REVIEW

Chemotherapy-Induced Anemia in Adults: Incidence and Treatment

Jerome E. Groopman, Loretta M. Itri

Affiliations of authors: J. E. Groopman, Harvard Medical School and the Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, MA; L. M. Itri, Ortho Biotech Inc., Raritan, NJ.

Correspondence to: Jerome E. Groopman, M.D., Division of Experimental Medicine, Beth Israel Deaconess Medical Center, 4 Blackfan Circle, Suite 351, Boston, MA 02115.


    ABSTRACT
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 
Anemia is a common complication of myelosuppressive chemotherapy that results in a decreased functional capacity and quality of life (QOL) for cancer patients. Severe anemia is treated with red blood cell transfusions, but mild-to-moderate anemia in patients receiving chemotherapy has traditionally been managed conservatively on the basis of the perception that it was clinically unimportant. This practice has been reflected in the relative inattention to standardized and complete reporting of all degrees of chemotherapy-induced anemia. We undertook a comprehensive review of published chemotherapy trials of the most common single agents and combination chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults to characterize and to document the incidence and severity of chemotherapy-induced anemia. Despite identified limitations in the grading and reporting of treatment-related anemia, the results confirm a relatively high incidence of mild-to-moderate anemia. Recent advances in assessing the relationships of anemia, fatigue, and QOL in cancer patients are providing new insights into these closely related factors. Clinical data are emerging that suggest that mild-to-moderate chemotherapy-induced anemia results in a perceptible reduction in a patient's energy level and QOL. Future research may lead to new classifications of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. Perceptions by oncologists and patients that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient and as research provides further insights into the relationships between hemoglobin levels, patient well-being, and symptoms.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 
Although correction of severe anemia in patients undergoing chemotherapy requires red blood cell (RBC) transfusions, mild-to-moderate anemia in patients receiving chemotherapy for nonmyeloid malignancies has traditionally been managed conservatively, with little consideration of its impact on patient well-being (1). Until the early 1980s, RBC transfusions—which were usually administered empirically when hemoglobin concentrations declined below 10 g/dL (2,3)—were the primary treatment of cancer-related anemia, including chemotherapy-induced anemia; however, concern about the safety of the blood supply, related to potential transmission of the human immunodeficiency virus (HIV), prompted clinicians to alter their treatment approach (4). With no alternative to transfusion, treatment of mild-to-moderate anemia was generally avoided; intervention was withheld until hemoglobin concentrations declined to more severe levels (i.e., 7-8 g/dL) or the patient experienced signs and symptoms of severe anemia (2,5). As a consequence, the perception developed that anemia that did not reach the transfusion trigger point was clinically unimportant in otherwise uncompromised patients. These factors likely contributed to a tendency for anemia and its management to receive less attention in published chemotherapy trials and in the literature.

New data are emerging that demonstrate that chemotherapy-induced anemia (including mild-to-moderate anemia) has an adverse impact on quality of life (QOL) that can be improved with epoetin alfa treatment (6-8). With the introduction of a new generation of promising chemotherapeutic agents, such as the taxanes and camptothecins, there has been rapid evolution of chemotherapy treatments and regimens for many of the major tumors. In this context, we reviewed the incidence and severity of anemia in adults associated with both traditional and new chemotherapy regimens and the management of chemotherapy-related anemia.


    ASSESSING CHEMOTHERAPY-INDUCED ANEMIA AND ITS IMPACT
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 
Anemia is common in patients with cancer and is a frequent complication of myelosuppressive chemotherapy. The severity of anemia depends on the extent of disease and the intensity of treatment. Repeated cycles of chemotherapy may impair erythropoiesis cumulatively. The symptoms of anemia can reduce QOL. The most common patient complaints are fatigue and dyspnea on exertion, which can have adverse effects on a patient's ability to perform normal daily activities. Because QOL is gaining greater importance in evaluating outcomes of patient care and new clinical research has better characterized the relationship between anemia and QOL, perceptions and attitudes regarding the treatment of anemia, particularly degrees of anemia that have been considered of lesser clinical importance or necessary for patients to tolerate to avoid transfusions, require reassessment.

The National Cancer Institute (NCI) and the World Health Organization (WHO) toxicity criteria, two of the most commonly used standard criteria for the assessment of therapy-induced toxicity, are the same in their classification of more severe grades of anemia (grade 3, 6.5-7.9 g of hemoglobin/dL; grade 4, <6.5 g of hemoglobin/dL) but differ slightly in their classification of lesser grades (Table 1Go). The major cooperative groups in the United States also have their own toxicity grading criteria for anemia, which are similar or identical to the NCI Common Toxicity Criteria, i.e., grade 1 (mild), 10.0 g hemoglobin/dL to within normal limits; grade 2 (moderate), 8.0-10.0 g of hemoglobin/dL; grade 3 (serious or severe), 6.5-7.9 g of hemoglobin/dL; and grade 4 (life threatening), less than 6.5 g of hemoglobin/dL. Only in this decade has there been a substantial increase in the use of these standardized toxicity grading systems in chemotherapy evaluation and reporting. In addition, numerous reports in the literature fail to specify the toxicity grading system used, report anemia in terms of decreases in hemoglobin levels rather than by grade, or even omit information on the incidence or severity of anemia. As a result, it can be difficult to fully characterize and directly compare toxicity across different regimens and different trials as reported in the literature. The lack of treatment options for lesser degrees of anemia, coupled with the perceived relative clinical importance of other cytopenias (i.e., neutropenia or thrombocytopenia), likely contributed to the reduced attention to standardized and complete reporting of all degrees of chemotherapy-related anemia.


View this table:
[in this window]
[in a new window]
 
Table 1. Grading systems for anemia*

 
Unfortunately, none of the standard toxicity grading systems, including the WHO and NCI toxicity criteria, are capable of clearly relating anemia, as measured by a numeric gradient in hemoglobin, to clinical symptomatology or to the patient's well-being. Evaluating fatigue, one of the cardinal symptoms of anemia, presents additional problems. Fatigue is the most frequently reported symptom in cancer patients, affecting an estimated 80% to almost 100% of the patients receiving anticancer therapy (9-11). Despite its high prevalence, fatigue is seldom discussed by patients and their oncologists, and it is infrequently treated (10,12). Fatigue can be physically and emotionally distressing to patients, causing some to withdraw from potentially curative treatment (13). Of all anemia-related symptoms, fatigue appears to exert the greatest adverse impact on QOL. However, it has been difficult to quantify the relationship between anemia and fatigue in the cancer population, in part because of these conditions' multifactorial causes and the lack of an instrument to assess the full spectrum of anemia-related symptoms.

Yellen et al. (14) recently developed and validated two new survey instruments that measure the impact of fatigue and other anemia-related symptoms in patients with cancer: 1) the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale, which contains a specific fatigue subscale, and 2) the FACT-Anemia (FACT-An), which contains the FACT-F plus questions related to anemia but unrelated to fatigue. With the use of these scales, it was possible to reliably discriminate patients on the basis of hemoglobin level and Eastern Cooperative Oncology Group performance status; the fatigue subscale and the nonfatigue items of the FACT-An also differentiated patients by these two measures. Higher hemoglobin levels were associated with less fatigue and better QOL. These scales have been proven to be reliable and valid measures of QOL in cancer patients, with particular focus on anemia and fatigue.

Cella et al. (6,15) used the FACT-An instrument to assess the impact of anemia and fatigue on QOL in 50 patients with a variety of malignancies who had hemoglobin levels determined within 48 hours before assessment and who were not currently receiving radiotherapy. Patients with hemoglobin levels greater than 12 g/dL reported statistically significantly less fatigue (P = .01), fewer nonfatigue anemia symptoms (P = .02), better physical (P = .003) and functional (P = .001) well-being, and higher overall QOL (P = .003) than those with hemoglobin levels less than or equal to 12 g/dL. To further evaluate the effect of hemoglobin levels on QOL, a multiple regression analysis was performed in which fatigue was removed as a variable. Statistically significant hemoglobin effects on ability to work (P = .005), leisure activities (P = .03), and overall QOL (P = .001) remained. Of the nonfatigue symptoms of anemia, dizziness accounted for the greatest functional difficulty. These results confirmed the impact of anemia-related fatigue and other symptoms on QOL in cancer patients.

Langer et al. (16) recently evaluated the effect of chemotherapy-induced anemia on QOL in patients with advanced non-small-cell lung cancer (NSCLC) by use of an index based on FACT-Lung subscales that measure physical and functional well-being plus symptoms specific to lung cancer. The incidence of at least grade 2 anemia was cumulative, increasing from 30% after the first cycle of treatment to 59% by the fourth cycle. A statistically significant correlation (r = .38; P<=.02), which was independent of tumor response status, was demonstrated between worsening anemia and declining QOL by the fourth cycle of chemotherapy.


