Preoperative intra-arterial infusion chemotherapy in locally advanced primary breast cancer-tissue concentrations of 5-fluorouracil and adriamycin, and the histological evaluation

The effect of preoperative intra-arterial infusion of mitomycin C, 5-fluorouracil (5-FU) and adriamycin (ADM) were studied in seven patients with locally advanced breast cancer, including five inflammatory carcinomas, and a patient with stromal sarcoma of the breast. Reducing rate of the primary tumor of more than 30% was observed in all cases, and remarkable degenerative changes of tumor cells were histologically noted in six out of eight surgical specimens. The tissue concentrations of 5-FU and ADM were also studied in five breast cancer patients. There was no correlation between the concentration of 5-FU or ADM and histological effect. In intra-arterial infusion, ADM seemed to have a high affinity to the regional lymphnode and breast tumor, compared to normal breast tissue and might also be applicable to the control of lymphnode metastasis. Three out of six cases which received radical mastectomy subsequently had recurrence except in the regional lymphnodes and the prognosis was unsatisfactory (5 year survival was 2/4). Other alternative or multi-disciplinary treatment seems to be necessary for improving the survival rate.     

Successfully treated locally advanced breast cancer by intra-arterial infusion chemotherapy: a case report]

A 40-year-old female was admitted to our hospital with a large right breast tumor that was over 15 cm in diameter. We treated this locally advanced breast cancer by intra-arterial infusion chemotherapy. Through a catheter placed in the right subclavian artery, doses of 20-30 mg of ADM were injected intermittently with MMC and 5-FU. When a total of 120 mg of ADM had been infused, leukopenia developed, but this was immediately improved by G-CSF. With this treatment, her breast tumor and lung metastases were almost completely disappeared. Thus, an intra-arterial infusion chemotherapy was considered to be an effective treatment for locally advanced breast cancer.     

A newly devised chemo-embolic agent, G. T. XIII-ADM

In order to bring about ideal chemotherapy, targeting, topical maintenance, sustained release and no side effects of the anticancer agent are essential. Adriamycin (ADM) was immobilized on absorbable gelatin material (G) together with thrombin (T) and factor XIII (XIII) to form such an agent, "G . T . XIII-ADM". The material was applied as an embolic agent in experimental transcatheter arterial chemo-embolization (TACE) in rabbits with VX2-carcinoma. Response rate of the tumor (CR + PR) was 75% for "G . T . XIII-ADM", and 28.6% for intra-arterial infusion (IA) of ADM. The ADM was maintained for a long period both in the tumors and the metastatic lymph nodes, in the animals given the chemo-embolic agent. The materials were then clinically prescribed as an embolic agent in preoperative TACE for patients with locally advanced breast cancer. The oncolytic effects obtained with the "G . T . XIII-ADM" were remarkably favorable and the side effects were almost nil. These positive data suggest that "G . T . XIII-ADM" has great potential as a new approach to cancer chemotherapy.     

Intra-arterial infusion chemotherapy with [Sar1, Ile8] angiotensin II in bladder cancer

Twenty patients with bladder cancer were treated with intra-arterial infusion chemotherapy using CDDP and ADM in combination with [Sar1, Ile8] angiotensin II. A catheter was introduced into internal iliac artery by Seldinger's technique, and 100 mg of CDDP, 50 mg of ADM and 1 mg of [Sar1, Ile8] angiotensin II were infused through the catheter for 40 minutes. CR was observed in 8 of 20 patients. PR in 11 and NC in 1. Therefore, the response rate (CR + PR) was 95% (19/20). Side effects were generally mild and consisted of leukopenia, nausea, vomiting, diarrhea, alopecia, skin pigmentation and headache. Catheter-related complications were not observed. This study demonstrated that intra-arterial infusion chemotherapy with CDDP and ADM in combination with [Sar1, Ile8] angiotensin II was extremely effective in treating patients with bladder cancer.     

