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Survival has become the gold standard for determining the relative effectiveness of chemotherapy regimens in phase III clinical trials and is measured generally as the median survival. Response could be a surrogate for survival in evaluating clinical trials for chemotherapy, but it has become a controversial measurement parameter because of the quantitative variability in measurement and the fact that differences in response rates are not commonly translated into differences in survival. However, if response is indeed a determinant of survival, the median survival (the point at which 50% of the patients are alive) will not be impacted because response rates (RR) for most advanced cancers are less than 50%. Nonetheless, a survival benefit has been identified for tumors in which response rates are 50% or less in 4 phase III randomized trials; 2 in breast cancer (a high response-rate tumor) also show significant differences in survival. These data would imply that factors other than tumor response could be operative in influencing survival. It is a categorical truth that "responders" live longer than "nonresponders," but the response and survival relationship is complex and both parameters are important in clinical trials.

Background: Introduced into clinical usage in 1992 as a platinum analogue with a distinctively different toxicity profile from cisplatin, carboplatin has become a commonly preferred agent over cisplatin. The comparative therapeutic efficacy of the two agents remains controversial however, prompting an analysis of the phase III trials in ovarian cancer and other tumors in which the two were compared., Methods: Clinical trials comparing carboplatin with cisplatin, both as single agents and in combination with other agents, were analyzed within the tumors for which platinum has become a standard or commonly employed agent. A Medline search identifying the randomized trials and references from these reports were collated for analysis., Results: The original clinical comparative trials as well as literature reviews and commentaries were reviewed. Five solid tumors were identified within which comparative trials had been conducted: ovary, 10 trials; lung, 2 trials; head and neck, 2 trials; germ cell tumors, 3 trials and 1 trial in bladder cancer. Depending upon the end point selected, cisplatin was superior or equivalent to carboplatin in therapeutic efficacy in all five tumors but was associated with an increased toxicity profile for gastrointestinal, renal and neurologic effects., Conclusions: For some tumors, cisplatin appears to be superior to carboplatin in terms of therapeutic effectiveness (germ cell tumors, bladder cancer, head and neck cancer), while for others, effectiveness is comparable (lung cancer, ovarian cancer). Toxicity profiles are distinctly different for the two analogues however, generally favoring carboplatin. The issue of potential carboplatin underdosing related to the lack of physiologic dose calculations (utilizing the AUC [area under the curve] method) in the comparative trials of cis- versus carboplatin is probably not clinically important since a dose response effect has not been established for carboplatin or for cisplatin. The selection of the optimal platinum analogue to be employed is dependent on the type of tumor, the treatment intention (palliative vs. curative) and the other component drugs being used in combination.

Problem: The dose intensity (DI) and the maximum tolerated dose (MTD) of anti-neoplastic agents is assumed to be a critical factor for achieving optimal therapeutic benefit. Each of these factors may be influenced by the schedule of drug administration, specifically infusional or bolus delivery., Objective: To review the literature for selected antineoplastic drugs to analyze the relative DI and MTD for bolus vs. infusional administration schedules., Methods: Clinical reports of bolus and infusional delivery of chemotherapeutic drugs in the categories of antimetabolites; alkylating agents; antibiotics; plant alkaloids and platinum analogues were collected focusing on phase I studies establishing the MTD per cycle and the DI. Infusional schedules were defined as continuous parenteral administration for more than 24 hours or, in some instances, daily bolus dosing for one hour for 3 to 5 days. Bolus schedules were defined as administration over minutes up to 24 hours and also included daily dosing in some cases., Results: For antimetabolites, the infusional schedule generally decreases the MTD and DI relative to bolus administration but for 5-FU, the MTD and DI both increase. For alkylating agents and the platinum analogues, the MTD and DI for bolus and infusional delivery are generally comparable; but infusional administration results in a slightly increased MTD for thiotepa and for ifosfamide, the MTD is increased depending upon the duration of the infusion. For the antibiotics and the plant alkaloids, the MTD and DI of infusional administration is variable related to the specific agent and the infusion duration and may be increased, decreased or comparable to the MTD of bolus schedules., Conclusions: The MTD and DI for most cytotoxic agents administered by bolus versus infusional schedules is unpredictable and variable and is influenced by the infusion duration and the interval between treatment cycles (for example three versus four week intervals). The MTD and DI increase substantially with infusional delivery for thiotepa, 5-FU and VM26 (the latter in leukemia specifically) and decrease substantially for the antimetabolites FUDR, ara-C, methotrexate and 6MP. For most other agents and in all four drug categories, the MTD and DI are relatively comparable although for ifosfamide and topotecan, the duration of infusion determines whether the MTD and DI increases, decreases or stays the same relative to bolus administration. The use of cytokines may substantially change the MTD and DI especially for bolus administration since dose limiting toxicity is hematologic for many agents.

