Acute lymphoblastic leukemia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [3] Carlos A Lopez, M.D. [4]
Overview
Chemotherapy is indicated for acute lymphocytic leukemia and can be divided in several phases: induction chemotherapy, consolidation therapy, CNS prophylaxis and maintenance treatments with chemotherapeutic drugs such as Prednisone plus Vincristine plus Cyclophosphamide plus Doxorubicin or Methotrexate plus 6-MP. Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a bone marrow transplant. Drugs approved for acute lymphoblastic leukemia include: Methotrexate, Nelarabine, Blinatumomab, Cyclophosphamide, Clofarabine, Cytarabine, Dasatinib, Doxorubicin hydrochloride, Mercaptopurine, Nelarabine, Pegaspargase, Prednisone and Mercaptopurine. A therapy that was recently approved by the Food and Drug Administration is chimeric antigen receptor T (CAR-T) cell therapy in the form of tisagenlecleucel, which is used in patients with B cell acute lymphoblastic leukemia.
Medical Therapy
Chemotherapy
- The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow).
Treatment for acute leukemia can include:
- chemotherapy
- steroids
- radiation therapy
- Intensive combined treatments (including bone marrow or stem cell transplants)
- Growth factors
Proper management of acute lymphoblastic leukemia focuses on control of bone marrow and systemic (whole-body) disease as well as prevention of cancer at other sites, particularly the central nervous system (CNS). In general, acute lymphoblastic leukemia treatment is divided into several phases:
- Induction chemotherapy
- Consolidation therapy
- CNS prophylaxis
- Maintenance treatment
- Follow-up therapy
Induction chemotherapy
- To bring about remission - that is, leukemic cells are no longer found in bone marrow samples
- For adult acute lymphoblastic leukemia standard induction plans include:
- Prednisone
- Vincristine
- Anthracycline drug
- Other drug plans may include:
- Patients will undergo this regimen for the first month of treatment
Low risk therapy
- Low risk therapy
- 1.1 Pediatric
- Preferred regimen(1): Vincristine 1.5 mg/m2/dose IV weekly, may increase to 2 mg/m2/dose IV. It is given in a span of 3 weeks, on the following days;0,7,14 and 21
- Preferred regimen(2): Prednisone 40 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
- Preferred regimen(3): Asparaginase 200 International Units/kg/day IV given for 28 days
- Preferred regimen(4): Imatinib 340 mg/m2/day PO administered once daily; maximum daily dose: 600 mg/day, given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
- Alternative regimen(1):Dasatinib 140 mg once daily PO, also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
- Alternative regimen(2):Dexamethasone basal surface area ≤0.6 m2: 2 mg every 12 hours and in a basal surface area >0.6 m2: 4 mg every 12 hours. Its is given PO in both cases
- Alternative regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
- Alternative regimen(5):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
- Alternative regimen (6):hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 and 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
- 1.1 Pediatric
- 1.2 Adult
- Preferred regimen(1): Vincristine 2 mg/m2/dose IV given on days 4 and 11 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase
- Preferred regimen(2): Prednisone 10 mg daily to 100 mg/m2/day PO . It is given in 2 divided doses on days 0 to 13
- Preferred regimen(3): Asparaginase 200 to 1,000 units/kg/day for 28 consecutive days and can be given IM or IV
- Preferred regimen(4): Imatinib 600 mg PO given once daily; given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
- Alternative regimen(1):Dasatinib 140 mg PO given once daily. It is also given in t(9;22)/BCR-ABL1 positive Acute lymphoblastic leukemia
- Alternative regimen(2):Dexamethasone 6–18 mg/m2/ a day IV
- Preferred regimen (2): hyper-CVAD: hyper-fractionated cyclophosphamide given 300 mg/m2 IV over 2 hours every 12 hours for 6 doses on days 1 to 3 with 600 mg/m2 Mesna daily intravenously via continuous infusion on days 1 to 3 beginning one hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide, vincristine 2 mg/m2/dose IV on days 4 and 11, doxorubicin (Adriamycin) 50 mg/m2 given IV over 24 hours and then IV through a central venous catheter on day 4 40 mg dexamethasone daily either PO or IV on days 1 to 4 and days 11 to 14.