Analysis of the Curative Effect of Preoperative Intra-Arterial Infusion Chemoembolization on Stage,IB2-IIB Uterine Cervix Cancer

OBJECTIVE To investigate the short-term and long-term therapeutic efficacy of preoperative intra-arterial infusion chemo-embolization on stage IB2-IIB Uterine cervix cancer (UCC). METHODS A total of 143 patients with Stage IB2-lIB UCC were divided into a clinical trial group and a control group. The patients in the clinical trial group (n/=86) were treated with a combined therapy, i.e. preoperative intra-arterial infusion chemo-embolization, surgical therapy and postoperative radiotherapy, and those in the control group(n=57)were given surgical therapy and post-operative radiotherapy. The adverse effects, changes in local lesion and pathological examinations of the cancer, and the state during the surgery were observed after the intra-arterial infusion chemo-embolization. The survival rate and recurrence rate between the two groups were compared. RESUITS The total effective rate of the intra- arterial infusion chemo-embolization on Stage IB2-IIB UCC was 93.02%. The treatment could reduce tumor size, bring about retro-conversions of the clinical stage of the tumors and pathological grade of the cancer cells, and decrease the quantity, of intra-operative blood loss as well as the operating time. It could significantly improve the 5-year survival rate (P<0.05), and reduce the 2 and 5-yeartumor recurrence rates(P<0.05). Moreover, its side effects were little. CONCLUSIOAN Preoperative intra-arterial infusion chemo-embolization can create conditions for radical operation, lower the postoperative recurrence rate, and improve the prognosis in the patients with UCC. It is an effctive therapy in treating UCC.     

Primary clinical effects of PP therapy (cisplatin and peplomycin) and TPP therapy (4′-O-tetrahydropyranyladriamycin,cisplatin and peplomycin) for oral cancer

Background A comparison of chemotherapy with PP (cisplatin, CDDP; and peplomycin, PEP) and TPP (4′-O-tetrahydropyranyladriamycin: THP-ADM, CDDP and PEP) in the treatment of oral cancer. Methods This study included 159 out of 199 patients who had visited the collaborating institutions' hospitals, and who had been registered in the Examination Meeting of Chemotherapy for Oral Cancer during the 2-year period from June 1990 to May 1992. Ninety-seven patients underwent PP therapy and 62 underwent TPP therapy. In PP intravenous infusion therapy, 60–80 mg of CDDP per m² was administered on day 1, followed by infusion of 5–7.5 mg of PEP per m² from day 2 until day 6. In the PP intra-arterial infusion therapy, in which the drugs were infused in a retrograde fashion into the superficial temporal artery, 50–70 mg of CDDP per m² was infused on day 1, followed by infusion of 5 mg of PEP per m² from day 2 until day 6. In both the intravenous and intra-arterial TPP therapy regimens, 20 mg of THP-ADM per m² was infused on day 1, followed by infusion of 50 mg of CDDP per m² on day 2, and infusion of 5 mg of PEP per m² from day 3 until day 7. Results The response rate of TPP therapy was 64.5%, which was not significantly different from the 53.6% obtained with PP therapy. However, the complete response (CR) rate with TPP therapy was 22.6%, significantly higher than the 9.3% with PP therapy. The response rate of TPP intra-arterial infusion therapy was particularly high (92.3%), and significantly higher than that of PP therapy. The response rate of TPP intra-arterial infusion therapy was very high (100.0%) in stage I and II patients and in primary cancers of the tongue, gingiva, buccal mucosa, and hard palate. The toxicity of TPP and PP therapies resulted in a high incidence of nausea/vomiting and anorexia. Skin disorders and epilation were observed at high rates with TPP therapy, and incidences were particularly high (100.0%) in the TPP intra-arterial infusion therapy group. The incidence of leukopenia was high in patients treated with TPP therapy but was not severe. Conclusion The results of this study suggest that TPP therapy is more effective than PP therapy in the treatment of oral cavity cancer. Although TPP therapy was associated with skin abnormalities, alopecia, and leukopenia as side effects, there was no influence on subsequent treatment. TPP intra-arterial infusion therapy appears promising in the treatment of oral cancer.     

