Question

What is the scoring system used to grade Hodgkin’s Lymphoma and what are the different stages?

Answer

The Ann Arbor staging system with Cotswolds modifications is the current staging system used for patients with Hodkin’s Lymphoma.  There has been a meeting a subsequent meeting in Lugano, Switzerland in 2014, but those recommendations are controversial and not universally used.  The Ann Arbor staging system has four stages based on:

• The sites of lymph node involvement
• Extent of systemic disease

References

1. Lister TA, Crowther D, Sutcliffe SB. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. Journal of Clinical Oncology. 1989;7(11):1630-6. [pubmed]
2. Cheson BD, Fisher RI, Barrington SF. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical Oncology. 2014;32(27):3059-68. [pubmed]

What is the scoring system used to grade Hodgkin’s Lymphoma and what are the different stages?

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Therapeutic Index

This is the balance between toxic and therapeutic dosing of pharmacotherapeutic agents, and can be described as the relationship between underdosing (seeing no effect), effective dosing (achieving desired results), and overdosing (having toxic complications).  Specifically, it is the difference between the toxic dose for 50% of the population and the effective dose for 50% of the population.

Types of Chemotherapy

Direct DNA-Interacting Agents

• Alkylating
  • Cyclophosphamide
  • Cisplatin
  • Carboplatin
• Antitumor Antibiotics and Topoisomerase Poisons
  • Bleomycin
  • Doxorubicin

Indirect DNA-Interacting Agents

• Antimetabolites
  • 5-Fluorouracil (5FU)
  • Methotrexate
  • 6-mercaptopurine (6MP)
  • Azithropine

Antimitotic Agents

• Vincristine
• Paclitaxel

Hormone Receptor-Targeted Agents

• Tamoxifen
• Diethylstilbestrol

Protein Kinase Antagonists

• Imatinib
• Gefitinib

Multikinase Inhibitors

• Sorafenib

Proteasome Inhibitors

• Bortezomib

Histone Deacetylase Inhibitors

• Vorinostat

mTOR Inhibitors

• Everolimus

Complications of Chemotherapy

Myelosuppression

By definition, chemotherapy is designed to destroy mature, cancer cells, so it only makes sense that bone marrow suppression is affected.  The most dreaded complication associated with myelosuppression is acquired neutropenia.  This can occur anywhere from 2-6 weeks after chemotherapy and the only presenting sign that something is wrong is a febrile episode (>38^oC).

Definition of neutropenia is an absolute neutrophil count (ANC) < 1500 cells/microL.  This can be automatically calculated by most labs, but it is calculated as follows:

ANC = WBC x 10(%PMN + %Bands)

Risk assessment is done via the Multinational Association for Supportive Care in Cancer (MASCC) index:

Neutropenic patients are at an increased risk of infection due to the inefficiency, or absence, of circulating WBC to combat infection.  The management of neutropenic patients should include

• Immediate contact precautions
  • Providers and visits
  • Gowns, gloves, hats, masks
• Broad spectrum antibiotics for duration of neutropenia
  • Low Risk
    • Outpatient oral antibiotics
      • Ciprofloxacin + amoxicillin/clavuanate
  • High risk
    • Initial management is monotherapy with antipseudomonal agent:
      • Pipercillin/tazobactam
      • Meropenem
      • Cefepime
      • Imipenem
      • Ceftazidime
    • May add other agents if clinical scenario suggests:
      • Vancomycin
      • Metronidazole
      • Antivirals
      • Antifungals

Nausea and Vomiting

N/V associated with chemotherapy can be acute (<24hr), delayed (>24hrs), or even anticipatory.  Chemoprophylaxis for N/V is based on risk and broken down into highly emetogenic, moderately emetogenic, low emetogenic, and minimally emetogenic therapies.  Treatment revolves around some combination of:

• Neurokinin 1 Receptor Antagonist (NK1)
  • Aprepitant
  • Fosaprepitant
  • Rolapitant
• 5-hydroxytryptamine-3 Antagonist (5-HT3)
  • Ondansetron
  • Palonosetron
  • Granistron
• Glucocorticoid
  • Dexamethasone

Mucositis

Profound inflammatory process of the mucous membranes and is characterized by:

• Initiation of insult (chemo)
• Upregulation/Generation of messenger signals and proinflammatory cytokines
• Signaling and Amplification
  • Damage of tissue by cytokines is amplified via feedback loops
• Ulceration and inflammation
• Healing

Symptoms generally start to begin after day 7 and can range from mild inflammation to complete ulceration and inability to take anything PO.  Epithelial sloughing after ulceration can produce the classic pseudomembane appearance.  This desquamation can now lead to bacterial translocation in an already immunocompromised host.

