Clinical UM Guideline

 

Subject: Doxorubicin Hydrochloride Liposome Injection
Guideline #:  CG-DRUG-49 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    05/04/2017

Description

This document addresses the indications for the use of doxorubicin hydrochloride liposome injection (Doxil® Janssen Products, LP; Horsham, PA), for intravenous use. Doxorubicin hydrochloride liposome injection is a cytotoxic, anthracycline topoisomerase II inhibitor used in the treatment of oncologic conditions.

Note: Please see the following related document for additional information:

Clinical Indications

Medically Necessary:

U.S. Food and Drug Administration approved doxorubicin hydrochloride liposome injection is considered medically necessary for the treatment of any of the following indications:

  1. Breast cancer when used as a single agent for recurrent or metastatic disease; or
  2. Kaposi's sarcoma, AIDS-related; or
  3. Hodgkin's Lymphoma (for example, classical Hodgkin lymphoma or nodular lymphocytic predominant Hodgkin lymphoma) when used as second-line or subsequent therapy for refractory or relapsed disease; or
  4. Non-Hodgkin lymphoma; or
  5. Multiple myeloma when agent used as second-line or later line of therapy; or
  6. Non-melanoma, dermatofibrosarcoma protuberans metastatic disease; or
  7. Ovarian cancer (including epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer) that is persistent or recurrent disease when one of the following is met:
    1. Agent used as a single agent; or
    2. Agent used in combination with carboplatin or cisplatin; or
    3. Agent used in combination with bevacizumab, if bevacizumab was not previously used for treatment of ovarian cancer; or
  8. Sarcomas, soft tissue when one of the following is met:
    1. Angiosarcoma when used as a single agent; or
    2. Desmoid tumors; or
    3. Retroperitoneal/Intra-abdominal sarcomas when used as a single agent; or
    4. Rhabdomyosarcoma when used as a single agent; or
    5. Soft tissue sarcoma of the extremity, superficial trunk, head or neck when used as a single agent; or
  9. Uterine neoplasm when one of the following is met:
    1. Endometrial carcinoma when used as a single agent; or
    2. Uterine sarcoma when used as a single agent for advanced or metastatic disease.

Not Medically Necessary:

Doxorubicin hydrochloride liposome injection is considered not medically necessary when the medically necessary indications are not met and for all other indications including, but not limited to the treatment of endometrioid adenocarcinoma for isolated metastases.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

Q2049

Injection, doxorubicin hydrochloride, liposomal, imported lipodox, 10 mg

Q2050

Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg [Doxil]

 

 

ICD-10 Diagnosis

 

B20

Human immunodeficiency virus [HIV] disease

C44.09

Other specified malignant neoplasm of skin of lip [dermatofibrosarcoma protuberans]

C44.191-C44.199

Other specified malignant neoplasm of skin of eyelid, including canthus

C44.291-C44.299

Other specified malignant neoplasm of skin of ear and external auricular canal

C44.390-C44.399

Other specified malignant neoplasm of skin of other and unspecified parts of face