    INCIDENCE AND SEVERITY OF CHEMOTHERAPY-INDUCED ANEMIA IN SELECTED NONMYELOID MALIGNANCIES
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 
The incidence and severity of chemotherapy-related anemia depend on a variety of factors, including the type, schedule, and intensity of therapy administered and whether the patient has received prior myelosuppressive chemotherapy, radiation therapy, or both. Symptom severity depends on the degree of anemia, the type of underlying malignancy, and the patient's pulmonary and cardiovascular function (17). Elderly cancer patients frequently manifest clinical symptoms of anemia at higher hemoglobin levels than do anemic patients without cancer. These factors must be considered in evaluating the toxicity data of individual chemotherapeutic agents or combination chemotherapy regimens. In addition to previously identified limitations associated with the grading and reporting of treatment-related anemia, published clinical trial reports in oncology tend to focus greater attention on the most severe toxic effects, sometimes incompletely reporting details on the incidence of lower grades of toxic effects. This reporting is potentially important for lesser degrees of anemia, because these degrees are being recognized to cause a perceptible reduction in a patient's energy level and QOL.

Retrospective reviews of the incidence of anemia that required RBC transfusions in patients with nonmyeloid malignancies who received cytotoxic chemotherapy indicate that the highest frequency occurs in those patients with lymphomas, lung tumors, and gynecologic (ovarian) or genitourinary tumors (18-20) in which the incidence may be as high as 50%-60% (17). In an audit of 28 oncology centers in the U.K. involving 2821 patients with solid tumors, 33% of the patients required at least one transfusion (range, from 19% for breast cancer to 43% for lung cancer) and 16% required multiple transfusions (18). The proportion of anemic (hemoglobin <11 g/dL) patients increased from 17% before the first chemotherapy cycle to 35% by the sixth cycle of treatment, with 49% and 51% of the patients with ovarian and lung tumors, respectively, anemic by the sixth cycle of chemotherapy. The mean hemoglobin concentration at which a transfusion was given decreased progressively with the treatment cycle.

To document the incidence of chemotherapy-related anemia associated with the most common single chemotherapeutic agents and combination chemotherapy regimens, including newer chemotherapeutic agents and evolving combination regimens used in the treatment of the major nonmyeloid malignancies in adults, we reviewed the literature published between 1990 and 1998. We identified the most commonly recommended chemotherapies for these tumors from multiple authoritative sources, including DeVita et al. (21) and Greco (22). In addition, The Medical Letter's Drugs of Choice for Cancer Chemotherapy (23) and available American Society of Clinical Oncology (24) and National Comprehensive Cancer Network guidelines (25-32) were consulted. Publications from the reference lists of these sources on phase II and III trials of the recommended chemotherapies were identified and retrieved. (For a few regimens, it was necessary to identify references published before 1990 to document reported anemia.) In addition, MEDLINE® searches were performed to identify phase II and III trials of new chemotherapy agents introduced during this decade (i.e., taxanes—docetaxel and paclitaxel; gemcitabine; vinorelbine; camptothecins—irinotecan and topotecan); this search was supplemented with manual searches of the Proceedings of the American Society of Clinical Oncology for 1994-1998. Only English-language publications reporting the incidence of the degrees of anemia were included. The chemotherapy regimen dose and schedule, previous treatment for metastatic disease, number of evaluable patients, incidence and severity of anemia, and toxicity grading system were specified (Tables 2-8).GoGoGoGoGoGoGo


View this table:
[in this window]
[in a new window]
 
Table 2. Chemotherapy-induced anemia: lung cancer*

 

View this table:
[in this window]
[in a new window]
 
Table 3. Chemotherapy-induced anemia: metastatic breast cancer*

 

View this table:
[in this window]
[in a new window]
 
Table 4. Chemotherapy-induced anemia: advanced ovarian cancer*

 

View this table:
[in this window]
[in a new window]
 
Table 5. Chemotherapy-induced anemia: lymphomas*

 

View this table:
[in this window]
[in a new window]
 
Table 6. Chemotherapy-induced anemia: advanced colorectal cancer*

 

View this table:
[in this window]
[in a new window]
 
Table 7. Chemotherapy-induced anemia: advanced head and neck cancer*

 

View this table:
[in this window]
[in a new window]
 
Table 8. Risks of blood transfusion (146)*

 
Non-Small-Cell Lung Cancer

Platinum-based combination chemotherapy is recommended as first-line treatment for advanced NSCLC (22-24,29). Because platinum is a mainstay in the treatment of lung cancer, patients with this disease commonly experience clinically important decreases in hemoglobin. In a study of 124 patients with NSCLC, a statistically significant inverse relationship was found between the accumulated dose of cisplatin and the lowest nadir of hemoglobin (P = .04) (33). Survival of the patients who required transfusion after chemotherapy was statistically significantly shorter than that of the patients not requiring transfusion (P<.05; Wilcoxon-Gehan test).

Chemotherapy with paclitaxel-platinum is one of the most active regimens available for the treatment of NSCLC (16,34-36). Paclitaxel-carboplatin produces an objective response rate of approximately 50%, 1-year survival rates ranging from 32% to 54%, and a median survival of at least 1 year in advanced-stage NSCLC patients (16,34-36). The addition of carboplatin or cisplatin to paclitaxel results in a slight increase in grade 3 or 4 anemia compared with paclitaxel alone in previously untreated patients with advanced disease (Table 2, A)Go (34,49-52). Paclitaxel-carboplatin produced grade 3 or 4 anemia in 5%-7% of the patients (49), and paclitaxel-cisplatin produced grade 3 or 4 anemia in 5%-23% of the patients with advanced NSCLC (50-52); the incidence of grade 3 or 4 anemia increased to 34% when the more myelosuppressive 24-hour paclitaxel infusion was combined with carboplatin dosed by the Calvert formula to an area under the concentration-versus-time curve of 7.5 (36).

Vinorelbine-cisplatin is also a regimen for the treatment of advanced NSCLC. In a phase III trial of vinorelbine-cisplatin, 24% of previously untreated patients with advanced NSCLC experienced grade 3 or 4 anemia (57). An older regimen used more widely outside the United States (i.e., mitomycin C-vinblastine-cisplatin) produced grade 1 or 2 anemia and grade 3 or 4 anemia in 61% and 9% of patients with NSCLC, respectively (58). Combination regimens of etoposide-cisplatin and gemcitabine-cisplatin produced grade 3 or 4 anemia in 42% and 13%-28% of previously untreated patients with NSCLC, respectively; milder degrees of anemia were not reported in these trials (53,55,56).

Numerous phase II studies have evaluated newer agents, such as the taxanes—paclitaxel and docetaxel—as well as vinorelbine and gemcitabine in previously untreated patients with advanced NSCLC. In general, these new agents are associated with high incidences of grade 1 or 2 anemia and low incidences of grade 3 or 4 anemia (Table 2, A)Go. Single-agent paclitaxel produced little grade 3 or 4 anemia (0%-5%) in previously untreated patients with NSCLC when administered over 3 or 24 hours (37-39); grade 1 or 2 anemia occurred in 23%-47% of the patients with a 3-hour paclitaxel infusion duration (37,38) and in 100% of the patients with a 24-hour infusion duration (39). Docetaxel produced grade 1 or 2 anemia in 73%-85% and grade 3 or 4 anemia in 2%-10% of previously untreated patients with advanced NSCLC (40-42). Vinorelbine produced low incidences of grade 3 or 4 anemia (1%-8%) in previously untreated patients with advanced disease but high incidences of grade 1 or 2 anemia (48%-75%) (47,48). Similar incidences of grade 1 or 2 anemia (8%-69%) and grade 3 or 4 anemia (2%-5%) have been observed with gemcitabine in patients with advanced NSCLC (43-45).

Small-Cell Lung Cancer

Combination chemotherapy produces higher response rates and higher percentages of long-term survivors in patients with advanced small-cell lung cancer (SCLC) than traditional single-agent chemotherapy and is considered to be first-line treatment for this tumor (27,60). The combination of cisplatin and etoposide is one of the most widely used regimens. Grade 3 or 4 anemia is commonly associated with this regimen, occurring in 16%-55% of the patients (Table 2, B)Go; several phase II and III trials did not report the incidence of lesser grades of anemia (67-69). Carboplatin plus etoposide is at least as active in patients with advanced SCLC as cisplatin plus etoposide but produces less nonhematologic toxicity (22). In previously untreated patients with advanced disease, carboplatin-etoposide produced grade 1 or 2 anemia in 39% of the patients, whereas the incidence was 59% with cisplatin-etoposide (70). The incidence of grade 3 or 4 anemia produced by carboplatin-etoposide (54%) in previously untreated patients with extensive-stage SCLC has been reported to be as high as that observed with cisplatin-etoposide (71).

