Safety Data From North American Trials of Vinorelbine

October 2, 1997

Data from North American clinical trials have shown that vinorelbine (Navelbine) is well tolerated when used as a single agent for the treatment of non-small-cell lung cancer, advanced breast cancer, or ovarian cancer. Myelosuppression is the primary dose-limiting toxicity.

ABSTRACT: Data from North American clinical trials have shown that vinorelbine (Navelbine) is well tolerated when used as a single agent for the treatment of non-small-cell lung cancer, advanced breast cancer, or ovarian cancer. Myelosuppression is the primary dose-limiting toxicity. Although the incidence of grade 4 granulocytopenia has been approximately 38%, the rate of related hospitalizations has been acceptable (10%). Moreover, hematologic toxicity is noncumulative and reversible. The rate of septic deaths is low, severe anemia is uncommon, and thrombocytopenia is rare. Most nonhematologic toxicities are of mild or moderate intensity, and severe complications are infrequent. Injection-site reactions are more common with longer infusions, whereas back pain is more likely to occur with shorter infusions; a 6- to 10-minute infusion has therefore been deemed optimal. Nausea and vomiting have occurred in approximately one-half of patients, but these effects have been severe in less than 3%. The incidence of neurotoxicity has been relatively low compared with other Vinca alkaloids. Respiratory reactions have been infrequent and have been similar to those reported with other Vinca alkaloids. Vinorelbine has maintained a favorable safety profile when used in combination with cisplatin (Platinol). [ONCOLOGY 11(Suppl 12):16-19, 1997]

Introduction

Intravenous vinorelbine (Navelbine) is an antineoplastic agent that has been evaluated for the treatment of non-small-cell lung cancer (NSCLC), advanced breast cancer, and ovarian cancer. Extensive data from North American studies have shed light on the safety profile of vinorelbine as a single agent. Additional sources of data have provided further insight into the safety of vinorelbine both as a single agent and in combination with cisplatin (Platinol).

North American Database

North American studies have assessed single-agent vinorelbine in a variety of settings and patient populations: as first-line treatment for stage IV non-small-cell lung cancer (N = 143),[1] as first- or second-line treatment for advanced breast cancer (N = 107),[2] as second- or third-line treatment for advanced breast cancer (N = 115),[3] as first-line treatment for advanced breast cancer in women ³ 60 years old (N = 39),[4] and as second-line treatment for advanced ovarian cancer (N = 38).[5]

Hematologic Toxicity

Data from the 442 patients in these five trials have shown that myelosuppression (specifically, granulocytopenia) is the primary dose-limiting toxicity of vinorelbine (Table 1). Thrombocytopenia has occurred in relatively few patients, and platelet counts have actually increased in some cases. The occurrence of grade 3 or 4 anemia has been low.

Despite the frequency of granulocytopenia, only 10% of patients have required hospitalization for related adverse events. The hospitalization rate has been split fairly evenly between patients with fever alone and those with infection, but sepsis-related deaths have been rare (less than 1% of hospitalized patients). In view of the fact that the nadir is generally reached at approximately day 14, the risk of sepsis can likely be further reduced by closely monitoring patients for granulocytopenia between the second and third week of treatment.

No evidence is available to indicate that hematologic toxicity is cumulative with vinorelbine. Data have shown that most patients experience their major toxicity during the first course of therapy (from weeks 1 to 8); thereafter, the incidence steadily decreases. Hematologic toxicity can usually be managed with careful monitoring and appropriate dose modifications. Moreover, all toxic effects are reversible upon discontinuation of the drug.

Myelosuppression has been less pronounced in patients with non-small-cell lung cancer than in those with breast cancer or ovarian cancer. This observation may relate to the fact that the non-small-cell lung cancer patients in these studies were chemotherapy-naive, whereas many of those in the latter two disease groups had received previous chemotherapy. However, it is noteworthy that rates of hospitalization for granulocytopenic complications have not differed by type of disease.

Patients ³ 65 years of age have had a slightly increased incidence of hematologic toxicity when compared with younger patients. Older patients have also had a slightly higher rate of hospitalization due to granulocytopenic complications than their younger counterparts (12% vs 8%, respectively).

Liver Function Tests

Tests of liver function have shown grade 3 elevation in alkaline phosphatase in 25% of patients treated with vinorelbine and grade 4 elevation in 3%. However, it is difficult to determine whether these findings are related to bone metastases or to vinorelbine therapy. Most patients in the database have had breast cancer and a fairly high frequency of bone metastases. Regardless, elevations in alkaline phosphatase levels have not limited the use of vinorelbine in any of the studies. The incidence of grade 3 or 4 elevation in total bilirubin levels has been acceptable (6%).

