Future directions in the treatment of non-small cell lung cancer.

In recent years significant advances have been made in the treatment of metastatic non-small cell lung cancer. These advances have been due to both the discovery of new, more active drugs and an enhanced understanding of the biology of the disease, which has guided treatment decisions. Today, agents such as paclitaxel, docetaxel, vinorelbine, irinotecan, and gemcitabine are used in combinations that have demonstrated higher overall response rates and longer median overall survival durations than the previous generation of regimens based primarily on cisplatin, etoposide, and vinblastine. Of these new agents, paclitaxel has been the most widely studied and has demonstrated considerable activity when administered in a wide range of doses and schedules. Regimens with significant activity include paclitaxel and carboplatin as well as paclitaxel, carboplatin, and gemcitabine. However, because the optimal doses and schedules have not been clearly elucidated, current research efforts continue to focus on variations of these regimens. Just as advances have been made in the treatment of metastatic disease, it also has been clearly demonstrated that preoperative chemotherapy (+/- radiation) dramatically improves the overall survival for patients with stage III disease. The identification of growth factors, growth factor receptors, oncogenes, and tumor suppressor genes, which influence this disease, is providing new targets for future treatment strategies. Likewise, new therapeutic entities such as antiangiogenesis agents and matrix metalloproteinase inhibitors are being evaluated.

Outcomes of antiemetic therapy after the administration of high-dose antineoplastic agents.

Patterns of antiemetic therapy and its outcomes in patients undergoing high-dose antineoplastic therapy were studied. The study, conducted at a cancer center, included both a retrospective evaluation of patients undergoing highly emetogenic high-dose chemotherapy with peripheral blood stem-cell rescue between November 1994 and December 1995 and a concurrent evaluation of patients treated between January and May 1996. During the study period the recommended antiemetic regimen for highly emetogenic chemotherapy was a single dose of granisetron 1 mg i.v. daily 30 minutes before treatment on days of chemotherapy. Severity of nausea and vomiting during both the acute phase (from day 1 of chemotherapy to 24 hours after its completion) and delayed phase (from 24 hours to five days after the end of chemotherapy) was graded according to the Common Toxicity Criteria Grading Scale. A total of 59 patients were evaluable; 41 were reviewed retrospectively, and 18 were reviewed concurrently. On day 1 of the acute phase, 53 patients (90%) had no vomiting and 51 patients (86%) had no nausea. The frequency and severity of nausea and vomiting increased on successive acute-phase days, and it was necessary to add other antiemetics. Nausea and vomiting continued to be significant problems throughout the delayed phase; 32 (54%) of the patients had a maximum of grade 3 nausea, and 29 patients (49%) had a maximum of grade 2 vomiting. Substantial numbers of patients who received selective serotonin type 3 receptor antagonists before high-dose antineoplastic agents had significant nausea and vomiting that required the addition of other antiemetics.

Patient care issues: the management of paclitaxel-related toxicities.

At the low-to-moderate doses that are recommended, paclitaxel is a well-tolerated drug. Although adverse reactions do occur, most of these are manageable and do not have a long-lasting effect on the patients' quality of life. The starting dose of paclitaxel, as approved by the Food and Drug Administration for refractory ovarian cancer, is 135 mg/m2. A slightly higher dose (175 mg/m2) is being investigated for heavily pretreated patients with metastatic breast cancer. In the investigational setting, the highest dose that may safely be administered when paclitaxel is used as a single agent is 250 mg/m2 for minimally pretreated patients. If G-CSF is also given, the same dose may safely be administered to heavily pretreated patients. When paclitaxel is administered in combination with cisplatin, a dose of 135 mg/m2 may safely be given prior to cisplatin, which is administered at a dose of 75 mg/m2. These dose levels may be increased when G-CSF is also used. Dose modifications should be considered only in patients who experience severe neutropenia or neurotoxicity. Patients who received high doses of paclitaxel in Phase II trials frequently required dose reductions. However, when the drug is administered at the recommended dose of 135 mg/m2, neutropenia does not often necessitate further dose reduction. Hematopoietic growth factors, such as G-CSF, seem to be helpful in preventing prolonged grade IV and febrile neutropenia, and in avoiding treatment delays for longer than one week.(ABSTRACT TRUNCATED AT 250 WORDS)

Double beta-lactam regimen compared to an aminoglycoside/beta-lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.

