|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Vinorelbine Is an Effective and Safe Drug for AIDS-Related Kaposi’s Sarcoma: Results of a Phase II StudyFrom the Division of Medical Oncology A and Epidemiology Unit, Centro di Riferimento Oncologico, Aviano; I and II Divisions of Infectious Diseases, Ospedale L. Sacco, Milano; Division of Medical Oncology, Ospedale Niguarda Cà Granda, Milano; Division of Infectious Diseases, Ospedale di Circolo, Varese; Institute of Infectious Diseases, Policlinico San Matteo, Pavia; and Division of Infectious Diseases B, Ospedale Amedeo di Savoia, Torino, Italy. Address reprint requests to Umberto Tirelli, MD, Division of Medical Oncology A, Centro di Riferimento Oncologico, via Pedemontana Occ.le 12, 33081 Aviano (PN), Italy; email oma{at}ets.it
PURPOSE: To assess the safety and efficacy of vinorelbine in patients with AIDS-related Kaposi’s sarcoma (KS). PATIENTS AND METHODS: From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS who experienced disease progression after one or more regimens of systemic chemotherapy. Patients were treated with vinorelbine 30 mg/m2 every 2 weeks by intravenous bolus. RESULTS: Of 35 assessable patients, three (9%) had a clinical complete response and 12 (34%) had a partial remission, for an overall objective response rate of 43% (95% confidence interval, 26% to 61%). For the 15 patients with objective responses, the median duration of response from the beginning of therapy until the development of progression was 176 days, whereas the median progression-free survival and the median survival durations for 35 assessable patients were 151 days and 216 days, respectively. Vinorelbine also induced responses in patients who had become resistant to regimens that included other vinca alkaloids. Overall, vinorelbine was well tolerated. Toxicity, including neurologic toxicity, was mild and reversible. Neutropenia was the most frequent dose-limiting toxicity. CONCLUSION: Vinorelbine is safe and effective in the treatment of patients with advanced KS who have been previously treated with one or more chemotherapy regimens.
ALTHOUGH THE percentage of Kaposi’s sarcoma (KS) as index diagnosis for AIDS has been declining since 1996, when potent antiretroviral combination regimens became available, KS remains the most common malignancy observed in patients with human immunodeficiency virus (HIV) infection.1,2 Generally, KS is a source of considerable morbidity and, when vital organs are involved, can be life-threatening.3 The treatment of AIDS-related KS is often problematic. It should be based on an accurate evaluation of prognostic factors, in particular, the extent and the rate of tumor growth, patient symptoms, immune system condition, and concurrent complications of AIDS. Nevertheless, considering the palliative role of KS therapy, the potential benefits of therapy must be weighed against the risk of toxicity.4 In patients with rapidly progressive cutaneous disease, widespread symptomatic disease, and/or visceral involvement, systemic chemotherapy is the treatment of choice. Among the cytostatic drugs tested so far, vincristine,5,6 vinblastine,5 bleomycin,6 etoposide,7 doxorubicin,7,8 paclitaxel,9-11 and liposomal anthracyclines12-15 are the most effective when used alone or in combination regimens (ie, doxorubicin, bleomycin, and vincristine [ABV]; bleomycin and vincristine [BV]). However, toxicity from these agents, especially when they are used in combination, may be significant, and responses are usually of short duration. For these reasons, the search for effective and safe new cytotoxic drugs is recommended. Vinca alkaloids are a major class of anticancer agents that are used in the treatment of numerous hematologic and solid tumors.16 Vinorelbine is a relatively new semisynthetic vinca alkaloid that disorganizes microtubules of the mitotic figure at a lower concentration than other vinca alkaloids and requires much higher concentrations to affect axonal microtubules, although favoring a better therapeutic index.17 This observation has led to the suggestion that vinorelbine might be less neurotoxic and more toxic to the cancer cell.18 During the past years, vinorelbine has undergone clinical evaluation in a number of malignancies,16 but to our knowledge, it has not been evaluated in KS. When we started the present study, we thought that this drug warranted evaluation in this setting in light of its activity in the various tumors types of the general population and, in particular, of its safety and tolerability.19 In addition, it is known that vinca alkaloids are active agents in the treatment of AIDS-KS and formed the basis for combination regimens.5-8,12,14,15 The potentiality of reducing neurologic toxicity with respect to other vinca alkaloids, especially when neurotoxic antiretroviral drugs (ie, stavudine, didanosine) are concomitantly administered, makes vinorelbine an attractive agent. We have already reported preliminary data in letter form on vinorelbine in 22 patients with previously treated AIDS-KS,20 and the encouraging results obtained led to the hypothesis that this drug could provide an important new treatment option for AIDS-KS. We report here a full description of vinorelbine treatment in 36 severely immunocompromised patients with advanced KS who had experienced disease progression after at least one regimen of systemic chemotherapy.