- Alternative regimen (2):Methotraxate 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
- Alternative regimen(3): Blinatumomab 9 mcg/day on Days 1–7 and at 28 mcg/day on Days 8-28, these are administered during the 1st cycle . For subsequent cycles, administer Blinatumomab at 28 mcg/day on Days 1–28
- 1.2 Adult
- 1.3 Renal impairment
- Pediatric
- Preferred regimen(1): Vincristine
- No adjustment required
- Preferred regimen(2): Prednisone
- No adjustment required
- Preferred regimen(3): Asparaginase
- No adjustment required
- Preferred regimen(4): Imatinib
- Mild impairment (CrCl 40 to 59 mL/minute): There are no pediatric-specific recommendations
- Moderate impairment (CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated
- Severe impairment (CrCl <20 mL/minute): There are no pediatric-specific recommendations
- Alternative regimen(1): Dexamethasone
- No adjustments required
- Alternative regimen(2):Daunorubicin
- CrCl <30 mL/minute: Administer 50% of dose
- Hemodialysis: Administer 50% of dose
- Preferred regimen(1): Vincristine
- Pediatric
- 1.3 Renal impairment
- Adult
- Preferred regimen(1): Vincristine
- No adjustment required
- Preferred regimen(2): Prednisone
- No adjustment required
- Preferred regimen(3): Asparaginase
- No adjustment required
- Preferred regimen(4): Imatinib
- Mild impairment(CrCl 40 to 59 mL/minute): Maximum recommended dose: 600 mg.
- Moderate impairment(CrCl 20 to 39 mL/minute): Decrease recommended starting dose by 50%; dose may be increased as tolerated; maximum recommended dose: 400 mg.
- Severe impairment(CrCl <20 mL/minute): Give with caution; a dose of 100 mg daily has been tolerated in a limited number of patients with severe impairment
- Alternative regimen(1): Dexamethasone
- No adjustments required
- Preferred regimen(1): Vincristine
- Adult
- 1.4 Hepatic impairment
- Pediatric
- Preferred regimen(1): Vincristine
- Serum bilirubin At the level 1.5 to 3 mg/dL: Give 50% of dose.At Serum bilirubin >3 mg/dL: Avoid giving medication.
- Preferred regimen(2): Prednisone
- There are no dosage adjustments usually required. Prednisone is not active and must be metabolized by the liver to prednisolone. This conversion may be disrupted in patients with liver disease; however, prednisolone levels are higher in patients with severe liver failure than in normal patients. Therefore, compensation for the inadequate conversion of prednisone to prednisolone occurs.
- Preferred regimen(3): Asparaginase
- Contraindicated in patients with hepatic failure, but can be given in older adolescents at the following levels:
- ALT/AST >3 to 5 times ULN (upper normal limit): No adjustment required; continue therapy.
- ALT/AST >5 to 20 times ULN (upper normal limit): Delay next dose until transaminases <3 times upper limit of normal
- ALT/AST >20 times ULN (upper normal limit): Discontinue therapy if takes longer than 1 week for transaminases to return to <3 times the upper limit of normal.
- Direct bilirubin <3 mg/dL: No adjustment required, continue therapy
- Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and resume when direct bilirubin is <2 mg/dL; then switch to alternate asparaginase product.
- Direct bilirubin >5 mg/dL: Stop asparaginase; do not change for other asparaginase products; do not make up for missed doses.