In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C +/- T), both agents being administered only if the initial granulocyte count was below 200/microliters, or ceftazidime plus piperacillin (C + P). The overall response rate was 71% (39 of 60 for C +/- T and 45 of 58 for C + P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C + P regimen (P = 0.06), there was no difference in response for patients with bacteremia and profound (< 100/microliters) sustained granulocytopenia. The double beta-lactam combination demonstrated in vitro synergism in 73%; antagonism was not seen. Both regimens produced excellent serum bactericidal levels (C +/- T geometric mean peak 1:170; C + P peak 1:137) against gram-negative but not gram-positive pathogens (1:4; 1:7 respectively) that had caused bacteremia. Emergence of resistance and significant coagulopathy and/or bleeding did not occur during therapy. Antibiotic-related nephrotoxicity was noted in 7 of 95 trials in the C + P and in 6 of 89 trials in the C +/- T group (P = 0.19). The incidence of secondary infections in patients with profound (< 100/microliters) sustained granulocytopenia was lower in the C +/- T group (P = 0.04). Alimentary canal anaerobic flora preservation with C +/- T, and suppression with C + P, was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug interactions in the oncology patient.

Cancer patients receiving chemotherapy often require a wide range of drugs to manage symptoms of their cancer, the side effects of the chemotherapy or radiation therapy, and other concomitant illnesses. The greater number of drugs the patient receives the greater the chance of adverse reactions. Clinical drug interactions may be direct, indirect, and additive. Toxicity or an altered therapeutic response secondary to a drug interaction may affect the cancer patient's ability to tolerate and safely receive chemotherapy.

Fludarabine: a review.

The new fluorinated adenine analog, fludarabine, has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are currently available for commercial use. Cytarabine is used principally as an antileukemic agent, and vidarabine as an antiviral. Unlike vidarabine, fludarabine is resistant to deactivation by adenosine deaminase. Data from Phase I and II trials suggest that fludarabine is potentially effective in a number of leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, and chronic lymphocytic leukemia (CLL). Unfortunately, the doses required to achieve adequate response in the acute leukemias (greater than 75 mg/m2) were above the maximum tolerated dose, resulting in intolerable granulocytopenia, thrombocytopenia, and a life-threatening neurotoxic syndrome. In CLL: however, the dose required to achieve a satisfactory response is well within tolerated limits. Long-term survival statistics are not yet available, but historical perspective strongly correlates response to other agents with increased survival times. Toxicities seen at dose regimens of 15-40 mg/m2/d for five consecutive days include somnolence, metabolic acidosis, confusion, fatigue, nausea, vomiting, increase in serum creatinine and aminotransferase concentrations, and pulmonary and hepatic abnormalities. Mild to severe hematologic toxicity has been observed at all dose levels.

Measuring the cost-effectiveness of hematopoietic growth factor therapy.

The increasing cost of and demand for health care have intensified the concern that some form of health care rationing is inevitable. Cost studies require the identification, measurement, and comparison of all significant positive and negative consequences of alternative interventions and may evaluate benefit value, effectiveness, and effect on quality or quantity of life. The hematopoietic growth factors (HGF) will have far-reaching effect on the practice of medicine and, therefore, the design of cost-effectiveness studies are critically important in assessing economic effect.

Pain management with spinally administered opioids.

The use of spinally administered opioids to manage pain is discussed. Central action on opioid receptors of the substantia gelatinosa allows opioids to be administered spinally for pain originating anywhere inferior to the cranial nerves. Spinal opioids are most commonly administered for intractable midline sacral and perineal pain. The best candidates for spinal opioids are patients in whom appropriate "conventional" therapy no longer provides adequate relief, patients who experience severe adverse effects from conventional therapy, and patients for whom alternative anesthetic procedures are inappropriate or have failed. A reasonably safe initial dose is morphine sulfate 1 mg intrathecally. The availability of preservative-free, concentrated morphine sulfate enables larger doses to be safely and comfortably administered. Increased dosage requirements may result from tolerance, progression of disease, increased systemic absorption, or slippage of the catheter tip. As with systemically administered opioids, care must be exercised when discontinuing spinal opioid therapy. Adjuvant drugs used with spinal opioids include systemically administered analgesics, antidepressants, corticosteroids, and spinal local anesthetics. The administration of spinal opioids with systemic opioids or other CNS depressants may result in excessive sedation, respiratory depression, nausea, vomiting, constipation, pruritus, and other adverse effects. Spinally administered opioids can be used to manage severe chronic pain effectively, safely, and comfortably.

Lung cancer: detection, prevention, and therapeutics.

Lung cancer remains the leading cause of cancer death in the U.S. adult population, and the American Cancer Society estimates that cigarette smoking is responsible for about 83% of all lung cancer cases. It is unlikely that significant reductions in the incidence and mortality associated with lung cancer will be realized without effective antismoking campaigns. Surgery, radiation therapy, and chemotherapy all play a role in the management of lung cancer. At the current time, NSCLC is generally curable only if it is diagnosed while the tumor is small and localized and can be surgically removed. Radiation therapy may also be effective in localized cases. Combination chemotherapy regimens have not consistently produced quality responses in patients with advanced tumors; however, newer regimens utilizing high doses of cisplatin, mitomycin and vinca alkaloids, or cisplatin and etoposide have produced encouraging results. In contrast to NSCLC, SCLC is responsive to combination chemotherapy regimens. Although many different agents are effective in this disease, most small-cell tumors eventually become refractory to chemotherapy and most patients do not survive longer than two years. Although progress has been made in the understanding and management of lung cancer, effective therapies that consistently produce major and durable responses are still lacking. Clinical trials must continue to evaluate therapeutic modalities for all types of lung cancer.