From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS in this phase II study. To be eligible for the study, patients were required to have histologically confirmed KS and measurable disease, serologic evidence of HIV infection, relapse after or progression during prior chemotherapy (including anthracyclines or vinca alkaloids), a performance status (Eastern Cooperative Oncology Group)18 of 0 to 3, and age  18 years. In particular, only patients with widespread cutaneous disease (> 25 lesions in > two different anatomic sites), lymphedema, symptomatic disease, and/or visceral involvement were eligible. All prior therapies for KS, including other than cytotoxic treatments, had to be completed at least 2 weeks before entry onto the study. Moreover, the minimum hematologic values for entry onto the study included a leukocyte count of greater than 1,000/mm3, platelet count of greater than 75,000/mm3, hemoglobin greater than 8 g/dL, a serum creatinine level of less than 150 µmol/L, and a serum bilirubin level of less than 30 µmol/L. Any antiretroviral therapy was allowed during chemotherapy, as decided by the treating physician. Exclusion criteria included the following: active opportunistic infections, severe peripheral neuropathy, history of clinically significant cardiac or renal disease, cirrhosis, and presence of any malignancy other than KS. Stage of AIDS-KS was defined according to AIDS Clinical Trials Groups (ACTG) staging criteria,21 which is based on the evaluation of tumor extension (T), CD4 cell count (I), and patient’s overall status (S). All patients underwent a complete history and physical examination with tumor measurements, blood counts, and chemistry profiles at study entry and the same day of each cycle of chemotherapy. CD4 lymphocyte count was performed at study entry and thereafter at the discretion of physicians. Chest x-ray and ear, nose, and throat examination control were performed at study entry and, if they were disease parameters, every two cycles of chemotherapy. Endoscopic evaluation for gastrointestinal and pulmonary disease were not performed routinely, but only at clinical request.
Patients were treated with vinorelbine (Navelbine; Glaxo Wellcome, Inc, Research Triangle Park, NC) 30 mg/m2 by intravenous bolus in 14-day cycles. The drug was diluted in 100 mL of 0.9% NaCl or dextrose 5% water and infused over at least 15 minutes. Dose modifications were based on hematologic and neurologic toxicity. When granulocyte count was between 500 and 1,000/µL and/or platelet count was between 50 and 75 x 109/L, vinorelbine was reduced by 50%; when granulocyte count was less than 500/µL and/or platelet count was less than 50 x 109/L, treatment was postponed for 1 week. In case of active uncontrolled infection, treatment was postponed until disappearance of infection. If a patient had neurologic signs or symptoms Patients entered onto the study were assessed for response to treatment and treatment-related toxicity before each cycle of therapy. Assessment of response was performed according to ACTG criteria, modified in that complete response was not required to be pathologically confirmed.21 Clinical complete remission (cCR) was defined as absence of any detectable residual disease, including tumor-associated edema and/or effusion, for at least 4 weeks. Partial response (PR) was defined as the absence of new lesions (skin or oral, or of new visceral sites of involvement, or the appearance of worsening of tumor-associated edema or effusion) and at least 50% decrease in the number of all previously documented lesions, or complete flattening of at least 50% of all previously raised lesions, or a 50% decrease in the sum of the products of the largest perpendicular diameters of the macular lesions, or patients with residual tumor-associated edema or effusion who otherwise met the criteria for a complete remission. A PR had to be maintained for at least 4 weeks. Progressive disease (PD) was defined on the basis of any of the following criteria: an increase of 25% or more in the size of previously existing lesions, the occurrence of new lesions or sites of disease, a change in the features