- Preferred regimen(4): Imatinib
- If elevations of bilirubin >3 times of upper normal limit or liver transaminases >5 times of the upper normal limit occur, withhold treatment until bilirubin <1.5 times upper normal limit and transaminases <2.5 times the upper normal limit
- Resume treatment at a reduced dose as follows: If dose is 340 mg/m2/day, decrease dose to 260 mg/m2/day; maximum daily dose range: 300 to 400 mg/day
- Alternative regimen(1): Dexamethasone
- No adjustment required
- Alternative regimen(2):Daunorubicin
- Serum bilirubin 1.2 to 3 mg/dL: Give 75% of dose
- Serum bilirubin >3 mg/dL: Give 50% of dose
- Preferred regimen(1): Vincristine
- Pediatric
- 1.4 Hepatic impairment
- Adult
- Preferred regimen(1): Vincristine
- Serum bilirubin 1.5 to 3 mg/dL: Give 50% of dose
- Serum bilirubin >3 mg/dL: Do not use
- Preferred regimen(2): Prednisone
- No adjustment required
- Preferred regimen(3): Asparaginase
- ALT/AST >3 to 5 times ULN: Continue use
- ALT/AST >5 to 20 times ULN: Give next dose until transaminases <3 times upper normal limit
- ALT/AST >20 times ULN: Stop therapy if takes longer than 1 week for transaminases to return to <3 times the upper normal limit
- Direct bilirubin <3 mg/dL: Continue use
- Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and start again when direct bilirubin <2 mg/dL; consider changing to alternate asparaginase product.
- Direct bilirubin >5 mg/dL: Stop asparaginase; do not use another asparaginase products; do not make up for missed doses.
- Preferred regimen(4): Imatinib
- Mild-to-moderate impairment: No dosage adjustment required
- Severe impairment: Decrease dose by 25%
- Alternative regimen(1): Dexamethasone
- No adjustments required
- Preferred regimen(1): Vincristine
- Adult
High risk therapy
- High-risk children may receive these drugs listed above plus an anthracycline such as daunorubicin.[1][2]
Consolidation therapy
- It is the stage in the treatment (1-3 months in adults; 4-8 months in children) that eliminates any leukemia cells that are still "hiding" within the body
- A combination of chemotherapeutic drugs is used to keep the remaining leukemia cells from developing resistance
- Patients with low- to average-risk acute lymphoblastic leukemia receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP)
- High-risk patients receive higher drug doses plus treatment with extra chemotherapeutic agents.[3]
- 1.1 Pediatric
- Preferred regimen(1): Methotraxate:
- High-dose : 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours; given IV (to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43
- Escalating-dose: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total and it is given IV
- Preferred regimen(2):Cytarabine 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase. It is given IV and/or subcutaneously
- Preferred regimen(3):Daunorubicin In infants and Children <2 years or BSA <0.5 m2: 1 mg/kg/dose on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), given IV. In Children and Adolescents ≥2 years and BSA ≥0.5 m2: 25 mg/m2 on day 1 every week for up to 4 to 6 cycles (in combination with vincristine and prednisone), also given IV
- Preferred regimen(4):Cyclophosphamide 1,200 mg/m2 on Day 2 , its given IV
- Preferred regimen(5):Etoposide 100 mg/m2 IV over 2 hours for 4 consecutive days
- Alternative regimen(1):Doxorubacin 30 mg/m2/dose, given IV. Its is given on days 0 and 1 of a 4-week cycle
- Preferred regimen(1): Methotraxate:
- 1.1 Pediatric
- 1.2 Adult
- Preferred regimen(1): Methotraxate 200 mg/m2 over 2 hours IV , followed by 800 mg/m2 over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD)
- Preferred regimen(2):Cytarabine 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles, given IV
- Preferred regimen(3):Daunorubicin 45 mg/m2 (in patients <60 years of age) or 30 mg/m2 (in patients ≥60 years of age) on days 1, 2, and 3 (Course I; 4 week cycle), given IV
- Preferred regimen(4):Cyclophosphamide 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase, given IV
- Preferred regimen(5):Etoposide 60 mg/kg IV over 4 hours as a single dose
- Alternative regimen(1):Doxorubacin 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7, given IV
- 1.2 Adult
CNS prophylaxis
- (preventive therapy) to stop the cancer from spreading to the brain and nervous system
- Standard prophylaxis may consist of:[4]
- Cranial (head) irradiation plus spinal tap or intrathecal (IT) delivery (into the space around the spinal cord and brain) of the drug methotrexate.