Combination cyclophosphamide-doxorubicin-vincristine (CAV) chemotherapy was one of the first standard regimens for SCLC and remains one of the most commonly used (22). Anemia of grades 1-4 was observed in 13% and 54% of the patients with SCLC with low and high doses of the CAV combination, respectively (Table 2, B)Go (72). A number of investigators have evaluated combinations of etoposide-ifosfamide-cisplatin (VIP) and ifosfamide-carboplatin-etoposide (ICE) in previously untreated patients with extensive-stage SCLC. Although the incidence of grade 3 or 4 anemia observed in the patients receiving VIP ranged from 31% to 53% (68,74), anemia of this degree occurred in only 6%-11% of the patients receiving ICE (73). However, more than 75% of the patients treated with two different dosing regimens of ICE experienced grade 1 or 2 anemia (73). The combination of carboplatin-paclitaxel-oral etoposide produced a similar incidence of grade 3 or 4 anemia (32%-35%) as did the VIP combination in previously untreated patients with SCLC; lesser grades were not reported (75).

Several new agents, including paclitaxel, docetaxel, vinorelbine, and topotecan, are currently being evaluated as single-agent therapies for the treatment of extensive-stage SCLC (Table 2, B)Go. Docetaxel and topotecan produced grade 1 or 2 anemia in 60% of the patients and in 87% of the courses, respectively, in previously treated patients with extensive-stage SCLC; grade 3 or 4 anemia was observed in 3% of the patients and in 12% of the courses, respectively (63,66). In previously untreated patients, topotecan produced grade 3 anemia in 15% of the patients (62).

Breast Cancer

Conventional therapeutic regimens for the treatment of metastatic breast cancer include various combinations of doxorubicin, mitoxantrone, cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) as well as mitomycin C with or without vinblastine (22,23,25,26). New active agents include paclitaxel, docetaxel, and vinorelbine (25,26). The reported incidence of grade 3 or 4 anemia associated with conventional combination chemotherapeutic regimens used in the treatment of breast cancer has ranged from less than 1% with the combination of 5-FU-doxorubicin-cyclophosphamide-methotrexate to 80% with high-dose cyclophosphamide-mitoxantrone-etoposide (Table 3)Go (89,90). The commonly used combination of cyclophosphamide-doxorubicin-5-FU produced grade 1 or 2 anemia in 55% and grade 3 or 4 anemia in 11% of previously treated patients with metastatic breast cancer (92).

Several new agents demonstrate high response rates in metastatic breast cancer, including paclitaxel, docetaxel, and vinorelbine (Table 3)Go (25,26). These agents also produce a high incidence of grade 1 or 2 anemia. Paclitaxel produced grade 1 or 2 anemia in 36%-51% of previously treated patients with metastatic breast cancer (81-83). With docetaxel, high incidences of grade 1 or 2 anemia have been observed (60%-97%) in both previously treated and previously untreated patients with metastatic breast cancer (77,84,85). Grade 3 or 4 anemia was observed in 30% of the patients with anthracycline-resistant disease receiving a high paclitaxel dose (250 mg/m2) administered over 24 hours compared with 2% of the patients with a lower dose (135 mg/m2) administered over 3 hours (81,83). Docetaxel produced grade 3 or 4 anemia in approximately 10% of the previously treated patients with metastatic disease (84,85) and approximately 7% of the previously untreated patients (77,78).

Compared with the taxanes, vinorelbine is associated with a low incidence of grade 1 or 2 anemia (6%-18%) in previously treated patients with metastatic breast cancer (86,87). In previously untreated patients with metastatic disease, vinorelbine produced higher incidences of grade 1 or 2 anemia (range, 67%-71%) (79,80). Grade 3 or 4 anemia has been observed in 3%-14% of the patients with metastatic breast cancer, regardless of previous exposure to chemotherapy (79,80,86-88).

Given their high activity, these newer agents are under extensive investigation in combination therapy. Combination paclitaxel-doxorubicin appears to be one of the most active chemotherapeutic regimens for the treatment of metastatic breast cancer. In previously untreated patients with metastatic breast disease, paclitaxel plus doxorubicin produced an overall response rate of 94%, including a complete response rate of 41% (91). This regimen produced a high incidence of grade 1 or 2 anemia (78%-84%); the incidence of grade 3 or 4 anemia ranged from 8% to 11% (91). In previously treated patients with metastatic breast cancer, paclitaxel-doxorubicin produced a lower incidence of both grade 1 or 2 anemia (59%) and grade 3 or 4 anemia (<1%) (93).

Ovarian Cancer

In advanced ovarian cancer, platinum-based combination regimens are preferred for initial chemotherapy, and single agents are generally used in patients with recurrent disease (23,31,94). Both paclitaxel and topotecan have been approved for the treatment of advanced ovarian cancer, and paclitaxel in combination with a platinum compound is considered the standard of care as first-line chemotherapy in the management of advanced disease (31,94). In general, higher doses and longer infusion durations of paclitaxel are associated with increased myelosuppression, including an increased incidence of grade 3 or 4 anemia (Table 4)Go (97,98). In patients with ovarian cancer who failed first-line therapy with a platinum-based chemotherapy regimen, paclitaxel doses of 135-175 mg/m2 administered over 3 hours were associated with grade 1 or 2 anemia in 62%-73% of the patients (97).

Topotecan is associated with a high incidence of grade 1 or 2 anemia and a higher incidence of grade 3 or 4 anemia than paclitaxel in previously treated patients (Table 4)Go (100,103,104). In a phase III trial comparing topotecan and paclitaxel in patients with recurrent advanced disease, topotecan at a dose of 1.5 mg/m2 was associated with a higher incidence of grade 3 or 4 anemia than paclitaxel at a dose of 175 mg/m2 (3-hour infusion) (40% versus 6%); grade 4 anemia occurred in 4% and 3% of patients, respectively (100). A high incidence of grade 3 or 4 anemia has been observed with docetaxel in patients with ovarian cancer who were previously treated with platinum-containing chemotherapy (105,106). In a phase II trial by Piccart et al. (107), the overall incidence of anemia in patients treated with docetaxel alone was 87%, although the incidence of anemia by grade was not reported. Incidences of grade 1 or 2 anemia are high and range from 18% to 76% with single-agent docetaxel, paclitaxel, and topotecan in patients with advanced ovarian cancer previously treated with platinum-containing chemotherapy (97-99,101-109).

Single-agent carboplatin and cisplatin in previously untreated patients are associated with relatively low incidences (0%-7%) of grade 3 or 4 anemia (95,96). Several phase III trials of combination chemotherapy have been conducted in previously untreated patients with advanced ovarian cancer, and platinum-based combinations consistently produced high incidences of grade 1 or 2 anemia (Table 4)Go. Carboplatin or cisplatin in combination with cyclophosphamide produced similar incidences of grade 1 or 2 anemia (98% and 97%, respectively) (115). The incidences of grade 3 or 4 anemia in phase III trials of combination chemotherapy ranged from 2% to 42% with cyclophosphamide-platinum (112,115-118) and from 2% to 8% with paclitaxel-platinum (112). In patients with advanced disease in phase III trials performed by the Southwest Oncology Group (115,118), platinum-based chemotherapy was associated with a 33% RBC transfusion rate (19). In a logistic regression analysis, baseline hemoglobin, age, and platinum analogue (cisplatin was more likely than carboplatin to induce anemia) were statistically significant (P<=.001) predictors of the need for RBC transfusion.

Lymphomas

Therapeutic regimens proven to be effective for the treatment of advanced Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL; specifically, large-cell follicular lymphoma and diffuse large-B-cell lymphoma) include various combinations of methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, dexamethasone or prednisone, vinblastine, etoposide, and bleomycin (21-23,32). Many of the standard combinations used in treating advanced HD and NHL are associated with anemia (Table 5)Go. Treatment with the combinations of procarbazine-methotrexate-leucovorin-doxorubicin-cyclophosphamide-etoposide, mechlorethamine-vincristine-procarbazine-prednisone (MOPP), and methotrexate-leucovorin-doxorubicin-cyclophosphamide-vincristine-prednisone-bleomycin produced grade 1 or 2 anemia in 63% and 55% and grade 3 or 4 anemia in 9% and 10% of the patients with NHL, respectively (120). Another combination chemotherapy for NHL (cyclophosphamide-doxorubicin-vincristine-prednisone) produced grade 3 anemia in 74% of the NHL patients by use of a standard dosing schedule and 79% of the patients with the use of a weekly schedule (121).

MOPP combination therapy is considered first-line treatment in older patients with advanced HD and in patients for whom anthracycline-containing regimens are contraindicated. In a phase III study comparing MOPP with combination doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD), MOPP produced a higher incidence of both grade 1 or 2 and grade 3 or 4 anemia (Table 5)Go (123). Grade 1 or 2 and grade 3 or 4 anemia was observed in 31% and 12% of patients who received MOPP, respectively, and in 5% and 0% of the patients who received ABVD, respectively (123). Attempts to improve salvage therapy in patients with relapsed or refractory HD with etoposide-vinblastine-doxorubicin resulted in "severe" anemia in 13% of the patients and "moderate or serious" anemia in 59% (124).

