InternalMed_Harrison

InternalMed_Harrison. Treatment is determined by the stage of disease. For patients with encapsulated tumors and stage I disease, complete resection is sufficient to cure 96% of patients. For patients with stage II disease, complete resection may be followed by 30–60 Gy of postoperative radiation therapy to the site of the primary tumor. However, the value of radiation therapy in this setting has not been established. The main predictors of long-term survival are Masaoka stage and completeness of resection. For patients with stage III and IV disease, the use of neoadjuvant chemotherapy followed by radical surgery, with or without additional radiation therapy, and additional consolidation chemotherapy has been associated with excellent survival. Chemotherapy regimens that are most effective generally include a platinum compound (either cisplatin or carboplatin) and an anthracycline. Addition of cyclophosphamide, vincristine, and prednisone seems to improve response rates. Response rates of 50–93% have been


InternalMed_Harrison

InternalMed_Harrison. platinum compound (either cisplatin or carboplatin) and an anthracycline. Addition of cyclophosphamide, vincristine, and prednisone seems to improve response rates. Response rates of 50–93% have been reported in series of patients each of which involved fewer than 40 patients. A single most effective regimen has not been defined. No randomized controlled phase III studies have been reported. If surgery after neoadjuvant chemotherapy fails to produce a complete resection of residual disease, radiation therapy (50–60 Gy) may help reduce recurrence rates.


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InternalMed_Harrison. This multimodality approach appears to be superior to the use of surgery followed by radiation therapy alone, which produces a 5-year survival of ≤50% in patients with advanced-stage disease. Some thymic carcinomas express c-kit, and one patient whose c-kit locus was mutated responded dramatically to imatinib. Many thymomas express epidermal growth factor receptors, but the antibodies to the receptor and the kinase inhibitors that block its action have not been evaluated systematically. Octreotide plus prednisone produces responses in about one-third of patients.


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InternalMed_Harrison. Neoplasia During pregnancy Michael F. Greene, Dan L. Longo Cancer complicates ~1 in every 1000 pregnancies. Of all the cancers that occur in women, less than 1% complicate pregnancies. The four cancers that most commonly complicate pregnancies are cervical cancer, breast cancer, melanoma, and lymphomas (particularly Hodgkin’s lymphoma); 124e however, virtually every form of cancer has been reported in pregnant women (Table 124e-1). In addition to cancers developing in other organs of the mother, gestational trophoblastic tumors can arise from the placenta. The problem of cancer in a pregnant woman is complex. One must take into account (1) the possible influence of the pregnancy on the natural history of the cancer, (2) effects on the mother and fetus of complications from the malignancy (e.g., anorexia, nausea, vomiting, malnutrition), (3) potential effects of diagnostic and staging procedures, and (4) potential effects of cancer treatments on both the mother and the developing


InternalMed_Harrison

InternalMed_Harrison. (e.g., anorexia, nausea, vomiting, malnutrition), (3) potential effects of diagnostic and staging procedures, and (4) potential effects of cancer treatments on both the mother and the developing fetus. Generally, the management that optimizes maternal physiology is also best for the fetus. However, the dilemma occasionally arises that what is best for the mother may be harmful to the fetus, and what is best for the fetus may compromise the ultimate prognosis for the mother. The best way to approach management of a pregnant woman with cancer is to ask, “What would we do for this woman in this clinical situation if she was not pregnant? Now, which, if any, of those plans need to be modified because she is pregnant?”


