C-STIM: Protocol for a randomized, single-blind, crossover study of cerebellar repetitive transcranial magnetic stimulation (rTMS) for postural instability in people with progressive supranuclear palsy (PSP).

Background: Methods for modulating the cerebellum with transcranial magnetic stimulation (TMS) are well established, and preliminary data from our group and others has shown evidence of transient improvements in balance after cerebellar repetitive transcranial magnetic stimulation (rTMS) in progressive suprancuclear palsy (PSP). This study examines extensive posturography measures before and after 10 sessions of cerebellar rTMS and sham TMS in PSP. Methods: Thirty subjects with PSP and postural instability will undergo cerebellar active and sham rTMS in a single-blind, crossover design with a randomized order of a 10-day intervention. Primary outcomes will be changes in sway area and medio-lateral range of sway with eyes open while standing on a stationary force-plate, and safety, tolerability, and blindedness. Secondary outcomes will include posturography and gait analysis with body-worn, triaxial inertial sensors, clinical balance scales and questionnaires, and a bedside test of vestibular function. Exploratory outcomes are changes in functional near infrared spectroscopy (fNIRS) signal over the prefrontal, supplementary motor, and primary motor cortices while standing and walking, and speech samples for future analysis. Discussion: The C-STIM crossover intervention study adds a longer duration of stimulation and extensive posturography measures to more finely measure the improvements in balance and exploratory functional near-infrared spectroscopy (fNIRS) over the prefronal, supplementary motor, and primary motor cortices during balance assessments before and after 10 sessions of cerebellar rTMS and 10 sessions of sham cerebellar TMS. This project will improve our understanding of the importance of the cerebellum for control of postural stability in PSP.

Proposal for classifying the acute emetogenicity of cancer chemotherapy.

PURPOSE: To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens. METHODS: A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials. RESULTS: Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. CONCLUSION: The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

A report on the comparative response of sheep epidermal squamous-cell carcinoma to intraarterial versus intravenous Cisplatin infusion.

There is an apparent lack of randomised clinical trials demonstrating a therapeutic advantage for intra-arterial, versus systemic, cisplatin administration as cancer treatment. A spontaneous, head and neck epidermal squamous cell carcinoma in sheep was used to compare intra-arterial and equivalent dose intravenous cisplatin infusion. The objective response rate for intra-arterially infused lesions was 73%, with a mean tumour regression for all carcinomas of 70% +/- 6 (sem). In comparison, 27% of intravenously treated carcinomas showed an objective response, the mean volume reduction being 42% +/- 6 (sem). Statistical comparison of the number of objective response lesions was significantly in favour of intra-arterial cisplatin therapy (p<0.05), as was the difference in the mean tumour response for both groups (p<0.005). The experimental data suggest that further study of the clinical application of intra-arterial induction cisplatin therapy is warranted.

Comparison of intra-arterial versus intravenous 5-fluorouracil administration on epidermal squamous cell carcinoma in sheep.

Clinical evidence that intra-arterial chemotherapy is more effective in regressing head and neck cancers than equivalent intravenous doses is lacking. Intra-arterial versus intravenous 5-fluorouracil infusion was compared in a naturally occurring, auricular epidermal squamous cell cancer in sheep. Of 18 lesions infused intra-arterially and of 18 infused intravenously with the same dose, 39 and 11%, respectively responded objectively (over 50% regression); mean (S.E.) tumour volume reduction was 37(23) and 18(22)%, respectively. There was a statistically significant difference in the mean tumour response and in numbers of tumours regressing by at least 40% of tumour volume (50% of intra-arterial treated tumours compared with 11% of intravenous treated lesions) after the 16 day total infusion time in favour of intra-arterial treatment. Technically, the intra-arterial route in this model was an improvement on previous small animal models. These findings lend support to the need for continuing clinical study of intra-arterial infusion.

A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy.

Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin as well as other chemotherapeutic agents. In this randomized, single-blind, multicenter, parallel group study, we compared the efficacy and safety of intravenous (IV) ondansetron with IV metoclopramide in the prevention of nausea and vomiting associated with high-dose (greater than or equal to 100 mg/m2) cisplatin chemotherapy. Three hundred seven patients receiving their first dose of cisplatin, either alone or in combination with other antineoplastic agents, were randomized to receive ondansetron 0.15 mg/kg IV every 4 hours for three doses or metoclopramide 2 mg/kg IV every 2 hours for three doses, then every 3 hours for three additional doses. The study prohibited the concurrent administration of other antiemetics or dexamethasone. Patients receiving ondansetron had a higher rate of complete protection from emesis (40% v 30%, P = .07), a higher complete plus major response rate (65% v 51%, P = .016), a lower rate of failure (21% v 36%, P = .007), and a lower median number of emetic episodes (one v two, P = .005) than did those receiving metoclopramide. The median time to the first emetic episode was longer on ondansetron (20.5 v 4.3 hours, P less than .001). Adverse events occurred in 48% of patients receiving ondansetron and 69% of those receiving metoclopramide (P less than .001). Akathisia and acute dystonic reactions occurred only on metoclopramide; headache (controlled with acetaminophen) was significantly more frequent with ondansetron. Ondansetron is more effective, produces fewer adverse events, and is easier to administer than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy.

