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?