Continuous Infusion Chemotherapy Research Articles

Treatment interruptions and complications with two continuous hepatic artery floxuridine infusion systems in colorectal liver metastases

Continuous hepatic artery floxuridine infusion benefits patients with colorectal liver metastases. Implanted infusion pumps are more expensive but may result in fewer treatment interruptions than when using an external pump connected to a port. We have assessed device-related complications, treatment interruptions and added nurse interventions in 95 patients undergoing a total of 959 treatment cycles via either implanted pump (64 patients) or port (31 patients). Compared with the implanted pump, the port was associated with a significant increase (P < 0.003) in catheter blockage (24/31 vs 2/64 patients), treatment interruption (15/265 vs 12/694 treatments) and added nurse intervention (80/265 vs 20/694 treatments). Survival in patients with colorectal liver metastases is limited and the complications of treatment should be kept to a minimum. An implanted subcutaneous infusion pump offers the benefit of a 3-fold lower incidence of treatment interruption and a 30-fold lower incidence of catheter blockage than when continuous infusion chemotherapy is given via an external infusion device.

A pilot study of mitomycin, cisplatin and continuous infusion 5-fluorouracil (MCF) in advanced non-small-cell lung cancer

A pilot study of continuous infusional 5-fluorouracil 200 mg m-2 per 24 h by ambulatory pump and Hickman line for the entire treatment cycle with mitomycin C 8 mg m-2 i.v. on day 1 and cisplatin 75 mg m-2 i.v. on day 1, both repeated every 28 days, was carried out in 31 previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Of 31 patients assessable for response, one attained a complete remission and eight a partial remission, an overall response rate of 29%. Haematological toxicity was minimal, with only 3% of patients developing WHO grade III/IV neutropenia and 13% grade III/IV thrombocytopenia. Significant side-effects included moderate to severe emesis (41%), mucositis (34%), diarrhoea (31%) and palmar-plantar syndrome (14%). Seven patients (23%) had Hickman line complications requiring line removal. Continuous infusional chemotherapy with this regimen is active in advanced non-small-cell lung cancer, but its complexity and associated treatment toxicity offer little advantage over equally active but simpler and less toxic cisplatin-based regimens.

The efficacy of continuous local arterial infusion of 5-fluorouracil and cisplatin through an implanted reservoir for severe advanced hepatocellular carcinoma.

There is not yet an effective standard therapy for severe advanced hepatocellular carcinoma (HCC). We attempted continuous local arterial infusion chemotherapy using 5-fluorouracil (5-FU) and cisplatin (CDDP) with an implanted reservoir for these patients, and evaluated its efficacy. Twenty-one HCC patients received continuous arterial infusion of 5-FU and CDDP for 1 week, followed by a 1-week no-infusion period; this regimen was repeated 1-32 times, and patients were observed for 36-549 days. The 1-year survival rate was 61.1%, and alpha fetoprotein levels decreased in 13 patients. All could continue as outpatients for 94.0% of the entire course of therapy. Because CDDP amplifies the effect of 5-FU as a biochemical modulator, and because continuous infusion strengthens the effect of 5-FU and reduces the side effects of CDDP, we consider this therapy to be effective for patients with severe advanced HCC, prolonging survival and improving the quality of life.

Continuous Infusion Chemotherapy as a Radiation-Enhancing Agent for Yttrium-90-Radiolabeled Monoclonal Antibody Therapy of a Human Tumor Xenograft