Analysis of the curative effect of preoperative intra-arterial infusion chemoembolization on stage IB2-IIB uterine cervix cancer

Objective  To investigate the short-term and long-term therapeutic efficacy of preoperative intra-arterial infusion chemoembolization on stage IB₂-IIB uterine cervix cancer (UCC). Methods  A total of 143 patients with Stage IB₂-IIB UCC were divided into a clinical trial group and a control group. The patients in the clinical trial group (n = 86) were treated with a combined therapy, i.e., preoperative intra-arterial infusion chemo-embolization, surgical therapy and postoperative radiotherapy, and those in the control group (n = 57) were given surgical therapy and post-operative radiotherapy. The adverse effects, changes in local lesion and pathological examinations of the cancer, and the state during the surgery were observed after the intra-arterial infusion chemo-embolization. The survival rate and recurrence rate between the two groups were compared. Results  The total effective rate of the intra-arterial infusion chemo-embolization on Stage IB₂-IIB UCC was 93.02%. The treatment could reduce tumor size, bring about retro-conversions of the clinical stage of the tumors and pathological grade of the cancer cells, and decrease the quantity of intra-operative blood loss as well as the operating time. It could significantly improve the 5-year survival rate (P< 0.05), and reduce the 2 and 5-year tumor recurrence rates (P < 0.05). Moreover, its side effects were little. Conclusion  Preoperative intra-arterial infusion chemo-embolization can create conditions for radical operation, lower the postoperative recurrence rate, and improve the prognosis in the patients with UCC. It is an effective therapy in treating UCC. Contributed equally to this work     

Intra-arterial infusion chemotherapy with epirubicin for advanced breast cancer

Thirty-two patients with locally advanced or disseminated breast cancer were treated with preoperative intra-arterial infusion chemotherapy with epirubicin (30 mg/m2, day 1, 4, 7). The results were as follows: 1) the response rate (CR + PR) was as high as 71.9% (23/32) in the primary lesions. Marked degenerative changes were, also, histologically observed in 22 cases (68.8%). 2) As for side effects, mild grade of leukopenia and hair loss were frequently encountered in 75.0% and 62.5%, respectively. Gastrointestinal disorders, however, was extremely rare (6.3%). 3) Follow-up time was not long enough, but considerable survival advantages were suggested. The author confirmed that intra-arterial infusion chemotherapy with epirubicin was an efficacious modality for the treatment of advanced breast cancer.     

Intra-arterial chemotherapy for head and neck cancer

There are historically speaking, three methods of intra-arterial infusion for head and neck cancer. Recently, daily concurrent chemoradiotherapy using new superselective intra-arterial infusion via superficial temporal arterial artery is noted. A catheter with a curved tip is inserted superselectively to the feeding artery of the tumor via the superficial temporal artery. Long-term catheterization is possible in this method. Thirty-five patients with stage III or IV oral cancer were treated. Radiotherapy (total dose:40 Gy/4 weeks) and superselective intra-arterial infusion chemotherapy using DOC (total dose: 60 mg/m2, 15 mg/m2/week) and CDDP total dose: 100 mg/m2, 5 mg/m2/day) were concurrently performed daily, followed by surgery. In 31 patients, intra-arterial infusion was successful(successful rate: 88.6%), and no major complication was observed. The clinical effects were CR in 25 patients(80.6%), and pathological effects of resected tumor after surgery were pathological CR in 28 (90.3%). This method promises to be new strategy of choice for the treatment of head and neck cancer.     

Chemotherapy of hepatocellular carcinoma--with special reference to one-shot intra-arterial infusion of a high dose of adriamycin

Twenty-two cases of non-operable hepatocellular carcinoma (HCC) were treated with three types of chemotherapy mainly with Adriamycin (ADM). In the group (A), one shot intraarterial infusion of 100 mg ADM into the hepatic artery (9 cases), group (B), one shot intraarterial infusion of 30 mg ADM (3 cases), and group (C), 20-60 mg of systemic administration of ADM (10 cases) were examined. The therapeutic effects and side effects were studied comparatively among these three groups. In terms of tumor regression, RR was 4 cases (44.4%), and MR was 4 (44.4%) in group (A), and PR was 1 (10%) in group (C). The average survival time was 8.3 months (5 cases are still alive) in group (A), 5.7 months in group (B), and 4.2 months in group (C), respectively As side effects, alopecia was found 100% in (A), 33% in (B); leukocytopenia was found 100% in (A), 33% in (B); but no serious complication due to leukocytopenia was observed in any of them. One shot of 100 mg of ADM intraarterial infusion therapy seemed to be superior in therapeutic effects against HCC over other therapies.     

