A nine year old boy was treated for pharyngitis one month ago. He is now brought in because his mother notes a decrease in energy, pallor, and easy bruising in his extremities. He complains of leg and arm pains over the last 2 weeks that seem to be aggravated by exercise. He has lost five pounds (2.4 kg) in the past month.
Exam: Vital signs are normal. His height is 130 cm and weight 27 kg (both 25th percentile). He is slightly pale and in no apparent distress. Some palpable nodes are present in the anterior triangle bilaterally. Heart and lungs are normal to auscultation and percussion. The tip of his spleen is 2 cm below the left costal margin and his liver is 3 cm below the right costal margin. His joints have full range of motion and no swelling. His skin shows bruises over the anterior tibial regions and five bruises over the left knee.
Labs: Hemoglobin 7.3. Platelet count 20,000. WBC 42,100 with 86% lymphocytes and 12% atypical lymphocytes. Bone marrow studies confirm B cell acute lymphoblastic leukemia (ALL).
He is treated with a four drug induction chemotherapy which achieves initial remission. Eighteen months later, he relapses requiring an allogeneic bone marrow transplant (BMT). After engraftment, he no longer needs medications or blood product transfusions. Eight months after the BMT, he develops shingles with vesicles on his face. This resolves with appropriate treatment.
Although only 1% of all cancers occur in children (<19 years of age), it is the second leading cause of childhood death. Early detection and prompt therapy have the potential to prolong survival and frequently cure the disease. Many factors are considered in determining the treatment goals for an individual patient: the type of cancer, its stage of growth, the patient's age, and family members' wishes. A team of experts (nurses, social workers, oncologists, surgeons, pathologists, psychologists) tries to meet the complexities of giving the children the most intense course of therapy possible, while not depriving them from having some level of normalcy (going to school, playing with friends).
A variety of modalities are currently employed to treat common malignancies. Surgery, the oldest treatment, provides the best chance of a cure for a localized tumor. It also plays a major role in other aspects of management, including diagnosis, staging, relieving symptoms, reconstruction, and prevention. Yet, its invasiveness physically challenges those undergoing the procedure.
Radiation therapy is used in 2/3 of cancer cases. It induces free radicals to target breaks in DNA, hence interfering with cell proliferation. It is used to treat the primary lesion, shrink a tumor prior to surgery, or palliatively relieve painful symptoms of bone metastasis. Radiation targets rapidly dividing cells, which includes cancer cells and normally dividing cells of the skin, hair, gastrointestinal mucosa, bone marrow, reproductive tissues, sweat glands, and lungs. These correlate with radiation's common side effects: alopecia, nausea, vomiting, pancytopenia, infertility, prostatitis or impotence in males, lung fibrosis and edema. Many of radiation's toxic effects can manifest many years after the treatment. Some examples are: asymmetry of the irradiated extremity, hypothyroidism, neurological dysfunction, growth retardation, and development of a secondary tumor.
Chemotherapy is one of the most common treatments for cancer. It was introduced in the 1940s when Goodman and Gilman first administered nitrogen mustard to patients with lymphoma. Nitrogen mustard, the first alkylating agent used, produced partial remission with considerable toxicity. The era of modern chemotherapy has since evolved to include several other classes of drugs: hormones (prednisone), antimetabolites (methotrexate, 5-fluorouracil), plant alkaloids (etoposide, vincristine, paclitaxel), and antibiotics (doxorubicin, bleomycin). Most of these work by inhibiting some metabolic pathway or DNA synthesis, which ultimately leads to cytotoxicity. Though chemotherapy has limited use for localized tumors, it is often the most effective agent for the management of disseminated or systemic cancer. These include the hematological malignancies (leukemias, lymphomas), metastasis of the primary solid tumor, and potential micro-metastasis after surgery or radiation.
Unfortunately, their utility is limited by the various acute and chronic complications involved with their use. Frequent side effects of chemotherapy include vomiting, diarrhea, cachexia, bone marrow suppression, and immunosuppression. Vomiting and diarrhea lead to fluid loss that often result in hyponatremia. Hyponatremia is also worsened by SIADH. Bone marrow suppression leads to anemia, thrombocytopenia, neutropenia, and hyper-leukocytosis (this is an abnormal increase of white blood cells while the others are an abnormal decrease of different blood precursor cells). Immunosuppression can increase the rate of tumor growth, promote graft versus host disease (GVHD), and predispose patients to opportunistic infections. In addition, the substantial break down of tumor cells by chemotherapy can lead to tumor lysis syndrome, in which a large amount of phosphate, potassium, and uric acids are released into the circulation, when large number of cancer cells are killed.