Nonhematologic Adverse Experiences

Overall, nonhematologic adverse experiences have occurred in 75% of patients in the North American database. The maximum intensity of the adverse experience has been grade 1 (mild) in 18% of patients, grade 2 (moderate) in 33%, grade 3 (severe) in 21%, and grade 4 (life-threatening) in 3%.

Table 2 presents an overview of nonhematologic adverse experiences in patients treated with single-agent vinorelbine. Asthenia has been the most common adverse event but has reached grade 3 in only 5% of patients. Again, it is difficult to distinguish whether asthenia is related to the natural history of the disease (particularly in patients with non-small-cell lung cancer or refractory breast cancer) or to the use of vinorelbine. Injection-site reactions, including phlebitis and pain at the injection site, are frequent adverse experiences linked to vinorelbine. Tumor pain has been noted as well.

Injection-Site Reactions have occurred in approximately 30% of patients who have received vinorelbine as a 20-minute infusion. These reactions have been characterized by mild-to-moderate erythema, pain, vein discoloration, and phlebitis. Vinorelbine may also act as a Vinca-like vesicant. Extravasation injuries have been reported, but few patients have required surgical management.

The 30% incidence of injection-site reactions may be reduced by administering vinorelbine over a shorter period. This observation emerged from a study in which patients were assigned to receive vinorelbine in an infusion of 1 to 2 minutes, 6 to 10 minutes, or 20 to 30 minutes.[6,7] Both the frequency and severity of venous irritation increased as the infusion time was prolonged. Notably, however, back pain tended to be more frequent with shorter infusion times. To achieve the most acceptable balance between the incidence of venous irritation and back pain, the current recommendation is that vinorelbine be administered over 6 to 10 minutes.

Digestive System—Nausea and vomiting have occurred in approximately one-half of patients treated with single-agent vinorelbine, but these effects have been severe in less than 3% (Table 3). It should be noted that most of the North American studies did not include the routine use of prophylactic antiemetics, and, therefore, these figures represent the true incidence. Mild-to-moderate nausea and vomiting can be controlled with standard antiemetics designed for use with agents that have low emetic potential.

Constipation has been noted in 29% of patients (grade 3 in 2%), primarily those receiving narcotic analgesics. Paralytic ileus has been infrequent; once again, its occurrence has been most likely in patients receiving narcotic analgesics.

Diarrhea, stomatitis, and dyspepsia, usually of mild or moderate severity, have occurred in less than 20% of patients.

Nervous System—Clinically evident neurotoxicity, usually of mild or moderate intensity, has occurred in approximately 30% of patients treated with single-agent vinorelbine. Paresthesia and hypesthesia have been relatively uncommon (Table 4). Muscle weakness and decreased deep-tendon reflexes have been reported, but the latter reactions are not associated with symptoms that can be recognized by the patient. All these effects are reversible.

Tumor pain, jaw pain, and back pain have also been noted. However, these effects have also been reported with other Vinca alkaloids and may represent idiosyncratic reactions.

Respiratory System—Respiratory reactions have been an infrequent occurrence among patients treated with vinorelbine. These events have been quantitatively and qualitatively similar to those seen with other Vinca alkaloids. Acute and subacute reactions have been observed, but no evidence of chronic effects has been uncovered to date.

Acute events are usually allergic in character and can be treated accordingly. Subacute reactions have primarily taken the form of dyspnea, cough, hypoxemia, or interstitial infiltrates. Dyspnea has occurred in only 5% of patients and has reached grade 3 or 4 in only 2%. All subacute reactions are reversible; steroids have proven effective in this regard. A higher frequency of subacute effects has been noted when vinorelbine has been coadministered with mitomycin (Mutamycin), as has been the case with other Vinca alkaloids.

Miscellaneous Adverse Experiences —Alopecia occurs in only 10% of patients receiving single-agent vinorelbine and is severe in less than 1%. Unlike the taxanes, vinorelbine is not associated with total hair loss. Rather, patients treated repetitively with vinorelbine tend to experience a thinning of hair over time.

Chest pain has been reported in approximately 6% of patients. Most of these patients have had a history of cardiovascular disease or have been smokers with lung cancer. Because of these confounding factors, it is unclear whether chest pain is a drug effect or is related to the natural history of cardiovascular disease or a history of smoking.

Rare Adverse Experiences—Vocal cord paralysis has been reported rarely in patients treated with single-agent vinorelbine. Most of these patients have had mediastinal involvement from their tumors, again raising the question of whether the adverse event was related to the drug or to the disease. The same question applies to rare occurrences of deep venous thrombosis. Bilateral cataracts have been reported in some patients, but the etiology of this effect remains unclear. The syndrome of inappropriate antidiuretic hormone has been seen rarely with vinorelbine, as with other Vinca alkaloids, and hemorrhagic cystitis has been noted in a few patients.

Additional Sources of Data

Data from additional sources have provided useful insights into the safety of vinorelbine as a single agent or in combination with cisplatin. These studies have not been included in the overall North American database because different modes of data collection were used.