of 25% or more of existing skin or oral lesions from macular to plaque-like or nodular, and the development of new or increasing tumor-associated edema or effusion. Any response that did not meet the criteria for cCR, PR, or PD was defined as stable disease. Chemotherapy was administered until cCR or two cycles beyond maximum response. Patients were not considered assessable for response if they had not completed at least two full cycles of chemotherapy. However, patients showing PD during these two cycles of chemotherapy were considered as having experienced treatment failure. Assessment of toxicity was performed according to the standard World Health Organization criteria.22 Overall survival was analyzed from the beginning of treatment to the date of death or last follow-up. The duration of cCR and PR was measured from the beginning of treatment until PD became evident. Progression-free survival time was measured from the beginning of treatment until either the patient had documented KS progression or died. For purposes of statistical analysis, patients who were found to have PD on their first posttreatment evaluation were considered to have experienced treatment failure after 1 day on study. All time-to-event variables were estimated by the Kaplan-Meier method.23
Differences between subgroups were assessed by means of the log-rank test.24 Results were considered to be statistically significant when P
Clinical Characteristics Thirty-six patients with AIDS-related KS and a median age of 36 years (range, 26 to 57 years) were enrolled onto the study. Patient characteristics at study entry are listed in Table 1. All patients except one were male, and the majority of them (64%) were homosexual. Fifty percent of patients had an Eastern Cooperative Oncology Group performance status of 2. Most patients were severely immunocompromised, with a median baseline CD4 lymphocyte count of 20/µL (range, 1 to 356/µL). Only nine patients (25%) had more than 50 CD4 cells/µL. At study entry, the median WBC count was 3,220/µL (range, 1,400 to 8,000/µL), and five patients presented with less than 2,000 WBCs/µL. Twelve patients were receiving antiretroviral therapies with nucleoside reverse transcriptase inhibitors. Of them, seven patients were on single-agent therapy (zidovudine [AZT], n = 4; didanosine [DDI], n = 3) and five patients were on dual-agent therapy (AZT + lamivudine [3TC], n = 3; stavudine [d4T] + 3TC, n = 1; d4T + DDI, n = 1). No patient was undergoing treatment with protease inhibitors.
In regard to KS staging, all patients met at least one of the risk features rated as poor by ACTG criteria (eg, T1 or I1 or S1), and the majority of patients (61%) had all of the poor-risk features (T1 I1 S1). In particular, 26 patients (72%) were T1, 35 patients (97%) were I1, and 18 patients (50%) were S1. All but one of the patients had cutaneous KS and 14 of them had only cutaneous involvement. Tumor-associated lymphedema was reported in 11 patients. Visceral disease was documented in 18 patients: nine had pulmonary, six had gastrointestinal, and three had involvement in both pulmonary and gastrointestinal. Thirteen patients had experienced an opportunistic infection before study entry; in particular, cytomegalovirus (CMV) infection (five patients), esophageal candidiasis (three patients), Mycobacterium infection (three patients), Pneumocystis carinii pneumonia (PCP; one patient), and toxoplasmosis encephalitis (one patient). All patients had received prior systemic chemotherapy for KS, and 11 patients (30%) had received more than one prior chemotherapy regimen. Thirty-three patients (91%) had been previously treated with vinca alkaloids, and 26 patients (72%) had been treated with anthracycline-containing regimens (ABV, 24 patients; BV, eight patients; vincristine, one patient; liposomal doxorubicin, one patient; liposomal daunorubicin, one patient). Ten patients had received etoposide (one patient as first-line and nine patients as second-line chemotherapy), and one patient had received paclitaxel as second-line chemotherapy. In addition, six patients had received systemic immunotherapy with interferon alfa-2b.