C44.49

Other specified malignant neoplasm of skin of scalp and neck

C44.590-C44.599

Other specified malignant neoplasm of skin of trunk

C44.691-C44.699

Other specified malignant neoplasm of skin of upper limb, including shoulder

C44.791-C44.799

Other specified malignant neoplasm of skin of lower limb, including hip

C44.89

Other specified malignant neoplasm of overlapping sites of skin

C44.99

Other specified malignant neoplasm of skin, unspecified

C46.0-C46.9

Kaposi’s sarcoma

C48.0-C48.8

Malignant neoplasm of retroperitoneum and peritoneum

C49.0-C49.9

Malignant neoplasm of other connective and soft tissue

C50.011-C50.929

Malignant neoplasm of breast

C54.0-C55

Malignant neoplasm of corpus uteri, uterus part unspecified

C56.1-C56.9

Malignant neoplasm of ovary

C57.00-C57.9

Malignant neoplasm of other and unspecified female genital organs

C79.81

Secondary malignant neoplasm breast

C81.00-C81.99

Hodgkin lymphoma

C83.00-C83.09

Small cell B-cell lymphoma

C83.30-C83.39

Diffuse large B-cell lymphoma

C83.80-C83.99

Other non-follicular lymphoma, non-follicular (diffuse) lymphoma, unspecified

C84.00-C84.19

Mycosis fungoides, Sézary disease

C84.40-C84.49

Peripheral T-cell lymphoma, not classified

C84.60-C84.79

Anaplastic large cell lymphoma

C84.A0-C84.A9

Cutaneous T-cell lymphoma, unspecified

C84.Z0-C86.6

Other mature T-NK cell lymphomas, other specified and unspecified types of non-Hodgkin lymphoma,

C88.4

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]

C90.00-C90.32

Multiple myeloma

D47.Z2

Castleman disease

D48.1

Neoplasm of uncertain behavior of connective and other soft tissue [desmoid tumor]

Z85.3

Personal history of malignant neoplasm of breast

Z85.43

Personal history of malignant neoplasm of ovary

Z85.71

Personal history of Hodgkin lymphoma

Discussion/General Information

Doxorubicin hydrochloride (HCL) liposome injection, also referred to as doxorubicin liposome, liposomal doxorubicin or pegylated liposomal doxorubicin (PLD) was granted initial approval in 1995 by the U.S. Food and Drug Administration (FDA), with current approval for the following uses (Product label information, 2016):

Additionally, there are non-FDA approved uses for doxorubicin HCL liposome injection. The non-FDA approved uses listed in this document are based on drug compendia (National Comprehensive Cancer Network® NCCN Drugs & Biologic Compendium™ and DrugPoints® Compendium) and published peer reviewed literature.

Breast Cancer

Breast cancer is a type of tumor comprised of malignant (cancerous) cells that start to grow in the breast and may spread (metastasize) to surrounding tissues and other areas of the body. According to the American Cancer Society (ACS), it is the most common cancer among American women, except for skin cancers (ACS, 2017). Breast cancer most commonly occurs in women, but may also develop in men. Breast cancer is commonly treated by various modalities which include combinations of surgery, radiation therapy, chemotherapy and hormone therapy (National Cancer Institute, 2016). The prognosis and selection of therapies can be affected by clinical and pathologic features of the tumor.

The NCCN clinical practice guideline (CPG) in Oncology® for breast cancer (2017) considers doxorubicin HCL liposome injection single agent a preferred treatment for recurrent or metastatic breast cancer. The category 2A recommendation is based on a phase III reported by O'Brien and colleagues (2004) comparing pegylated liposomal doxorubicin (PLD) to conventional doxorubicin for first-line treatment of metastatic breast cancer. Progression free survival (PFS) was comparable among the PLD (6.9months) and doxorubicin (7.8 months) groups; hazard ratio (HR) = 1.00; 95% confidence interval (CI) 0.82-1.22). Risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR = 3.16; 95% CI 1.58-6.31; P<0.001) while the overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR = 0.94; 95% CI0.74-1.19).

Kaposi's sarcoma, AIDS related

KS is a cancer that develops from abnormal cells appearing as tumors most commonly on the skin or mucosal surfaces of the body. Approximately 6 cases per every million people in U.S. are diagnosed with KS annually, more commonly seen in individuals infected with HIV (ACS, 2017). Nearly 1 in every 200 transplant recipients in the United States will get KS as a result of the suppressed immune system, allowing KS to develop.