Radioimmunotherapy using monoclonal antibodies is a promising investigational treatment modality for solid tumors. Use of radiation-enhancing agents could significantly impact on the therapeutic response of this treatment. We evaluated the potential interaction of a known radiation-enhancing agent, 5-fluorouracil (5-FU), with the radioimmunotherapeutic effect of a yttrium-90 ( 90Y)-labeled monoclonal antibody in a human adenocarcinoma xenograft. Athymic mice were inoculated subcutaneously with the human colon carcinoma cell line LS-174T. All mice had intraperitoneal 3-day osmotic infusion pumps placed by laparotomy. Half of the pumps were filled with 0.9% saline solution and half were filled with a solution containing 5-FU. Three activity levels of 90 Y-radiolabeled CC49 antibody were injected into tail veins of the mice. Each activity level was injected into a group of animals with saline-filled pumps and a group with 5-FU-filled pumps. A significant interaction between treatment group and time was found suggesting that the rate of tumor growth for the group of animals receiving 90Y at 100 μCi plus 5-FU compared to the group of animals receiving 90Y alone was significantly delayed ( P = 0.0055), showing a radiation enhancing effect by 5-FU. These results suggest that the addition of the radiation-enhancing agent 5-FU to radiolabeled antibody may increase the ability to treat solid tumors. Further investigations with other antibodies, radionuclides, and tumor models are indicated.

Reirradiation for rectal cancer and surgical resection after ultra high doses

Purpose : Local recurrence of rectal cancer following high-dose pelvic radiation presents a difficult management challenge. Conventional wisdom suggests that reirradiation should be avoided and radical pelvic surgery is hazardous after ultra high-dose radiation. Methods and Materials : In a unique Phase I/II pilot study, 32 patients with recurrent rectal cancers following previous pelvic radiation underwent planned reirradiation to the pelvis. Initial radiation doses had ranged from 30–64.87 Gy (median dose 45 Gy). Seventeen patients underwent reirradiation followed by radical resection. Fifteen patients were reirradiated for palliative relief of symptoms. Treatment techniques consisted of two lateral fields (7 × 7 to 12 × 10 cm) encompassing the tumor with 2 cm margins. Reirradiation doses ranged from 19.80–47.66 Gy, (median 34.2 Gy). Patients also received concurrent low-dose continuous infusion chemotherapy, (5-FU 200–300 mg/day). Total cumulative radiation doses ranged from 70.6 to 111.6 Gy. Results : Treatment was well tolerated. Four patients had radiation interrupted/discontinued for diarrhea or leukopenia. Follow-up ranges from 6 months to 36 months. No late sequelae of radiation have been observed to date. Seventeen patients underwent surgical exploration 6–8 weeks following reirradiation. Two patients had extensive disease and were not resected. Fifteen patients underwent radical resection of residual tumor (4 posterior exenterations, 6 APR, 3 transanal abdominal transanal proctocolectomy with coloanal anastomosis (TAATA), and 2 LAR). No patients died postoperatively. No excessive edema, hemorrhage, or adhesions were observed. Two patients developed pelvic abscess and one developed a coloanal stricture. Eleven of 15 resected patients are alive from 6 to 36 months with a 2-year survival of 66%. Of the patients treated palliatively, symptomatic relief was observed in 13 15 patients. No objective complete response was observed, but 6 15 patients had measurable partial response. Median survival in this group was 14 months. Conclusion : Based on this experience, we believe that in selected patients radical surgical resection after cumulative ultra high doses (70–90 Gy) of radiation can be performed safely. A viable anastomosis is also possible in spite of these high doses. Planned reirradiation for palliative relief of symptoms can be effective without unusual risks of complication. Long-term effects of such ultra high dose radiation and surgery continue to be monitored.

Ambulatory continuous infusion ifosfamide with oral etoposide in advanced sarcomas