Diarrhea

3 main mechanisms that cause chemotherapy-related diarrhea:

• Secretory Diarrhea
  • Increased intraluminal secretion of electrolytes from epithelial damage
• Osmotic Diarrhea
  • Increased intraluminal osmotic substances from brush border damage
• Altered GI motility
  • Increased peristalsis and emptying

Different types of colitis syndromes may also occur and cause diarrhea:

• Neutropenic entrocolitis
  • A form of necrotizing enterocolitis, or typhlitis
• Ischemic colitis
  • Associated with docetaxel regimens
• Diff associated colitis

Outpatient management can be:

• Loperamide 4mg initial dose followed by 2mg every 2-4 hours
• Octreotide 100-150 mcg SQ every 8 hours (can increase to 500-1500 mcg/dose)

Inpatient/Emergency management:

• Octreotide 25-50 mcg/hour infusion

Tumor Lysis Syndrome

Occurs after massive tumor cell lysis (most commonly with high-grade lymphomas and ALL) and can cause the following biochemical abnormalities:

• Hyperuricemia
  • Can cause uric acid nephropathy and AKI
• Hyperkalemia
  • From the lysis and intracellular distribution
• Hyperphosphatemia
  • Can cause calcium phosphate deposition in the renal tubules and precipitate AKI
• Hypocalcemia
  • Hyperphosphatemia causes significant hypocalcemia and can precipitate dysrhythmias

The Cairo-Bishop scale is used for grading severity of disease:

Diagnosis can be made with 2 or more laboratory abnormalities, or one laboratory abnormality and one clinical abnormality.

Treatment is multitiered and consists of:

• Fluid resuscitation
• Electrolyte correction
• Renal protection
• Rasburicase – oxidizes uric acid

Cottage Physician

References

1. Information for Health Care Providers. (2016, December 14). Retrieved February 27, 2017, from https://www.cdc.gov/cancer/preventinfections/providers.htm
2. Sausville EA, Longo DL. Principles of Cancer Treatment. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130&sectionid=71748332. (Accessed February 27, 2017).
3. Freifeld AG, Bow EJ, Sepkowitz KA. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America. 2011;52(4):e56-93. [pubmed]
4. Klastersky J, Paesmans M, Rubenstein EB. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology. 2000;18(16):3038-51. [pubmed]
5. Hesketh PJ, Kris MG, Grunberg SM. Proposal for classifying the acute emetogenicity of cancer chemotherapy. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology. 1997;15(1):103-9. [pubmed]
6. Hesketh PJ, Bohlke K, Lyman GH. Antiemetics: American Society of Clinical Oncology Focused Guideline Update. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology. 2016;34(4):381-6. [pubmed]
7. Roila F, Molassiotis A, Herrstedt J. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Annals of Oncology : official journal of the European Society for Medical Oncology. 2016;27(suppl 5):v119-v133. [pubmed]
8. Sonis ST, Elting LS, Keefe D. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9 Suppl):1995-2025. [pubmed]
9. Sonis ST. The pathobiology of mucositis. Nature reviews. Cancer. 2004;4(4):277-84. [pubmed]
10. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, June 2010, National Institutes of Health, National Cancer Institute. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (Accessed February 27, 2017).
11. Benson AB, Ajani JA, Catalano RB. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology. 2004;22(14):2918-26. [pubmed]
12. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. The American Journal of Medicine. 1993;94(2):133-9. [pubmed]
13. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. British journal of haematology. 2004;127(1):3-11.  [pubmed]

31-year-old female, with a history of controlled SLE, presents to your office with a 2 week history of headache, weakness, dizziness, and nausea.  She also reports a new rash on her legs that is non-pruritic.  She denies any recent illnesses, sick contacts, vomiting, abdominal pain, cough, or shortness of breath.  She has been taking hydroxychlorquine for her SLE and has had little complications from this disease.

