Patients Starting Treatment:
Treatment Options - Doxil
Doxil (Doxorubicin HCl Liposome Injection)
|Full Name:||Doxorubicin HCl Liposome Injection|
|Other Names:||Caelyx® (outside the US)|
|Description:||Doxorubicin HCl encapsulated in long-circulating STEALTH® |
liposomes for intravenous administration
|Phase:||Approved in the US in combination with Velcade® (bortezomib, Millennium Pharmaceuticals, Inc.)|
|Manufacturer:||Ortho Biotech (Doxil®)|
Schering Plough Corporation (Caelyx®)
|DOXIL SUPPLY UPDATE|
|Doxil Supply Restored|
What It Is
Doxil (doxorubicin HCl liposome injection) is a chemotherapy drug used in cancer treatment. It is a reformulated version of doxorubicin (Adriamycin®), a cancer drug that has been used for many years in standard chemotherapy regimens, including VAD (vincristine, Adriamycin, and dexamethasone) in myeloma.
In May 2007, Doxil was approved for use in combination with Velcade® (bortezomib, Millennium) to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy. Doxil has also been evaluated in Phase III trials as a component of initial therapy for multiple myeloma.
Doxil is also indicated for the treatment of patients with ovarian cancer and in patients with AIDS-related Kaposi's sarcoma. Caelyx is approved for use in certain countries outside the United States for the treatment of breast and ovarian cancer and AIDS-related Kaposi's sarcoma.
How It Works
It is believed that the actions of doxorubicin HCl are mediated through its ability to bind to DNA and inhibit nucleic acid synthesis. Doxorubicin also inhibits topoisomerases, enzymes important to many DNA-related functions such as gene transcription, and generates oxygen radicals that damage tumor cell DNA, eventually leading to death of myeloma cells. The STEALTH® liposomes utilized in Doxil® are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by monocytes and macrophages in the liver and spleen. This in part allows for a prolonged circulation time within the bloodstream. STEALTH® liposomes have a half-life of up to 80 hours in humans and remain stable in blood, so that more than 90% of the active drug, doxorubicin, remains encapsulated during transport through the system. How the drug is released upon arrival at target tissues is not well understood, but studies using Kaposi's sarcoma lesions indicate a concentration that is a median of 19 times higher in tumor tissue than normal tissue.
Details on Doxil®'s Mechanism of Action
Encapsulation within long-circulating STEALTH® liposomes seems to increase the tolerance of doxorubicin without harming its efficacy. Distribution of Doxil® appears to occur in two phases, first in a short phase of about 5 hours, and then over a prolonged phase of up to 80 hours.
Doxil® has not yet been specifically evaluated in special patient groups, such as those with hepatic or renal insufficiency. No studies have been conducted that compare the effects across gender or ethnic group. Likewise, drug-to-drug interactions have not been evaluated, except as they apply to doxorubicin.
Dosage and Administration
Doxil® is available only for intravenous use. The indicated dosage for ovarian cancer is 50 mg doxorubicin HCl in a sterile, translucent, red liposomal dispersion of 30 mL, at an initial rate of 1 mg/min to minimize the risk of infusion reactions. In clinical trials underway in multiple myeloma, patients have generally been given a lower dosage of Doxil® (40 mg/m2), in combination with other agents. Patients are given 1 infusion every 4 weeks for approximately 4 courses of therapy, depending on their side effects and the response of their cancer to treatment.
Length of Therapy
The median response time in patients with ovarian cancer is documented at 4 months. The length of therapy in multiple myeloma has not been determined, in part because VAD with Doxil® is often given as part of preparation for later transplantation.
Potential Side Effects
Infusion-related reactions were reported in 7.1% of patients treated with Doxil® for ovarian cancer, and were usually observed with the first infusion. Symptoms included flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness of the chest and throat, fever, tachycardia, pruritis, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. If these side effects occur, depending on their severity, it may be necessary to slow or stop the infusion until they improve. In some cases it may later be possible to resume therapy after pre-medication with acetaminophen, or diphenhydramine, or corticosteroids, or some combination of these drugs.
Occasional side effects reported specifically with Caelyx® may include diarrhea, sun sensitivity, and temporary hair loss, in addition to the infusion-related effects discussed above.
Hand-foot syndrome (HFS), characterized by swelling, pain, erythema, and, in some cases, cracking, blistering, and desquamation of the skin of the hands and feet, was reported by 50.6% of patients treated at the 50 mg dose. Ten of the subjects in the original ovarian cancer study discontinued use due to HFS. In multiple myeloma, lower doses of Doxil® are used, and the risk of HFS is much lower, at about 25%. Symptoms of HFS usually accumulate after multiple doses, but may appear after the first dose and generally resolve in 1-2 weeks. Patients can help to decrease the chance that this side-effect occurs by avoiding very hot water, and any activities that might cause trauma to the hands and feet such as vigorous rubbing. Dose adjustments may be necessary to reduce discomfort, and there may be a benefit to dietary supplementation with vitamin B6 at 200 mg daily starting with the first therapy.