Chemotherapy given by continuous infusion may have different toxicity profiles and different degrees of therapeutic efficacy than when given by bolus administration. The potential therapeutic benefits of continuous infusion chemotherapy and the advantages of outpatient treatment led us to study a continuous infusion of ifosfamide with mesna and oral etoposide. The authors performed a Phase I-II trial in which 9 g/m2 ifosfamide was administered for 6 days and 10.5 g/m2 mesna was administered for 7 days, both by continuous infusion, in combination with 50 mg/m2/d oral etoposide for 8 days in 21 patients with sarcomas or other solid tumors. Courses were repeated every 28 days. A total of 65 treatment cycles were given. Only six patients required hospitalization for treatment, all because of an initial poor performance status, and most carried out normal activities on an ambulatory basis. Treatment was stopped during the first course in five patients because of central nervous system toxicity, each with a poor pretreatment performance status; neurologic recovery was complete in each patient. The dose of etoposide was decreased by 20% in 11 patients and unchanged in 7 following the first treatment. Hematologic toxicity was predominantly manifested by leukopenia. An absolute neutrophil count less than 500 neutrophils/microliters occurred in 22 of 50 cycles; thrombocytopenia (platelets less than 100,000/microliters) was seen in two patients, requiring platelet transfusion in one. Neutropenic fevers occurred in 13 of 65 cycles; in 4 of these, cultures demonstrated a bacterial infection. Nausea and vomiting were mild. Objective responses occurred in 6 of 16 patients with soft tissue sarcomas (6 partial responses [PR]) (95% confidence interval, 15-65%), and 3 of 5 bone sarcomas, all of whom had been previously treated with doxorubicin and dacarbazine. The authors concluded that ifosfamide and mesna given by ambulatory continuous intravenous infusion with wearable pump systems in combination with oral etoposide was well tolerated and showed substantial anti-tumor activity. This combination represents a rational therapeutic approach to patients with advanced soft tissue sarcomas and may have application to other malignancies.

The myeloprotective effect of recombinant human granulocyte-macrophage colony-stimulating factor given sequentially with continuous infusion vinblastine in metastatic breast cancer patients.

Colony-stimulating factors have been shown to have a myeloprotective effect when administered following chemotherapy. Chemotherapy of short duration with predominantly cell-cycle nonspecific agents has been most used. The myeloprotective effects of colony-stimulating factors given after cell-cycle specific or continuous infusion chemotherapy have not previously been assessed. Twenty-one evaluable patients with metastatic breast cancer progressing after one prior chemotherapy regimen were treated with continuous infusion vinblastine 2.0 mg/m2/day for 5 days. After the second chemotherapy cycle, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for 10 days. Serial complete blood counts, differential, and platelet counts were obtained to document myelotoxicity. GM-CSF administration resulted in a significantly shorter duration of granulocytopenia, < 500/microliters, at the maximum GM-CSF dose. Significantly more rapid recovery of granulocytes to > 500/microliters, > 1000/microliters, and > 1500/microliters was seen with all doses and schedules of GM-CSF administered. The nadir absolute granulocyte counts were unaffected. GM-CSF given after continuous infusion cell-cycle specific chemotherapy is therefore myeloprotective.

Endometrial carcinoma. Influence of prognostic factors on radiation management.

The earliest intracavitary radium treatment for uterine cancer was reported in 1908. Refinements reported during the next 20 years, using an intrauterine tube and colpostats or radium capsules, established a treatment philosophy of preoperatively irradiating uterine and parauterine tissues. Thus, preoperative intracavitary irradiation became entrenched as therapy for all endometrial cancers for the better part of four decades. In the 1950s and 1960s, the ability of external irradiation to eradicate cancer in regional lymphatic vessels prompted the use of pelvic field irradiation in Stage II and III and recurrent disease. The results of surgical exploratory studies in the 1970s established more refined criteria for preoperative or postoperative external pelvic irradiation in high-grade infiltrating Stage I cancers. In the 1980s, it became apparent that, for tumors with lymphovascular invasion, clear cell, and serous papillary histologic types, the disease spread to the upper abdomen and the paraaortic nodes might benefit from extended field and/or whole abdominal irradiation, with or without systemic bolus or concomitant continuous-infusion chemotherapy. In the 1980s, a subset of patients was identified with high-grade lymphovascular invasion clear cell and papillary serous histologic types or with positive peritoneal cytologic findings who were at high risk of failing in the paraaortic nodes and/or the upper abdomen for whom extended field or whole abdominal irradiation have been advocated. Given the fraction and dose limitation for a large abdominal field, the addition of systemic concomitant bolus or continuous infusion of chemotherapy currently is proposed to improve the control of intraabdominal failure in these high-risk patients.