Colorectal Cancer

5-FU has been the mainstay of chemotherapy for advanced colorectal cancer for the past 40 years, and it is frequently used in combination with leucovorin or levamisole (23,28). Single-agent 5-FU administered by continuous or bolus IV infusion produces grade 1 or 2 anemia in approximately 50% and grade 3 or 4 anemia in 5%-8% of previously untreated patients with advanced disease (Table 6)Go (125-127). Modulation of 5-FU and UFT (tegafur and uracil), a 5-FU prodrug, has been shown to be effective for the treatment of advanced colorectal cancer. Overall, therapy with bolus 5-FU plus leucovorin (126,131,132) or UFT-leucovorin produces little to no grade 3 or 4 anemia (0%-5%) (133,134). However, bolus 5-FU plus leucovorin produced frequent grade 1 or 2 anemia (27%-53%) (126,131).

Irinotecan, a camptothecin, was recently introduced for the treatment of advanced colorectal cancer. Irinotecan is associated with a high incidence of grade 1 or 2 anemia (49%-60%) (128); grade 3 or 4 anemia occurs in 8%-10% of the patients (128,130). Topotecan, another camptothecin, has also been investigated in the treatment of advanced colorectal cancer. Blood transfusions were required in 58% of the patients during treatment cycle 1 and in 90% of the patients during treatment cycle 6 with single-agent therapy (129).

Head and Neck Cancer

The most active single agents for head and neck cancer are methotrexate, bleomycin, cisplatin, carboplatin, 5-FU, and the new agents docetaxel, paclitaxel, and gemcitabine (22,23,30,135). Overall, single-agent therapies for the treatment of advanced-stage disease are associated with high incidences of grade 1 or 2 anemia and low incidences of grade 3 or 4 anemia (Table 7)Go. Single-agent paclitaxel and single-agent methotrexate produced grade 1 or 2 anemia in 39% and 25% and grade 3 anemia in 13% and 3% of the previously untreated patients with advanced head and neck cancer, respectively (136,140). Docetaxel produced grade 1 or 2 anemia in 74% and grade 3 or 4 anemia in 5% of the patients with advanced disease (137).

Numerous trials of platinum-based combination chemotherapy have been conducted in patients with head and neck cancer in an effort to improve response rates and survival. Although carboplatin is generally less toxic than cisplatin, combination chemotherapy with 5-FU-cisplatin, 5-FU-carboplatin, paclitaxel-cisplatin, and paclitaxel-carboplatin produced similar incidences of grade 1 or 2 and grade 3 or 4 anemia (Table 7)Go (139-141,144). 5-FU-cisplatin produced grade 1 or 2 anemia in 55%-74% (140,141) and grade 3 or 4 anemia in 5%-12% (139,140) of the patients. Paclitaxel-5-FU-cisplatin produced grade 1 or 2 anemia in 35% and grade 3 anemia in 12% of the patients (142). Blood transfusions were required in 12% of patients with advanced head and neck tumors treated with paclitaxel-ifosfamide-cisplatin (143).


    MANAGEMENT OF CHEMOTHERAPY-INDUCED ANEMIA
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 
Because anemia in cancer patients can result from many factors, treatment must be individualized and accompanied by correction or management of simple nutritional deficiencies, underlying infectious or inflammatory processes, hemolytic diseases, occult blood loss, or hemolysis. The management of anemia resulting from myelosuppressive chemotherapy depends on its severity. Treatment options include crystalloid and hematinic treatment, RBC transfusion, epoetin alfa administration, or a combination of options.

RBC Transfusions

Patients with symptomatic, but transient, anemia resulting from acute blood loss or those with symptomatic chronic anemia should receive crystalloids to replace intravascular volume (145). If symptoms persist despite replacement therapy, patients should receive an RBC transfusion. Patients with normovolemic, but symptomatic, anemia should be assessed for iron, folate, or vitamin B12 deficiency and should receive appropriate replacement therapy to correct the deficiency. RBC transfusions are indicated in cancer patients with acute anemia following acute blood loss when crystalloid infusions do not adequately correct intravascular volume, in those with chronic symptomatic anemia unresponsive to iron replacement, and in those in whom medical necessity does not allow adequate time for epoetin alfa to be effective (145). RBC transfusions, while ameliorating anemia, are associated with risks, the most serious of which is the potential transmission of infectious diseases (Table 8)Go. Although the blood supply is now carefully screened and the risk of HIV transmission is negligible, infectious agents, such as the hepatitis viruses, cytomegalovirus, Epstein-Barr virus, and exotic microbes, remain a concern. Other serious adverse events associated with allogeneic transfusion include alloimmunization, allergic reactions, hemolytic reactions, iron and circulatory overload, and possible immunosuppression. Milder side effects, such as fever and urticaria, are frequent (155). Concern over the safety of the blood supply led to a downturn in blood donation rates during the 1980s (156); although collections have increased in the 1990s, this increase has been offset by increased demand, continuing the strain on the blood supply. For these reasons, transfusion is generally reserved for an acute emergency (e.g., hypovolemia secondary to blood loss), severely anemic patients with serious symptoms (e.g., syncope, dyspnea, angina), or when other underlying disease puts patients at risk for an adverse cardiac event in the setting of mild-to-moderate anemia (145).

Epoetin Alfa

Erythropoietin is a hematologic growth factor that regulates the proliferation, maturation, and differentiation of RBCs. Several large, prospective, placebo-controlled studies have demonstrated the value of epoetin alfa, the human recombinant form of erythropoetin, for the treatment of anemia in cancer patients. The largest study included 413 patients, 68% of whom had solid tumors (157). Patients were grouped according to treatment regimen—no chemotherapy, myelosuppressive non-cisplatin-containing chemotherapy, and myelosuppressive cisplatin-containing chemotherapy—and randomly assigned to receive either placebo or epoetin alfa. Patients in the no-chemotherapy arm received epoetin alfa at a dose of 100 U/kg three times weekly for 8 weeks, and those in the two chemotherapy arms received epoetin alfa at a dose of 150 U/kg three times weekly for 12 weeks. In all three groups, patients receiving epoetin alfa had a statistically significant increase in hematocrit compared with placebo-treated patients (P<.004; all tests were two-sided). Transfusions were reduced in the two chemotherapy groups but not in the nonchemotherapy group; the lack of a reduction in the nonchemotherapy group may have been related to the lower dose and shorter treatment duration in this arm. Compared with patients who received placebo, those who received epoetin alfa and who had an increase in hematocrit of at least 6% also had statistically significant improvements in energy level, ability to perform daily activities, and overall QOL (P<.05). The double-blind phase of this trial was followed by an open-label phase in which 347 patients continued to receive epoetin alfa doses up to 300 U/kg three times weekly for up to 6 additional months. By the end of the treatment, an increase in hematocrit of at least 6% was observed in 40%, 56%, and 58% of no-chemotherapy, non-cisplatin-containing chemotherapy, and cisplatin-containing chemotherapy patients, respectively; requirements for transfusions decreased from 31%, 25%, and 43%, respectively, to 10%, 13%, and 12%, respectively.

In another study, 100 patients with cisplatin-induced anemia were randomly assigned to receive epoetin alfa or placebo. Statistically significant increases in mean hemoglobin levels occurred in the epoetin alfa group after the 3rd, 6th, and 9th weeks of therapy compared with baseline (P<=.01, two-sided tests); increases were not observed in patients receiving placebo. In addition, 20% of the patients in the epoetin alfa arm required transfusions compared with 56% of the patients receiving placebo (158).

The beneficial effects of epoetin alfa on anemia, functional status, and QOL are also supported by two large, nonrandomized, open-label, multicenter community studies (7,8). In the first study, the impact of epoetin alfa therapy on hemoglobin, transfusion requirements, and QOL was evaluated in more than 2000 anemic cancer patients with various nonmyeloid malignancies receiving cytotoxic chemotherapy (7). Patients were treated with epoetin alfa at a dose of 150 U/kg three times weekly for up to 4 months; the dose could have been doubled after 8 weeks if there was an inadequate therapeutic response. Of 2030 patients, 1047 completed all 4 months of epoetin alfa therapy. Patients who received epoetin alfa treatment had a 1.8-g of hemoglobin/dL increase from baseline to final hemoglobin level (P<.001; all tests were two-sided) and experienced progressive and statistically significant increases in hemoglobin levels at each monthly visit (P<.001). In addition, statistically significantly fewer patients who received epoetin alfa were transfused (P<.001), and fewer transfusions were administered per patient per month after the first month of treatment. Epoetin alfa treatment was associated with statistically significant increases in mean self-rated scores on the Linear Analog Scale Assessment (LASA) for energy level (P<.001), activity level (P<.001), and overall QOL (P<.001). A direct and statistically significant correlation was observed between the magnitude of the increase in hemoglobin level and the magnitude of improvement in each of the QOL parameters (energy: r = .30, P<.001; activity: r = .28, P<.001; overall QOL: r = .27, P<.001). In a retrospective analysis of a subgroup of patients for whom tumor response data were available, these improvements were also independent of tumor response and even occurred in a subgroup of patients with progressive disease whose hemoglobin levels increased by 4 g/dL, thus providing strong evidence that the increases in QOL were in part because of increases in hemoglobin (7).