InternalMed_Harrison

InternalMed_Harrison. Pregnancy is associated with a number of physiologic changes that frequently result in symptoms that may make it difficult to recognize symptoms or physical findings suggestive of a neoplasm. Increased sensitivity of central chemoreceptors to Pco2 drives an increase in minute ventilation that many women perceive as dyspnea at rest or with minimal exertion. The combination of increased total body water, decreased colloid oncotic pressure, and some obstruction of venous return from the lower extremities causes demonstrable dependent edema in more than 50% of pregnant women. Decreased gastrointestinal motility due to high serum progesterone levels and mechanical compression from an enlarging uterus cause early satiety, gastroesophageal reflux, nausea, vomiting, and constipation. Hemorrhoids develop and often bleed. Breasts enlarge and increase in density and “lumpiness.” These changes may result in delayed recognition and more advanced disease at diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Physiologic changes in the maternal immune system necessary to facilitate retention of the fetal semi-allograft raise concerns that the relationship of a cancer with its host may be altered to the detriment of the maternal host. One half of all the genes necessary to create a new individual by sexual reproduction come from each parent. This provides the opportunity for many antigenic differences between the conceptus and the mother. Mammalian placentation has been a very successful method of reproduction, but it has necessitated some combination of both fetal and maternal evolutionary immune adaptations. These mechanisms are incompletely understood and remain an area of active investigation. It does seem likely, however, that this has been accomplished without a general, nonspecific blunting of the maternal Incidence per 10,000 Tumor Type Pregnanciesa % of Casesb Cervical cancer 1.2–4.5 25% Thyroid cancer 1.2 15% Hodgkin’s disease 1.6 10% Melanoma 1–2.6 8% Ovarian cancer 0.8 2%


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InternalMed_Harrison. Incidence per 10,000 Tumor Type Pregnanciesa % of Casesb Cervical cancer 1.2–4.5 25% Thyroid cancer 1.2 15% Hodgkin’s disease 1.6 10% Melanoma 1–2.6 8% Ovarian cancer 0.8 2% All sites 10 100% aThese are estimates based on extrapolations from a review of more than 3 million pregnancies (LH Smith et al: Am J Obstet Gynecol 184:1504, 2001). bBased on accumulating case reports from the literature; the precision of these data is not high.


InternalMed_Harrison

InternalMed_Harrison. immune response, which would be maladaptive to the mother. The 124e-1 multiple mechanisms likely include some “masking” of fetal antigens from recognition by the maternal immune system, blunting the maternal inflammatory response locally at the placental–maternal interface and induction of fetal-specific maternal immune tolerance to avoid rejection. Attention has turned to a subset of CD4+ induced, peripherally produced regulatory T cells that express the X chromosome encoded transcription factor Foxp3 (so-called Tregs). When these Foxp3 cells develop centrally in the thymus, they are termed “Tregs.” When Foxp3-expressing cells develop peripherally, they are called “Pregs.” These regulatory cells suppress the immune response against “self” and foreign antigens. They seem to be capable of suppressing the maternal response to paternal antigens expressed by the fetus and creating memory cells that retain tolerance to the same paternal antigens in subsequent pregnancies. Unfortunately, in


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InternalMed_Harrison. the maternal response to paternal antigens expressed by the fetus and creating memory cells that retain tolerance to the same paternal antigens in subsequent pregnancies. Unfortunately, in a mouse model, the interleukin (IL) 10 produced by these cells enhanced susceptibility to infection by Listeria and Salmonella, while ironically not proving essential for retaining the fetal graft. Undoubtedly much remains to be learned about this critical immune balance.


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InternalMed_Harrison. Exposure of developing fetuses to ionizing radiation may cause adverse fetal effects; awareness among physicians of this potential toxicity has resulted in a disproportionate aversion to diagnostic imaging in pregnancy. First, it must be stated that there are very useful imaging modalities (i.e., ultrasound and magnetic resonance imaging [MRI]) that do not use any ionizing radiation and are not associated with any demonstrable adverse fetal effects. There are three potential adverse fetal effects of ionizing radiation: teratogenesis (induction of anatomic birth defects), mutagenesis, and carcinogenesis. The fetus is most sensitive to teratogenesis during organogenesis in the first trimester. The dose of ionizing radiation necessary to induce birth defects in human fetuses is derived from studies of the survivors of the atomic bomb explosions and by extrapolation from controlled experiments in nonhuman mammals. From these data sources, it is clear that a minimum of 5 rem and more