Pulsed arterial infusions. Chemotherapeutic implications

To simulate the intra-arterial infusion of chemotherapy, ink was infused at a steady rate through a vascular catheter inserted in a transparent tube carrying water at a rate similar to that of arterial blood. The ink ran in one or two discrete streams for 10 to 15 cm before mixing with the water, and there were substantial differences in the concentrations of ink in the water collected from side holes made at various distances from the catheter tip. If the ink was delivered in short pulses, however, it mixed with the water 2 to 3 cm beyond the catheter tip, and the samples collected from the side holes showed similar concentrations of ink. A similar situation may be encountered when chemotherapeutic agents are infused into patients. Therefore, pulsation may produce a more homogeneous drug distribution in the infused tissue. The in vitro data was substantiated in patients by the following: (1) the intra-arterial administration of technetium 99m(99mTc)labeled macroaggregated albumin (MAA) by both steady and pulsed infusions; and (2) changes in the severity of inflammatory skin reactions frequently associated with intra-arterial chemotherapy of the extremities. Improved isotope distribution was noted in 19.3% of the liver and 40% of the extremity studies. Reduced skin reactions were observed in approximately 90% of the extremities receiving pulsed chemotherapeutic infusions.     

Intra-arterial infusion chemotherapy and transcatheter arterial chemo-embolization for patients with simultaneous bilateral breast cancer

We have treated 2 cases of simultaneous bilateral breast cancer by intra-arterial infusion chemotherapy (IA) and transcatheter arterial chemo-embolization (TAC-E), respectively. In the former case treated by I. A., both the treated tumor and the contralateral mass were remarkably regressed and necrotized. However, serious systemic side effects due to the intraarterially infused drug were observed. In the latter case treated by TAC-E, chemo-embolic effects were selectively observed in the treated tumor, and side effects were slight. On the other hand, a non-treated mass showed no changes. From these findings, we concluded that I. A. serves as a semisystemic therapy, and that TAC-E, at least in our subjects, works as a loco-regional cancer chemotherapy.     

Intra-arterial chemotherapy with cis-diamminedichloroplatinum (CDDP) for primary mediastinal seminoma

Primary mediastinal malignant germinoma is a rare disease, and only about 15 patients have been reported in Japan. We treated a patient with this disease by intra-arterial CDDP infusion and observed good effects. A 29 year-old male was admitted to our hospital due to SVC syndrome in 1980. A right mediastinal tumor was detected, and the resection of this tumor was performed. Histological examination showed seminoma. Though postoperative Co irradiation was performed, radiation pneumonitis developed in the right lung. Subsequently, the tumor metastasized to the right kidney and spinal cord. After removal of the right kidney followed by Co irradiation, the clinical course was good. In 1987, a mass (10 x 6 cm) was detected in the left mediastinum, suggesting recurrence. Four courses of CDDP infusion into the left bronchial artery and left internal thoracic artery (1 course: 45-70 mg) were performed, and good effects were obtained. No side effects were observed, and the clinical course has been good until now. This case is of interest in evaluating the multidisciplinary treatment for mediastinal seminoma.     

Recurrence of right breast cancer at the thoracic wall successfully treated with intra-arterial infusion of doxorubicin hydrochloride--a case report

We report a recurrent case of breast cancer successfully treated with intra-arterial infusion of doxorubicin hydrochloride (ADM) combined with systemic CAF therapy. The patient, a 37-year-old woman, was diagnosed with a recurrence at the thoracic wall 55 months after curative resection for right breast cancer. She was treated with intra-arterial infusion chemotherapy of ADM, 30 mg, combined with systemic CAF therapy of cyclophosphamide, 100 mg from days 1 to 14, ADM, 30 mg on days 1 and 8, and 5-fluorouracil, 500 mg on days 1 and 8, as one course. Two courses of the treatment resulted in a complete response of the tumor. This result suggests that local and systemic chemotherapy could be effective for the treatment of local recurrence of breast cancer.     