New advances in radiation oncology for gynecologic cancer.

In 1992, the American Cancer Society anticipates that there will be 1,130,000 new cases of invasive cancer diagnosed in the United States. About 66,500 will be invasive cancers of the cervix, uterus, and ovary. About 22,400 patients will die during 1992, with 50-60% of those deaths being due to persistent local regional disease. Data are available to suggest that a reduction in local failure will be reflected by an increase in survival free of disease. In 1992, major efforts are being made to reduce the incidence of local failure. Three areas in this regard are innovative uses of brachytherapy, intraarterial chemotherapy and radiation therapy, and continuous infusion chemotherapy and radiation therapy. These new techniques show significant reduction in local failure with associated improvement in survival. The data will be presented to illustrate the impact of these techniques.

Outpatient continuous infusion of chemotherapy; An alternative treatment modality

Outpatient continuous infusion of chemotherapy; An alternative treatment modality

Refractory Acute Myelogeneous Leukemia Successfully Treated with a Continuous Infusion Chemotherapy of Low Dose Aclarubicin and Cytosine Arabinoside: a Case Report

Refractory Acute Myelogeneous Leukemia Successfully Treated with a Continuous Infusion Chemotherapy of Low Dose Aclarubicin and Cytosine Arabinoside: a Case Report

Chemoirradiation: a new initiative in cancer treatment. 1991 RSNA annual oration in radiation oncology.

The use of concomitant continuous infusion chemotherapy and radiation therapy in the treatment of a variety of tumors has produced, in relatively limited clinical experience, substantial improvements in complete response and survival rates. Although there is still a need to establish the most effective combinations, concentrations, and scheduling of drugs, as well as optimum dose and fractionation of radiation, a number of benefits have already been recorded with this approach. Organ preservation is maximized in all but the most advanced cancers of the anus, esophagus, and bladder. In advanced head and neck cancers, particularly in the paranasal sinuses when bone destruction and infiltration have occurred, the total dose required for effective therapy can be reduced by 15%-30%, which substantially lowers the rate of complications. Therapeutic gains have also been seen in the treatment of other primary and recurrent gastrointestinal and gynecologic malignancies and their hepatic metastases. Finally, there is considerable potential for this approach in the treatment of bulky or recurrent soft-tissue sarcomas, particularly in the extremities.

Should whole pelvic radiation therapy become past history? A case for the routine use of extended field therapy and multimodality therapy

Total pelvis radiation therapy as refined over the past 40 years has impacted positively on gynecologic cancer management. Improved overall results on a worldwide basis reflect a broader application of contemporary radiation treatment plans. Individual clinical stages of disease and subsets have not seen improvement in several decades. Currently available techniques for the safe application of extended field radiation therapy strongly support its routine use. Concomitant continuous infusion chemotherapy (CCIC) with radiation therapy (RT) should be strongly considered. Primary radical surgery is employed in our hands prior to extended RT and CCIC for most Stage I and II cases.

Rapid Development of Resistance to Antifolates In Vitro: Possible Clinical Implication