On November 17, 1995 the FDA granted accelerated approval of doxorubicin HCL liposomal injection as first-line therapy for the treatment of advanced AIDS-related KS after failure or intolerance to prior systemic chemotherapy. The original approval was based on unpublished data of a phase 2 open-label, single-arm, multicenter study, demonstrating tumor response in 77 participants. Participants were retrospectively identified from interim analysis of 383 refractory participants enrolled in single-arm, open-label, multicenter study. Participants had disease progression on two of three prior treatments (bleomycin, vincristine, vinblastine, doxorubicin HCL), with 64% of participants (45/77) previously treated with standard doxorubicin HCL. The population was divided into two groups based on prior treatment; 34 were assigned for investigator assessment and 42 participants to the evaluable for indicator lesion assessment (previously received standard doxorubicin). Partial responses were observed in 27% of participants (n=34) in the investigator assessment group, with median duration of response of 73 days (range 42-210 days); and in participants previously treated with standard doxorubicin, partial response were reported in 30% (n=20), 89 day (range 42-210 days) for median duration of response.

The therapeutic effectiveness of systemic chemotherapy is profoundly limited for those individuals with KS, due to the already depressed immune system. More recent systemic chemotherapy studies in KS populations, used as a single-agent, showed significant clinical benefit with favorable toxic effects profile for pegylated liposomal doxorubicin compared to other combinations, for example doxorubicin, bleomycin, and vincristine or bleomycin and vincristine. Doxorubicin HCL liposomal injection is now a preferred first-line therapy for individuals with AIDs-related KS for whom systemic chemotherapy is indicated (Ciafrocca, 2010; Gill, 1996).

Hodgkin's Lymphoma

There are two main types of Hodgkin lymphoma, classical Hodgkin lymphoma (CHL) that accounts for approximately all Hodgkin disease, distinguished by the presence of an abnormal Reed-Sternberg cell in the lymphoma tissue. Lymphocyte-predominant Hodgkin lymphoma (LPHL) accounts for the remaining Hodgkin lymphoma cases. Lymphocyte predominant cells, also called "popcorn cells" are present in the lymphoma tissue instead of the Reed-Sternberg cells (NCCN, 2017).

The Revised European American Lymphoma (REAL)/World Health Organization (WHO) modified Classification of Lymphoproliferative Diseases (NCI, 2017): 
Hodgkin Lymphoma

  1. Nodular lymphocyte-predominant Hodgkin lymphoma
  2. Classical Hodgkin lymphoma:
    1. Nodular sclerosis Hodgkin lymphoma
    2. Lymphocyte-rich classical Hodgkin lymphoma
    3. Mixed-cellularity Hodgkin lymphoma
    4. Lymphocyte-depleted Hodgkin lymphoma.

The NCCN Drugs and Biologics Compendium and NCCN CPG in Oncology for Hodgkin disease (2016) include 2A recommendation for pegylated liposomal doxorubicin when used as second-line or subsequent therapy for refractory or relapsed disease Hodgkin lymphoma (HL) based on uniform consensus and results from a phase II trial reported by Bartlett and colleagues (2007). Ninety one participants received combination therapy with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) as salvage regimen in relapsed Hodgkin's lymphoma. The overall response rate among participants was 70% (95% CI; 59.8, 79.7) with 19% complete remission. For transplant-naïve participants, mucositis was the dose-limiting toxicity reported while febrile neutropenia limited therapy in those with prior transplant. The authors concluded that "GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens".

Non-Hodgkin lymphoma (NHL):

NHL is a diverse group of more than a dozen different lymphoproliferative neoplasms, that is, cancers of the lymphatic system which generates the body's immune defenses. This system includes a network of channels akin to blood vessels through which lymphocytes, important white blood cells of the immune system, patrol the body for invading microbes. Along these lymphatic routes in the neck, armpits, abdomen, and groin are clusters of bean-shaped lymph nodes that house groups of infection-fighting lymphocytes. These cells also cluster in areas that serve as gateways to the body, including the mucous membranes lining the respiratory and digestive tracts, and the skin. Lymphocytes travel in the bloodstream, as well. The lymphatic system also includes such organs as the spleen, thymus and tonsils. Symptoms often include lymph nodes that are larger than normal, fever, and weight loss. NHL can occur at any age, typically affects an older population, and is the sixth most deadly form of cancer.

Throughout the years, the methods to classify the various types of lymphomas have been modified as technology and understanding of the role of genetics and immunology have increased. The historical table of classifying NHL by the International Working Formulation (IWF) had been updated by the REAL classification. Subsequently, the classification has been updated as a result of collaboration between the European and American hematology and pathology societies and WHO. For clinical utility, NHL can also be divided into indolent or aggressive lymphomas (NCI, 2017). The use of a particular classification is based on the practitioner's preference. A widely utilized tool as a prognostic indicator for NHL is the International Prognostic Indicator.

Individuals with indolent lymphoma may experience a relapse with a more aggressive histology. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type. Histologic conversions or transformations are typically treated with the regimens prescribed for aggressive NHL (NCI, 2017).

Modified REAL Classification of Lymphoproliferative Diseases (NCI, 2017):
Non-Hodgkin
Indolent lymphoma/leukemia

  1. Follicular lymphoma (follicular small cleaved cell [grade 1], follicular mixed small cleaved and large cell [grade 2], diffuse small cleaved cell)
  2. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
  3. Lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia)
  4. Extranodal marginal zone B-cell lymphoma (MALT lymphoma)
  5. Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma)
  6. Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes)
  7. Hairy cell leukemia
  8. Mycosis fungoides/Sézary syndrome
  9. T-cell granular lymphocytic leukemia
  10. Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+)
  11. Nodular lymphocyte predominant Hodgkin lymphoma

Aggressive lymphoma/leukemia

  1. Diffuse large cell lymphoma (includes diffuse mixed cell, diffuse large cell, immunoblastic, T-cell rich large B-cell lymphoma)
    1. Mediastinal large B-cell lymphoma
    2. Follicular large cell lymphoma (grade 3)
    3. Anaplastic large cell lymphoma (CD30+)
    4. Extranodal NK/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma
    5. Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma)
    6. Angioimmunoblastic T-cell lymphoma
    7. Peripheral T-cell lymphoma, unspecified
      1. Subcutaneous panniculitis-like T-cell lymphoma
      2. Hepatosplenic T-cell lymphoma
    8. Enteropathy-type T-cell lymphoma
    9. Intravascular large B-cell lymphoma
  2. Burkitt's lymphoma/Burkitt's cell leukemia/Burkitt's-like lymphoma
  3. Precursor B- or T-cell lymphoblastic lymphoma/leukemia
  4. Primary central nervous system (CNS) lymphoma
  5. Adult T-cell leukemia/lymphoma (HTLV 1+)
  6. Mantle cell lymphoma
  7. Polymorphic post-transplantation lymphoproliferative disorder (PTLD)
  8. AIDS-related lymphoma
  9. True histiocytic lymphoma
  10. Primary effusion lymphoma
  11. B- or T-cell prolymphocytic leukemia
  12. Plasmablastic lymphoma

The NCCN Drugs and Biologics Compendium (2017) and the NCCN CPG for B-cell lymphomas and T-cell lymphomas (2017), list off-label use of liposomal hydrochloride for individuals with both indolent and aggressive forms of NHL. The recommendations were based on a 2A category of evidence and uniform consensus. The peer reviewed literature consists of phase II clinical studies and case series. (Dummer, 2012; Evens, 2013; Levine, 2013; Martino, 2002; Quereux, 2008; Wollina, 2013; Zaga, 2006).

Multiple myeloma:

Multiple myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, leading to destruction of bone and failure of the bone marrow and accounting for approximately 10% of all hematologic cancers. The ACS has estimated 30,300 new cases of multiple myeloma will be diagnosed in the United States in 2017, with an estimated 12,600 deaths. The disease is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M-protein) in the serum and/or urine along with various clinical parameters, such as the hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. The stage of the disease at presentation is a strong predictor of survival, but has little influence on the choice of therapy since almost all individuals (except for those with solitary bone tumors or extramedullary plasmacytomas) have generalized disease. The age and general health of the individual, prior therapy and the presence of complications of the disease influence treatment selection.

The FDA expanded use of liposomal doxorubicin in combination with bortezomib in of individuals with multiple myeloma with prior failure to at least one prior treatment based on a randomized phase III, multicenter open-label study reported by Orlowski and colleagues (2007). The study enrolled 646 participants, evaluating efficacy and safety of PLD plus bortezomib (n=324) compared with bortezomib alone (n=322) in relapsed or refractory disease. Grade 3 or 4 adverse events occurred in 46% of study participants treated with combination therapy and 37% of those who received bortezomib alone. Common adverse events associated with the use of combination therapy were asthenia, diarrhea, fatigue, hand-foot syndrome, neutropenia and thrombocytopenia. The authors reported:

Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with PLD + bortezomib combination (P= .000004); hazard ration, 1.82 [monotherapy versus combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P =.03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant.

Orlowski and colleagues concluded that combination therapy was superior for the treatment of multiple myeloma and represented a new standard of care for this patient population that had failed a prior line of therapy.

The NCCN CPG in Oncology (2016) for multiple myeloma offers a category 1 recommendation for liposomal doxorubicin in combination with bortezomib as a preferred regimen for the treatment of relapsed or refractory multiple myeloma, based on results from multicenter, phase III randomized controlled trial (Orlowski, 2007). The NCCN panel provides a category 2B recommendation for the primary use of liposomal doxorubicin/vincristine/dexamethasone (DVD) regimen.

Non-melanoma, dermatofibrosarcoma protuberans (DFSP)

DFSP is a rare slow growing tumor that begins in the dermal layer of the skin. The occurrence of metastatic disease is rare but often regrows after tumor is surgically removed. The NCCN Drug and Biologics Compendium (2016) and the NCCN CPG for dermatofibrosarcoma protuberans (2016) offer a category 2A recommendation for the use of liposomal doxorubicin as a single agent, in the treatment of individuals with metastatic disease.

Ovarian cancer:

The majority of ovarian tumors are epithelial cell tumors originating from outer surface cells. Other types of ovarian tumors are germ cell tumors that originate from the ova and stromal tumors that originate from ovarian structural tissue cells. Fallopian tube and primary peritoneal cancers are rare forms and are similar to epithelial cell tumors.

Gordon and colleagues (2001) reported on a randomized phase III, open-label, multicenter study of single agent pegylated liposomal doxorubicin (n=239) versus topotecan (n=235) in recurrent epithelial ovarian cancer, unresponsive to first-line platinum-based chemotherapy. The authors concluded:

The overall progression-free survival rates were similar between the two are (P=.095). The overall response rates for PLD and topotecan were 19.7% and 17.0% respectively (P=.390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. Data analyzed in platinum-sensitive patients demonstrated a statistically significant benefit from PLD for progression-free survival (P=.037), with medians of 28.9 for PLD versus 23.3 weeks for topotecan. The overall survival, PLD was significantly superior to topotecan (P =.008), with a median of 108 weeks versus 71.1 weeks.

The NCCN Drugs and Biologics Compendium and the NCCN CPG in oncology for ovarian cancer (2016) list off-label use for liposomal doxorubicin as a preferred agent in combination with carboplatin based on category 1 evidence for platinum-sensitive (disease relapsed six months or more after receiving platinum based chemotherapy) for recurrent epithelial ovarian cancer/fallopian tube cancer and peritoneal cancer based on recent data and uniform consensus from the panel. Carboplatin/liposomal doxorubicin is equivalent to carboplatin/paclitaxel, although the toxicity profiles are different, carboplatin/liposomal doxorubicin is easier to tolerate. (Lawrie, 2013; Pujade-Lauraine, 2010; Wagner, 2012) The NCCN panel offers a category 2A recommendation for liposomal doxorubicin as a preferred single agent or in combination with carboplatin as treatment of platinum-resistant disease (reoccurred less than six months after platinum based chemotherapy) based on recent data from randomized phase III trials and uniform consensus form the panel (Ferrandina, 2008; Mutch, 2007). The single agent response rate for liposomal doxorubicin was 26% for individuals with platinum-resistant disease. Both recommendations exclude use for immediate treatment of a biochemical relapsed disease, defined as increased CA-125 level.

The NCCN panel now provides a category 2A recommendation for combination regimen with liposomal doxorubicin/bevacizumab for individuals with platinum-resistant recurrent ovarian cancer, if not previously used for treatment of ovarian cancer based on results from the phase III randomized trials (AURELIA, OCEANS) (Aghajanian, 2012; Pujade-Lauraine, 2014).

Soft tissue sarcoma (STS):

STS are a heterogeneous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathologic features usually divided into 2 broad categories:

Collectively, sarcomas account for approximately 1% of all adult malignancies and 15% of pediatric malignancies. In 2016, the NCI estimates 12,310 people will be diagnosed with STS in the United States and approximately 4990 deaths will occur as a result of the disease. More than 50 different histologic subtypes of STS have been identified; the most common are undifferentiated pleomorphic sarcoma, gastrointestinal stromal tumors (GISTs), liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors (MPNSTs). Metastasis most commonly occurs in the lungs; liver and peritoneum. Rhabdomyosarcoma is the most common STS of children and adolescents (NCCN, 2017).

Surgical resection is the standard primary treatment for most individuals with STS. Radiation therapy and/or chemotherapy may be used prior to surgery to downstage large high-grade tumors to enable effective surgical resection. Radiation therapy may also be administered either as primary, preoperative, or postoperative treatment. For individuals with advanced, unresectable, or metastatic disease, chemotherapy with single agents (such as dacarbazine, doxorubicin HCL liposome injection, epirubicin, or ifosfamide) or anthracycline-based combination regimens have been used.

The NCCN CPG for soft tissue sarcoma (2017) and NCCN Drugs and Biologics Compendium (2017) has recommended doxorubicin HCL liposome injection for use as a single agent for the treatment of STS subtypes with non-specific histologies including angiosarcoma, retroperitoneal/abdominal sarcoma, pleomorphic rhabdomyosarcoma, and STS of the extremity/superficial trunk or head/neck. This category 2A off-label recommendation is based on uniform consensus and the results of a phase II trial that evaluated doxorubicin HCL liposome injection as single-agent therapy for STS subtypes. According to the NCCN, "pegylated liposomal doxorubicin had equivalent activity and improved toxicity profile compared to doxorubicin; response rates were 9% and 10% for doxorubicin and pegylated liposomal doxorubicin, respectively, in patients with advanced or metastatic STS." The NCCN CPG offers recommendation for use of doxorubicin-based regimens for individuals with of primary, recurrent, or progressive disease for STS desmoid tumor (aggressive fibromatosis). This 2A recommendation is based on uniform consensus and long-term results from a phase II trial that found doxorubicin HCL liposome therapy to be effective treatment for desmoid tumors.

Uterine neoplasm:

Uterine neoplasms include endometrial carcinoma and uterine sarcoma. Adenocarcinoma of the endometrium (also known as endometrial carcinoma or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. Uterine sarcomas are less common and account for only 3% of uterine neoplasms (Koh, 2014).

The NCCN guideline for uterine neoplasms (2016) offers a 2A recommendation for doxorubicin HCL liposomal injection as a single-agent option, for both endometrial carcinoma and advanced or metastatic uterine sarcomas. Several phase II clinical trials (Judson, 2001; Muggia, 2002; Sutton, 2005) have demonstrated efficacy of chemotherapeutic regimens containing doxorubicin HCL liposome injection when used as treatment for endometrial carcinomas and uterine sarcomas.

Other indications:

Doxorubicin HCL liposome injection has been investigated for other uses, including isolated metastatic endometrioid adenocarcinoma. However the published peer reviewed literature regarding other off-label uses of doxorubicin HCL liposomal injection in the treatment of other uses is not sufficient to draw reasonable conclusions regarding the long-term clinical effectiveness and improvement on net health outcomes and safety. Currently there are ongoing clinical trials investigating the use of doxorubicin HCL liposomal injection as a treatment option for these conditions. The NCCN Drugs and Biologics Compendium and the NCCN CPG in oncology (2016) on uterine cancer provide a Category 3 recommendation for doxorubicin HCL liposome injection as a treatment of endometrioid adenocarcinoma for isolated metastasis.

The FDA product information label (2016) for Doxorubicin HCL liposome (Doxil) includes the following boxed warning, contraindications, warning and precautions:

Boxed Warning on Drug Label:
Warning: cardiomyopathy and infusion-related reactions

Contraindications:

  Hypersensitivity reactions to doxorubicin HCL or the components of Doxil.

Warnings and Precautions:

Use in Specific Populations:

Lactation: Because of the potential of serious adverse reactions in nursing infants, discontinue nursing during treatment with Doxil.

Another form of doxorubicin HCL liposome injection specifically, LipoDox is available outside the United States. However, it has not received FDA approval for marketing in the U.S.

Definitions

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals.

Complete response (CR): The disappearance of all signs of cancer as a result of treatment; also called complete remission; does not indicate the cancer has been cured.

Cytotoxic: Treatment that is destructive to cells.

Line of therapy:

Off-Label: Utilization of an FDA approved drug for uses other than those listed in the FDA approved label.

Partial response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment. Also called partial remission.

Platinum-resistant: Disease reoccurs in less than six months after receiving platinum based chemotherapy.

Platinum-sensitive: Disease relapses after six months or more after receiving platinum based chemotherapy.

Progressive disease (PD): Cancer that is growing, spreading, or getting worse.

Relapse or recurrence: After a period of improvement, during which time a disease (for example, cancer) could not be detected, the return of signs and symptoms of illness or disease. For cancer, it may come back to the same place as the original (primary) tumor or to another place in the body.

Stable disease (SD): Cancer that is not decreasing or increasing in extent or severity.

References

Peer Reviewed Publications:

  1. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012; 30:2039-2045.
  2. Bartlett NL, Niedzwiecki D, Johnson JL, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol. 2007; 18(6):1071-1079.
  3. Cianfrocca M, Lee S, Von Roenn J, et al. Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy. Cancer. 2010; 116(16):3969-3977.
  4. Constantinidou A, Jones RL, Scurr M, et al. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009, 45:2930-2934.
  5. Dummer R, Quaglino P, Becker JC, et al. Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol. 2012; 30:4091-4097.
  6. Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008; 26:890-896.
  7. Gibson JM, Alzghari S, Ahn C, et al. The role of pegylated liposomal doxorubicin in ovarian cancer: a meta-analysis of randomized clinical trials. Oncologist. 2013; 18:1022-031.
  8. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996; 14(8):2353-2364.
  9. Gladieff L, Ferrero A, De Rauglaudre G, et al. Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. Ann Oncol. 2012, 23:1185-1189.
  10. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001; 19(14):3312-3322.
  11. Gordon AN, Tonda M, Sun S, Rackoff W. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004; 95:1-8.
  12. Judson I, Radford J, Harris M, et al. Randomized phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001: 37:870-877.
  13. Koh WJ, Greer BE, Abu-Rustum NR, et al. Uterine neoplasms, version 1.2014. J Natl Compr Canc Netw. 2014; 12(2):248-280.
  14. Lawrie TA, Bryant A, Cameron A, et al. Pegylated Liposomal doxorubicin for relapsed epithelial ovarian cancer. Cochrane Database. Syst Rev 2013; 7.CD006910.
  15. Levine AM1, Tulpule A, Espina B, et al. Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma: results of therapy and correlates of response. J Clin Oncol. 2004; 22(13):2662-670.
  16. Martino R, Perea G, Caballero MD, et al. Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx), vincristine and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: Results form a prospective phase II study. Haematologica. 2002; 87:822-827.
  17. Muggia FM, Blessing JA, Sorosky J, Reid GC. Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2002; 20:2360-2364.
  18. Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007: 25:2811-2818.
  19. O'Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCL (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004: 15:440-449.
  20. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998; 16(7):2445-2451.
  21. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007; 25(25):3892-3901.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Cancer facts & figures 2017. Atlanta: American Cancer Society; 2017.
  2. Doxorubicin hydrochloride Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised October 30, 2011. Accessed on March 14, 2017.
  3. Doxorubicin hydrochloride liposomal (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 12, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 14, 2017.
  4. Doxil [Product Information], Horsham, PA. Janssen Products, LP; June 2016. Available at: http://www.doxil.com/shared/product/doxil/doxil-prescribing-information.pdf. Accessed on March 14, 2017.
  5. National Comprehensive Cancer Network® . NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on March 14, 2017.
  6. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology™. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 14, 2017.
    • B-Cell Lymphomas (V.3.2017). Revised March 27, 2017.
    • Breast cancer (V.1.2017). Revised March 10, 2017.
    • Dermatofibrosarcoma protuberans (V.1.2017). Revised October 3, 2016.
    • Hodgkin Lymphoma (V.1.2017). Revised March 1, 2017.
    • Multiple myeloma (V.3.2017). Revised November 28, 2016.
    • Ovarian cancer (V.1.2016). Revised June 30, 2016.
    • Soft tissue sarcoma (V.2.2017). Revised February 8, 2017.
    • T-Cell Lymphomas (V.2.2017). Revised February 21, 2017.
    • Uterine neoplasms (V.1.2017). Revised November 21, 2016.
Websites for Additional Information
  1. American Cancer Society. Learn about cancer. Revised February 27, 2012. Available at: http://www.cancer.org/cancer/index. Accessed on March 14, 2017.
  2. National Cancer Institute. Available at: http://www.cancer.gov/publications/pdq. Accessed on March 14, 2017.
    • Adult Hodgkin lymphoma (PDQ® ). Last modified January 27, 2017.
    • Adult Non-Hodgkin's lymphoma (PDQ). Last modified January 26, 2017.
    • Adult soft tissue sarcoma. (PDQ). Last modified January 31, 2017.
    • Breast cancer (PDQ). Last modified February 3, 2017.
    • Endometrial cancer (PDQ). Last modified February 2, 2017.
    • Kaposi's sarcoma (PDQ). Last modified October 1, 2015.
    • Ovarian epithelial, fallopian tube, and primary peritoneal cancer (PDQ). Last modified January 5, 2017.
    • Plasma cell neoplasms (Including multiple myeloma) (PDQ). Last modified February 3, 2017.
Index

Doxil
Doxorubicin hydrochloride (HCL) liposome injection
Doxorubicin liposome
Liposomal doxorubicin
Pegylated liposomal doxorubicin (PLD)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

  12/27/2017 The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with ICD-10-CM diagnosis codes C84.Z0-C86.6.
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Updated Coding, Discussion, References and Websites sections.
Reviewed 11/03/2016 MPTAC review.
Reviewed 11/02/2016 Hematology/Oncology Subcommittee review. Updated formatting in Clinical Indications section. Updated Discussion, References and Websites sections.
  10/01/2016 Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.
New 05/05/2016 MPTAC review.
New 05/04/2016 Hematology/Oncology Subcommittee review. Initial document development.