Analysis of the curative effect of preoperative intra-arterial infusion chemoembolization on stage IB<Subscript>2</Subscript>-IIB uterine cervix cancer

OBJECTIVE To investigate the short-term and long-term therapeutic efficacy of preoperative intra-arterial＇infusion chemoembolization on stage IB2-IIB uterine cervix cancer （UCC）.
METHODS A total of 143 patients with Stage IB2-IIB UCC were divided into a clinical trial group and a control group. The patients in the clinical trial group （n = 86） were treated with a combined therapy, i.e., preoperative intra-arterial infusion chemoembolization, surgical therapy and postoperative radiotherapy, and those in the control group （n = 57） were given surgical therapy and post-operative radiotherapy. The adverse effects, changes in local lesion and pathological examinations of the cancer, and the state during the surgery were observed after the intra-arterial infusion chemo-embolization. The survival rate and recurrence rate between the two groups were compared.
RESULTS The total effective rate of the intra-arterial infusion chemo-embolization on Stage IB2-IIB UCC was 93.02%. The treatment could reduce tumor size, bring about retro-conversions of the clinical stage of the tumors and pathological grade of the cancer cells, and decrease the quantity of intra-operative blood loss as well as the operating time. It could significantly improve the 5-year survival rate （P〈 0.05）, and reduce the 2 and 5-year tumor recurrence rates （P 〈 0.05）. Moreover, its side effects were little.
CONCLUSION Preoperative intra-arterial infusion chemoembolization can create conditions for radical operation, lower the postoperative recurrence rate, and improve the prognosis in the patients with UCC. It is an effective therapy in treating UCC.     

间歇和连续热灌注对兔 VX-2肿瘤内阿霉素浓度的影响

背景与目的:已证实阿霉素热化疗对体外兔 VX-2细胞的抑制作用比常温阿霉素的作用强,而热灌注对机体的生命体征有一定影响.本研究在兔 VX-2移 植瘤模型建立基础上,比较间歇性热灌注与连续性热灌注对兔呼吸、心率、体温及 VX-2肿瘤内阿霉素浓度的影响,验证间歇性热灌注的有效性和安全性,以寻找更安全有效的灌注方式.方法:在 30只新西兰大白兔后腿上建立 VX-2肿瘤模型,并随机分为常温灌注组、 60℃连续灌注组和 60℃间歇灌注组(每组 10只).经股动脉插管、 DSA证实为肿瘤供血动脉后,分别给予常温 100 ml盐水加阿霉素 (ADM)灌注、 60℃热盐水 100 ml加阿霉素连续灌注、 60℃热盐水 100 ml加阿霉素间歇性灌注.灌注过程中,测量 60℃热灌注组与 60℃间歇灌注组肿瘤组织内 43℃～ 45℃持续时间;灌注后即时检测各组兔呼吸(次 /分)、心率(次 /分)、体温(℃)及肿瘤组织内阿霉素浓度.结果:常温灌注组阿霉素浓度为( 7.115± 2.180)μ g/ml, 60℃连续灌注组为( 17.213± 1.657)μ g/ml, 60℃间歇性灌注组为( 16.545± 3.426)μ g/ml;60℃间歇灌注组阿霉素浓度与 60℃连续灌注组无显著性差异( P >0.05), 60℃连续组、间歇组阿霉素浓度与常温灌注组均有显著性差异( P< 0.05). 60℃间歇性灌注组 43℃～ 45℃持续时间为( 24.31± 2.45) min, 60℃连续灌注组为( 22.53± 1.44) min,两组之间无显著性差异( P >0.05).连续灌注组与常温灌注组兔的呼吸、心率、体温变化有显著性差异( P< 0.05),而间歇灌注组与常温灌注组兔的呼吸、心率、体温变化无显著性差异( P >0.05).结论:常温灌注组与连续灌注组的药物浓度无显著性差异;与连续性热灌注相比,经动脉间歇性热灌注化疗方法更安全.     

Intra-arterial infusion chemotherapy with anticancer agents for advanced breast cancer--effect and toxicity of mitomycin C and adriamycin

In 23 cases of primary advanced breast cancer, intra-arterial infusion chemotherapy of Adriamycin (ADR) and Mitomycin C (MMC), which were injected jointly or individually, was performed and its effects and side effects were studied. As for the clinical effects, the response rate (CR + PR) was 73.9% (17/23 cases) and the histological response rate (greater than grade IIb) was 82.6% (19/23 cases). ADR alone (100-150 mg) and MMC (28 mg) + ADR (42 mg) combined regimens were especially superior in both their clinical and histological effects. In metastatic lymph nodes, the histological response rate was 78.9% (15/19 cases). As for the side effects, in the cases treated with MMC, bone marrow suppression such as leukocytopenia and thrombocytopenia was remarkable and took a long time to recover. The above results suggested that the most effective regimen for primary advanced breast cancer using intra-arterial infusion chemotherapy is ADR alone, in single doses of 50 mg up to a total dose of 150-200 mg. Histological examination of the effective cases revealed that the central region of the tumor was more markedly recrotic than the periphery. It was suggested that the grade of the effects on tumor tissues is related to the mechanism of anticancer agents.     