In a second trial, Demetri et al. (8) prospectively evaluated the potentially confounding effect of tumor response in 2289 patients with nonmyeloid malignancies receiving chemotherapy who received epoetin alfa at a dose of 10 000 U three times weekly, for a maximum of 16 weeks. Doubling of the dose could occur after 4 weeks if the hemoglobin increase was less than 1 g/dL. Statistically significant increases in the hemoglobin level (P<.001) and statistically significant decreases in the percentage of patients who required transfusions (P<.001) were observed for all tumor types. QOL was measured by use of two validated instruments, FACT-An and LASA. Epoetin alfa therapy was associated with statistically significant improvements in FACT-An and Anemia Subscale scores (both P<.001) and with statistically significant increases in QOL measures on the LASA—i.e., scores for energy level (P<.001), activity level (P<.001), and overall well-being (P<.001). Increases in QOL measures based on the LASA were observed as soon as 1 month after the start of therapy. The increase in overall QOL was statistically significantly correlated (r = .235, P<.001) with an increase in hemoglobin level and was independent of tumor response, indicating that both hemoglobin level and disease response are independent variables that significantly impact QOL. Collectively, these results suggest that cancer patients undergoing chemotherapy can achieve important therapeutic benefit from treatment of anemia with epoetin alfa and that treating anemia may greatly improve patient functional ability and QOL.

Before epoetin alfa therapy is initiated in anemic cancer patients receiving chemotherapy, patients should be evaluated for causes of anemia. The initial dosage of epoetin alfa is 10 000 U subcutaneously three times weekly (8). After 4 weeks of therapy, if the hemoglobin level is not increased by at least 1 g/dL, dosage should be increased to 20 000 U three times weekly. Patients who do not respond to the higher dosage are unlikely to respond with further dosage increases. Patients may require supplemental iron to avoid depletion of iron stores and to adequately support the erythropoiesis stimulated by epoetin alfa administration; iron stores should be monitored over time as appropriate.

Studies (159,160) have been performed to determine the potential role of epoetin alfa in preventing chemotherapy-induced anemia. Crawford et al. (159) compared the effect of epoetin alfa with placebo for the prevention of chemotherapy-related anemia in 27 patients with SCLC who received cyclophosphamide, doxorubicin, etoposide, and granulocyte colony-stimulating factor. In a previous clinical trial (161), this chemotherapy regimen had produced anemia in 100% of the patients, with 80% requiring transfusions. Patients received either placebo (n = 13) or epoetin alfa (75 U/kg per day, subcutaneously; n = 14) beginning on day 1 and continuing through six chemotherapy cycles. The study drug was unblinded if patients developed anemia (hematocrit <32% on day 1 of any cycle after cycle 1) that required transfusion. Patients who received epoetin alfa completed a median of 3.7 cycles before requiring transfusion compared with a median of 1.5 cycles for those receiving placebo (P = .01). The median time to transfusion was 96 days and 43 days in patients receiving epoetin alfa and placebo, respectively. In a recent phase I trial in previously untreated patients with advanced head and neck carcinoma (160), patients received up to three cycles of paclitaxel and carboplatin with (n = 14) or without (n = 22) epoetin alfa before radiation therapy or surgery. Patients treated with epoetin alfa experienced a mean hemoglobin decrease of 0.5 g/dL during preoperative chemotherapy versus a decrease of 3.3 g of hemoglobin/dL in patients who did not receive epoetin alfa (P<.0001). In addition, fewer patients treated with epoetin alfa received RBC transfusions during preoperative chemotherapy (0% versus 18%). The results of these trials suggest that epoetin alfa can prevent chemotherapy-induced anemia and can reduce the need for RBC transfusions when administered concomitantly with chemotherapy regimens that produce a high incidence of anemia.


    CONCLUSIONS
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 
The incidence of chronic anemia in adult cancer patients is determined by numerous factors, particularly the type, stage, and duration of malignancy and the type and intensity of previous and current treatment. Despite identified limitations in the grading and reporting of treatment-related anemia, which are evidenced in this review, the collective results confirm a relatively high incidence of mild-to-moderate anemia across the major nonmyeloid tumors treated with the most commonly used single agents and combination chemotherapy regimens. Platinum-based therapies, which are well recognized to cause anemia, continue to play a major role in the treatment of lung, ovarian, and head and neck malignancies. The highest incidence of anemia requiring transfusion occurs in patients with lymphomas, lung tumors, and gynecologic (e.g., ovarian) or genitourinary tumors, in whom the incidence may be as high as 50%-60%. The incidence of mild-to-moderate anemia is often even higher across many of the major solid tumors. The new generation of chemotherapeutic agents, particularly the antimicrotubular agents (taxanes, vinorelbine) and camptothecins, is myelosuppressive; many of these agents also exhibit radiosensitizing properties. These agents can be anticipated to play greater roles, especially in combination chemotherapy and combined modality regimens, in the treatment of major solid tumors. Thus, anemia will continue to affect large numbers of cancer patients, leading to a decrease in functional capacity and QOL, with the potential need for RBC transfusions and attendant risks and inconvenience.

Results of recent clinical trials suggest that mild-to-moderate anemia that is not routinely treated with, or persists after, RBC transfusions—and which frequently has been considered by clinicians to be clinically unimportant and asymptomatic—may be associated with decreased QOL. Advances in assessing the relationships between anemia, fatigue, and QOL in cancer patients are providing new insights, suggesting that the tradition of leaving lesser degrees of anemia untreated may compromise patients' functional ability and QOL. Consideration of treatment of mild-to-moderate anemia will likely become important as greater emphasis is placed on QOL in the management of the oncology patient. Future research on the relationships between hemoglobin levels, patient well-being, and symptoms may lead to new classifications of chemotherapy-induced anemia that would allow the more effective development of appropriate therapeutic interventions based on outcomes as well as hemoglobin levels. These new classifications may help to overcome the perception by oncologists and patients that lesser degrees of anemia must be endured without treatment.


    NOTES
 
Editor's note: J. E. Groopman is a member of the Speaker's Bureau and L. M. Itri is vice president for medical affairs of Ortho Biotech, Inc. (Raritan, NJ), a distributor of epoetin alfa.


    REFERENCES
 Top
 Abstract
 Introduction
 Assessing Chemotherapy-Induced...
 Incidence and Severity of...
 Management of Chemotherapy...
 Conclusions
 Notes
 References
 

1 Glaspy J. The impact of epoetin alfa on quality of life during cancer chemotherapy: a fresh look at an old problem. Semin Hematol 1997;34(suppl 2):20-6.[Medline]

2 Consensus conference. Perioperative red blood cell transfusion. JAMA 1988;260:2700-3.[Medline]

3 Welch HG, Meehan KR, Goodnough LT. Prudent strategies for elective red blood cell transfusion. Ann Intern Med 1992;116:393-402.[Medline]

4 Surgenor DM, Wallace EL, Hale SG, Gilpatrick MW. Changing patterns of blood transfusions in four sets of United States hospitals, 1980 to 1985. Transfusion 1988;28:513-8.[Medline]

5 Silberstein LE, Kruskall MS, Stehling LC, Johnston MF, Rutman RC, Samia CT, et al. Strategies for the review of transfusion practices [published erratum appears in JAMA 1990;263:2302]. JAMA 1989;262:1993-7.[Abstract]

6 Cella D, Mo F, Peterman A. Anemia, fatigue and quality of life in people with cancer and HIV infection [abstract]. Blood 1996;88(suppl 1):146a.

7 Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, Vadhan-Raj S. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997;15:1218-34.[Abstract]

8 Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998;16:3412-25.[Abstract]

9 Ferrell BR, Grant M, Dean GE, Funk B, Ly J. "Bone tired": the experience of fatigue and its impact on quality of life. Oncol Nurs Forum 1996;23:1539-47.

10 Groopman JE. Fatigue in cancer and HIV/AIDS. Oncology (Huntingt) 1998;12:335-44.[Medline]

11 Irvine D, Vincent L, Graydon JE, Bubela N, Thompson L. The prevalence and correlates of fatigue in patients receiving treatment with chemotherapy and radiotherapy. A comparison with the fatigue experienced by healthy individuals. Cancer Nurs 1994;17:367-78.[Medline]

12 Vogelzang NJ, Breitbart W, Cella D, Curt GA, Groopman JE, Horning SJ, et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 1997(suppl 2); 34:4-12.

13 Winningham ML, Nail LM, Burke MB, Brophy L, Cimprich B, Joned LS, et al. Fatigue and the cancer experience: the state of the knowledge. Oncol Nurs Forum 1994;21:23-36.[Medline]

14 Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63-74.[Medline]

15 Cella D. The Functional Assessment of Cancer Therapy—Anemia (FACT—An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 1997;34(suppl 2):13-9.[Medline]

16 Langer C, Barsevick A, Bruner D, Grindel C, Leighton J, Luckscheiter C, et al. Correlation of quality of life (QOL) with survival, treatment response, and anemia in patients with advanced non-small cell lung cancer (NSCLC) treated with carboplatin and paclitaxel [abstract]. Lung Cancer 1997;18:23.