Response and Clinical Benefit
For the 15 patients with objective responses, the median duration of response from the beginning of therapy until development of PD was 176 days (95% CI, 159 to 652 days; Fig 1). The median progression-free survival and the median survival durations for 35 assessable patients were 151 days (95% CI, 65 to 176 days) and 216 days (95% CI, 183 to 414 days), respectively (Fig 1). Visceral involvement at baseline, CD4 lymphocyte count of less than 50 cells/µL, and concomitant therapy with antiretroviral drugs did not influence survival. As expected, a significant difference in survival was found in patients who received HAART (nine patients) during follow-up (median, 900 days) compared with those who did not receive HAART (median, 195 days; P = .002).
Of the 36 patients enrolled, 25 died. The principal causes of death were progressive KS in eight patients, opportunistic infections in six, both progressive KS and opportunistic infections in six, non-Hodgkin’s lymphoma (NHL) in two, and wasting syndrome in one. In two patients, the cause of death was unknown. Of the 11 patients who were alive at the last follow-up visit, four have since been lost to follow-up, six maintain good control of KS while on HAART without any further chemotherapy, and one patient who is not on HAART presents with progressive KS.
Toxicity Overall, 159 cycles of vinorelbine were administered, with a median number of four cycles (range, one to 11 cycles) per patient. Early withdrawal from the study occurred in 13 patients, whereas the remaining patients received all of the planned cycles. The majority of these interruptions were related to the progression of KS (five patients) and to complications associated with HIV infection (three patients). Early termination due to chemotherapy-related adverse events occurred only in one patient because of a grade 2 peripheral neuropathy; however, the patient completely recovered after discontinuation of chemotherapy. Other reasons for discontinuation were progressive clinical deterioration (two patients) and lost to follow-up (two patients). Overall, 66% of patients reported at least one adverse event that was possibly related to vinorelbine. Myelotoxicity was the major toxic effect of the regimen. The overall clinical toxicity observed in this trial is listed in Table 3. Grade 3 to 4 neutropenia was the most common adverse event and occurred in 17 patients (51%) during at least one cycle of treatment. Absolute neutrophil counts decreased to less than 500/µL in 10 patients (30%), and grade 3 to 4 nadirs generally lasted no more than 5 days. Twenty-two patients (66%) received G-CSF during the course of chemotherapy. Of these, 12 patients received primary prophylaxis because they had less than 3,000 WBCs/µL at study entry. The majority of such patients recovered before the next cycle of therapy was scheduled. Among a total of 158 cycles, a reduction of dose was required for eight patients in 16 cycles. Of the 10 patients in whom neutrophil counts decreased to less than 500/µL, two patients were receiving concomitant co-trimoxazole; two patients were receiving ganciclovir; one patient was receiving foscarnet, isoniazid, and ethambutol; and two patients were receiving the combination of zidovudine and lamivudine. Anemia was the second most common myelotoxic event encountered, with five patients experiencing grade 3 toxicity. Grade 3 thrombocytopenia was observed in one patient. No patient was taken off study because of hematologic toxicity.
Nonhematologic toxicity was uncommon. Peripheral neuropathy was observed in three patients. Of these, one patient developed a progressive neurologic impairment, characterized by sensorial and motor dysfunction, after two cycles of therapy. All three patients had been previously treated with vinca alkaloid–containing regimens. Mild to moderate paresthesia and constipation occurred in three and four patients, respectively. Moderate nausea/vomiting were observed in four patients. No grade 3 to 4 alopecia was observed. During the course of the study, 12 patients (33%) experienced an opportunistic infection. CMV infection was the most frequent (n = 9). Three patients had a CMV sepsis, three patients had a recurrent CMV retinitis, two patients developed a new CMV retinitis, and one patient developed a symptomatic CMV colitis. The latter had a complicated course, with intestinal perforation and peritonitis. This patient required a definitive interruption of chemotherapy, whereas the other patients were able to continue chemotherapy during ganciclovir or foscarnet therapy. Other opportunistic infections consisted of PCP (n = 1), esophageal candidiasis (n = 1), and herpes zoster infection (n = 1). Of the 12 patients who developed opportunistic infections, three patients were receiving concomitant antiretroviral therapy during chemotherapy (AZT, one patient; AZT + 3TC, two patients). It should be noted, however, that during the study period, protease inhibitors were not available, and the majority of patients were as yet undergoing treatment with a single-agent therapy. Nine patients began protease inhibitor–containing regimens (HAART) late in the course of the study. During the follow-up period, four patients developed opportunistic infections (PCP, toxoplasmosis, CMV infection, and tuberculosis, all one patient each), and two patients developed NHL. Of these six patients, two were receiving HAART during the onset of AIDS-related disease (NHL, one patient; PCP, one patient).