As with any IV therapy, signs of irritation at the infusion site may occur in the form of stinging or burning. If this occurs, the infusion should be terminated and restarted at another site. Ice should be immediately applied to the irritated area and maintained for 30 minutes.
Because infusion-related events are less commonly reported after conventional doxorubicin administration, many of these effects are believed to be related to the liposomal component of Doxil®. Most patients are able to continue infusion at a slower rate. Less than 1% (0.8%) of patients in the ovarian cancer discontinued treatment due to adverse events (AEs).
Potential for Toxicity
The doxorubicin component in Doxil® may exacerabate the toxic potential of other cancer therapies, particularly cyclophosphamide and radiation therapies.
Myocardial toxicity is a risk of cumulative doxorubicin therapy, and therefore, careful assessment of cardiovascular function should be undertaken first, and patients at risk should be monitored for cardiac damage. Echocardiography and multigated radionuclide scans are often used to monitor patients on doxorubicin therapy, and endomyocardial biopsy may need to be performed in rare cases to definitively identify damage.
The cardiotoxicity of Doxil® is potentially much less than with doxorubicin for a number of reasons. The slow-release mechanism allows for much lower circulating levels of free drug in the bloodstream. Additionally, preferential accumulation of the drug at the tumor site, less exposure to the rest of the body, and a shorter infusion time all contribute to lower risk of myocardial damage generally associated with the higher doses of doxorubicin.
A clinical study of breast cancer patients being given Doxil® therapy (50 mg/every 4 weeks) showed a risk of cardiotoxicity of 11% in these patients associated with the doxorubicin component.
The most common hematologic adverse event reported from three single-arm studies in patients with ovarian cancer was anemia (52.6%), followed by leukopenia (42.2%), thrombocytopenia (24.2%) and neutropenia (19%). A larger randomized study comparing Doxil® to topotecan also found a high incidence of anemia (40.2%), followed by leukopenia (38.6%), neutropenia (35.1%) and thrombocytopenia (13.0%). To counter the myelosuppressive effects of Doxil®, 4.6% of patients with relapsed ovarian cancer received G-CSF.
Clinical Trials in Multiple Myeloma
The combination of Doxil®/Caelyx®, vincristine, and reduced dose dexamethasone (DVd) has recently been shown to be effective as induction therapy, as the new formulation provides for a slow release of the drug, thus exposing myeloma cells to the drug for a longer period of time.
Substituting Doxil® for doxorubicin in the VAD regimen and reducing the schedule of dexamethasone appears to improve the safety profile and convenience of the induction regimen without compromising efficacy. (Hussein et al. Cancer. 2002;95(10):2160-2168.) In a Phase II study in 33 newly diagnosed patients, 67% of patients achieved at least a 50% reduction in their myeloma monoclonal (M) protein and the patient survival rate at 3 years was 67%. No patients required discontinuation of treatment due to side effects, and only one patient experienced damage to the heart muscle. The most common severe (Grade 3) toxicities were swelling, itching, and peeling skin on the hands and feet (a disorder known as hand-foot syndrome (HFS), or previously palmar-plantar erythrodysesthesia (PPE), a common side effect of certain types of chemotherapy), mouth sores, and neutropenia (low neutrophil white blood cell counts). The incidence of PPE was significantly reduced when patients were given instructions on preventive strategies.
Various DVd and VAd regimens are being compared in Phase II and III clinical trials. Results of a randomized Phase III study conducted in Europe showed that DVd (n=132), the version of VAd with liposomal doxorubicin, was as effective as VAd (n=127). In this study, VAd was given daily as an intravenous bolus for four days in a row, while DVd was administered as a short infusion on one day of each month. Using this approach with a modified, shorter version of high-dose dexamethasone as part of an outpatient regimen, objective responses were seen in 61% of patients receiving either combination. (Dimopoulos et al. Ann Oncol. 2003;14:1039-1044.) Side effects were reported as mild to moderate and were similar between the two groups, except that hair loss was more common with VAD, and PPE/HFS was more common with DVd.
