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 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.

Hodgkin's disease: evaluation of staging procedures for abdominal involvement.

Results of preoperative assessment procedures and subsequent staging laparotomy are evaluated in 32 consecutive patients who presented with extra-abdominal Hodgkin's disease which was not already known to be in an advanced stage. Disease was found in the abdominal cavity of 10 of the 27 patients who presented with disease above the diaphragm, and of two of the five patients in whom disease presented in the inguinal nodes. In patients who initially presented with disease above the diaphragm, the spleen was involved in all 10 cases where abdominal disease was detected. Lymphography was not found to be reliable as a diagnostic aid in doubtful cases. Neither liver nor spleen scans were found to be helpful in assessment of these patients.