In patients with aggressive and extensive mucocutaneous disease or with visceral KS localizations, systemic chemotherapy is considered the treatment of choice. In this setting, the optimal treatment has yet to be found. Because there is no single best regimen, physicians should choose the most suitable treatment for each patient on the basis of an accurate benefit/risk ratio assessment. In a disease such as AIDS-related KS, where only palliative treatments are available, information on the toxicity of the drugs and their impact on the quality of life is particularly important in assessing their role in disease management. In light of these considerations, research of new, effective, cytotoxic agents having minimal toxicity is clearly recommended. So far, there are several therapeutic choices available to patients with advanced KS. Doxorubicin-based regimens (ABV, BV)5-8 and liposomal anthracyclines12-15 are associated with good overall response rates and, in general, are indicated as first-line treatment for patients with visceral or life-threatening disease. Paclitaxel,9-11 another cytotoxic agent, has recently been shown to be effective, with comparable ranges of response rates and also response duration. These drugs, however, often cause significant toxicity, and, in particular, leukopenia is the major dose-limiting adverse event. Nausea/vomiting and alopecia, which usually create much discomfort in this setting, are other common adverse events, especially for patients who receive chemotherapy with doxorubicin-based regimens. To date, only one trial has specifically investigated cytotoxic agents in patients who were unsuccessfully treated with or were intolerant to their first-line chemotherapy regimen. Northfelt et al13 evaluated liposomal doxorubicin after failure of standard chemotherapy in 53 patients. Thirty-six percent had a PR, and one patient had a cCR. The median duration of response was 128 days. The most common adverse event was leukopenia, which occurred in 40% of patients. Of these, five patients experienced an episode of sepsis while on study. Nausea and vomiting occurred in 15% and alopecia occurred in 9% of patients. Within a more extensive study, Welles et al10 evaluated paclitaxel in 11 patients who had experienced treatment failure with a prior cytotoxic therapy and reported 10 PRs. Despite these favorable results, toxicity (including that of chemotherapy-naive patients) was significant, with grade 3 to 4 neutropenia in 90% of patients and alopecia (any grade) in 100% of patients. In this trial, however, hematologic toxicities should be evaluated carefully, because the paclitaxel dose was escalated until the development of grade 3 to 4 neutropenia, and colony-stimulating factors were not used. However, considering only patients who received the initial dose of 135 mg/m2 (and considering also patients who received support with colony-stimulating factors), 21 (72%) of 29 patients developed grade 4 neutropenia, which is comparable to the overall hematologic toxicity. These data were substantially confirmed by Gill et al11 in a second study of paclitaxel in KS patients. They treated 40 patients who had received prior systemic chemotherapy and obtained an overall response rate of 59% (including also chemotherapy-naive patients), with a median duration of response of 10.4 months and grade 3 to 4 neutropenia occurring in 62% of patients. In light of these results, liposomal doxorubicin—and, in the second instance, paclitaxel—are considered the best options in the management of patients with advanced KS who failed to respond to a prior chemotherapeutic regimen. This trial is the first study of vinorelbine in the treatment of KS thus far. The findings of our study demonstrate that vinorelbine is safe and active in patients with HIV-associated KS. It is noteworthy that this result was obtained in severely immunocompromised patients with advanced stage KS and in patients who had experienced treatment failure with one or more lines of chemotherapy. Overall responses (43%) and median duration of response (174 days) are similar to those achieved by Northfelt et al13 with liposomal doxorubicin. Also, the toxicity profile is comparable to that reported for liposomal doxorubicin, with leukopenia being the most frequent dose-limiting toxicity. Although the definition and application of response criteria may differ between studies, and, therefore, no firm conclusion can be drawn in the