Continuous Infusion Of Cisplatin Research Articles

293 Non-resectable non-small-cell lung carcinoma: Continuous infusion of cisplatin and concurrent radiotherapy plus adjuvant surgery

293 Non-resectable non-small-cell lung carcinoma: Continuous infusion of cisplatin and concurrent radiotherapy plus adjuvant surgery

308 A phase I–II study of the combination of radiotherapy and continuous infusion of cisplatin in advanced non small cell lung cancer (NSCLC)

308 A phase I–II study of the combination of radiotherapy and continuous infusion of cisplatin in advanced non small cell lung cancer (NSCLC)

Continuous infusion of 5-fluorouracil plus low-dose cisplatin in tumor-bearing mice.

Combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin is widely used but the optimal daily dose of the latter has not been established. The present study was designed to determine the pharmacodynamic interaction and antitumor effect of these drugs when used at clinically relevant doses in animals. Male ddY mice were injected with Sarcoma 180 cells and then given a continuous infusion of 5-FU (10 mg/kg/day) for 5 days (via an implanted micropump) +/- cisplatin 1 mg/kg by i.p. bolus (pharmacodynamic study). Alternatively, mice were given 5-FU +/- cisplatin (0.2 mg/kg/day), cisplatin alone for 5 days or no treatment (anti-tumor effect study). Tissue and serum samples were taken for analysis. No significant differences in serum pharmocokinetics were observed between the groups at any timepoint but 0.5 h after the start of infusion, where the serum 5-FU concentration was lower with monotherapy than with combination therapy. 5-FU alone had a slight antitumor effect, while low-dose cisplatin alone had no noticeable effect. 5-FU + cisplatin produced a favorable response, with a significantly lower treated/control tumor weight ratio than in the non-treated and cisplatin monotherapy groups (p < 0.05), although this was not significantly different from the response to 5-FU monotherapy. In conclusion, the dose of cisplatin used in the present study was insufficient to generate a significant tumor response alone but it did tend to enhance the antitumor efficacy of 5-FU. Continuous 5-FU infusion plus low-dose daily cisplatin may become clinically useful after further investigation.

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC)

Introduction: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50–70% resection rate and a 3–5 year survival of 20–32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m 2/day 1–5, 5-fluorouracil 800 mg/m 2/day 2–5, and high-dose leukovorin 500 mg/m 2/day 1–5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171–1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3 91 and 10 92 . Methods: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54–60 Gy. Results: Median age was 57 (42–68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33–50) months, four of whom had achieved pathologic complete response at time of surgery. Conclusions: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

135 Results of radiation and concomitant continuous infusion 5-fluorouracil and cis-platin for anal cancer

135 Results of radiation and concomitant continuous infusion 5-fluorouracil and cis-platin for anal cancer

Neoadjuvant Chemotherapy with Continuous Infusion of Cisplatin and Fluorouracil in Stage II-IV, M0 Squamous Cell Carcinoma of the Head and Neck

The aim of the study was to assess the activity and the toxicity of cisplatin (DDP) and fluorouracil (FU) administered by continuous infusion as neoadjuvant chemotherapy for patients with stage II-IV, M0 squamous cell carcinoma of the head and neck. Thirty previously untreated patients were submitted to chemotherapy with DDP (20 mg/m2) and FU (1000 mg/m2), both in continuous infusion for 5 days, repeated every 21 days, for a maximum of 5 cycles. Following completion of chemotherapy, the patients underwent radiotherapy; in some patients surgery was performed immediately after chemotherapy. All patients were monitored for response, time to failure, survival, treatment-related events and toxicity. All patients were evaluated for response; after chemotherapy the complete response rate was 27% and the partial response rate 33%. Twenty-four patients underwent radiotherapy: the overall response rate was 83% (complete response 79%). After a median follow-up of 34 months, the median survival time was 22 months with a median time to failure of 15 months. Acute vascular accidents were the main and unexpected adverse events, with 2 deaths for pulmonary embolism and 1 for stroke. The response rate to the regimen does not seem to be better than that obtained with the standard combination of cisplatin bolus and fluorouracil continuous infusion. The disadvantage of the regimen is that it causes more discomfort for the patient in that it requires hospitalization. For this reason, we believe that there are no elements for recommending the schedule as neoadjuvant treatment of patients with squamous cell carcinoma of the head and neck or as an experimental arm in a randomized trial.