Thermochemotherapy in inoperable head and neck cancer.

A combined hyperthermia and chemotherapy approach was used to treat five patients with locally advanced or recurrent squamous cell carcinoma of the head and neck whose tumors had failed to respond to chemotherapy. In two patients, tumor had recurred after initial combined modality therapy (surgery/radiation) and had failed to respond to one course of cisplatin/5-fluorouracil (cisplatin/5-FU) chemotherapy. The three remaining patients were enrolled onto a phase II evaluation of induction chemotherapy with cisplatin/fluorouracil for advanced head and neck carcinomas and had failed to achieve a partial remission after one treatment cycle. Palpable cervical tumors were heated to 40 degrees to 42 degrees C for 30 to 40 minutes, during which time cisplatin (100 mg/m2) was infused intravenously. A 5-day infusion of 5-fluorouracil (1000 mg/m2/d) followed. Despite less than a partial response to previous cisplatin/fluorouracil chemotherapy alone, two patients had complete clinical resolution of the heated tumor volume with two cycles of the combined thermochemotherapy approach. One patient achieved a partial remission with this approach. The remaining two patients died shortly after the initial thermochemotherapy treatment, as a result of progressive tumor growth. The two complete responders were subsequently treated with radiation (1 patient) and radical neck dissection (1 patient) and remained without evidence of disease 2 and 26 months after the completion of therapy, respectively. The toxicity of this combined modality approach was acceptable and appeared to be no greater than had been experienced during earlier treatment with chemotherapy alone. Further studies using a combination of these treatment modalities for locally advanced head and neck carcinomas are warranted.

Prognostic indicators in head and neck cancer patients receiving combined therapy.

In 1983 we initiated a prospective nonrandomized study of the value of preoperative chemotherapy in previously untreated patients with stages III and IV squamous cell carcinoma of the head and neck. In 1983 and 1984, 50 patients were entered in the study. Prior to therapy all patients were evaluated by a representative from the Medical Oncology, Radiation Therapy, and Head and Neck Surgery Divisions, University of Utah School of Medicine, Salt Lake City. In addition to the standard preoperative evaluation, pretreatment computed tomographic scans were performed on all patients. Follow-up computed tomographic scans were performed after the second cycle of chemotherapy and at the completion of treatment. Initial therapy in all patients consisted of induction chemotherapy with cisplatin (day 1, 100 mg/m2) and fluorouracil (days 1 through 5, 1000 mg/m2). Several factors were examined for their utility in predicting response to therapy and survival. Factors evaluated included: (1) extent and timing of chemotherapeutic response; (2) computed tomographic quantitated primary tumor size; (3) size of computed tomographic quantitated regional (neck) metastases; (4) performance status; (5) cancer stage; (6) total lymphocyte count; and (7) serum liver function tests. The factor found to be most useful in predicting improved survival was the extent of response to chemotherapy. The remaining factors, performance status, regional lymph node status, serum gamma-glutamyltransferase levels, and cancer stage, were also found to correlate with length of survival but were much less important than the response to chemotherapy.

Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: a Southwest Oncology Group Study.

The Southwest Oncology Group performed a study for patients with extensive small cell lung cancer in which two hypotheses were tested: that combined alkylating agents for induction might improve the initial response rate; and that multiple-site, involved-field consolidation with irradiation in patients with response to chemotherapy might further improve response quality and duration. A regimen of combined alkylating agents plus vincristine [carmustine, thiotepa, vincristine, and cyclophosphamide (BTOC)] was compared to our standard program of cyclophosphamide, doxorubicin, and vincristine (CAV). Patients with bone marrow metastases and/or disseminated bone metastases were randomized to BTOC or CAV as initial induction therapy, but received no multiple-field irradiation afterward. Among 189 such patients, the overall response rates were similar (48% to BTOC and 61% to CAV, with complete remission in 5% and 15%, respectively). Toxic effects were also comparative, with 23% sustaining life-threatening or fatal complications on BTOC and 16% on CAV. Median survival (5.9 and 7 months for BTOC and CAV, respectively) and overall survival were not different, and are superimposable upon our previously reported results with CAV alone. For patients with no evidence of bone marrow involvement and no metastases identified beyond the confines of ipsilateral hemithorax, liver, and brain, the plan of therapy consisted of induction chemotherapy (BTOC or CAV) every 3 weeks for three cycles, followed by multiple-field irradiation consolidation to sites of prior involvement. Among 239 such patients, response rates to therapy initiated with BTOC and CAV were also similar: 54% for BTOC and 62% for CAV, with complete response in 16% and 13%, respectively. However, the program of BTOC followed by multiple-site irradiation was associated with a higher incidence of severe or life-threatening thrombocytopenia (23% versus 8% for CAV), accounted for almost entirely by patients receiving hepatic irradiation after chemotherapy, among whom the incidence of this complication (grade 3 or 4) was 76% and 14%, respectively. Other toxic effects, including granulocytopenia, were comparable. With the exception of thrombocytopenia in the cited subgroup, multiple-field irradiation consolidation proved feasible and tolerable, with improved quality of response evident after its initiation in 24% of 135 patients. However, a similar proportion developed disease progression during or shortly after radiation therapy, and the median survival of patients who received irradiation was only 9 months (7 months from the start of consolidation).(ABSTRACT TRUNCATED AT 400 WORDS)

