Shear fracture through the body of the axis vertebra.

STUDY DESIGN: Three cases of a previously undescribed body fracture of the axis vertebra are presented. OBJECTIVES: To describe the radiographic features of the fracture are described, and to point out the differences to other axis body fractures regarding the mechanism of injury, stability, and treatment. SUMMARY OF BACKGROUND DATA: Fractures involving the odontoid process usually are caused by indirect forces, and they are considered unstable injuries. Anderson and D'Alonzo Type III odontoid fractures usually are hyperflexion injuries. Superior articular process fractures with or without associated odontoid peg fractures are caused by lateral hyperflexion injuries. METHODS: Three cases of body fractures of the axis vertebra are described. These fractures occur in an oblique plane shearing off in one piece the odontoid process together with one of the superior articular processes. The fragment displaces anterocaudally, and the odontoid process tilts toward the affected side. RESULTS: All fractures were managed nonsurgically. The two displaced fractures did not reduce in traction, and they had united in the displaced position after the 12 weeks of halo treatment. One patient reported only minor problems, but showed radiologic evidence of facet joint arthritis at 20 months. The second patient was lost to follow-up after discontinuation of halo treatment at 12 weeks. The only undisplaced fracture was managed in a halo body jacket for 10 weeks. The patient was pain free and had regained a full range of movement at 7 months. CONCLUSIONS: The presumed mechanism of injury in the described fracture is one of asymmetrical axial compression. The fracture can be managed safely in a halo jacket.

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229).

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.

Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study.

Deoxyspergualin (DSG) is an analog of the polyamine spergualin with preclinical evidence of activity in murine and human tumor models. This phase I study examined a 120 h continuous infusion schedule in 56 patients with refractory solid tumors at doses ranging from 80 to 2792 mg/m2/day. Dose-limiting toxicity was reversible hypotension and appeared to be associated with plasma levels of DSG > 4 micrograms/ml. Other dose-dependent effects noted were pruritus and circumoral paresthesias. Myelosuppression and gastrointestinal toxicities were mild and sporadic. Two patients with refractory head and neck cancer had minor responses. The recommended phase II dose on this schedule is 1800 mg/m2. Additional monitoring to identify immunologic properties included immunophenotyping of peripheral lymphocytes and cytotoxic activity by means of standard 51Cr-release assays. These studies revealed a non-dose-dependent increase in the number of cells expressing T cell antigens predominantly the T suppressor (CD8) phenotype posttreatment. In three patients, a mild increase in LAK activity was noted post-treatment without a consistent relationship to dose or change in cell surface antigens. Pharmacokinetic studies were completed on 26 patients ranging from doses of 80 to 2792 mg/m2. The average plasma concentration ranged from 0.07 to 7 micrograms/ml. DSG was rapidly cleared from the plasma with a mean terminal half-life of 1.9 h. Mean total body clearance was 25.24 l/h/m2. Further in vivo immunologic studies should be pursued while the agent is studied in fixed dosage phase II clinical trials.

Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer.

PURPOSE: We initiated a large multicenter phase II trial in stage IV non-small-cell lung cancer (NSCLC) to evaluate the activity and safety of an oral gelatin-based formation of vinorelbine. PATIENTS AND METHODS: Twenty-three centers participated in this uncontrolled phase II study, which accrued patients between August 1991 and March 1992. Eligible patients had previously untreated measurable or assessable stage IV NSCLC, age more than 18 years, and Karnofsky performance status > or = 70%. The treatment plan initially was to administer 100 mg/m2/wk of oral vinorelbine or 80 mg/m2/wk for patients who had received prior radiation therapy. After the observation of grade IV granulocytopenia in six of the first 25 patients, subsequent doses were reduced by 40 mg (one capsule) in all patients. RESULTS: One hundred sixty-two patients were treated: 138 with measurable and 24 with assessable disease. One hundred two patients were men and 60 women. The mean age was 62 years (range, 36 to 83). The overall response rate was 14.5% for patients with measurable disease (95% confidence interval, 9.3% to 21.7%). The median time to treatment failure (TTF) for all patients was 9 weeks. The median survival time was 29 weeks; the 1-year survival rate was 22%. Toxicities included grade 3 or 4 neutropenia in 40%, which was dependent on the vinorelbine dose. Other toxicities included mild to moderate nausea/vomiting, diarrhea, and stomatitis. The mean dose intensity of vinorelbine was 53 mg/m2. CONCLUSION: Oral vinorelbine administered once weekly is an active agent in stage IV NSCLC. The median survival time of 29 weeks is similar to that achieved with single-agent intravenous vinorelbine and more aggressive cisplatin-based combinations. Further studies of this compound in the palliative-intent care setting appear to be indicated.

Phase II trial of amonafide for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group study.