Concurrent Cisplatin and Radiotherapy for Patients with Muscle Invasive Bladder Cancer Who are not Candidates for Radical Cystectomy

Purpose We assessed the results and prognostic factors in patients with bladder cancer treated conservatively with concurrent cisplatin and radiotherapy. Materials and Methods A total of 109 patients with localized muscle invasive bladder cancer who were not candidates for radical cystectomy underwent concomitant chemotherapy and radiation. Median patient age was 70 years. Of the patients 36 percent had stages T3B and 4 tumors, and 37 percent had benefited from prior macroscopically complete transurethral resection. Pelvic irradiation consisted of 40 to 45 Gy., and was followed by a boost to the bladder to a total dose of 55 to 60 Gy. Continuous infusion cisplatin (20 to 25 mg./m. 2 daily for 5 days) was delivered during weeks 2 and 5 of radiation therapy. Results Median followup was 54.8 months. The projected 4-year locoregional control rate was 47.6 percent for the 109 patients and 61.2 percent for 76 with a complete response. Projected overall 4-year survival was 41.9 percent for all patients and 51.4 percent for complete responders. Univariate analysis of prognostic factors was done for local control and survival. Local control was statistically better in patients with a good performance status, stages T2 and 3A disease, complete initial transurethral resection and without hydronephrosis. In terms of overall survival 4 factors were significant: 1) performance status, 2) T stage, 3) absence of hydronephrosis and 4) complete response. By multivariate analysis performance status, hydronephrosis and T stage were significant factors for local control, while T stage and complete response were the strongest determinants for survival. Conclusions Concurrent cisplatin and radiation therapy is a potentially curative and conservative treatment for patients with localized muscle invasive bladder cancer who are not candidates for radical surgery, particularly those with intravesical stages T2 and T3A tumors.

Extended intraarterial cisplatin infusion for treatment of gynecologic cancer after alteration of intrapelvic blood flow and implantation of a vascular access device.

Twenty-two patients with advanced gynecologic cancer underwent extended intraarterial cisplatin infusion after alteration of the intrapelvic blood flow and implantation of a vascular access device (VAD). To maximize concentrations of cisplatin at the target lesion, the superior and inferior gluteal arteries were embolized with steel coils. The tip of the catheter was inserted into the internal iliac artery; the opposite end of the catheter was connected to the VAD. Intensive radioisotope accumulation was demonstrated in the anterior division of the pelvis, seen by scintigraphy performed with technetium 99m macroaggregated albumin via the VAD. Local perfusion in the tumor was well seen by ultrasonographic angiography with CO2 microbubbles via the VAD. Continuous consecutive infusion of cisplatin at a rate of 12.5 mg/day via the VAD minimized the toxicity. The overall response rate was 73%. Radical surgery was possible in 16 of the 22 patients after this intraarterial infusion. This method was useful for treating advanced gynecologic cancer without significant toxicity.

Concurrent 72-Hour Continuous Infusion of Etoposide and Cisplatin in Metastatic Breast Cancer

We conducted a multiinstitutional phase II clinical trial to determine the toxicity, response, and survival rate of concurrent 72-h continuous infusion of etoposide and cisplatin in patients with metastatic breast cancer. A total of 26 women were enrolled, 4 of whom received no prior chemotherapy for metastatic disease. All patients were evaluated for toxicity, response, and survival employing the National Cancer Institute (NCI) Common Toxicity Criteria and the Eastern Cooperative Oncology Group (ECOG) response criteria. A total of 84 cycles of therapy were administered, median 3 (range 1 to 6). Severe grade 3 and grade 4 neutropenia occurred in 22 cycles (26%), and there were only 11 episodes (11%) of similar grade thrombocytopenia. Nausea and vomiting were seen in one third of cycles. A single patient (4%) had a complete remission, and seven patients (27%) had partial remissions for an overall objective response rate of 31% (95% confidence interval, 13 to 49%). Three of four patients (75%) without prior therapy for metastatic disease had objective responses. Median survival was 7 months. This combination regimen is active in extensively treated patients with metastatic breast cancer. It is responsible to further investigate the role of etoposide-cisplatin combination chemotherapy as firstline therapy for patients with metastatic breast cancer.