Within three repeated 7-day incubation periods with either methotrexate (MTX) or trimetrexate (TMTX), human colon adenocarcinoma cells (HCT-8) developed high levels of resistance to these drugs, as evidenced by approximately 20- and 50-fold increases, respectively, in the median effective doses. Similarly, within six short-term exposures (4 hours) to the same drugs, a high degree of resistance developed in the cells. Alternating 4-hour treatment cycles with MTX and TMTX did not delay the onset of resistance to these antimetabolites in the HCT-8 cells. The same strategy produced no better results than giving either MTX or TMTX alone to (C57BL/6 x DBA/2)F1 mice bearing murine leukemia P388 cells. Furthermore, HCT-8 cells resistant to short-term (4-hour) exposure to MTX were cross-resistant to the same drug given for 7 days continuously, and cells resistant to MTX given continuously for 7 days were cross-resistant to the same drug given for 4 hours. Analogous results were obtained with TMTX, indicating that, under these circumstances, changing the schedule of administration of the same agent does not overcome resistance to it. The clinical relevance of these data to prolonged adjuvant chemotherapy, as well as loco-regional and continuous-infusion chemotherapy, is discussed.

Continuous infusion of chemotherapy on an outpatient basis via a totally implanted venous access port

170 patients were treated with continuous infusion of epirubicin, mitoxantrone, carboplatin or 5-fluorouracil through an implanted venous access port with a portable infusion pump. A total of 440 cycles were given on an outpatient basis. The patients were instructed how to dissolve their drugs and to change the syringes. The complication rate was low. 10 patients developed a thrombosis of the subclavian vein, resulting in cessation of therapy in 5. Pulmonary embolism occurred twice, in 1 patient during a period of subclavian vein thrombosis. Needle dislocation occurred 6 times and catheter occlusion 20 times. Patency was restored with saline or urokinase. Local infection occurred 3 times and systemic infection only once. This technique is suitable for continuous infusion of different cytostatic drugs on an outpatient basis. Patients were able to prepare their drugs at home and the system can remain in situ for 3 weeks without increasing the complication rate.

Mechanisms to improve chemotherapy effectiveness

Although many effective anti-cancer agents are now available, their curative potential is compromised by a variety of problems related to tumor sensitivity, drug access, and pharmacokinetics. Central to the problem of inadequate chemotherapy is drug resistance. Drug resistance may be intrinsic, acquired, or induced, and it may develop to one drug or it may occur simultaneously to multiple agents (pleiotropic). Substantial progress has been made in our understanding of the mechanisms of drug resistance and techniques for overcoming that resistance. New evidence has emerged that highlights the importance of dose intensity in achieving successful drug treatment outcomes. Retrospective analysis of studies in breast, ovarian, colon cancer, and lymphoma suggest that new studies designed to optimize dose intensity may yield improved results. Several prospective trials have now corroborated the retrospectively derived importance of dose intensity as an independent factor in achieving improved survival. Finally, new techniques for drug delivery offer considerable promise. Chemotherapy by regional infusion and perfusion, implantable drug delivery systems, and continuous infusion of chemotherapy are unique novel techniques that may improve the efficacy of presently available chemotherapeutic agents even as new agents are developed.