A preliminary report on the suitability of sheep epidermal squamous cell carcinoma as a solid tumor model in the evaluation of intra-arterial methotrexate administration.

A preliminary study was undertaken to assess the sensitivity of sheep epidermal squamous cell carcinoma, in the head and neck region, to intra-arterial (IA) methotrexate (MTX) infusion. There was an objective tumor response (40-56% regression) in all three IA-infused sheep, whereas tumor progression was observed in all three animals treated intravenously (IV). Regional and systemic side effects were negligible in all cases. Technically, IA drug infusion in the sheep was an improvement on previous small animal models, with no problems related to arterial catheter insertion, blockage, or dislodgement, and tolerable infusion times being of markedly longer duration. The histological differentiation of moderately differentiated stage II lesions improved during therapy irrespective of clinical response, whilst the histology of well-differentiated stage III and IV tumors remained unchanged. Tumor cell cycle stage and ploidy characteristics, as determined by flow cytometric DNA analysis, were little affected by either mode of drug administration. It is concluded that sheep epidermal carcinoma is responsive to IA MTX, and that this animal model is the most appropriate yet utilised to study the comparative effects of IA and IV chemotherapy in the head and neck region.

Ploidy and proliferative characteristics of sheep epidermal squamous cell carcinoma determined by flow cytometric DNA analysis.

Multiple biopsies from each of 22 primary sheep epidermal squamous cell carcinomas were analysed by flow cytometry to determine the G0/G1 modal DNA content ("ploidy") and cell cycle characteristics within each tumour. Ten of 12 tumours where aneuploidy was present demonstrated uniform intra-tumour aneuploid populations regardless of the site of biopsy. Increasing tumour volume (from stage I/II to stage III/IV lesions) was associated with increased histological variability and ultimate heterogeneity of G0/G1 DNA content, whilst the mean numbers of S phase cells decreased. These features were consistent with the effects of variable tissue hypoxia seen with changes in effective vascularity in developing tumours. Decreasing histological differentiation was associated with an increase in numbers of cells synthesising DNA within 44 biopsies with measurable S phase, and, in stage I/II biopsies, correlated with an increased incidence of aneuploidy.

Cell cycle homogeneity in bone marrow samples from different sites: flow cytometric evaluation of multiple samples from sheep.

The distributions of cells in each of the phases of the cell cycle, determined by flow cytometry (FCM), were compared in multiple marrow trephine biopsy samples from 3 sites (both iliac bones and sternum) in 5 sheep. Within any one animal no significant differences could be found between the proportions of cells in the G0/G1, S or G2 + M phases of the cycle from different sites. Differences between animals were detected and these were consistent for any of the sites sampled. We conclude that the proliferative characteristics of marrow cells as determined by FCM in any one animal at one time are comparable at anatomically distinct marrow sites, and that a sample from one site is representative of the whole.

Treatment of advanced cancer of the lower lip--the use of intraarterial or intravenous chemotherapy as basal treatment.

Since the linear accelerator was installed in Sydney Hospital in 1964, 27 patients who presented with previously untreated but advanced deep carcinoma of the lower lip have been treated with initial megavoltage or orthovoltage radiotherapy with or without follow-up surgery. In 17 of these, the tumor appears to have been eradicated, but in the other ten (approximately one-third), the tumor was not controlled. These results are similar to those reported from other major centers. Since January, 1974, six patients with the most advanced lesions have been treated with "basal" chemotherapy (in four cases given intra-arterially and in two cases given intravenously) prior to radiotherapy. Follow-up surgery in the form of block dissection was required in one patient, and wedge resection of a residual focus of tumor was required in a second patient, but all six patients remain well and free of disease, with from three to six years follow-up to date. A further seven patients with advanced recurrent lesions were also treated using "basal" chemotherapy as the initial treatment. In three of these the carcinoma remained uncontrolled, but in four the tumor appears to have been controlled with subsequent follow-up radiotherapy being used in two cases, surgery in a third, and intermittent chemotherapy in the fourth. The numbers of patients treated in this series are insufficient to allow conclusions to be drawn concerning present management methods. However, the trend of the results to date suggests that for advanced lesions, improved survival may well result from the combination of basal chemotherapy with subsequent radiotherapy and/or surgery.