Cisplatin, 5-Fluorouracil, and High-Dose Folinic Acid in Patients with Advanced Unresectable Head and Neck Cancer

For patients with advanced, unresectable head and neck (HN) cancer, surgery and/or radiotherapy are the standard treatments but have poor results. A phase II trial of a continuous infusion of cisplatin, 5-FU, and high dose folinic acid (PFL) as induction chemotherapy in patients with previously untreated, locally advanced HN cancer was performed in an attempt to confirm the encouraging results reported by Dana Farber investigators using an identical regimen. Forty-five consecutive patients with unresectable HN cancer were treated every 28 days with a continuous infusion of cisplatin 25 mg/m(2)/day (days 1-5), 5-FU 800 mg/m(2)/day (days 2-6), and folinic acid 500 mg/m(2)/day (days 1-6). After three courses of chemotherapy, patients were treated with surgery and/or radiotherapy. Objective responses were observed in 26 of 38(69%) evaluable patients with 14(37%) clinical complete responses. Grade III-IV toxicity was important and consisted mainly of mucositis and neutropenia that were found in 47 and 18%, respectively , of patients after the first course. There was one toxic death. PFL is an active, toxic induction regimen for far-advanced HN cancer, yielding a response rate in the range of the widely used cisplatin and 5-FU (PF) schedule; a comparative trial is warranted before concluding that PFL is superior to the latter combination.

Preoperative Infusional Chemoradiation, Selective Intraoperative Radiation, and Resection for Locally Advanced Pelvic Recurrence of Colorectal Adenocarcinoma

The results of preoperative infusional chemoradiation, resection, and selective intraoperative radiation (IORT) boost in 43 previously nonirradiated patients with locally advanced pelvic recurrence of colorectal adenocarcinoma are described. After surgery alone 10% to 30% of patients with carcinoma of the distal colon and rectum will develop isolated pelvic recurrence. In most cases, the disease is locally advanced and not amenable to curative resection. Preoperative infusional chemoradiation has been shown to increase resectability and decrease local recurrence in primary locally advanced colorectal cancer. Based on this experience, we initiated a multimodality treatment protocol to treat patients with pelvic recurrence of colorectal adenocarcinoma. Forty-three consecutive patients with histologically proven pelvic recurrence of colorectal adenocarcinoma were enrolled on a multimodality treatment protocol. The treatment plan consisted of 5 weeks of concurrent pelvic external beam radiotherapy (45 Gy) with continuous intravenous infusion of 5-fluorouracil and/or cisplatin. This was followed by surgery that included IORT boost (10-20 Gy) for 21 patients and brachytherapy for 4 patients. Forty patients (93%) underwent operation and 33 (77%) underwent resection with curative intent. There were 29 (88%) margin-negative resections. Fifteen patients (48%) underwent sphincter-preserving operations. There were no treatment-related deaths. Twenty-two patients experience perioperative complications. Median follow-up for the 43 patients was 26 months. The local recurrence rate was 36%. Median survival for the patients who underwent resection was 34 months, and actuarial 5-year disease-free and overall survival were 37% and 58%, respectively. Tumor cytoreduction by preoperative chemoradiation can increase resectability and enable sphincter-preserving surgery in patients with locally advanced pelvic recurrence of colorectal cancer.