absence of randomized studies, the comparison of the results of our trial with those of Northfelt et al13 is interesting; especially considering that liposomal doxorubicin is, to date, the standard of care for advanced KS and that the two study populations present similar baseline immunologic and clinical characteristics. Moreover, vinorelbine compares favorably in terms of costs with respect to liposomal doxorubicin. In particular, in Italy, one cycle of vinorelbine (Navelbine 30 mg/m2 in a patient of 1.7 m2 of body area) costs Lit 145,000 (US $80), whereas one cycle of pegylated liposomal doxorubicin (Caelyx [Schering-Plough, Heist op den Berg, Belgium] 20 mg/m2 in a patient of 1.7 m2 of body area) costs Lit 1,458,600 (US $810). Overall, vinorelbine seemed to be well tolerated. Toxicity, including neurologic, was mild and reversible. Although myelosuppression was the dose-limiting toxicity, this side effect was not cumulative. At study entry, 12 patients (33%) had less than 3,000 WBCs/µL, and, in this setting, use of G-CSF was necessary to achieve the scheduled dose-intensity. No patient was taken off study for dose-limiting or refractory neutropenia. It is noteworthy that neutrophil nadirs were generally brief and no patient experienced morbidity or died as a result of granulocytopenic infections, although many patients received concomitant medications (ie, ganciclovir/foscarnet and antiretroviral drugs). Of practical interest, two of the most unpleasant side effects of palliative treatments (nausea/vomiting and alopecia) were virtually absent in our case series. In this regard, vinorelbine presents the same characteristics of liposomal doxorubicin while comparing favorably with respect to other chemotherapeutic regimens (ie, paclitaxel, ABV). Also, neurotoxicity, which represents one of the most troublesome adverse events of vinca alkaloids, was mild in our study. Peripheral neuropathy was observed in three patients. Of them, only one patient developed grade 2 neuropathy, which required early termination of chemotherapy. Other neurologic toxicity, including constipation and paresthesia, were negligible. The low neurologic toxicity observed in our study is consistent with that observed in other studies.19 Actually, among the vinca alkaloids, vinorelbine seems to have a potent activity on mitotic microtubules and a weak activity on axonal microtubules. This characteristic could explain the efficacy of the drug in addition to its minor neurotoxic effects. The incidence of opportunistic infections did not differ significantly from that observed in other studies for similar patients with AIDS-related KS who received chemotherapy. In particular, only one patient discontinued chemotherapy for the occurrence of CMV colitis. It should be noted that this study was designed before the availability of protease inhibitors, and only a few patients received them later during the follow-up period of the study. Twelve patients (33%) received only either mono or dual antiretroviral therapy with reverse transcriptase inhibitors, whereas the majority of patients did not receive any antiretroviral therapy. Considering the low toxic profile of vinorelbine, concomitant use of HAART should always be considered, and this will likely offer a potential for reducing opportunistic infections during chemotherapy. In conclusion, this trial has yielded the first evidence that vinorelbine has activity against KS. This study suggested that vinorelbine is effective in the treatment of patients with advanced KS who were previously treated with one or more lines of chemotherapy. Results with vinorelbine are similar to those obtained with liposomal doxorubicin in pretreated patients, as it was associated with significant clinical benefit and acceptable toxicity while comparing favorably in terms of cost. Of particular interest, vinorelbine induced responses also in patients who had become resistant to drug regimens that include other vinca alkaloids. Further studies to investigate the role of vinorelbine within combination regimens are needed. In particular, clinical data suggest that the association of vinorelbine and taxane may led to a synergy, and we believe that this potentiality should be evaluated in patients with AIDS-related KS.
Supported by grants of the Istituto Superiore di Sanità and Associazione Italiana per la Ricerca sul Cancro. We thank Daniela Furlan for expert assistance in the preparation of the manuscript.