Kumar et al. found high microvessel density (MVD) in the bone marrow of multiple myeloma patients, indicative of an angiogenic process. Antiangiogenic activity of doxorubicin may account for some of the efficacy of the DVd regimen. Data from a Phase II trial being conducted by the Cleveland Clinic has demonstrated an overall response rate of 96%, with 15% of patients achieving complete remission in the 33 patients inducted into the study. Time to progression was 23 months on average, with an overall 3-year survival rate of 67%.
A phase III study comparing VAd and DVd, both with reduced dose dexamethasone, has also recently been completed in the United States and, unlike the prior Greek study, used traditional infusional VAd. Data from this trial was recently presented at the 2004 meeting of the American Society of Clinical Oncology. (Rifkin et al. Proc. Amer. Soc. Clin. Oncol. 2004; 22. Abstract 6509.) The outpatient DVd regimen did not require a central venous catheter and had generally fewer side effects than VAd, with less hair loss, fewer reactions at the injection sites, less neutropenia, and fewer days in the hospital for patients, though they did have more hand-foot syndrome. Response rates were the same for the two regimens, with a similar number of patients proceeding on to later stem cell transplant. (Hussein et al. Blood. 2003;102(11). Abstract 1653.)
The combination of Doxil®, vincristine, reduced-dose dexamethasone (DVd) and thalidomide is being evaluated in patients with newly diagnosed myeloma. Preliminary data on this regimen presented at the American Society of Hematology in 2003 are encouraging. (Agrawal et al. Blood. 2003;102(11). Abstract 831; Zervas et al. Blood. 2003;102(11). Abstract 1643.) In one of these studies (Agrawal et al), 46% of evaluable patients achieved a complete response or near-complete response. Prior to the institution of preventive measures, low white blood cell and platelet counts, infections, and deep vein thrombosis (DVT) were frequent events. However, with precautionary measures, such as use of antibiotics and antiviral drugs, growth factors to increase blood cell counts if needed, aspirin to prevent blood clots, and vincristine dose reduction, the frequency of these complications were greatly reduced.
The table below lists conventional chemotherapy regimens utilizing doxorubicin or Doxil® that are commonly used or under investigation for the treatment of multiple myeloma. Most of these regimens produce similar results, but they differ in various ways, including how fast they work and how well they are tolerated. In addition, these drugs vary in their suitability for use as induction therapy.
Examples of Treatment Regimens Containing Doxil®
*These regimens can be used as part of initial therapy for multiple myeloma, but they
contain alkylating agents that damage stem cell DNA. Many authorities therefore
recommend avoiding these combinations prior to possible stem cell collection and
Search the MMRF's Clinical Trials Monitor for trials testing new treatment regimens for myeloma.
Chemotherapy may be used as salvage therapy, that is, treatment for patients who have not responded to primary or subsequent therapy, or who experience relapsed disease after an initial response to therapy. If longer than 6 months has passed since a patient had initially responded to primary conventional therapy, the primary therapy can be repeated as salvage therapy following relapse. The combinations of Doxil® (liposomal doxorubicin), vincristine, reduced-dose dexamethasone (DVd) and Doxil® (liposomal doxorubicin), vincristine, reduced-dose dexamethasone, thalidomide (DVd-T) are both undergoing investigation as salvage therapies.
The Cleveland Clinic is currently evaluating the safety of DVd in patients who had already failed VAD and other regimens. A total of 24 patients were given Doxil® 40 mg/m2 IV and bolus vincristine 2 mg in an outpatient setting every 4 weeks for a minimum of 6 cycles. Upon plateau, prednisone 50 mg was added to the regimen every other day for maintenance therapy. Myelosuppression has been observed more frequently in relapsed/refractory patients than among the newly diagnosed, and to date, 16 of the 24 patients have relapsed at a median time to progression of 16 months. For these reasons, and due to significantly higher toxicity in this group of patients, DVd may not be as desirable a therapy regimen in the relapsed/refractory population as it is for newly diagnosed patients.
Doxil® in combination with the proteasome inhibitor bortezomib (VELCADE®) has also been studied in the relapsed/refractory population with encouraging results. (Orlowski et al. Blood. 2005;105(8):3058-3065.) Adverse events of moderate or higher severity seen in 10% or more of patients included decreased platelets, lymphocytes, or neutrophils, fatigue, pneumonia, peripheral neuropathy, fever with neutropenia, and diarrhea. Out of 22 patients with myeloma who were treated and evaluated, 36% had a complete or near-complete response, with 73% having a partial response or better. A similar complete response rate was seen in patients who had previously received other forms of doxorubicin including Doxil® and not responded optimally. This combination is now in phase II and III trials both in front-line and relapsed/refractory multiple myeloma to determine the best use of this regimen.
For Current Clinical Trials:
Robert Z. Orlowski, MD, PhD
University of North Carolina, Chapel Hill