- High-dose systemic and IT methotrexate, without cranial irradiation
- IT chemotherapy.
- Only children with T-cell leukemia, a high white blood cell count, or leukemia cells in the cerebrospinal fluid (CSF) need to receive cranial irradiation as well as IT therapy.
Radiotherapy in CNS prophylaxis
- Craniospinal radiotherapy has been exchanged for intrathecal chemotherapy in several CNS prophylactic therapy protocols. Current protocols do not really have CNS radiotherapy.In the cases where a radiotherapy protocol has been recommended; the radiation dosage is at 12 to 18 Gy.
- Removing radiotherapy from the CNS prophylaxis regimen has shown no change in survival rates
- Craniospinal radiotherapy was once considered the standard of care, and was effective in preventing CNS leukemia but was associated with major toxicity.Such as cognitive impairment and white matter volume loss
- When an MRI was done the following was seen:
- atrophy
- leukoencephalopathy
- calcifications, or grey matter abnormalities
- The irradiation would also cause secondary brain tumors to arise, causing further complications in the treatment
Maintenance treatments with chemotherapeutic drugs (e.g., prednisone plus vincristine plus cyclophosphamide plus doxorubicin; methotrexate plus 6-MP) to prevent disease recurrence once remission has been achieved. Maintenance therapy usually involves drug doses that are lower than those administered during the induction phase. In children, an intensive 6-month treatment program is needed after induction, followed by 2 years of maintenance chemotherapy.
Follow-up therapy for acute lymphoblastic leukemia patients usually consists of:
- Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), especially in patients with prolonged granulocytopenia; that is, too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
- Transfusions with red blood cells and platelets
A laboratory test known as polymerase chain reaction (PCR) is advisable for acute lymphoblastic leukemia patients, since it may help to identify specific genetic abnormalities. Such abnormalities have a large impact upon prognosis and, consequently, treatment plans. PCR testing is especially important for patients whose disease is B-cell in type. B-cell acute lymphoblastic leukemia cyclophosphamide-based regimens that are used for non-hodgkin's lymphoma.
Among acute lymphoblastic leukemia patients, 3-5% children and 25-50% of adults are positive for the Philadelphia chromosome (Ph1). Because these patients have a worse prognosis than other individuals with acute lymphoblastic leukemia, many oncologists recommend allogeneic bone marrow transplantation (alloBMT), since remission may be brief following conventional acute lymphoblastic leukemia chemotherapy.
People who receive bone marrow transplantation will require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.
Recurrent acute lymphoblastic leukemia patients usually do not benefit from additional chemotherapy alone. If possible, they should receive re-induction chemotherapy, followed by allogeneic bone marrow transplant (alloBMT).
Alternatively, patients with recurrent acute lymphoblastic leukemia may benefit from participation in new clinical trials of alloBMT, immune system agents, and chemotherapeutic agents, or low-dose radiotherapy, if the cancer recurs throughout the body or CNS.
Chemotherapy is the initial treatment of choice. Most acute lymphoblastic leukemia patients end up receiving a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells.
As the chemotherapy regimens can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; about 3 years for males on COG protocols), many patients have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath (a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath). Since acute lymphoblastic leukemia cells sometimes penetrate the Central Nervous System CNS, most protocols include delivery of chemotherapy into the CNS fluid. More advanced centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the CNS fluid and to extract CNS fluid for various tests). More traditional centers would perform multiple lumbar punctures as needed for testing and treatment delivery.