1. Brodt HR, Kamps BS, Gute P: Changing incidence of AIDS-defining illness in the era of antiretroviral combination therapy. AIDS 11:1731-1738, 1997[Medline] 2. Jacobson LP: Impact of highly effective anti-retroviral therapy on the incidence of malignancies among HIV-infected individuals. Syndr 17:A39, 1998 (abstr) 3. Beral V, Peterman TA, Berkelman RL, et al: Kaposi’s sarcoma among persons with AIDS: A sexually transmitted infection? Lancet 335:123-128, 1990[Medline] 4. Nasti G, Errante E, Santarossa S, et al: Risks and benefits of treatment for AIDS-related Kaposi’s sarcoma. Safety 20:403-425, 1999 5. Kaplan L, Abrams D, Volberding P: Treatment of Kaposi’s sarcoma in AIDS with an alternating vincristine-vinblastine regimen. Cancer Treat Rep 70:1121-1122, 1986[Medline] 6. Gill P, Rarick M, Bernstein-Singer M, et al: Treatment of advanced Kaposi’s sarcoma using a combination of bleomycin and vincristine. Am J Clin Oncol 13:315-319, 1990[Medline] 7. Laubenstein LJ, Kriegel RL, Odajnyk CM, et al: Treatment of epidemic Kaposi’s sarcoma with etoposide or a combination of doxorubicin, bleomycin and vinblastine. J Clin Oncol 2:1114-1118, 1984 8. Gill PS, Rarick M, McCutchan JA, et al: Systemic treatment of AIDS-related Kaposi’s sarcoma: Results of a randomized trial. Am J Med 90:427-433, 1991[Medline] 9. Saville MW, Lietzau J, Pluda JM, et al: Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet 346:26-28, 1995[Medline] 10. Welles L, Saville W, Lietzau J, et al: Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol 16:1112-1121, 1998[Abstract] 11. Gill P, Scadden D, Groopman J, et al: Low dose paclitaxel (Taxol) is highly effective in the treatment of patients with advanced AIDS-related Kaposi’s sarcoma. Syndr 14:A35, 1997 (abstr) 12. Gill PS, Wernz J, Scadden DT, et al: Randomized phase III trial of liposomal daunorubicin (DaunoXome) versus doxorubicin, bleomy-cin, vincristine (ABV) in AIDS-related Kaposi’s sarcoma. Oncol 14:2353-2364, 1996
13.
Northfelt DW, Dezube BJ, Thommes JA, et al: Efficacy of pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi’s sarcoma after failure of standard chemotherapy. J Clin Oncol 15:653-660, 1997 14. Northfelt DW, Dezube BJ, Thommes JA, et al: Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, vincristine in the treatment of AIDS-related Kaposi’s sarcoma: Results of a randomized phase III clinical trial. J Clin Oncol 16:2445-2451, 1998[Abstract] 15. Stewart S, Jablonowsky H, Goebel FD, et al: Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. Oncol 16:683-691, 1998
16.
Sørensen JB: Current position of vinorelbine in cancer chemotherapy. Ann Oncol 6:105-107, 1995 17. Fellons A, Ohayon R, Vacassin T, et al: Biochemical effects of Navelbine on tubulin and associated proteins. Semin Oncol 16:9-14, 1989
18.
Pinedo HM, Van Groeningen CJ: Vinorelbine: A horse of a different color? J Clin Oncol 12:1745-1747, 1994 19. Hohneker JA: A summary of vinorelbine (Navelbine) safety data from North America Clinical Trials. Semin Oncol 21:42-47, 1994 (suppl 10) 20. Errante D, Fasan M, Rizzardini G, et al: Evidence of activity of vinorelbine in patients with previously treated AIDS-associated Kaposi’s sarcoma. AIDS 10:1472-1473, 1996 21. Krown SE, Metroka C, Wernz JC, et al: Kaposi’s sarcoma in the acquired immune deficiency syndrome: A proposal for uniform evaluation response and staging criteria. Clin Oncol 7:1201-1207, 1989 22. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[Medline] 23. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 24. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] Submitted June 1, 1999; accepted December 9, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
.05 (two tails). 