Compassionate-Use Program in Advanced Breast Cancer

In a compassionate-use program, vinorelbine was administered to patients with advanced breast cancer who had not responded to or were intolerant of anthracycline, as well as taxane treatment. Women with hormone-receptor–positive disease were also required to have been unresponsive to tamoxifen (Nolvadex).

Consistent with the observations from the North American database, granulocytopenia was common among these previously treated patients. The overall incidence was 94%, with grade 4 granulocytopenia observed in 53%. The incidences of grade 3 or 4 anemia and thrombocytopenia were 18% and 14%, respectively.

Investigational New Drug Program in Non-Small-Cell Lung Cancer

During regulatory review of the investigational new drug application for vinorelbine, the drug was made available to patients with unresectable, stage III or IV non-small-cell lung cancer who were not candidates for more aggressive local therapy. A total of 504 patients were treated between May 1994 and January 1996. At enrollment, these patients had a mean Karnofsky performance score of 84% (range, 50% to 100%), and 76% of patients had stage IV disease. The patients and their physicians had the option of using vinorelbine as a single agent (N = 260) or in combination with cisplatin (N = 244).

Using the US Food and Drug administration definition of “serious,” the percentage of patients with serious leukopenia (for example, requiring hospitalization) was slightly lower with vinorelbine alone (6.9%) than with vinorelbine plus cisplatin (12.7%). Fever was reported in 2% vs 7% of patients, respectively. Sepsis and nausea occurred in 2% of patients in both groups.

Some unexpected serious adverse experiences also occurred. Cataracts were reported in one patient who received vinorelbine alone and in two patients who received vinorelbine plus cisplatin. One patient developed severe mucositis following radiation therapy, which was undertaken soon after the completion of treatment with vinorelbine alone. Vinorelbine was believed to have accelerated the toxicity from radiation therapy, a concept borne out by studies showing that the agent acts as a radiation sensitizer.[8-10]

There were two reports of atrial fibrillation attributed to the combination of vinorelbine plus cisplatin. Vocal cord paralysis occurred in one patient in the vinorelbine-alone group, whereas cardiac arrest was reported in one patient in the combination-therapy group; in neither case was it clear whether the adverse experience was related to the drug or to underlying disease.

Conclusions

The North American studies have shown that vinorelbine is well tolerated and can be easily given in the outpatient setting. Although myelosuppression is the predominant toxicity, only 10% of patients required hospitalization for complications related to grade 3 or 4 granulocytopenia. This low rate of hospitalization is of particular interest in view of the current emphasis on reducing the overall cost of cancer care.

The data have also shown that vinorelbine is associated with a relatively low incidence of thrombocytopenia, symptomatic neuropathy, total alopecia, and nausea and vomiting. Furthermore, none of these toxicities seems to be cumulative, and all are reversible on discontinuation of the drug.

References:

1. Crawford J, O’Rourke M, Schiller J, et al: A randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small cell lung cancer. J Clin Oncol, 1997 (in press).

2. Weber B, Vogel C, Jones S, et al: Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 13:2922-2230, 1995.

3. Jones S, Winer E, Vogel C, et al: Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 13:2567-2574, 1995.

4. Vogel C, O’Rourke M, Winer E, et al: A clinical trial of intravenous (IV) Navelbine (NVB) (vinorelbine tartrate) for first line treatment of women ³ 60 years of age with advanced breast cancer. Proc Am Soc Clin Oncol 15:101, 1996.

5. Burger R, Burman S, White R, et al: Phase II trial of Navelbine in advanced epithelial ovarian cancer. Proc Am Soc Clin Oncol 15:286, 1996.

6. Rittenberg C, Gralla R, Rehmeyer T: Assessing and managing venous irritation associated with vinorelbine tartrate (Navelbine). Oncol Nurs Forum 22:707-710, 1995.

7. Rittenberg C, Reymeyer T, Gralla R, et al: Reducing venous irritation in chemotherapy administration: An investigation during the new agent testing of Navelbine with development of an appropriate recording instrument. Oncol Nurs Forum 21:377, 1994.

8. Edelstein M, Wolfe L, Duch D: Potentiation or radiotherapy by Navelbine (NVB) in a human non-small cell lung cancer (NSCLC) line. Proc Am Assoc Cancer Res 36:611, 1995.

9. Edelstein M, Wolfe L, Duch D: Potentiation of radiation therapy by vinorelbine (Navelbine) in non-small cell lung cancer. Semin Oncol 23(suppl 5):41-47, 1996.

10. Vokes E, Haraf D, Masters G, et al: Vinorelbine (Navelbine), cisplatin, and concomitant radiation therapy for advanced malignancies of the chest: A phase I study. Semin Oncol 23(suppl 5):48-52, 1996.