Chimeric antigen receptor T (CAR-T) cell therapy
Chimeric antigen receptor T (CAR-T) cell therapy has recently been approved by the Food and Drug Administration for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma in the second- or third-line settings. This form of therapy involves the engineering of a patient's own T lymphocytes to create genetically engineered cells that have anti-tumor immune responses. The process of CAR-T construction involves first performing leukopheresis to collect peripheral blood mononuclear cells, which contain the T cell population. The T cells are stimulated to proliferated via treatment with interleukin-2 (IL-2) or anti-CD3 agonist antibody.[5] A lentivirus or retrovirus is transfected into the T cells, and this lentivirus contains the DNA sequence that encodes for the CAR gene. The final CAR-T cell product is usually composed of 3 components: a single-chain variable fragment, a transmembrane domain, and an intracellular signal transduction domain. This structure allows for antigen recognition that parallels B lymphocyte activity and effector function that parallels T lymphocyte activity, hence the name "chimeric."[5] CAR-T cells are a combination of T cells and antibodies and are thus sometimes known as "T-bodies." In acute lymphoblastic leukemia, the specific tumor antigen against which CAR-T cells are engineered is CD19, which is a B cell marker. The current FDA-approved product is tisagenleclucel, which is used in patients up to 25 years of age with relapsed or refractory B cell acute lymphoblastic leukemia.
Radiation Therapy
Radiation therapy is used on painful bony areas in severe disease or as part of the preparations for a bone marrow transplant (total body irradiation). Radiation in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of children’s acute lymphoblastic leukemia. Recent studies showed that CNS chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited.[6]
Drugs Approved for acute lymphoblastic leukemia
The following pharmaclogic agents have been aproved for the treatment of acute lymphoblastic leukemia:[7]
- Methotrexate
- Nelarabine
- Asparaginase Erwinia chrysanthemi
- Blinatumomab
- Cyclophosphamide
- Clofarabine
- Cytarabine
- Dasatinib
- Doxorubicin Hydrochloride
- Mercaptopurine
- Nelarabine
- Pegaspargase
- Prednisone
- Mercaptopurine
Late Effects of Treatment for Adult acute lymphocytic leukemia
Long-term follow-up of 30 patients with acute lymphocytic leukemia in remission for at least 10 years has demonstrated ten cases of secondary malignancies. Of 31 long-term female survivors of acute lymphoblastic leukemia or acute myeloid leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.[7]
References
- ↑ Tsuchida M, Ohara A, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, Saito M, Akiyama M, Fukushima T, Koike K, Shiobara M, Ogawa C, Kanazawa T, Noguchi Y, Oota S, Okimoto Y, Yabe H, Kajiwara M, Tomizawa D, Ko K, Sugita K, Kaneko T, Maeda M, Inukai T, Goto H, Takahashi H, Isoyama K, Hayashi Y, Hosoya R, Hanada R (February 2010). "Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999". Leukemia. 24 (2): 383–96. doi:10.1038/leu.2009.260. PMID 20033052.
- ↑ Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM (June 2008). "Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study". Blood. 111 (12): 5477–85. doi:10.1182/blood-2008-01-132837. PMC 2424148. PMID 18388178.
- ↑ Cooper SL, Brown PA (February 2015). "Treatment of pediatric acute lymphoblastic leukemia". Pediatr. Clin. North Am. 62 (1): 61–73. doi:10.1016/j.pcl.2014.09.006. PMC 4366417. PMID 25435112.
- ↑ Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S (May 2010). "Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies". Cancer. 116 (10): 2290–300. doi:10.1002/cncr.25008. PMID 20209620.
- ↑ 5.0 5.1 Makita S, Yoshimura K, Tobinai K (2017). "Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma". Cancer Sci. 108 (6): 1109–1118. doi:10.1111/cas.13239. PMC 5480083. PMID 28301076.
- ↑ Cherlow JM, Steinherz PG, Sather HN, Gaynon PS, Grossman NJ, Kersey JH, Johnstone HS, Breneman JC, Trigg ME, Hammond GD (December 1993). "The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group". Int. J. Radiat. Oncol. Biol. Phys. 27 (5): 1001–9. PMID 8262820.
- ↑ 7.0 7.1 "National Cancer Institurte".