Amonafide (benzisoquinolinedione; NSC 308847) was subjected to a Phase II trial for the treatment of advanced hormone-refractory carcinoma of the prostate. In addition to adequate baseline organ functions, patients were required to have a favorable performance status, bidimensionally measurable disease and no prior chemotherapy. Amonafide was given at a dose of 225 mg/m2 intravenously daily for 5 days. Treatment cycles were repeated every 21 days. Dose escalation and reduction schema were used based upon toxicities from preceding cycles. Of 47 patients enrolled, 43 were evaluable. The most common toxicities were hematologic to include leukopenia (72%), granulocytopenia (32.6%), and thrombocytopenia (44.2%). There were no complete responses and only 5 partial responses for an overall response rate of 12% (95% confidence interval: 4-25%). The results indicate that Amonafide, in the dose and schedule tested, lacks sufficient activity against hormone-refractory prostate cancer to warrant further trials.

Phase I trial of sulofenur (LY186641) given orally on a daily x 21 schedule.

Sulofenur (LY186641), a diarylsulfonylurea, was evaluated clinically utilizing either a daily x 21 schedule or a daily x 5 (with 2 days off) for 3 weeks schedule. Eighteen patients with refractory solid tumors received 47 evaluable courses of sulofenur given p.o. daily x 21 every 28 days at five dose levels while 14 received 29 courses of sulofenur given daily x 5 for 3 weeks every 28 days at three dose levels. Toxicities included anemia, methemoglobinemia and hemolysis. One patient experienced a fatal subendocardial infarction on the daily x 21 schedule. One partial response was observed in a patient with a sertoli cell tumor on the daily x 5 for 3 weeks schedule. Daily x 5 for 3 weeks is the schedule recommended for phase II trials.

Phase II trial of amonafide in patients with advanced metastatic or recurrent endometrial adenocarcinoma. A Southwest Oncology Group study.

Amonafide, a benzisoquinoline-1,3-dione was administered to 38 patients with recurrent or metastatic, bidimensionally measurable endometrial cancer. There were 34 patients with no prior cytotoxic chemotherapy, performance status of 0-2, and normal bone marrow, renal, and hepatic function were eligible for response and toxicity evaluation. Amonafide, 300 mg/m2, was administered intravenously over 1 hour daily for 5 consecutive days. Courses were repeated every 21 days. The major grade 3 or 4 toxicities were hematologic with granulocytopenia in 18 patients (53%), thrombocytopenia in 6 patients (18%), and anemia in 8 patients (24%). Infectious complications occurred in 3 patients (9%). Other side effects included cardiac dysrhythmias, hypotension, pain and phlebitis at the site of injection, nausea, vomiting, and flu-like symptoms. The overall objective response rate was 6% (95% confidence interval of 1-20%); 2 patients had a complete response (6%), 9 patients had stable disease (26%) and 21 patients had progressive disease (62%). Two patients had insufficient follow-up for response determination and are assumed to be nonresponders. The median survival of the eligible patients was 8 months. With the toxicity observed and the low response rate, amonafide at this dose and schedule has no efficacy in the treatment of endometrial cancer.

Evaluation of amonafide in disseminated malignant melanoma. A Southwest Oncology Group study.

Amonafide (AMF), NSC 308847 is an investigational anticancer drug acting as a DNA intercalating agent. This paper presents results of a phase II clinical study of AMF in disseminated malignant melanoma. Twenty patients, eleven males and nine females, with biopsy proven malignant melanoma, performance status 0-2; median age 59 (range 29-74), and no previous chemotherapy, were treated with AMF 300 mg/m2/day by 60 min i.v. infusion for five days repeated every three weeks. Fifteen patients had lung (9 patients) and/or liver (8 patients) involvement. None had known brain metastasis at entry. All 20 patients were evaluated for response and toxicity. Six patients had stable disease and fourteen had increasing disease. With 0/20 responses, the upper 95% confidence limit for the response rate was 14%. The median survival time was 5.7 months. Hematologic toxicity was dose limiting with the incidence of leucopenia 45% and thrombocytopenia 20%. The nonhematologic toxicities included nausea and vomiting (60%), alopecia (20%), headaches (15%), diarrhea (10%), and phlebitis (10%). We conclude that AMF administered at this dose and schedule is not active in the treatment of patients with malignant melanoma, previously untreated with chemotherapy.

A phase I trial of trimetrexate (NSC352122) on a daily x 5 schedule in patients with refractory adult leukemia.

Seven adult patients with refractory acute leukemia were administered trimetrexate (TMTX), a non-classical folate antagonist, in a phase I trial. TMTX was administered as an intravenous bolus for five consecutive days at doses of 9-12 mg/m2 based on marrow response. The maximum tolerated dose was 12 mg/m2. Hepatotoxicity was the dose-limiting toxicity. Initial dosage reductions in patients with liver disease and/or low protein concentrations may be necessary since TMTX is significantly protein bound and cleared primarily by hepatic metabolism. The recommended phase II dose on this dosing schedule is 9 mg/m2.