17 Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol 1998; 25(suppl 7):2-6.

18 Dalton JD, Bailey NP, Barrett-Lee PJ, O'Brien MER. Multicenter UK audit of anemia in patients receiving cytotoxic chemotherapy [abstract]. Proc ASCO 1998;17:418a.

19 Heddens DK, Alberts DS, Garcia DJ, Hannigan EV, Rothenberg ML. Factors associated with platinum-induced anemia in ovarian cancer (OVCA) patients (pts) in Southwest Oncology Group (S) studies [abstract]. Proc ASCO 1998;17:359a.

20 Skillings JR, Sridhar FG, Wong C, Paddock L. The frequency of red cell transfusion for anemia in patients receiving chemotherapy. A retrospective cohort study. Am J Clin Oncol 1993;16:22-5.[Medline]

21 DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia (PA): Lippincott-Raven; 1997.

22 Greco FA, ed. Handbook of commonly used chemotherapy regimens. Chicago (IL): Precept Press; 1996.

23 Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 1997;39:21-8.[Medline]

24 Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997, by the American Society of Clinical Oncology. J Clin Oncol 1997;15:2996-3018.[Abstract]

25 Carlson RW, McCormick B, Goldstein LJ, Moe RE, Gradishar WJ, Theriault RL, et al. Update of the NCCN guidelines for treatment of breast cancer. Oncology 1997;11(11A):199-220.[Medline]

26 Carlson RW, Goldstein LJ, Gradishar WJ, Lichter AS, McCormick B, Moe RE, et al. NCCN Breast Cancer Practice Guidelines. The National Comprehensive Cancer Network. Oncology (Huntingt) 1996;10(11 suppl):47-75.[Medline]

27 Demetri G, Elias A, Gershenson D, Fossella F, Grecula J, Mittal B, et al. NCCN Small-Cell Lung Cancer Practice Guidelines. The National Comprehensive Cancer Network. Oncology (Huntingt) 1996;10(11 suppl):179-94.[Medline]

28 Engstrom PF, Benson AB 3rd, Cohen A, Doroshow J, Kiel K, Niederhuber J, et al. NCCN Colorectal Cancer Practice Guidelines. The National Comprehensive Cancer Network. Oncology (Huntingt) 1996;10(11 suppl):140-75.[Medline]

29 Ettinger DS, Cox JD, Ginsberg RJ, Komaki R, Kris MG, Livingston RB, et al. NCCN Non-Small-Cell Lung Cancer Practice Guidelines. The National Comprehensive Cancer Network. Oncology (Huntingt) 1996;10(11 suppl):81-111.[Medline]

30 Forastiere A, Goepfert H, Goffinet D, Hong KW, Laramore G, Mittal B, et al. NCCN Practice Guidelines for Head and Neck Cancer. Oncology (Huntingt) 1998;12:39-147.

31 Ozols RF. Update of the NCCN ovarian cancer practice guidelines. Oncology (Huntingt) 1997;11:95-105.[Medline]

32 Shipp MA, Horning SJ, Ambinder RF, Pezner RD, Appelbaum FR, Rodriguez MA, et al. NCCN preliminary non-Hodgkin's lymphoma practice guidelines.Oncology (Huntingt) 1997;11:281-346.[Medline]

33 Okamoto H, Saijo N, Shinkai T, Eguchi K, Sasaki Y, Tamura T, et al. Chemotherapy-induced anemia in patients with primary lung cancer. Ann Oncol 1992;3:819-24.[Abstract]

34 Greco FA, Hainsworth JD. Paclitaxel (1-hour infusion) plus carboplatin in the treatment of advanced non-small cell lung cancer: results of a multicenter phase II trial. Semin Oncol 1997;24(suppl 12):S12-14-S12-17.[Medline]

35 Johnson DH, Paul DM, Hande KR, Shyr Y, Blanke C, Murphy B, et al. Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 1996;14:2054-60.[Abstract]

36 Langer CJ, Leighton JC, Comis RL, O'Dwyer PJ. McAleer CA, Bonjo CA, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995;13:1860-70.[Abstract]

37 Ranson MR, Jayson G, Perkins S, Anderson H, Thatcher N. Single-agent paclitaxel in advanced non-small cell lung cancer: single-center phase II study using a 3-hour administration schedule. Semin Oncol 1997;24(suppl 12):S12-6-S12-9.[Medline]

38 Millward MJ, Bishop JF, Friedlander M, Levi JA, Goldstein D, Olver IN, et al. Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 1996;14:142-8.[Abstract]

39 Murphy WK, Fossella FV, Winn RJ, Shin DM, Hynes HE, Gross HM, et al. Phase II study of Taxol in patients with untreated advanced non-small-cell lung cancer.J Natl Cancer Inst 1993;85:384-8.[Abstract]

40 Miller VA, Rigas JR, Francis PA, Grant SC, Pisters KM, Venkatraman ES, et al. Phase II trial of a 75-mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer. Cancer 1995;75:968-72.[Medline]

41 Francis PA, Rigas JR, Kris MG, Pisters KM, Orazem JP, Woolley KJ, et al. Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer. J Clin Oncol 1994;12:1232-7.[Abstract]

42 Fossella FV, Lee JS, Murphy WK, Lippman SM, Calayag M, Pang A, et al. Phase II study of docetaxel for recurrent or metastatic non-small-cell lung cancer. J Clin Oncol 1994;12:1238-44.[Abstract]

43 Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1994;12:1821-6.[Abstract]

44 Stadler WM, Kuzel T, Roth B, Raghaven D, Dorr FA. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 1997;15:3394-8.[Abstract]

45 Gatzemeier U, Shepherd FA, Le Chevalier T, Weynants P, Cottier B, Groen HJ, et al. Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study. Eur J Cancer 1996;32A:243-8.

46 O'Rourke M, Crawford J, Schiller J, Laufman L, Yanovich S, Ozer H, et al. Survival advantage for patients with stage IV NSCLC treated with single agent Navelbine® in a randomized controlled trial [abstract].Proc ASCO 1993;12:343.

47 Navelbine® (vinorelbine tartrate injection) prescribing information. Physicians' desk reference. 52nd ed. Montvale (NJ): Medical Economics Co.; 1998. p. 1162-5.

48 Vokes EE, Rosenberg RK, Jahanzeb M, Craig JB, Gralla RJ, Belani CP, et al. Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer. J Clin Oncol 1995;13:637-44.[Abstract]

49 Kosmidis P, Mylonakis N, Fountzilas G, Samantas E, Athanasiadis A, Pavlidis N, et al. Paclitaxel (175 mg/m2) plus carboplatin versus paclitaxel (225 mg/m2) plus carboplatin in non-small cell lung cancer: a randomized study. Semin Oncol 1997;24(suppl 12):S12-30-S12-33.[Medline]

50 Pirker R, Krajnik G, Zochbauer S, Malayeri R, Kneussl M, Huber H. Paclitaxel/cisplatin in advanced non-small-cell lung cancer (NSCLC). Ann Oncol 1995;6:833-5.[Abstract]

51 von Pawel J, Wagner H, Niederle N, Heider A, Koschel G, Gromotka E, et al. Paclitaxel and cisplatin in patients with non-small cell lung cancer: results of a phase II trial. Semin Oncol 1996;23:7-9.

52 Postmus PE, Giaccone G, Debruyne C, Sahmoud T, Splinter TA, van Zandwijk N. Results of the phase II EORTC study comparing paclitaxel/cisplatin with teniposide/cisplatin in patients with non-small cell lung cancer. EORTC Lung Cancer Cooperative Group. Semin Oncol 1996;23(suppl 12):10-3.

53 Miller AA, Niell HB, Griffin JP. Phase II study of prolonged oral etoposide in combination with intravenous cisplatin in advanced non-small cell lung cancer. Lung Cancer 1995;12:59-65.[Medline]

54 Robert F, Wheeler RH, Molthrop D, Bailey A, Chen S. Phase 2 study of prolonged administration of oral etoposide in combination with weekly cisplatin in advanced non-small cell lung cancer. Am J Clin Oncol 1994;17:383-6.[Medline]

55 Shepherd FA, Cormier Y, Burkes R, Evans WK, Goss G, Klimo P, et al. Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer.Semin Oncol 1997;24(suppl 8):S8-27-S8-30.

56 Abratt RP, Hacking DJ, Goedhals L, Bezwoda WR. Weekly gemcitabine and monthly cisplatin for advanced non-small cell lung carcinoma. Semin Oncol 1997;24(suppl 8):S8-18-S8-23.