Supportive care is therefore essential with chemotherapy. Hyponatremia can be corrected by limiting fluid intake, diuresis, or demeclocycline, an ADH antagonist. Vomiting may be prevented by metoclopramide, some H1 antihistamines (diphenhydramine), 5-HT3 inhibitors (ondansetron, granisetron and dolasetron), phenothiazines, dronabinol (marijuana active ingredient), as well as corticosteroids (dexamethasone). Patients undergoing chemotherapy often have a decreased appetite and consequently are malnourished. Enteral tube feeding and parenteral hyperalimentation may become necessary when oral intake is severely inadequate.
Myelosuppression can be treated with transfusion of packed red blood cells, platelet infusions, leukapheresis, or granulocyte-colony stimulating factor (G-CSF). Graft versus host disease may be prevented by irradiating all blood products. Febrile neutropenia may require G-CSF as well as empiric broad spectrum IV antibiotics.
In situations of continual febrile illness for more than 1 week, fungal and viral infections must be considered. Common opportunistic infections include candidiasis, aspergillosis, and Pneumocystis carinii. Temporary prophylactic treatment with trimethoprim/sulfamethoxazole is often prescribed in anticipated bone marrow suppression. Children on chemotherapeutic protocols are prone to complications from disseminated viral infections. They should not be given live attenuated vaccines, since these attenuated organisms may still cause disseminated disease in immunocompromised hosts. Children who are exposed to chickenpox during their chemotherapy should be given IV varicella zoster immunoglobulin. If clinical symptoms develop, hospitalization and IV acyclovir should be instituted.
Although the acute complications of chemotherapy are relatively manageable, some of its long-term consequences are devastating and often cause significant morbidity and mortality. Irreversible complications include leukoencephalopathy following high-dose intrathecal methotrexate, infertility in male patients treated with cyclophosphamide, myocardial damage from anthracyclines, pulmonary fibrosis after bleomycin, pancreatitis after asparaginase, and hearing loss associated with cisplatin. Chemotherapy or radiation may also cause the development of a secondary tumor. There is a 0.5% risk after the first year, but it increases to 25% 12 years after treatment. It is strongly recommended that children be checked annually post chemotherapy to detect a secondary malignancy.
Most of the chemotherapeutic complications result from their nonspecific targeting of both malignant and normally dividing cells. Hence, the newer tumor specific-agents, antisense messenger RNA, anti-angiogenic agents (angiostatin and endostatin), anti-angiogenic monoclonals attempt to overcome some of the side effects of the older chemotherapeutic agents. One of the huge advantages of newer agents is their minimal degree of dose-limiting toxicities. Clinical trials of these agents are currently underway.
Stem cell transplantation has revolutionized the therapeutic options for primary bone marrow diseases and systemic neoplasms. Both autologous and allogeneic transplants have been employed successfully for a variety of hematological and oncological conditions in which chemotherapy and/or radiation have failed to induce remission. Examples include juvenile myelomonocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia in first or second remission, chronic myelogenous leukemia, severe combined immunodeficiency, hemophagocytic lymphohistiocytosis, aplastic anemia, Diamond-Blackfan anemia, beta-thalassemia major, and some inborn errors of metabolism.
Perhaps, the most challenging aspect of peripheral blood stem cell transplantation (PBSC) is finding a donor with sufficiently matching HLA haplotypes (i.e., chromosome 6, which encodes HLA). To minimize rejection and GvHD, more rigorous conditions, with serological as well as molecular matches, are now required to ensure closer HLA match. Once donors are identified, they are treated with G-CSF or GM-CSF (colony stimulating factors) to increase the proliferation of precursor stem cells. Collection of stem cells is made at various sites in the body: bone marrow, peripheral blood, and sometimes even cord blood.