Two cases of alpha-fetoprotein producing gastric cancer, showing marked response to continuous hepatic arterial infusion (HAI) chemotherapy with adriamycin

We report two cases of alpha-fetoprotein producing gastric cancer (AFPGC) with multiple liver metastases showing marked response to continuous HAI chemotherapy with adriamycin (ADM). In both cases, 5-FU 500 mg/body/day and Leucovorin (LV) 30 mg/body/day was infused continuously for 7 days and ADM 30 or 60 mg/body/day was infused continuously for 4 hours on day 7 as preoperative HAI chemotherapy. The primary gastric lesions were reduced and became resectable. After gastrectomy, they were treated with 4-hour continuous HAI of ADM 30 or 60 mg/body with or without 5-FU and LV once a week several times in our outpatient clinic. After these treatments, the multiple liver metastases were reduced remarkably, with a marked decrease of serum AFP levels. During these treatments, neither patient showed remarkable side effects, so they could work as before. This frequently low-dose ADM administration resulted in a high local response without severe side effects.     

Intra-arterial chemotherapy of ovarian cancer using a subcutaneously embedded reservoir--a case showing remarkable response to intermittently repeated low-dose intra-arterial infusion chemotherapy

By fitting a subcutaneously embedded reservoir to an aged patient with ovarian cancer in whom exploratory laparotomy was performed, we attempted intermittent intraarterial infusion chemotherapy using small doses of CDDP and ADM, and obtained favorable results. The catheter was inserted at an artery in the lower abdominal wall, attached at the site where the pointed end reached the upper margin of L3, and fixed to the fascia recta, connecting with the reservoir on the reverse side. As drug solutions, 5 mg of CDDP and 5 mg of ADM were transcutaneously infused twice per week. Results 1) A marked necrotic tendency was noted in the tumor, and retention of ascites was remarkably decreased. 2) Hardly any nausea and vomiting as side effects were noted, and decreases in leucocyte and platelet counts were mild, recovering rapidly due to dropout. 3) Anxiety regarding infection was minimal at times other than when the drug solution was being infused, and patient was able to take a bath. From the above-mentioned results, it was considered that maintenance chemotherapy on an outpatient basis using approximately one dose per week would be possible in the future for ovarian cancer.     

Effect of intra-arterial infusion of adriamycin on locally advanced primary breast cancer--third report. Clinical Study Group of Adriamycin for Breast Cancer in Japan

The purpose of this study was to define the optimal dose and schedules for intra-arterial administration of adriamycin (ADR) in the treatment of locally advanced breast cancer. ADR was given intra-arterially to 110 patients with locally advanced breast cancer at a dose of 30 mg/time or 50 mg/time twice or once a week, respectively, with a total dose of 150 mg. The local effects and side effects of ADR as well as the prognosis were analysed in 91 evaluable cases. Overall response rates for ADR were as high as 62.2% (63/91) in the primary lesions and 80.0% (40/50) in metastatic lymph nodes. There was no difference in the response rate between cases receiving 30 mg and those receiving 50 mg at each infusion. However, a significantly higher response rate was noted, in patients infused ADR through both the subclavian and internal thoracic arteries (dual route group) in comparison with those infused through the subclavian artery alone (single route group). Histological effects of ADR on the primary lesion were assessed in accordance with the criteria proposed by Shimosato et al. Overall histological response rate (greater than Grade II b) was obtained in 29.4% (16/51), which was lower than the clinical effects. Histological effects were more potent in the 30 mg group than in the 50 mg group, but in relation to the route of administration, there was no significant difference between the groups. As for side effects, signs of systemic toxicity such as alopecia, leukopenia and gastrointestinal disorders were frequently observed, but there was no difference between the dose groups, and these side effects were considered to be tolerable. Prognostically, 50% survival time was 32.6 months, and the patients who received dual-route administration showed better survival.