defined as animals alive 120 days after tumor implantation), which was superior to the combination of local TMZ and local BCNU (median survival, 95 days; long-term survival, 25%) and the combination of oral TMZ, local BCNU, and XRT (median survival, 62 days; long-term survival, 12.5%). To simulate the effect of this treatment in chemoresistant gliomas, a second rodent model was used with the F98 glioma, a cell line relatively resistant to alkylating agents. F98 glioma cells express high levels of alkyltransferase, an enzyme that deactivates alkylating agents and is the major mechanism of resistance of gliomas. The triple therapy showed a significant improvement in survival when compared with controls (P = .0004), BCNU (P = .0043), oral TMZ (P = .0026), local TMZ (P = .0105), and the combinations of either BCNU and XRT (P = .0378) or oral TMZ and BCNU (P = .0154). CONCLUSIONThe survival of tumor-bearing animals in the 9L and F98 glioma models was improved with the local delivery of BCNU and TMZ combined with XRT when compared with either treatment alone or oral TMZ, local BCNU, and XRT.

A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats: Laboratory investigation

OBJECT Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma. METHODS Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5. RESULTS Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point. CONCLUSIONS OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.

Posterior-only approach for total en bloc spondylectomy for malignant primary spinal neoplasms: Anatomic considerations and operative nuances

MALIGNANT PRIMARY SPINAL tumors are rare tumors that are locally invasive and can metastasize. The majority of these tumors have a poor response rate to chemotherapy and conventional radiotherapy. Studies have shown that long-term survival and the potential for cure is best achieved with en bloc surgical excision of these tumors with negative surgical margins. Total en bloc spondylectomy involves removal of vertebral segment(s) in whole to achieve wide tumor excision. Total en bloc spondylectomy can be performed through staged or combined anterior and posterior approaches, or from a posterior-only approach. The posterior-only approach offers the advantage of achieving complete tumor excision and circumferential spinal reconstruction in a single setting. In this report, we discuss the operative management of malignant primary vertebral tumors using the posterior-only approach for total en bloc spondylectomy. The oncological considerations and surgical nuances that allow for safe but aggressive surgical excision of primary spinal tumors to achieve favorable oncological and neurological outcomes are highlighted.

Superficial siderosis associated with multiple cavernous malformations: Report of three cases

OBJECTIVE AND IMPORTANCE Superficial siderosis is a rare but potentially devastating syndrome caused by recurrent subarachnoid hemorrhage. We present three cases of superficial siderosis associated with multiple cavernous malformations, and we review previous reports of superficial siderosis attributable to vascular malformations. CLINICAL PRESENTATION Patients most commonly present with progressive sensorineural hearing loss, cerebellar ataxia, and pyramidal signs. Magnetic resonance imaging diagnosis may precede symptom development, however. In two of our cases, superficial siderosis was identified on magnetic resonance imaging scans in the absence of clinical symptoms. INTERVENTION Magnetic resonance imaging studies revealed hemosiderin deposition, characteristic of superficial siderosis, and multiple cavernous malformations in all three cases. Surgical intervention was not pursued. CONCLUSION We conclude that patients with multiple cavernous malformations and those with perisubarachnoid lesions are at risk for the development of superficial siderosis. Clinicians should recognize the radiographic appearance of superficial siderosis and its clinical presentation in patients with vascular malformations.

Minimally invasive circumferential spinal decompression and stabilization for symptomatic metastatic spine tumor: Technical case report

OBJECTIVEMetastatic epidural spinal cord compression is a potentially devastating complication of cancer and is estimated to occur in 5% to 14% of all cancer patients. It is best treated surgically. Minimally invasive spine surgery has the potential benefits of decreased surgical approach–related morbidity, blood loss, hospital stay, and time to mobilization. CLINICAL PRESENTATIONA 36-year-old man presented with worsening back pain and lower extremity weakness. Workup revealed metastatic adenocarcinoma of the lung with spinal cord compression at T4 and T5. INTERVENTION AND TECHNIQUET4 and T5 vertebrectomy with expandable cage placement and T1–T8 pedicle screw fixation and fusion were performed using minimally invasive surgical techniques. RESULTThe patient improved neurologically and was ambulatory on postoperative day 1. At the 9-month follow-up point, he remained neurologically intact and pain free, and there was no evidence of hardware failure. CONCLUSIONMinimally invasive surgical circumferential decompression may be a viable option for the treatment of metastatic epidural spinal cord compression.

L-buthionine sulfoximine potentiates the antitumor effect of 4-hydroperoxycyclophosphamide when administered locally in a rat glioma model

OBJECTIVEl-buthionine sulfoximine (BSO) inhibits glutathione synthesis and may modulate tumor resistance to some alkylating agents, but it has not been proven effective in the treatment of intracranial neoplasms. To evaluate this drug for the treatment of brain tumors, we studied the use of BSO for potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model. METHODSThe survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, BSO, 4-HC, or both BSO and 4-HC. The efficacy of intracranial 4-HC treatment was assessed with and without serial systemic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO. RESULTSThe median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO therapy did not improve survival time. In animals that were treated systemically, both liver and tumor glutathione levels were significantly lower than they were in control animals. In the locally treated animals, glutathione levels were reduced in the brain tumor but not in the liver. CONCLUSIONThese results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma model. In addition, because local delivery of BSO within the brain did not deplete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.