A phase I trial of 5-day continuous infusion cisplatin and interferon α

A phase I trial of 5-day continuous infusion cisplatin and interferon α

Prolonged Continuous Infusion Cisplatin and 5-Fluorouracil with Radiation for Locally Advanced Carcinoma of the Vulva

Twelve patients ages 37-85 years (mean, 59 years) with locoregionally advanced vulvar carcinoma were treated with a combination of irradiation and chemotherapy using prolonged continuous infusions of 5-fluorouracil (5-FU) and cisplatin. Eleven patients had advanced vulvar disease with tumors 5-18 cm in maximum diameter (mean, 8.7 cm), eight had palpable inguinal nodes with biopsy-proven metastatic carcinoma, and five had fixed nodes. Patients received weekly 96-hr infusions of cisplatin (4 mg/m 2/day) and 5-FU (250 mg/m 2/day) for a total of 64 mg/m 2 of cisplatin and 4 g/m 2 of 5-FU in 4 weeks. Concurrent radiation therapy was delivered to the lower pelvis, vulva, and inguinal nodes to a total dose of 40-50 Gy at 2 Gy per fraction in 11 patients. One patient who had been previously treated for cervical cancer received radiation only to the vulva with an appositional electron beam field. Chemoradiation was well tolerated with virtually no hematologic toxicity and no unscheduled breaks in treatment. Eleven of 12 patients had at least a partial clinical response; one patient had a minimal response of unresectable vulvar disease. Of eight patients who underwent vulvar resection 6 weeks after chemoradiation, four had no residual disease in the resected vulvar specimen and remain disease-free 17, 20, 25, and 37 months, respectively, after surgery. Another patient is disease-free 28 months after a complete clinical response without vulvar resection. However, of four patients who had residual disease in the vulvar surgical specimen, disease has recurred within the irradiation field in three. Overall, 6 of 12 patients treated with this chemoradiation regimen remain disease-free 17-30 months after treatment. This is a well-tolerated outpatient regimen that yields a high response rate in patients with massive vulvar carcinomas.

Ambulatory low-toxicity chemotherapy in non-small-cell lung carcinoma by continuous 28-day infusion of alternating cisplatin and 5-fluorouracil

One regimen consisting of a continuous infusion of cisplatin and fluorouracil was designed to be minimally toxic, and suitable for application with radiotherapy in non-small-cell lung carcinoma (NSCLC). Forty-four NSCLC patients received daily 8 mg/m2 of cisplatin on days 1-2, 8-9, 15-16, 22-23, and 300 mg/m2 of fluorouracil on days 3-7, 10-14, 17-21, 24-28 (35-day courses). Two patients experienced grade 3-4 toxicities. Eleven achieved objective responses. The median progression-free and observed survival was 22 and 39.5 weeks. The schedule management was fully ambulatory. Toxicity was negligible. The activity was moderate, but the combination with radiotherapy is advisable due to the radioenhancing properties of both of the drugs.

Accelerated induction therapy and resection for poor prognosis stage III non-small cell lung cancer

Induction therapy and resection may improve the survival of patients with poor prognosis stage III non-small cell lung cancer, at the cost of significant treatment prolongation. The purpose of this study was to assess toxicity, response, and survival of an accelerated induction regimen and resection in poor prognosis stage III non-small cell lung cancer. Forty-two surgically staged patients with poor prognosis stage III non-small cell lung cancer received 11 days of induction treatment consisting of 96 hours of continuous chemotherapy infusions of cisplatin (20 mg.m-2.day-2), 5 fluorouracil (1,000 mg.m-2.day-2), and etoposide (75 mg.m-2.day-2) concurrent with accelerated fractionation radiation therapy (1.5 Gy twice a day, to a dose of 27 Gy). Induction was followed in 4 weeks by resection. Postoperatively, a second course of continuous chemotherapy and concurrent accelerated fractionation radiation therapy (postoperative dose 13 to 36 Gy) was given. Despite some degree of induction toxicity in all patients there was only one induction death (2.4%). A clinical partial response was seen in 24 patients (57%). Thirty-six patients (86%) underwent thoracotomy, and resection was possible in 33 (79%). Pathologic downstaging was seen in 17 patients (40%), and 2 patients (5%) had no residual carcinoma at operation. There were 11 postoperative complications (31%) and 4 postoperative deaths (11%). Thirteen patients (31%) are alive and disease-free, 24 (57%) have persistent disease or have recurred (15 distant, 5 locoregional, 4 both), and 9 patients are alive with disease. The median survival is 21 months and the 2-year Kaplan-Meier survival is 43%, with no differences identified between stages IIIA and IIIB patients (p = 0.63). We conclude that accelerated induction therapy and resection in poor prognosis stage III non-small cell lung cancer (1) is toxic, with a 12% treatment mortality; (2) is effective with a 79% resection rate and 40% pathologic downstaging rate; (3) provides excellent local control; (4) may prolong survival; and (5) is of value in stage IIIB as well as stage IIIA patients.