Concomitant continuous infusion chemotherapy and radiation

Attempts to duplicate the cytotoxic effect of oxygen on radioresistant tissues spurred a search by radiation oncologists for other radiosensitizing techniques. This led to large-scale investigations using neutrons and other heavy particle radiations, hyperthermia, altered fractionation schedules, and the systemic use of the halogenated pyrimidines and the electron-affinic compounds. Unfortunately, the promise that the nitroimidazole compounds would selectively sensitize the radioresistant tumor cells and prove to be an effective systemic agent has not been borne out in clinical trials thus far. Existing pharmokinetic and cytokinetic studies have suggested that continuous infusion chemotherapy given concomitantly (CCIC) with irradiation (RT) acts synergistically, resulting in a significant increase in tumor cell killing. These observations have been supported by clinical research studies treating certain epithelial cancers that have resulted in considerably higher locoregional control rates and improved survival. Although initially used in treatment of only advanced or inoperable epithelial carcinomas, CCIC and RT are now being employed in the treatment of lower staged cancers as an organ-sparing procedure. Carcinoma of the anus treated by anteroposterior (AP) resection alone have reported 5-year survival rates of 30% to 60%. CCIC and RT using 5-fluorouracil (5-FU) and mitomycin C have achieved a local control rate of 90% to 100% and a 5-year survival rate of 80% to 86% with sphincter preservation in 90% of these cases. The 5-year survival rate in advanced urinary bladder carcinoma is 25% to 30% for either radiation or surgery and 42% when combined in a preoperative radiation schedule. Using 5-FU CCIC and RT, the local control rate of transitional cell carcinoma of the bladder has been 71% to 86% with a 5-year survival of 62%. 5-FU CCIC and cisplatin and RT used in the treatment of Stages III and IV carcinoma of the cervix yields a locoregional control of 74% compared with the radiation alone local control of 63% for Stage III and 30% for Stage IV disease. Advanced head and neck and paranasal sinus carcinomas treated by cisplatin CCIC and RT show improved tumor clearance even in the presence of bone destruction. A complete response rate of 87% has been reported with the use of cisplatin CCIC and hyperfractionated radiation. Hyperfractionated radiation also appears to improve the local control of advanced head and neck cancers over patients treated with single fractions of radiation with 66% surviving at 22 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Continuous Infusion Chemotherapy with Epirubicin and Vincristine in Relapsed and Refractory Acute Leukemia

Twenty-three patients admitted for treatment of refractory or relapsed acute leukemias (12 acute nonlymphocytic leukemias, 4 acute lymphocytic leukemias, 1 acute undifferentiated leukemia, 6 chronic myeloid leukemias in blast crisis) received a regimen employing a 4-day continuous intravenous infusion of epirubicin followed by a 4-day continuous infusion of vincristine. The remission rate (complete and partial) was 52%. This treatment was associated with minimal extrahematologic toxicity, particularly cardiac and gastrointestinal toxicity. This method of administration should be considered a reasonable therapeutic approach to pretreated acute leukemia patients, particularly in elderly patients wishing to avoid chemotherapy-related side effects.

INTRAHEPATIC RECURRENT MODES AND THERAPY OF HEPATOCELLULAR CARCINOMA

Cumulative recurrence rate and modes of intrahepatic recurrence were studied on 59 patients underwent curative and relative curative hepatectomies. Intrahepatic recurrences were occurred in 24 patients (40.7%) and the cumulative recurrence rate was significantly higher in patients underwent noncurative hepatectomies, and in those with large tumor sizes (>3cm in diameter)and positive tumor invasion to the portal vein at the time of hepatectomy. Eight solitary intrahepatic and 16 multipe intrahepatic recurrences were noted. Relevant factors to multiple recurrent modes included factor T, stages and positive tumor embolus in the portal vein. In all solitary recurrent cases including 3 resection cases, active regional therapies such as transcatheter arterial embolization and continuous intrahepatic arterial infusion chemotherapy were successfully performed. In the multiple recurrent cases, however 7 cases could not receive such regional therapies but only systemic chemotherapy because of impaired liver function. Cumulative survival rate after recurrence in patients with solitary recurrences was significantly better than those in multiple ones. Regional therapies are effective in prolonging the survival period of patients bearing intrahepatic recurrences after hepatectomy.

Implantable venous access device: use in patients with advanced head and neck cancer.

As a result of prolonged hospitalizations and the frequent administration of sclerosing antibiotics and/or chemotherapeutic agents, vascular access frequently becomes difficult in patients with advanced head and neck carcinoma. Eighty-six totally implantable venous access devices were placed in 83 patients with advanced head and neck cancer to facilitate the administration of continuous intravenous infusion chemotherapy. Complications relating to surgical placement or usage of the device occurred in 29 of 86 ports (34%), leading to the removal of eight devices (9%). The implantation of two devices required revision. There were no serious sequelae from any of the complications. The port facilitated the administration of home chemotherapy in 11 patients. Because of our favorable experience, we now routinely recommend placement of these devices to all patients with advanced head and neck cancer at our institution.