Phase II trial of amonafide in advanced colorectal cancer: a SouthWest Oncology Group study.

Amonafide is a substituted benzisoquinolinedione that exerts its cytotoxicity through effects on macromolecular synthesis and intercalation of DNA. In this trial, 44 patients with advanced colorectal cancer and without prior chemotherapy received amonafide at a starting dose of 300 mg/m2 intravenously over one hour, on a daily x 5 schedule every 3 weeks. Toxicities of grade 3 or above included granulocytopenia, thrombocytopenia, sepsis, anaphylaxis and transient aphasia. Forty-seven % of patients had grade 3 or higher toxicity of any type. There were no complete or partial responses for an overall response rate of 0%, with a 95% confidence interval of 0-9%. The level of toxicity observed on this trial suggests an appropriate dose intensity of amonafide, despite lack of knowledge of patients' acetylator phenotypes.

Neurofibromatosis of the cervical spine. A report of eight cases.

Eight patients with neurofibromatosis presented with symptoms of cervical spine involvement over a period of 17 years, five of them within the second decade of life. The symptoms included neurological deficit in five, a neck mass in four, and deformity in three; only two complained of pain. Osteolysis of vertebral bodies with kyphosis of more than 90 degrees was the most common radiological feature. Posterior fusion failed in the one patient in whom it was performed. Good results were achieved by anterior fusion, alone, or combined with posterior fusion. Surgical complications included one death in a patient with a malignant neurofibroma, and one case of transient neurological deterioration.

Evaluation of amonafide in cervical cancer, phase II. A SWOG study.

The Southwest Oncology Group conducted a Phase II study of amonafide in patients with metastatic or recurrent squamous cell cervical cancer. Twelve of the 15 patients were fully evaluable for response and toxicity. There were no clinical responses seen; 2 patients had stable disease while 13 had progressive disease. The major complication of this therapy was myelosuppression. Four patients had life-threatening granulocytopenia (less than 500/microliters), 3 patients had life-threatening leukopenia (less than 1000/microliters), while 2 patients had life-threatening thrombocytopenia (less than 25,000/microliters). Amonafide has significant toxicity but appears to be an inactive drug in metastatic or recurrent squamous cell cancer of the cervix.

Phase II evaluation of amonafide in renal cell carcinoma. A Southwest Oncology Group study.

Twenty four patients with advanced renal cell carcinoma were treated in a phase II trial with amonafide 300-450 mg/m2/day on days 1-5 every 21 days. There were no responders, 6 patients had stable disease, 14 experienced progressive disease and 4 were assumed to be non-responders as no evaluation was performed. There were no fatal toxicities although 8 patients had grade 3 or 4 granulocytopenia, 1 patient had grade 4 thrombocytopenia. Other toxicities included grade 3 diarrhea in 1 patient, grade 3 myopathy in 1 patient, severe nausea and vomiting in 1 patient and a facial rash, possibly a hypersensitivity reaction, in 1 patient. The median survival is 7.5 months. At this dosage and schedule, there is no evidence that amonafide has meaningful anti-tumor activity in patients with advanced renal cell carcinoma.

Superior facet fractures of the axis vertebra.

Nine cases of superior facet fractures of the axis vertebra are reported. In seven cases, there were associated odontoid fractures. These fractures can occur in a coronal or sagittal direction, shearing off the anterior or lateral plateau of the facet. In addition, the lateral mass of the atlas may sublux into the depressed facet fracture. The fracture complex should be well documented with conventional radiography and tomography. Computerized tomographic scanning has been found to be particularly helpful in diagnosing these fractures and other injuries about the axis or atlas. Patients with undisplaced or well-reduced facet fractures can be managed satisfactorily by conservative means, but surgery (posterior atlantoaxial fusion) should be considered for unreduced fractures in order to prevent long-term instability, nonunion, malunion, and degenerative arthritis.

Posterior atlantoaxial arthrodesis. A simplified method.

A simplified method of posterior atlantoaxial arthrodesis allowing immediate stabilization and mobilization is described. This method of fixation has been used since 1984 in 33 cases, with the indications being nonunion of odontoid peg fractures, atlantoaxial dislocation, and other traumatic conditions about the axis. A solid fusion was noted in all 33 patients by 3 months postsurgery, and the complication rate was minimal. This method of atlantoaxial arthrodesis is simple, allows immediate mobilization, controls rotation and lateral bending, and is inexpensive.

Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.

The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.

Phase I clinical and pharmacokinetic trial of flavone acetic acid.

Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2, the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2, the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.

Phase I evaluation of crisnatol (BWA770U mesylate) on a monthly extended infusion schedule.

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.