Despite great efforts to match HLA genotypes, stem cell transplant is currently not widely used. Its limitations still include the non-availability of the "right" donors, concern about the lack of randomized comparisons to less risky chemotherapy in certain diseases where chemotherapy alone may induce remission, and chronic graft versus host disease. Certain measures may be instituted to decrease the prevalence and severity of GvHD. The combination of cytotoxic drugs such as methotrexate with inhibitors of T cells activation such as cyclosporin and FK 506 has dramatically reduced the severity of both acute and chronic GvHD. In addition, depletion of donor T-cells essentially eliminates GvHD. However, donor immunosuppression inadvertently increases the risk of infections and decreases the graft versus leukemia response that may lead to the higher relapse rate in these cases. Hence, it is a fine balance between the absolute prevention of GvHD and the risk of relapse.
Pain management, an essential component of oncological therapy, has recently become a focus of attention. Children were once believed to not feel as much pain because of their underdeveloped nervous system. However, cancer causes tremendous pain in children. Prolonged pain saps spiritual energy and diminishes the body's ability to heal. Pain therefore should be managed in a stepwise fashion, and should be a top priority for any oncological patient, especially those needing palliative care.
The magic bullet is hard to come by. The major challenge in oncology treatment is to find the right combination of type and amount of chemotherapy, right amount of radiation, and the best timing of stem cell transplantation for each individual patient. Future therapeutic approaches include immunotherapy as well as gene therapy. Immunotherapy can be viewed as fine-tuning of the GvHD reaction in order to have it work towards the body's advantage to fight against cancer. In several animal models, it has been successfully proven that the immune system can be an important component in fighting off cancer. The immune system provides high precision in selectively targeting cancer cells. If there is some means to engraft a competent immune system to a leukemic patient, it hopefully will stimulate an immune response against leukemic cells. Several research groups have tested interleukins, notably IL-2 and IL-4, which stimulate both T and B-lymphocytes in ways that theoretically inhibit tumor growth. Other interleukins, IL-6 and IL-10, promote the development of B cell malignancies because they inhibit the synthesis of antiviral cytokines (interferons) and IL-2. Future drug development may consider inhibiting these tumor-promoting compounds.
Gene therapy is an exciting possibility for essentially curing cancer. The principle behind this approach is that cancer is inherently a genetic defect. Hence, if it is possible to use a vector to carry the good genes to target the malignant cells, the deposit of the good genes into cancerous cells may lead to tumor regression. Gene therapy is still in the study phase.
1. What are some common opportunistic infections associated with immunosuppression induced by chemotherapy? What is the appropriate prophylaxis for these patients?
2. Give an example of a drug from each of the five classes of current chemotherapy in use.
3. What is a serious side effect for methotrexate use especially intrathecally delivered?
4. What is the mechanism responsible for most chemotherapeutic complications?
5. Where are various places that stem cells may be harvested from in the body?
1. National Cancer Institute. Leukemia. http://www.cancer.gov/cancer_information/cancer_type/leukemia/
2. Brenner MK, Pinkel D. Cure of Leukemia. Semin Hematol 1999;36(4 Suppl 7):73-83.
3. Klastersky K, Schimpff S, Senn H. Supportive Care in Cancer, 2nd edition. 1999, New York: Marcel Dekker.
4. Young G, Toretsky JA, Campbell AB, Eskenazi A. Recognition of Common Childhood Malignancies. Am Fam Physician 2000;61:2144-2154.
5. Foltin J, Leboxitz H, Boyle PJ. Cancer Chemotherapy. In: Trevor AJ, Katzung BG, Masters SB (eds). Katzung and Trevor's Pharmacology, 6th edition. 2002, New York: Lange Medical Books/McGraw-Hill, pp. 476-491.
6. Crist WL. Principles of Treatments. Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B Saunders Company, pp. 1537-1543.
Answers to questions
1. Common infections include candidiasis, aspergillosis, and Pneumocystis carinii. Prophylactic treatment with trimethoprim/sulfamethoxazole is indicated.
2. Hormones (prednisone), antimetabolites (methotrexate, 5-fluorouracil), plant alkaloids (etoposide, vincristine, paclitaxel), antibiotics (doxorubicin, bleomycin), anti-angiogenesis drugs.
4. Most of these work by inhibiting some metabolic pathway or DNA synthesis, which ultimately leads to cytotoxicity
5. Bone marrow, peripheral blood, and sometimes even cord blood.