Phase II study of a continuous five-day intravenous infusion of cisplatin and etoposide with concurrent chest radiation therapy in limited stage small cell lung cancer: Sugita T, Matsunaga K, Kobayashi H, Horikawa S, Suzuki Y, Nishiyama H et al. Dept. of Respiratory Medicine, Wakayama Red Cross Hospital, Wakayama. Jpn J Cancer Chemother 1994;21:2479–2483

The efficacy of continuous five-day intravenous infusion of cisplatin (CDDP) and etoposide with concurrent chest radiation therapy was evaluated in patients with limited stage small cell lung cancer. The first group of patients registered from February 1989 to September 1990 received three courses of chemotherapy (CDDP 20 mg/m2/day x 5 days, etoposide 40 mg/m2/day x 5 days) and concurrent chest radiation therapy on the third course with dose reduction of etoposide. The second group of patients registered after February 1991 received four courses of chemotherapy (CDDP 20 mg/m2/day x 5 days, etoposide 50 mg/m2/day x 5 days) and concurrent chest radiation therapy on the first and second courses with dose reduction of etoposide. The response rates were 91.7% and 93.3%, respectively. The median duration of survival was 32.0 months and 20.1 months, respectively. Major toxicity was leukocytopenia and 64% and 80% of patients encountered leukocytopenia of Grade 3 or 4. In conclusion, these regimens show remarkable efficacy with acceptable toxicity.

Plasma 5-fluorouracil and α-fluoro-β-alanin accumulation in lung cabcer patients treated with continuous infusion of cisplatin and 5-fluorouracil: Thiberville L, Compagnon P, Moore N, Bastian G, Richard MO, Hellot MF et al. Clinique Pneumologique, CHU de Rouen, 1 rue de Germont, F-76031 Rouen Cedex. Cancer Chemother Pharmacol 1994;35:64–70

Plasma 5-fluorouracil and α-fluoro-β-alanin accumulation in lung cabcer patients treated with continuous infusion of cisplatin and 5-fluorouracil: Thiberville L, Compagnon P, Moore N, Bastian G, Richard MO, Hellot MF et al. Clinique Pneumologique, CHU de Rouen, 1 rue de Germont, F-76031 Rouen Cedex. Cancer Chemother Pharmacol 1994;35:64–70

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.

Plasma 5-fluorouracil and ?-fluoro-?-alanin accumulation in lung cancer patients treated with continuous infusion of cisplatin and 5-fluorouracil

Plasma 5-fluorouracil and ?-fluoro-?-alanin accumulation in lung cancer patients treated with continuous infusion of cisplatin and 5-fluorouracil

T4 and/or N2 non-resectable non small-cell lung carcinoma (NSCLC): Continuous infusion of cisplatin and concurrent radiotherapy (plus adjuvant surgery) : G Ravasi, AV Bedini, L Tavecchio, F Milani, A Gramaglia, S Villa, M Palazzi. Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano. Italy

T4 and/or N2 non-resectable non small-cell lung carcinoma (NSCLC): Continuous infusion of cisplatin and concurrent radiotherapy (plus adjuvant surgery) : G Ravasi, AV Bedini, L Tavecchio, F Milani, A Gramaglia, S Villa, M Palazzi. Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano. Italy