Intra-arterial infusion chemotherapy in the treatment of advanced squamous carcinoma of the tongue and floor of the mouth.

Our present experience with Stage III disease suggests that the most effective means of treating advanced carcinoma of the floor of the mouth and tongue are with initial chemotherapy given as basal treatment by intra-arterial infusion followed by planned radiotherapy or operation, or both. Early carcinoma of the floor of the mouth and tongue can be managed effectively with conventional techniques using surgical treatment or radiotherapy, or both, and probably does not justify the increased time and increased problems of management involved in the use of chemotherapy regimens. Our experience in comparing the two programs of treatment in patients classified as having Stage IV lesions is too small to justify valid comparisons to be made at this stage, although we currently have under investigation similar management programs for these patients.

The intraarterial infusion of chemotherapeutic agents as "basal" treatment of cancer: evidence of increased drug activity in regionally infused tissues.

There is evidence from a number of centres that some forms of locally advanced and aggressive cancers which are difficult to eradicate by standard means can be reduced by the use of "basal" chemotherapy and/or surgery. Clinicians have been divided as to whether there is an advantage in giving the chemotherapeutic agents directly into a regional artery of supply where this is feasible, as opposed to their systemic administration. This paper documents supportive evidence that some and possibly many chemotherapeutic agents are more effective if given regionally into an artery of supply. There is a higher incidence of local side-effects in the region infused, including loss of hair, inflammatory changes, and ulceration of the skin or mucosa of the region infused. After intraarterial infusion of tagged bleomycin (indium-III bleomycin) into a limb, the radioactive isotope remained more concentrated in the limb infused than in the opposite limb for at least 24 hours. Systemic side-effects, including bone-marrow depression, are less frequent and less severe in patients given chemotherapeutic agents by intra-arterial infusion than if the same doses of agents are given intravenously. There is now sufficient evidence of the value of basal chemotherapy used in this way to make it mandatory that medical oncologists and surgeons, working together, should plan controlled studies to determine the most appropriate applications of this technique of management.

Intra-arterial chemotherapy as basal treatment in advanced and fungating primary breast cancer.

Occasionally patients present with stage III breast carcinoma so advanced that local radiotherapy is unlikely to achieve more than a partial and temporary local regression. 3 such patients with grossly advanced cancer involving virtually the whole of the breast, skin, and underlying muscle were treated with a regimen of intra-arterial infusion chemotherapy as basal treatment before planned irradiation. All 3 patients responded significantly to intra-arterial chemotherapy and subsequent definitive radiotherapy seems to have resulted in total regression of tumour and involved nodes in 2 patients. In the 3rd patient the response of the tumour mass to subsequent radiotherapy was considerable but incomplete; subsequent surgical resection seems to have eradicated the small foci of residual disease buried in fibrous tissue in the breast and one axillary node. All patients were given routine adjuvant chemotherapy after completion of irradiation. A 4th patient with a huge fungating breast carcinoma which was bleeding and foul-smelling who also had evidence of liver metastasis (stage IV disease) was treated in a similar manner. Local tumour regression was achieved and although the patient still requires treatment for metastatic disease there is no evidence of residual carcinoma in the breast or axilla 12 months after treatment. Further investigation of this treatment seems worthwhile, since it may be effective not only in the management of large breast cancers but also in patients with less advanced disease who refuse mastectomy or wish to avoid it.

Intraarterial infusion chemotherapy in salvage of limbs involved with advanced neoplasms.

Partial or complete limb salvage has been achieved in seven patients by the use of basal intraarterial infusion chemotherapy. All had either refused amputation or had been considered unsuitable for it. Results in all cases showed marked tumour regression to a size where local measures were then successful in controlling the disease. Six of the patients are alive and well with no sign of recurrence at periods ranging from four months to six years.

Preoperative basal chemotherapy in the management of cancer of the stomach: a preliminary report.

Nine patients with advanced gastric carcinoma have been treated with a programme of chemotherapy as the first stage of management with the objective of reducing tumour extent and viability in preparation for subsequent surgery where feasible. In eight patients the chemotherapy was given by intraarterial infusion into the coeliac axis, and the remaining patient was given intravenous chemotherapy. Most patients gained symptomatic improvement, including pain relief, and in seven patients tumour regression was achieved. In six patients tumour regression was followed by gastrectomy. Residual tumour was found in five of these six patients, and was not found in one.