Vital Signs

BP-131/72, HR-116, RR-15, O2-100%, T-101.2 F

Physical Exam

General – Mild distress

Skin

HEENT

Neck – Supple, no LAD

Pulmonary – CTA without adventitial breath sounds

CV – Tachycardic without M/G/R

Abdomen – S/NT/ND

PV – 2+ throughout

Neurologic – 5/5 strength throughout, 2+ reflexes throughout

Psychiatric – A&Ox3

Laboratory Screening

Answer

1. This patient has thrombotic thrombocytopenia purpura (TTP), which is a thrombotic microangioapathy caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13 and small-vessel platelet-rich thrombi.  Classically it is associated with a pentad of symptoms (but current research only shows 5% of patients with all five):
   1. Hemolytic anemia
      1. Low H/H and high LDH
   2. Thrombocytopenia
      1. <150,000
   3. Neurologic symptoms
      1. Confusion, headache, focal deficits
   4. Fever
   5. Acute Kidney Injury
      1. Elevated creatinine
2. Addition findings in this patient that support the diagnosis are:
   1. Purpuric rash from small-vessell thrombosis
   2. Scleral icterus from elevated indirect bilirubin from hemolysis
3. Additional laboratory studies to help with the diagnosis of TTP are:
   1. Hemolysis labs
      1. Serum haptoglobin
         1. Often elevated
      2. Direct antiglobulin (Coombs) test (DAT)
         1. Often negative
   2. Fibrinogen and D-Dimer
      1. Evaluate for DIC as severely ill patient can progress to this very quickly
   3. ADAMTS13 activity and inhibitor testing
      1. Gold standard and confirmatory test of choice

References

1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. The New England Journal of Medicine. 2014;371(7):654-66. [pubmed]
2. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116(20):4060-9.  [pubmed]
3. Griffin D, Al-Nouri ZL, Muthurajah D. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion. 2013;53(1):235-7.  [pubmed]

31-year-old female, with a history of controlled SLE, presents to your office with a 2 week history of headache, weakness, dizziness, and nausea.  She also reports a new rash on her legs that is non-pruritic.  She denies any recent illnesses, sick contacts, vomiting, abdominal pain, cough, or shortness of breath.  She has been taking hydroxychlorquine for her SLE and has had little complications from this disease.

Vital Signs

BP-131/72, HR-116, RR-15, O2-100%, T-101.2 F

Physical Exam

General – Mild distress

Skin

HEENT

Neck – Supple, no LAD

Pulmonary – CTA without adventitial breath sounds

CV – Tachycardic without M/G/R

Abdomen – S/NT/ND

PV – 2+ throughout

Neurologic – 5/5 strength throughout, 2+ reflexes throughout

Psychiatric – A&Ox3

Laboratory Screening

1. What is the most likely diagnosis?

2. What other laboratory tests can be helpful in making the diagnosis?

Question #1

Which of the following genetic mutations is seen with chronic myelogenous leukemia?

Answer:

Translocation of chromosome 9 and 22.  This new chromosome 22 is called “Philadelphia chromosome” after the city where the two hospitals that first identified the gene mutation in 1960 were both located.

http://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq

Question #2

Which of the following cancer markers are classically associated with ovarian cancer?

Answer:

CA-125

Definition

The textbook definition of anemia is a reduction of the absolute number or mass of circulating red blood cells.  This then causes a global reduction in the oxygen carrying capacity of the patient’s circulatory system.  Clinically, we use hemoglobin and hematocrit as the surrogate markers and define anemia as 2 SD below the mean for gender:

• Men
  • Hemoglobin < 13.5 g/dL
  • Hematocrit < 41%
• Women
  • Hemoglobin < 12.0 g/dL
  • Hematocrit < 36%

Patel KV. Haematologica. 2008;93(9):1281-1283.

• Special Populations
  • Athletes
    • May have a baseline anemia due to:
      • Dilution from increased plasma volume
      • Hemolytic breakdown from exercise
      • Exercise induced cytokines decreases RBC production
    • A normal H/H in a competitive athlete may suggest performance enhancing drugs
  • High altitudes
    • May have elevated hemoglobin concentration as baseline
  • Smokers
    • Baseline higher hemoglobin due to carboxyhemoglobin

General Causes of Anemia

There are two general approaches you can use to help identify the cause of anemia in adults.

• The Kinetic Approach (the mechanisms responsible for the low hemoglobin)
  • 3 independent mechanisms
    • Decreased RBC production
      • Lack of nutrients
      • Bone marrow failure
      • Decreased erythopoetic stimulation factors
        • Erythropoietin, T3, androgens
      • Inflammation
    • Increased RBC destruction
      • Hemolysis, hypersplenism
    • Blood loss
• The Morphologic Approach (categories based on RBC size and reticulocyte response)
  • Macrocytic (MCV > 100 fL)
    • Vitamin B12, folate, EtOH, liver disease
    • Any condition causing reticulocytosis
  • Microcytic (MCV < 80 fL)
    • 3 most common in clinical practice
      • Iron deficiency
        • ↓ serum iron, ↓ serum ferritin, ↑ TIBC
      • Alpha or beta thalassemia minor
        • Normal iron studies
      • Anemia of chronic disease
        • ↓ serum iron, normal serum ferritin, ↓ TIBC

History Questions

• Is the patient symptomatic?
  • Fatigue, dyspnea, bleeding, bruising, dizziness, syncope
• Any history of weight loss, night sweats, fever, anorexia?
  • Infection or malignancy
• Past medical history for chronic illness
  • PUD, renal disease, autoimmune conditions, liver disease, past malignancies
• Family history for hemoglobinopathies
• Social history for alcohol use
• Occupational exposures