57 Wozniak AJ, Crowley JJ, Balcerzak SP, Weiss GR, Spiridonidis CH, Baker LH, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 1998;16:2459-65.[Abstract]

58 Ellis PA, Smith IE, Hardy JR, Nicolson MC, Talbot DC, Ashley SE, et al. Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 1995;71:366-70.[Medline]

59 Kosty MP, Fleishman SB, Herndon JE 2nd, Coughlin K, Kornblith AB, Scalzo A, et al. Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol 1994;12:1113-20.[Abstract]

60 Ihde DC, Pass HI, Glatstein E. Small cell lung cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Vol 1. 5th ed. Philadelphia (PA): Lippincott-Raven Publishers; 1997. p. 911-49.

61 Ettinger DS, Finkelstein DM, Sarma RP, Johnson DH. Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 1995;13:1430-5.[Abstract]

62 Schiller JH, Kim K, Hutson P, DeVore R, Glick J, Stewart J, et al. Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1996;14:2345-52.[Abstract]

63 Smyth JF, Smith IE, Sessa C, Schoffski P, Wanders J, Franklin H, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC. Eur J Cancer 1994;30A:1058-60.

64 Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe CH, van Glabbeke M, Noseda MA, Ardizzoni A, et al. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative Group. Eur J Cancer 1993;29A:1720-2.

65 Furuse K, Kubota K, Kawahara M, Ogawara M, Kinuwaki E, Motomiya M, et al. A phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small-cell lung cancer. Japan Vinorelbine Lung Cancer Study Group. Lung Cancer 1994;11:385-91.[Medline]

66 Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997;15:2090-6.[Abstract]

67 Hainsworth JD, Levitan N, Wampler GL, Belani CP, Seyedsadr MS, Randolf J, et al. Phase II randomized study of cisplatin plus etoposide phosphate or etoposide in the treatment of small-cell lung cancer. J Clin Oncol 1995;13:1436-42.[Abstract]

68 Loehrer PJ Sr, Ansari R, Gonin R, Monaco F, Fisher W, Sandler A, et al. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol 1995;13:2594-9.[Abstract]

69 Miller AA, Herndon JE 2nd, Hollis DR, Ellerton J, Langleben A, Richards F 2nd, et al. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: a randomized phase III study of the Cancer and Leukemia Group B. J Clin Oncol 1995;13:1871-9.[Abstract]

70 Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas P, et al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994;5:601-7.[Abstract]

71 Luikart SD, Goutsou M, Mitchell ED, Van Echo DA, Modeas CR, Propert KJ, et al. Phase I/II trial of etoposide and carboplatin in extensive small-cell lung cancer. A report from the Cancer and Leukemia Group B. Am J Clin Oncol 1993;16:127-31.[Medline]

72 Figueredo AT, Hryniuk WM, Strautmanis I, Frank G, Rendell S. Co-trimoxazole prophylaxis during high-dose chemotherapy of small-cell lung cancer. J Clin Oncol 1985;3:54-64.[Abstract]

73 Wolff AC, Ettinger DS, Neuberg D, Comis RL, Ruckdeschel JC, Bonomi PD, et al. Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group pilot study. J Clin Oncol 1995;13:1615-22.[Abstract]

74 Faylona EA, Loehrer PJ, Ansari R, Sandler AB, Gonin R, Einhorn LH. Phase II study of daily oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung cancer: a Hoosier Oncology Group Trial. J Clin Oncol 1995;13:1209-14.[Abstract]

75 Hainsworth JD, Gray JR, Stroup SL, Kalman LA, Patten JE, Hopkins LG, et al. Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities. J Clin Oncol 1997;15:3464-70.[Abstract]

76 Davidson NG. Single-agent paclitaxel as first-line treatment of metastatic breast cancer: the British experience. Semin Oncol 1996;23(suppl 11):6-10.

77 Chevallier B, Fumoleau P, Kerbrat P, Dieres V, Roche H, Krakowski I, et al. Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 1995;13:314-22.[Abstract]

78 Hudis CA, Seidman AD, Crown JP, Balmaceda C, Freilich R, Gilewski TA, et al. Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer. J Clin Oncol 1996;14:58-65.[Abstract]

79 Weber BL, Vogel C, Jones S, Harvey H, Hutchins L, Bigley J, et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 1995;13:2722-30.[Abstract]

80 Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, et al. Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 1993;11:1245-52.[Abstract]

81 Nabholtz JM, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, et al. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 1996;14:1858-67.[Abstract]

82 Dieras V, Marty M, Tubiana N, Corette L, Morvan F, Serin D, et al. Phase II randomized study of paclitaxel versus mitomycin in advanced breast cancer. Semin Oncol 1995;22(suppl 8):33-9.

83 Seidman AD, Reichman BS, Crown JP, Yao TJ, Currie V, Hakes TB, et al. Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response. J Clin Oncol 1995;13:1152-9.[Abstract]

84 Valero V, Holmes FA, Walters RS, Theriault RL, Esparza L, Fraschini G, et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 1995;13:2886-94.[Abstract]

85 Ravdin PM, Burris HA 3rd, Cook G, Eisenberg P, Kane M, Bierman WA, et al. Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 1995;13:2879-85.[Abstract]

86 Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, et al. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol 1994;12:2094-101.[Abstract]

87 Degardin M, Bonneterre J, Hecquet B, Pion JM, Adenis A, Horner D, et al. Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol 1994;5:423-6.[Abstract]

88 Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, et al. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 1995;13:2567-74.[Abstract]

89 Budd GT, Green S, O'Bryan RM, Martino S, Abeloff MD, Rinehart JJ, et al. Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an Intergroup study. J Clin Oncol 1995;13:831-9.[Abstract]

90 Bezwoda WR, Seymour L, Dansey RD. High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial. J Clin Oncol 1995;13:2483-9.[Abstract]

91 Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995;13:2688-99.[Abstract]

92 Aisner J, Cirrincione C, Perloff M, Perry M, Budman D, Abrams J, et al. Combination chemotherapy for metastatic or recurrent carcinoma of the breast—a randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: Cancer and Leukemia Group B Study 8281. J Clin Oncol 1995;13:1443-52.[Abstract]

93 Gehl J, Boesgaard M, Paaske T, Vittrup Jensen B, Dombernowsky P. Combined doxorubicin and paclitaxel in advanced breast cancer: effective and cardiotoxic. Ann Oncol 1996;7:687-93.[Abstract]

94 Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Vol 2. 5th ed. Philadelphia (PA): Lippincott-Raven Publishers; 1997. p. 1502-34.

95 Jones A, Wiltshaw E, Harper P, Slevin M, Shepherd J, Mansi J, et al. A randomized study of high vs conventional-dose carboplatin for previously untreated ovarian cancer [abstract]. Br J Cancer 1992;65(suppl 16): 15.

96 Rozencweig M, Martin A, Beltangady M, Bragman K, Goodlow J, Wiltshaw E, et al. Randomized trials of carboplatin versus cisplatin in advanced ovarian cancer. In: Bunn PA, Canetta R, Ozols RF, Rozencweig M, editors. Carboplatin: current perspectives and future directions. Philadelphia (PA): Saunders; 1990. p. 175-86.

97 Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, Gianni L, Myles J, van der Burg ME, et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994;12:2654-66.[Abstract]

98 Taxol® (paclitaxel) injection prescribing information. In: Physicians' desk reference. 52nd ed. Montvale (NJ): Medical Economics Co.; 1998. p. 762-6.

99 Thigpen JT, Blessing JA, Ball H, Hummel SJ, Barrett RJ. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 1994;12:1748-53.[Abstract]

100 ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183-93.[Abstract]

101 Einzig AI, Wiernik PH, Sasloff J, Runowicz CD, Goldberg GL. Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 1992;10:1748-53.[Abstract]

102 Kohn EC, Sarosy G, Bicher A, Link C, Christian M, Steinberg SM, et al. Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 1994;86:18-24.[Abstract]

103 Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 1996;14:3056-61.[Abstract]

104 Kudelka AP, Tresukosol D, Edwards CL, Freedman RS, Levenback C, Chantarawiroj P, et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996;14:1552-7.[Abstract]

105 Francis P, Schneider J, Hann L, Balmaceda C, Barakat R, Phillips M, et al. Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer. J Clin Oncol 1994;12:2301-8.[Abstract]

106 Kavanagh JJ, Kudelka AP, de Leon CG, Tresukosol D, Hord M, Finnegan MB, et al. Phase II study of docetaxel in patients with epithelial ovarian carcinoma refractory to platinum. Clin Cancer Res 1996;2:837-42.[Abstract]

107 Piccart MJ, Gore M, Ten Bokkel Huinink W, Van Oosterom A, Verweij, Wanders J, et al. Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 1995;87:676-81.[Abstract]

108 Hoskins PJ, Swenerton KD. Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 1994;12:60-3.[Abstract]

109 Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998;16:405-10.[Abstract]

110 Dorval T, Soussain C, Beuzeboc P, Garcia-Giralt E, Jouve M, Livartowski A, et al. Ifosfamide seven-day infusion for recurrent and cisplatin refractory ovarian cancer. J Infus Chemother 1996;6:47-9.[Medline]

111 Sutton GP, Blessing JA, Homesley HD, Berman ML, Malfetano J. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1989;7:1672-6.[Abstract]

112 McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6.[Abstract/Free Full Text]

113 Skarlos DV, Aravantinos G, Kosmidis P, Athanassiadis A, Stathopoulos GP, Pavlidis N, et al. Paclitaxel with carboplatin versus paclitaxel with carboplatin alternating with cisplatin as first-line chemotherapy in advanced epithelial ovarian cancer: preliminary results of a Hellenic Cooperative Oncology Group study. Semin Oncol 1997;24(suppl 15):S15-57-S15-61.