Norfloxacin for prevention of bacterial infections in granulocytopenic patients.

The efficacy and safety of norfloxacin were compared with those of placebo, vancomycin-polymyxin, and trimethoprim-sulfamethoxazole (TMP/SMX) for prophylaxis of bacterial infections in granulocytopenic patients. The study results showed that norfloxacin treatment, which was well tolerated and not associated with any serious systemic adverse effects, prevented acquisition of gram-negative bacillary organisms. Fewer norfloxacin-treated patients (38 of 108 patients, or 35 percent) experienced microbiologically documented infections compared with patients receiving placebo (27 of 40 patients, or 68 percent), vancomycin-polymyxin (16 of 30 patients, or 53 percent), or TMP/SMX (14 of 28 patients, or 50 percent). Gram-negative bacteremia developed in five of 108 norfloxacin-treated patients (5 percent), compared with 17 of 40 placebo-treated patients (43 percent), five of 30 treated with vancomycin-polymyxin (17 percent), and one of 28 patients treated with TMP/SMX (4 percent). The incidence of gram-positive bacteremia was similar in all study groups and was not affected by norfloxacin or any other oral prophylactic antibiotics. These results suggest that norfloxacin is both safe and effective for the prevention of serious gram-negative bacillary infections in granulocytopenic patients. More effective prophylaxis of gram-positive bacterial infections, however, is needed.

A double beta-lactam combination versus an aminoglycoside-containing regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients.

The double beta-lactam combination of moxalactam plus piperacillin was compared with the aminoglycoside-containing regimen of moxalactam plus amikacin in a prospective, randomized trial of empiric therapy for 302 febrile episodes in granulocytopenic cancer patients. The moxalactam/piperacillin regimen was found to be as effective as the moxalactam/amikacin regimen (70 percent overall responses); responses with moxalactam/piperacillin and moxalactam/amikacin were similar for microbiologically documented infections (24 of 37, 65 percent, versus 20 of 35, 57 percent), for the subgroup with bacteremias (19 of 32 versus 14 of 28), and for clinically documented infections (41 of 58, 71 percent, versus 40 of 48, 83 percent). Responses were similar also for bacteremia in patients with persistent, profound (less than 100/microliter) granulocytopenia. Among profoundly (less than 100/microliter) granulocytopenic patients with gram-negative bacteremia, an increase in the granulocyte count to more than 100/microliter during therapy and a peak bactericidal activity of 1:16 or more (the latter noted in seven of nine moxalactam/piperacillin trials and six of nine moxalactam/amikacin trials) correlated with a favorable clinical response in 85 percent (p less than or equal to 0.00003) and 92 percent (p less than or equal to 0.044), respectively. Although serious side effects were minimal with either regimen, the double beta-lactam combination was associated with significantly less frequent nephrotoxicity (two of 145 versus 12 of 130; p less than or equal to 0.003) and ototoxicity (none of 34 versus seven of 34; p less than or equal to 0.006). The double beta-lactam combination of moxalactam plus piperacillin was found to be as effective as moxalactam plus amikacin but to have significantly less nephro- and ototoxicity.

Cisplatin nephrotoxicity: a summary of preventative interventions.

Nephrotoxicity is usually the dose-limiting toxicity associated with cisplatin therapy. Frequently the nephrotoxicity is mild and reversible. However, it is both dose-related and cumulative and may become life-threatening and irreversible at higher dosages. Many interventions such as vigorous hydration, osmotic or loop diuretics, and alterations of infusion times have been evaluated in the hope of ameliorating this serious toxicity, and are summarized. More recently, hypertonic NaCl 0.9% has been reported to decrease the incidence of cisplatin nephrotoxicity. In addition, newer platinum analogs are currently undergoing clinical trials to ascertain if they retain the antitumor properties of cisplatin but produce less toxicity.

Combination antiemetic therapy in the control of chemotherapy-induced emesis.

Severe nausea and vomiting are frequent complications of cancer chemotherapy. Historically, single-agent antiemetic therapy frequently has been less than optimal. Because multiple sites of emetogenic activity may be involved in chemotherapy-induced nausea and vomiting, many investigators are now using combinations of antiemetics in an effort to block multiple receptor sites. Several preliminary studies using combinations of antiemetic agents that have shown encouraging results are summarized.

Trimethoprim/sulfamethoxazole versus placebo: a double-blind comparison of infection prophylaxis in patients with small cell carcinoma of the lung.

The suppression of pathogenic aerobes and the preservation of anaerobes provides a degree of infection prevention during granulocytopenia. Trimethoprim/sulfamethoxazole (TMP/SMZ) suppresses Enterobacteriaceae and probably maintains colonization resistance through sparing of anaerobes. TMP/SMZ (320/1600 mg/day) treatment was compared to placebo in a double-blind, randomized trial in patients with newly diagnosed small cell carcinoma of the lung during the initial courses of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. Infections were evaluated as microbiologically documented, with or without bacteremia, and clinically documented and were correlated to granulocytopenia. Of the 61 patients evaluated, 32 were given TMP/SMZ and 29 were given placebo; both groups had similar characteristics with regard to disease extent, performance status, age, sex, chemotherapy, and days of granulocytopenia. Incidence of infection at less than 100 granulocytes/microliters was significantly reduced in the TMP/SMZ group (2 infections/100 days) compared to placebo (11 infections/100 days, p = 0.005). Also reduced were the number of bacteremias and the mean proportion of study time on broad-spectrum antibiotics (p less than 0.01). Compared to placebo, TMP/SMZ provided infection prophylaxis without an increase in marrow suppression among patients with small cell carcinoma of the lung receiving intensive chemotherapy.

Piperacillin sodium: antibacterial spectrum, pharmacokinetics, clinical efficacy, and adverse reactions.

Piperacillin sodium is a beta lactam antibiotic with a broad range of antibacterial activity that includes gram-negative bacilli, gram-positive cocci (except penicillinase-producing S. aureus) and anaerobic pathogens such as Clostridium difficile, and Bacteroides fragilis. Piperacillin inhibits many of the members of the Enterobacteriaceae, including Klebsiella sp and Pseudomonas, at lower concentrations than required for carbenicillin and ticarcillin. Piperacillin sodium is administered by intramuscular and intravenous injection and is widely distributed throughout body fluids and tissues. Like other newer penicillins, piperacillin is excreted by both renal and biliary mechanisms. The primary route of elimination is by glomerular filtration, which results in high urinary concentrations of the unchanged compound. Piperacillin has been approved for patients with serious infection caused by susceptible strains of specific organisms in intra-abdominal, urinary tract, gynecologic, lower respiratory tract, skin and skin structure, bone and joint, and gonococcal infections and septicemia. As with other penicillins, piperacillin has a low frequency of toxicity. The usual dose of piperacillin in adults with serious infections with normal renal function is 3-4 g every 4-6 hr as a 20-30 min infusion, with a maximum dose of 24 g per day. It is stable in most large volume parenteral solutions. Less serious infectins (requiring smaller dosages) may be treated by intramuscular injection; however, no more than 2 g should be given at any one injection site. Overall, piperacillin has a greater degree of activity than other penicillins. Evidence from prospective studies indicates that piperacillin is a highly effective agent for the treatment of patients with infections caused by susceptible organisms.

Comparison of standard versus pharmacokinetically adjusted amikacin dosing in granulocytopenic cancer patients.

The capabilities of two pharmacokinetic amikacin dosing methods were evaluated and compared with the standard amikacin dosage recommended by the manufacturer. Study patients participated in two consecutive prospective randomized double-blind trials of empiric antibiotic therapy for febrile episodes during granulocytopenia. Patients in study 1 received amikacin at a dosage of 15 mg/kg per day in four divided doses in combination with either ticarcillin or piperacillin. Patients in study 2 received either ticarcillin or moxalactam in combination with amikacin. Amikacin dosages in study 2 were adjusted to achieve a 1-h-postinfusion concentration of approximately 25 micrograms/ml and a trough concentration of approximately 8 micrograms/ml. Initial amikacin dosage requirements were established based on the lean body weight and estimated renal function of the patient. If amikacin serum concentrations were not within acceptable ranges, further dosage adjustments were made by using patient-specific pharmacokinetic parameters. The median 1-h-postinfusion concentration of amikacin in study 1 was 13.0 micrograms/ml, with a median trough concentration of 6.1 micrograms/ml. In study 2 the median 1-h-postinfusion concentration was 20.8 micrograms/ml, with a median trough of 6.4 micrograms/ml. Patients in study 2 required a mean dosage of 29.4 mg/kg per day. The incidence of amikacin-induced nephrotoxicity was not increased despite the substantial increase in dosage. Ototoxicity was not evaluated in study 1, but the incidence of ototoxicity in study 2 (17%) exceeded the incidence observed in a previous amikacin-plus-ticarcillin trial in which patients received 15 mg of amikacin per kg per day.