Clinical studies of infusional chemotherapy at The Cancer Center of Boston began in 1980 at the New England Deaconess Hospital and from 1986 to the present have continued under the auspices of a network of free-standing ambulatory cancer treatment centers in Massachusetts. Over 50 peer-reviewed articles on infusional chemotherapy and 3 textbooks on the topic have been published by clinical investigators associated with The Center, including phase I, II, and III trials, multidrug infusion programs, and combined chemo/radiotherapy programs. Bringing together the total experience in this review provides a perspective to address those areas that have been inadequately explored and a framework for future development in the field. This paper represents a comprehensive synthesis and analysis of clinical infusional studies carried out at The Center to the present with the goal of achieving those objectives.

The practice of infusional cancer chemotherapy has evolved over the past decade as our increased understanding of tumor cell kinetics and drug pharmacology has brought into focus the concentration x time formulation and its importance in tumor cell killing and host tolerance. Technologic advances have contributed substantially to the practical capability of infusional drug delivery, with improved vascular access and ambulatory infusion pumps. In the past 10 years, infusional schedules have been used for virtually every class of antineoplastic agent and have demonstrated an improved therapeutic index by reduced or altered toxicity (doxorubicin, fluorouracil, ifosfamide, platinum analogs) or increased tumor cell killing (fluorouracil, etoposide, cladribine). Although there are few phase III trials comparing infusion and bolus administration, the evidence is clear that toxicity is altered and therapeutic benefit is not diminished by infusional schedules of drug administration.

Technetium-99m macroaggregated albumin is used to assess the proper location and condition of a totally implanted venous and arterial access system prior to infusion therapy. The risk of drug extravasation is thus avoided. Delivery of the chemotherapeutic agents to the intended location is assured.

The preoperative use of chemotherapy in the management of soft tissue sarcoma is a recent concept in the multidisciplinary management of neoplasia related to the development of more effective drug combinations. The reason for chemotherapy preoperatively is to define the effectiveness of drug treatment, permitting a rational basis for long term adjuvant treatment. In addition, major surgical morbidity may be precluded if chemotherapy is effective, allowing lesser surgical procedures, such as limb-sparing local resection. Patient selection for this approach must be individualized and is based upon the major determinants of prognosis, including the stage of the tumor according to the TNM and G--grade--classification. Radiation therapy is an essential component of the multimodality approach to soft tissue sarcomas, and the interaction of all three therapeutic modalities must provide optimal tumor control and minimal morbidity.

Twenty-two of 53 (42%) patients developed subclavian vein thrombosis (SVT) while receiving chemotherapy for advanced malignancy by an ambulatory pump constant infusion delivery system. The median time to thrombosis was 30 days (range, 5-270 days). Seven patients (36%) were asymptomatic and received no specific anticoagulation. Twelve patients (50%) received heparin followed by coumadin for 2 to 3 months. None of the 19 patients developed complications of the SVT. In three patients (14%), acute SVT progressed to complete or partial superior vena cava syndrome. The use of fibrinolytic therapy was successful in all three patients, and was adequate to lead to complete clinical resolution. Predisposing factors in the patient population included: (1) decreased antithrombin III levels prior to catheter insertion; (2) intrathoracic tumor, possibly creating low flow rates; and (3) improper or suboptimal home management of the catheter. The development of SVT was not related to the chemotherapeutic agent infused or the duration of therapy. The frequency of SVT in this patient population necessitates consideration of prophylactic methods in high-risk patients.

One hundred twenty-four patients with metastatic malignancy were treated with four different single agent infusion programs by constant intravenous infusion for 30 or more days. Drug was administered via a tunneled subclavian line by a battery-driven peristaltic pump (Cormed model ML6) on an ambulatory basis. This schedule allowed for increased cumulative drug dose for 5-Fu, decreased tolerated dose for vinblastine, and comparable doses for adriamycin and mitomycin-C relative to that delivered with the standard intermittent bolus schedule. Therapeutic effects were observed for three of four drugs studied: 5-Fu 13/31 colorectal cancer; adriamycin 7/29; and vinblastine 4/12, including 2/4 melanoma. Adverse effects were significantly reduced, particularly with regard to gastrointestinal toxicity, but also in adriamycin-associated cardiac effects and hair loss. Phase III comparative trials of intermittent bolus therapy with protracted infusion therapy are in progress for 5-Fu in advanced colorectal cancer and for adriamycin in specific tumors. Ambulatory pump infusion (API) chemotherapy is technically feasible and has improved patient tolerance to chemotherapy while demonstrating similar, if not comparable, antitumor effects.

Fifty chemotherapy trials with 5-fluorouracil; mitomycin C; vinblastine; Adriamycin; and cis-platinol were initiated employing constant (24-hour) intravenous infusion for protracted periods (14-94 days). The use of the tunneled subclavian line for greater than 2200 patient days was associated with minimal complications and no instances of thrombosis or infection were observed. The use of an ambulatory infusion pump was associated with a pump efficiency of greater than 85% in 38 of 39 evaluable trials. Only four of 50 trials were associated with excess drug infusion and in no instance was a drug complication encountered. Constant infusion cancer chemotherapy is feasible, reliable, and safe. Objective tumor regression is observed but the superiority of this drug schedule over the standard intermittent bolus schedule is yet to be determined. Nonetheless, drug toxicity patterns are altered substantially and, in particular, gastrointestinal side effects of chemotherapeutic drugs may be eliminated without compromising cumulative dose.

The effects of short-term cancer chemotherapy on the liver-spleen scintiscans of 15 patients were assessed. Half of these exhibited minimal and transient changes in the pattern of radiocolloid distribution and/or chemical liver-function tests. No examples of new focal defects were seen. The data suggest that cytotoxic drugs are capable of inducing minor scan changes that might be attributed erroneously to intrinsic hepatic disease.

Prolonged central venous access for outpatient chemotherapy was achieved in 74 patients utilizing a totally implantable access disc system. The system consists of a stainless steel drug reservoir implanted in the subcutaneous tissue of the anterior chest wall. The reservoir is attached to a Silastic catheter which is then tunneled to a central vein and positioned in the superior vena cava. In 6,762 patient days of observation, there was a high degree of patient acceptance and a low incidence of complications. There were four instances of thrombosis and two of catheter-related sepsis among 17 complications. Seven access discs required removal. The implantable nature of this system offers an attractive alternative to other available methods of prolonged central venous access.

Objective tumor regression in response to therapy invariably results in prolonged patient survival and often improves the quality of remaining life. The author describes criteria for determining, and clinical guidelines for predicting, tumor response. Further, he reviews tactics of cancer chemotherapy with regard to dose-response relationships and kinetics of tumor response.

In this multi-institutional study of advanced gastric cancer, 73 patients were evaluable for response or survival. Patients were treated with either triazinate (Baker's antifol), standard-dose methotrexate, or ICRF-159 (razoxane). Objective responses were seen in four patients receiving Baker's antifol, in three receiving methotrexate, and in none receiving razoxane. Baker's antifol produced a median survival of 18 weeks and methotrexate and razoxane produced a median survival of 8 and 9 weeks, respectively. Seventy of the 73 patients entered in this study had been previously treated, most frequently with combination chemotherapy regimens containing 5-FU or doxorubicin. This study appears to demonstrate that Baker's antifol is an active drug for patients with advanced gastric cancer, according to both response and survival criteria. Examination of the pretreatment prognostic characteristics of the patients further suggests that a possible survival advantage is due to treatment with Baker's antifol rather than the prognostic characteristics of the patients.

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250?mg?m-2 twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.British Journal of Cancer (2004) 90, 1190-1197. doi:10.1038/sj.bjc.6601676 www.bjcancer.com Published online 24 February 2004 [ABSTRACT FROM AUTHOR]

Discusses the introduction of three oral fluoropyrimidine preparations to the antineoplastic armamentarium that has been a major step in providing a patient-convenient delivery system for 5-fluorouracil (5-FU). Benefit of three oral fluoropyrimidine; Process followed for the administration of 5-FU; Oral fluoropyrimidine that is processed in the body in three enzymatic steps.

Objective: To determine whether very low doses of warfarin are useful in thrombosis prophylaxis in patients with central venous catheters.Design: Patients at risk for thrombosis associated with chronic indwelling central venous catheters were prospectively and randomly assigned to receive or not to receive 1 mg of warfarin, beginning 3 days before catheter insertion and continuing for 90 days. Subclavian, innominate, and superior vena cava venograms were done at onset of thrombosis symptoms or after 90 days in the study.Results: One hundred twenty-one patients entered the study, and 82 patients completed the study. Of 42 patients completing the study while receiving warfarin, 4 had venogram-proven thrombosis. All 4 had symptoms from thrombosis. Of 40 patients completing the study while not receiving warfarin, 15 had venogram-proven thrombosis, and 10 had symptoms from thrombosis (P less than 0.001). There were no measurable changes in the coagulation values assayed due to this warfarin dose, except in occasional patients who had become anorectic because of their disease or chemotherapy.Conclusions: Very low doses of warfarin can protect against thrombosis without inducing a hemorrhagic state. This approach may be applicable to other groups of patients. [ABSTRACT FROM AUTHOR]