114 Coeffic D, Benhammouda A, Antoine EC, Rixe O, Paraiso D, Auclerc G, et al. Preliminary results of a phase I/II study of paclitaxel, cisplatin, and cyclophosphamide in advanced ovarian carcinoma. Semin Oncol 1997;24(suppl 2):S2-38-S2-40.[Medline]

115 Alberts DS, Green S, Hannigan EV, O'Toole R, Stock-Novack D, Anderson P, et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer [published erratum appears in J Clin Oncol 1992;10:1505]. J Clin Oncol 1992;10:706-17.[Abstract]

116 Swenerton K, Jeffrey J, Stuart G, Roy M, Krepart G, Carmichael J, et al. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1992;10:718-26.[Abstract]

117 McGuire WP, Hoskins WJ, Brady MF, Homesley HD, Creasman WT, Berman ML, et al. Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 1995;13:1589-99.[Abstract]

118 Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950-5.[Abstract/Free Full Text]

119 Conte PF, Bruzzone M, Chiara S, Sertoli MR, Daga MG, Rubagotti A, et al. A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer [published erratum appears in J Clin Oncol 1986;4:1284]. J Clin Oncol 1986;4:965-71.[Abstract]

120 Sertoli MR, Santini G, Chisesi T, Congiu AM, Rubagotti A, Contu A, et al. MACOP-B versus ProMACE-MOPP in the treatment of advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the Non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1994;12:1366-74.[Abstract]

121 Meyer RM, Browman GP, Samosh ML, Benger AM, Bryant-Lukosius D, Wilson WE, et al. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma. J Clin Oncol 1995;13:2386-93.[Abstract]

122 Gordon LI, Harrington D, Andersen J, Colgan J, Glick J, Neiman R, et al. Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 1992;327:1342-9.[Abstract]

123 Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478-84.[Abstract]

124 Canellos GP, Petroni GR, Barcos M, Duggan DB, Peterson BA. Etoposide, vinblastine, and doxorubicin: an active regimen for the treatment of Hodgkin's disease in relapse following MOPP. Cancer and Leukemia Group B. J Clin Oncol 1995;13:2005-11.[Abstract]

125 Hill M, Norman A, Cunningham D, Findlay M, Watson M, Nicolson V, et al. Impact of protracted venous infusion fluorouracil with or without interferon alfa-2b on tumor response, survival, and quality of life in advanced colorectal cancer. J Clin Oncol 1995;13:2317-23.[Abstract]

126 Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group [published erratum appears in J Clin Oncol 1990;8:185]. J Clin Oncol 1989;7:1419-26.[Abstract]

127 Greco FA, Figlin R, York M, Einhorn L, Schilsky R, Marshall EM, et al. Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol 1996;14:2674-81.[Abstract]

128 Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997;15:251-60.[Abstract]

129 Creemers GJ, Gerrits CJ, Schellens JH, Planting AS, van der Burg ME, van Beurden VM, et al. Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer. J Clin Oncol 1996;14:2540-5.[Abstract]

130 Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996;14:1128-35.[Abstract]

131 Corfu-A Study Group. Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol 1995;13:921-8.[Abstract]

132 Kosmidis PA, Tsavaris N, Skarlos D, Theocharis D, Samantas E, Pavlidis N, et al. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group. J Clin Oncol 1996;14:2682-7.[Abstract]

133 Gonzalez Baron M, Feliu J, Garcia Giron C, Espinosa J, Martinez B, Blanco E, et al. UFT modulated with leucovorin in advanced colorectal cancer: Oncopaz experience. Oncology 1997;54 Suppl 1:24-9.[Medline]

134 Sanchiz F, Milla A. Tegafur-uracil (UFT) plus folinic acid in advanced rectal cancer. Jpn J Clin Oncol 1994;24:322-6.[Abstract]

135 Schantz SP, Harrison LB, Forastiere AA. Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, oropharynx. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Vol 1. 5th ed. Philadelphia (PA): Lippincott-Raven Publishers; 1997. p. 741-801.

136 Forastiere AA, Neuberg D, Taylor SG 4th, DeConti R, Adams G. Phase II evaluation of Taxol in advanced head and neck cancer: an Eastern Cooperative Oncology Group trial. J Natl Cancer Inst Monogr 1993;15:181-4.[Medline]

137 Catimel G, Verweij J, Mattijssen V, Hanauske A, Piccart M, Wanders J, et al. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:533-7.[Abstract]

138 Smith RE, Lew D, Rodriguez GI, Taylor SA, Schuller D, Ensley JF. Evaluation of topotecan in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. A phase II Southwest Oncology Group study. Invest New Drugs 1996;14:403-7.[Medline]

139 Jacobs C, Lyman G, Velez-Garcia E, Srihhar KS, Knight W, Hochster H, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257-63.[Abstract]

140 Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10:1245-51.[Abstract]

141 Paredes J, Hong WK, Felder TB, Dimery IW, Choksi AJ, Newman RA, et al. Prospective randomized trial of high-dose cisplatin and fluorouracil infusion with or without sodium diethyldithiocarbamate in recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 1988;6:955-62.[Abstract]

142 Hussain M, Salwen W, Kucuk O, Ensley J. Paclitaxel, cisplatin, and 5-fluorouracil in patients with advanced or recurrent squamous cell carcinoma of the head and neck: a preliminary report. Semin Oncol 1997;24(suppl 19):S19-43-S19-45.

143 Shin DM, Glisson BS, Khuri FR, Ginsberg L, Papadimitrakopoulou V, Lee JJ, et al. Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 1998;16:1325-30.[Abstract]

144 Fountzilas G, Skarlos D, Athanassiades A, Kalogera-Fountzila A, Samantas E, Bacoyiannis C, et al. Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck. A phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 1997;8:451-5.[Abstract]

145 Koeller JM. Clinical guidelines for the treatment of cancer-related anemia. Pharmacotherapy 1998;18:156-69.[Medline]

146 Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two parts—blood transfusion. N Engl J Med 1999;340:438-47.[Free Full Text]

147 Dodd RY. Adverse consequences of blood transfusion: quantitative risk estimates. In: Nance ST, editor. Blood supply: risks perceptions and prospects for the future. Bethesda (MD): American Association of Blood Banks; 1994. p. 1-24.

148 Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med 1996;334:1685-90.[Abstract/Free Full Text]

149 Lackritz EM, Satten GA, Aberle-Grasse J, Dodd RY, Raimondi VP, Janssen RS, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 1995;333:1721-5.[Abstract/Free Full Text]

150 Sazama K. Reports of 355 transfusion-associated deaths: 1976 through 1985. Transfusion 1990;30:583-90.[Medline]

151 Linden JV, Paul B, Dressler KP. A report of 104 transfusion errors in New York State. Transfusion 1992;32:601-6.[Medline]

152 Ness PM, Shirey RS, Thoman SK, Buck SA. The differentiation of delayed serologic and delayed hemolytic transfusion reactions: incidence, long-term serologic findings, and clinical significance. Transfusion 1990;30:688-93.[Medline]

153 Shulman IA. The risk of an overt hemolytic transfusion reaction following the use of an immediate spin crossmatch. Arch Pathol Lab Med 1990;114:412-4.[Medline]

154 Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 1985;25:573-7.[Medline]

155 Rieger PT, Haeuber D. A new approach to managing chemotherapy-related anemia: nursing implications of epoetin alfa. Oncol Nurs Forum 1995;22:71-81.[Medline]

156 Surgenor DM, Wallace EL, Hao SH, Chapman RH. Collection and transfusion of blood in the United States, 1982-1988. N Engl J Med 1990;322:1646-51.[Abstract]

157 Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer 1993;29A Suppl 2:S2-8.[Medline]

158 Cascinu S, Fedeli A, Del Ferro E, Luzi Fedeli S, Catalano G. Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo. J Clin Oncol 1994;12:1058-62.[Abstract]

159 Crawford J, Blackwell S, Shoemaker D, Pupa MR, Mulhausen T, Herndon J, et al. Prevention of chemotherapy related anemia by recombinant human erythropoietin (EPO) in patients with small cell lung cancer (SCLC) receiving cyclophosphamide, doxorubicin, and etoposide (CAE) chemotherapy with G-CSF support [abstract].Lung Cancer 1997;18(suppl 1):205.

160 Dunphy FR, Dunleavy TL, Harrison BR, Boyd JH, Varvares MA, Dunphy CH, et al. Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. Cancer 1997;79:1623-8.[Medline]

161 Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;315:164-70.

Manuscript received November 5, 1998; revised July 7, 1999; accepted August 6, 1999.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 1999 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement