This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Atezolizumab (Tecentriq) may be considered medically necessary for ANY of the following conditions:

Bladder (Urothelial) Cancer

• Treatment of individuals with locally advanced or metastatic bladder (urothelial) carcinoma who:
  • Are not eligible for cisplatin-containing chemotherapy (preferred*); or
  • Have disease progression during or following any platinum-containing chemotherapy (alternative preferred*), or within 12 months of neoadjuvant or adjuvant chemotherapy; or
  • Have recurrence post cystectomy as first-line single agent therapy.

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra:

• Treatment of individuals with primary carcinoma of the urethra:
  • As a single agent for primary treatment for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes in cisplatin ineligible individuals (preferred*) (Note: Chemotherapy regimen based on histology); or
  • As a single agent for recurrent or metastatic disease as:
    • First-line therapy in cisplatin ineligible individuals; or
    • Subsequent systemic therapy post-platinum (alternative preferred*) (Note: Chemotherapy regimen based on histology); or
  • For locally advanced or metastatic urothelial carcinoma who:
    • Are not eligible for cisplatin-containing chemotherapy; or
    • Have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy.

Bladder (Urothelial) Cancer - Upper Genitourinary (GU) Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with upper GU tract tumors or urothelial carcinoma of the prostate:
  • Used as a single agent for metastatic disease as:
    • First-line therapy in cisplatin ineligible individuals (preferred*); or
    • Subsequent systemic therapy post-platinum (alternative preferred regimen*).

Non-Small Cell Lung Cancer (NSCLC) – Adenocarcinoma (with mixed subtypes), Squamous Cell Carcinoma, Large Cell Carcinoma

• Treatment of individuals with metastatic NSCLC:
  • Who have disease progression during or following platinum-containing chemotherapy; or
  • With epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations with disease progression on FDA approved therapy; or
  • Preferred single agent (if systemic immune checkpoint inhibitors not already given) as subsequent therapy for metastatic disease in individuals with performance status (PS) 0-2, with disease progression.

The use of atezolizumab (Tecentriq) is considered experimental/investigational and, therefore, non-covered for any other indication not listed above. Scientific evidence does not support the use for any other indication.

Avelumab (Bavencio) may be considered medically necessary for ANY of the following conditions:

Bladder (Urothelial) Carcinoma

• Treatment of individuals with bladder (urothelial) carcinoma:
  • With metastatic or locally advanced urothelial carcinoma with progression during or after platinum-containing chemotherapy; or
  • Within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or
  • As a single agent for clinical stage T4b or T2-4a, N1-3 disease, or for recurrence post cystectomy as subsequent systemic therapy post-platinum (alternative preferred*).

Bladder Cancer - Primary Carcinoma of the Urethra, Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with primary carcinoma of the urethra, upper GU tract tumors or urothelial carcinoma of the prostate:
  • As single agent subsequent systemic therapy for recurrent or metastatic disease post-platinum (alternative preferred regimen*) (Note: Chemotherapy regimen based on histology).

Merkel cell carcinoma (MCC)

• Treatment of adult and pediatric individuals greater than or equal to twelve (12) years of age with metastatic MCC with or without surgery and/or radiation therapy.

The use of avelumab (Bavencio) is considered experimental/investigational and, therefore, non-covered for any other indication. Scientific evidence does not support the use for any other indication.

Durvalumab (Imfinzi) may be considered medically necessary for ANY of the following conditions:

Bladder (Urothelial) Carcinoma

• Treatment of individuals with bladder (urothelial) carcinoma:
  • With locally advanced or metastatic urothelial carcinoma who:
    • Have disease progression during or following platinum-containing chemotherapy; or
    • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or 
  • For recurrence post cystectomy.

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra, Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with primary carcinoma of the urethra, upper GU tract tumors or urothelial carcinoma of the prostate:
  • As single agent subsequent systemic therapy for recurrent or metastatic disease post-platinum (alternative preferred*) (Note: chemotherapy regimen based on histology).

NSCLC – Adenocarcinoma (with mixed subtypes), Squamous Cell Carcinoma or Large Cell Carcinoma

• Treatment of individuals with NSCLC:
  • As consolidation therapy for individuals with unresectable stage III disease, PS 0-1; and
  • No disease progression after two (2) or more cycles of definitive chemoradiation.

The use of durvalumab (Imfinzi) is considered experimental/investigational and, therefore, non-covered for any other indication not listed above. Scientific evidence does not support the use for any other indication.

Nivolumab (Opdivo) may be considered medically necessary for ANY of the following conditions:

Anal Carcinoma – Squamous Cell

• Treatment of individuals with anal carcinoma as single agent second-line therapy for metastatic disease

Bladder (Urothelial) Carcinoma

• Treatment of individuals with locally advanced or metastatic urothelial carcinoma:
  • With disease progression during or following platinum-containing chemotherapy (alternative preferred*); or
  • With disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy; or  
  • As single agent for clinical stage T4b or T2-4a, N  1-3 disease; or
  • For recurrence post cystectomy.

Bladder (Urothelial) Carcinoma - Primary Carcinoma of the Urethra, Upper Genitourinary (GU) Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with primary carcinoma of the urethra, upper GU tract tumors or urothelial carcinoma of the prostate:
  • As single agent subsequent systemic therapy for recurrent or metastatic disease post-platinum (alternative preferred*) (Note: Chemotherapy regimen based on histology). 

Brain Metastases – Limited or Extensive

• Treatment of individuals with limited or extensive brain metastases:
  • In combination with ipilimumab as treatment for newly diagnosed or recurrent brain metastases in individuals with melanoma and stable systemic disease or reasonable systemic treatment options.

Classical Hodgkin Lymphoma (cHL)

• Treatment of adult individuals (greater than or equal to18 years of age) with cHL that has relapsed or progressed after:
  • Autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin; or
  • Three (3) or more lines of systemic therapy that includes autologous HSCT; or
• As a single agent for relapsed or refractory disease following high-dose therapy and autologous stem cell rescue (HDT/ASCR); or
• Palliative therapy as a single agent for relapsed or refractory disease in older adults (greater than 60 years of age).

Colon and Rectal Cancer - Adenocarcinoma

• Treatment of individuals with colon or rectal cancer:
  • In adult and pediatric (greater than or equal to twelve (12) years of age) individuals with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic disease that has progressed following treatment with a FOLFOXIRI (fluoropyrimidine, oxaliplatin, and irinotecan); or
  • As primary treatment as a single agent for unresectable metachronous metastases (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
  • As initial therapy as a single agent for individuals with unresectable advanced or metastatic disease (dMMR/MSI-H only) who are not appropriate for intensive therapy; or
  • As subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for unresectable advanced or metastatic disease (dMMR/MSI-H only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy.

Head and Neck Cancers – Squamous Cell Carcinoma with Mixed Subtypes

• Treatment of individuals with head and neck cancers (very advanced and recurrent/persistent):
  • As single agent second-line or subsequent therapy for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy in:
    • Newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, or  who are unfit for surgery and PS 3; or
    • Metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable loco regional recurrence or second primary with prior radiation therapy (RT) and PS 0-2; or
    • Unresectable loco regional recurrence without prior RT and PS 3.

Hepatocellular Carcinoma (HCC) - Adenocarcinoma    

• As a single agent as treatment of individuals with HCC who:
  • Have been previously treated with sorafenib; and
  • Are Child-Pugh Class A or B7 only; and
    • Are non-transplant candidates with unresectable disease; or
    • Are inoperable by performance status or comorbidity (local disease or local disease with minimal extrahepatic disease only); or
    • Have extensive liver tumor burden; or
    • Metastatic disease.

Kidney (Renal) Cell Carcinoma (RCC) – Clear Cell or Non-Clear Cell

• Treatment of individuals with renal cancer:
  • With advanced disease who have received prior antiangiogenic therapy; or
  • With relapse or stage IV disease as a single agent; or
  • As preferred subsequent therapy for predominant clear cell histology; or
  • As systemic therapy for non-clear cell histology; or
  • As combination with ipilimumab for the treatment of individuals with intermediate or poor-risk, previously untreated advanced renal cell carcinoma.

Malignant Pleural Mesothelioma

• Treatment for individuals with malignant pleural mesothelioma as subsequent systemic therapy as a single agent or in combination with ipilimumab.

Melanoma

• Treatment of individuals with melanoma:
  • As adjuvant therapy as a single agent:
    • For resected stage IIIB/C sentinel node positive disease following active nodal basin surveillance or complete lymph node dissection (preferred immunotherapy regimen*); or
    • For stage III disease with clinically positive node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection (preferred immunotherapy regimen*); or
    • For stage III disease with clinical satellite or in-transit metastases if no evidence of disease post-surgery; or
    • For local, satellite and/or in-transit recurrence if no evidence of disease post-surgery; or
    • Following complete lymph node dissection and/or complete resection of nodal recurrence (preferred immunotherapy regimen*); or
    • For adjuvant treatment of distant metastatic disease after complete resection with no evidence of disease; or
  • As adjuvant therapy as a single agent or in combination with ipilimumab forunresectable or metastatic melanoma as:
    • First-line therapy; or
    • Second-line or subsequent therapy after disease progression or maximum clinical benefit from BRAF targeted therapy if anti PD-1 therapy (either alone or in combination with ipilimumab) not previously used; or
    • Second line or subsequent therapy after disease progression or maximum clinical benefit from BRAF targeted therapy if prior anti-PD-1 therapy (either alone or in combination with ipilimumab) resulted in disease control (complete response, partial response, or stable disease) and no residual toxicity, and disease progression/relapse occurred greater than three (3) months after treatment discontinuation; or
  • As a single agent is indicated for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma.

Merkel Cell Carcinoma

• Treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy.

NSCLC – Adenocarcinoma (with mixed subtypes), Squamous Cell Carcinoma, Large Cell Carcinoma

• Treatment of individuals with metastatic NSCLC with progression on or after platinum-based chemotherapy or other systemic therapy (preferred*); or
• Individuals with EGFR or ALK genomic tumor aberrations with disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab (Opdivo).

Small Cell Lung Cancer (SCLC)

• Treatment of individuals with SCLC:
  • Subsequent systemic therapy for PS 0-2 as a single agent or in combination with ipilimumab for:
    • Relapse within six (6) months following complete or partial response or stable disease with initial treatment; or
    • Primary progressive disease. 

Uveal Melanoma

• Treatment of individuals with metastatic or unresectable uveal melanoma as single agent therapy or in combination with ipilimumab

The use of nivolumab (Opdivo) is considered experimental/investigational and, therefore, non-covered for any other indication not listed above. Scientific evidence does not support the use for any other indication.

Pembrolizumab (Keytruda) may be considered medically necessary for ANY of the following conditions:

Anal Carcinoma – Squamous Cell Carcinoma

• Treatment of individuals with squamous cell anal carcinoma as second-line, single agent therapy for metastatic disease.

B-Cell Lymphomas – Diffuse Large B-Cell Lymphoma

• Treatment of individuals with diffuse large B-cell lymphoma for treatment of relapsed or refractory primary mediastinal disease.

Bladder (Urothelial) Carcinoma

• Treatment of individuals with bladder (urothelial) carcinoma:
  • Diagnosed with locally advanced or metastatic urothelial carcinoma and are ineligible for cisplatin-containing chemotherapy (preferred*); or
  • Diagnosed with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy (preferred*); or
  • Within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; or
  • Used as a single agent for recurrence post cystectomy.

Bladder (Urothelial) Cancer - Primary Carcinoma of the Urethra

·         Treatment of individuals with primary carcinoma of the urethra:

o    Used as a single agent for recurrent or metastatic disease as:

§  First-line therapy in cisplatin ineligible individuals (preferred*); or

§  Subsequent systemic therapy post-platinum (preferred*); or

o    Used as a single agent for primary treatment for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes as first-line therapy in cisplatin ineligible individuals (preferred*) (Note: Chemotherapy regimen based on histology). 

Bladder Cancer - Upper GU Tract Tumors or Urothelial Carcinoma of the Prostate

• Treatment of individuals with upper GU tract tumors or urothelial carcinoma of the prostate:
  • Used as a single agent for metastatic disease as:
    • First-line therapy in cisplatin ineligible individuals (preferred*); or
    • Subsequent systemic therapy (preferred*).

Central Nervous System Cancers - Limited Brain Metastases or Extensive Brain Metastases

• As single agent treatment of individuals with newly diagnosed or recurrent brain metastases with melanoma or NSCLC and stable systemic disease or reasonable systemic treatment options.

cHL

• Treatment of adult and pediatric individuals with refractory cHL or who relapsed after three (3) or more prior lines of therapy; or
• Treatment of individuals greater than 60 years of age as palliative therapy as a single agent for relapsed or refractory disease.

Colon and Rectal Cancer

• See below Microsatellite Instability-High (MSI-H)/Mismatch Repair Deficient (dMMR) Cancer      

Esophageal and Esophagogastric Junction Cancers – Squamous Cell Carcinoma or Adenocarcinoma

• Treatment of individuals as palliative therapy for non-surgical candidates or have unresectable locally advance, recurrent, or metastatic disease and Karnofsky performance score greater than or equal to 60% or Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to two (2) as:
  • Second-line or subsequent therapy as a single agent for MSI-H or dMMR tumors; or
  • Third – line or subsequent therapy as a single agent for PD-L1 positive disease.

Gastric Cancer

• Treatment of individuals with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma:
  • Whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test; and
  • With disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy; or
• Treatment of individuals as Palliative therapy for non-surgical candidates or have unresectable locally advance, recurrent, or metastatic disease and Karnofsky performance score greater than or equal to 60% or ECOG performance score less than or equal to two (2) as:
  • Second-line or subsequent therapy as a single agent for MSI-H or dMMR tumors; or
  • Third – line or subsequent therapy as a single agent for PD-L1 positive disease.

Microsatellite Instability-High (MSI-H)/Mismatch Repair Deficient (dMMR) Cancer      

FDA Approved Indications

• Treatment of adult and pediatric individuals with unresectable or metastatic, MSI-H or mismatch repair deficient:
  • Solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options; or
  • Colorectal cancer that has progressed following treatment with a FOLFOXIRI.

NCCN Approved IndicationsMSI-H central nervous system cancers in pediatric individuals is considered experimental/investigational and, therefore, non-covered. The safety and effectiveness of pembrolizumab (Keytruda) in pediatric individuals with MSI-H central nervous system cancers have not been established.

• Treatment of individuals with ANY of the following MSHI-H/dMMR Cancers:
• As single agent, primary therapy for unresectable or metastatic:
  • Gallbladder Adenocarcinoma; or
  • Intrahepatic Cholangiocarcinoma – Adenocarcinoma; or
  • Extrahepatic Cholangiocarcinoma – Adenocarcinoma; or
• As single agent, second line therapy for unresectable or metastatic:
  • Pancreatic Adenocarcinoma; or
• As single agent, subsequent therapy for unresectable or metastatic:
  • Ewing Sarcoma; or
  • Ewing Sarcoma – mesenchymal chondrosarcoma; or
  • Osteosarcoma – dedifferentiated chondrosarcoma; or
  • Osteosarcoma – High-Grade undifferentiated pleomorphic sarcoma (UPS); or
  • Penile Cancer; or
• As second line for recurrent or metastatic:
  • Vulvar Squamous Cell Carcinoma; or
  • Cervical Squamous Cell Carcinoma; or
  • Cervical Adenocarcinoma; or
• As subsequent therapy for progression following prior cytotoxic chemotherapy for:
  • Endometrial Carcinoma; or
• As single agent subsequent therapy for progressed metastatic:
  • Prostate Cancer – Adenocarcinoma; or
• As single agent subsequent or third line therapy for progression after prior chemotherapy as palliative treatment for:
  • Testicular Non-seminoma cancer; or
  • Testicular Pure seminoma cancer; or
• As single agent subsequent therapy for recurrent or persistent:
  • Ovarian Cancer/Fallopian Tube/Primary Peritoneal Cancer – Serous, Endometrioid, Carcinosarcoma, Clear Cell or Mucinous; or
• As single agent, initial therapy for unresectable, advanced or metastatic disease not appropriate for intensive therapy for:
  • Rectal Adenocarcinoma; or
  • Colon Adenocarcinoma; or
• As single agent, primary therapy for unresectable metachronous metastases with previous FOLFOX or CapeOx with in the last twelve (12) months for:
  • Rectal Adenocarcinoma; or
• As single agent, subsequent therapy for unresectable, advanced or metastatic disease following oxaliplatin- irinotecan- and/or fluoropyrimidine based therapy for:
  • Colon Adenocarcinoma; or
  • Rectal Adenocarcinoma; or
• As single agent, primary therapy for unresectable disease with previous FOLFOX or CapeOx within the last twelve (12) months for:
  • Colon Adenocarcinoma; or
• As subsequent therapy for unresectable metastatic adrenocortical tumors that have progressed following prior treatment with no satisfactory alternative treatment options.

Head and Neck Cancer

• Treatment of individuals with advanced and recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy; or
• Therapy as single agent second line or subsequent therapy for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy or for previously treated PD-L1 positive recurrent or metastatic nasopharyngeal cancer in:
  • Newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases or for individulas who are unfit for surgery and PS 3; or
  • Metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable loco regional recurrence or second primary with prior radiation therapy (RT) and PS 0-2; or
  • Unresectable loco regional recurrence without prior RT and PS 3.

Melanoma

• Single-agent therapy for metastatic or unresectable disease as:
  • First-line therapy; or
  • Second-line or subsequent therapy for disease progression or maximum clinical benefit from BRAF targeted therapy if anti PD-1 monotherapy not previously used; or
  • As second-line or subsequent therapy after disease progression or maximum clinical benefit from BRAF targeted therapy if prior anti-PD-1 therapy resulted in disease control (complete response, partial response, or stable disease) and no residual toxicity, and disease progression occurred greater than three (3) months after treatment discontinuation.

Merkel Cell Carcinoma

• Treatment of individuals with disseminated, clinical M1 disease with or without surgery and/or radiation therapy.

Non-Hodgkin Lymphoma (NHL) – T-Cell Lymphomas

 Mycosis Fungoides (MF)/Sezary Syndrome (SS)

Extranodal Natural Killer T-Cell (NK/T-cell) Lymphoma, Nasal Type

• For treatment of relapsed/refractory disease following:
  • Additional therapy with clinical trial; or
  • Combination chemotherapy regimen (asparaginase-based); or
  • Best supportive care.

NSCLC

• Treatment of individuals with NSCLC:
  • As a single agent for first-line treatment for metastatic NSCLC whose tumors have high PD-L1 expression [(Tumor Proportion Score (TPS) greater than or equal to 50%)] as:
    • Determined by a Food and Drug Administration (FDA)-approved test, with no EGFR or ALK genomic tumor aberrations; or
  • First-line therapy for tumors that are EGFR, ALK, and ROS1 and BRAF negative or unknown and PD-L1 less than 50% or unknown; or
  • First-line or subsequent therapy for BRAF V600E-mutation positive tumors; or
  • Subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, or osimertinib therapy; or
  • Subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib or brigatinib therapy; or
  • Subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy; or
  • Subsequent therapy for PD-L1 expression-positive (greater than or equal to 50%) tumors and EGFR, ALK, ROS1, and BRAF negative or unknown; or
  • A single agent for the treatment of metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal to1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy; individuals with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab (Keytruda); or
  • Preferred single agent (if systemic immune checkpoint inhibitors not already given) as subsequent therapy for metastatic disease in individuals with PS 0-2 and tumors with PD-L1 expression levels greater than or equal to 1%:
    • Following progression on a first-line cytotoxic regimen; or
    • For further progression on other systemic therapy; or
  • In combination with carboplatin/pemetrexed, as first-line treatment of individuals with metastatic non-squamous NSCLC.

• Treatment for individuals with malignant pleural mesothelioma as:
  • Subsequent systemic therapy as a single agent.

Uveal Melanoma

• Consider as single agent therapy for metastatic or unresectable disease.

The use of pembrolizumab (Keytruda) is considered experimental/investigational and, therefore, non-covered for any other indication. Scientific evidence does not support the use for any other indication.

Experimental/Investigational (E/I) services are not covered regardless of place of service.

The administration of PD-1/PD-L1 blocking antibodies is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.

Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

• Link to Provider Resource Center for the Medical Policy Update

09/2017, Coverage Criteria and Policy Title Revised for PD-1 and PD-L1 Blocking Antibodies
05/2018, Coverage Guidelines Updated for PD-1 and PD-L1 Blocking Antibodies

• Link to Diagnosis Codes

• Link to References