Physical Exam Findings

• Pallor
  • Palms, nail beds, face, conjunctiva
• Jaundice
• Hepatosplenomegaly
• Lymphadenopathy
• Petechiae, purpura, bruising
• Bone tenderness

Laboratory Testing

Anemia is usually first diagnosed by CBC.  Once you have a documented low H/H, then you need order follow-up studies to help differentiate the cause of the anemia.  These include:

• RBC indices
  • MCV, MCH, MCHC, RDW
• Reticulocyte count and index
• Peripheral smear
  • Helmet cells or schistocytes à microangiopathic hemolysis
  • Microspherocytes à autoimmune hemolysis
  • Tear drop RBC à myelofibrosis
  • Bite cells à oxidative hemolysis
  • Parasites à malaria, babeosis
  • Hypersegmented neutrophils à Vitamin B12 or folate deficiency
  • Nucleated RBC
  • Siderocytes
  • Target cells à thalassemias
• WBC and platelet count from CBC
• If hemolysis is suspected:
  • ↑ Serum LDH, ↓ serum haptoglobin, and ↑ serum indirect bilirubin
  • Direct Coombs test (antibodies against RBC)
• Bone marrow evaluation

Schrier SL, et al. Approach to adults with anemia. In: Up To Date. Waltham, MA (Accessed 03/23/2016)

The Cottage Physician Management

Something new I thought I would bring to the PAINE Podcast.  As you all know, I am quite a fan of medicine and antiquity.  Shortly after I married my wife, her grandfather past away from a progressive esophageal cancer.  One of the things I was able to keep when helping clean out his house, was a copy of The Cottage Physician printed in 1893.  It was basically a handbook on how to treat common ailments of the time. I will try to add excerpts from this book when appropriate so you can have a sense of how medicine was practiced in the late 19^th century.

The Cottage Physician. 1863

References

1. Patel KV. Variability and heritability of hemoglobin concentration: An opportunity to improve understanding of anemia in older adults.  Haematologica.  2008;93(9):1281-1283.
2. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?. Blood. 2006;107(5):1747-50.
3. Shaskey DJ, Green GA. Sports haematology. Sports Med. 2000;29(1):27-38.
4. Ruíz-argüelles GJ. Altitude above sea level as a variable for definition of anemia. Blood. 2006;108(6):2131.
5. Nordenberg D, Yip R, Binkin NJ. The effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA. 1990;264(12):1556-9.
6. Hillman RS, Ault KA, Leporrier M, Rinder HM. Clinical Approach to Anemia.  In: Hematology in Clinical Practice.  5^th McGraw-Hill. New York. 2010.
7. Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc. 2003;78(10):1274-80.
8. Nardone DA, Roth KM, Mazur DJ, Mcafee JH. Usefulness of physical examination in detecting the presence or absence of anemia. Arch Intern Med. 1990;150(1):201-4.
9. Hung OL, Kwon NS, Cole AE, et al. Evaluation of the physician’s ability to recognize the presence or absence of anemia, fever, and jaundice. Acad Emerg Med. 2000;7(2):146-56.

No case this week…..just a few quick oncology questions

Answer:

Check a methylmalonic acid level

This patient has had a history of gastric cancer with a partial gastrectomy and now presents with a fatigue and gait disturbances.  CBC reveals a macrocytic aneamia and peripheral smear shows multinucleated neutrophils.  The gait disturbances are most likely due to the progressive peripheral neuropathy.  This is most consistent with vitamin B12 deficiency.  Intrinsic factor, which is secreted by the parietal cells of the stomach, is required for vitamin B12 absorption in the terminal ileum.

Work-Up for Vitamin B12 Deficiency

Serum B12 Level

• < 300 pg/dL is diagnostic

Metobolites

• Methylmalonic acid
  • < 70 nanomol/L is diagnostic
• Homocysteine
  • < 5 micromol/L is diagnostic

Possible additional testing in the setting of macrocytic anemia:

• If pernicious anemia is suspected:
  • Anti-intrinsic factor antibodies
• If folate deficiency is suspected:
  • Serum folate level
    • < 2 ng/mL is diagnostic
  • RBC folate level (reserved for indeterminate serum levels)
    • < 280 ng/mL is diagnostic

Treatment for B12 Deficiency

• Intramuscular
  • 1mg daily x 7 days, then 1mg weekly for 4 weeks, then 1mg monthly
• Oral
  • 1000-2000mg daily

References

1. Antony AC. Megaloblastic anemias. In: Hematology: Basic principles and practice, 4th ed, Hoffman R, Benz EJ, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 2005. p.519.
2. Butler CC, Vidal-alaball J, Cannings-john R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials. Fam Pract. 2006;23(3):279-85.