InternalMed_Harrison

InternalMed_Harrison. from studies of the survivors of the atomic bomb explosions and by extrapolation from controlled experiments in nonhuman mammals. From these data sources, it is clear that a minimum of 5 rem and more likely greater than 10 rem exposure is needed to induce birth defects in the first trimester. The fetal doses of radiation associated with some common diagnostic radiologic procedures are displayed in Table 124e-2. The data in Table 124e-2 show that no single procedure or selective combination of diagnostic procedures will exceed the very conservative 5 rem teratogenic threshold. Teratogenic effects later in pregnancy are largely limited to microcephaly and require exposures exceeding 25 rem. The reason for the disproportionate concern about radiation exposure and birth defects is that 2.5% of all fetuses are affected with birth defects without radiation exposure and, therefore, 2.5% of women undergoing any diagnostic imaging procedure will deliver malformed fetuses. Spontaneous mutations


InternalMed_Harrison

InternalMed_Harrison. all fetuses are affected with birth defects without radiation exposure and, therefore, 2.5% of women undergoing any diagnostic imaging procedure will deliver malformed fetuses. Spontaneous mutations occur relatively infrequently, and high doses of radiation (>150 rem) are required to cause a demonstrable increase in that rate. The magnitude of the risk of carcinogenesis in offspring exposed as fetuses to diagnostic doses of radiation has been very difficult to


InternalMed_Harrison

InternalMed_Harrison. Source: Data from FG Cunningham et al: General considerations and maternal evaluation. In Williams Obstetrics, 21st ed. New York: McGraw-Hill; 2001, pp. 1143–1158.


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InternalMed_Harrison. measure due to the relative rarity of cancer in children and the long duration of follow-up that might credibly be needed to see the effect. The inconsistent results and small effect sizes observed from diagnostic exposures make it likely that, if there is an effect, it is very small and, if there is not a significant effect, it will be impossible to prove that fact to everyone’s satisfaction. No imaging using ionizing radiation should be done without a compelling reason and due consideration to obtaining the necessary information by other imaging modalities. Exposure to diagnostic and therapeutic radionuclides, especially radioactive iodine, poses unique risks, but a full discussion of these is beyond the scope of this chapter. Radiation therapy uses radiation doses three orders of magnitude greater than diagnostic procedures, entails substantial risks if the fetus is in the radiation field, and is rarely appropriate in pregnancy. Finally, although difficult to prove, it is likely


InternalMed_Harrison

InternalMed_Harrison. greater than diagnostic procedures, entails substantial risks if the fetus is in the radiation field, and is rarely appropriate in pregnancy. Finally, although difficult to prove, it is likely that more harm has come to pregnant women from failing to perform appropriate diagnostic procedures than has been done to their offspring from performing appropriate diagnostic procedures.


InternalMed_Harrison

InternalMed_Harrison. There are a number of reasons why it is impossible to make many definitive statements regarding the safety and efficacy of chemotherapy in pregnancy. All of the available data in the literature are published as case reports or case series. The quality and completeness of the data are inconsistent and often poor. Reports may come from medical oncologists, obstetricians, pediatricians, or other treating physicians familiar with the information important to the report from their own perspective but missing information important for other specialty areas. Reports frequently lack critical details of drug administration, such as dose, duration, cumulative dose, and timing of exposure in gestation, and outcomes, including birth weight and gestational age at delivery, indication for or cause of premature delivery, and follow-up of offspring beyond the immediate neonatal period. There are a wide variety of agents available to treat cancer, and they are usually used in combinations. This


InternalMed_Harrison

InternalMed_Harrison. of premature delivery, and follow-up of offspring beyond the immediate neonatal period. There are a wide variety of agents available to treat cancer, and they are usually used in combinations. This results in the fact that every patient is almost unique (an experiment of one) in the combination of agents, doses, durations, and gestational ages of administration, making it very difficult to attribute what benefit or toxicity accrues to which agent. Fortunately, cancer in pregnant women is sufficiently rare that it takes quite a while to accumulate enough information for any one agent or combination of agents to be confident about what toxicities (including congenital malformations) are truly associated with which agents. There is such rapid progress in cancer chemotherapy that by the time there may seem to be enough information about the agents currently in use to use them intelligently and counsel patients meaningfully, the cancer community has moved on to newer, more efficacious, and


InternalMed_Harrison

InternalMed_Harrison. may seem to be enough information about the agents currently in use to use them intelligently and counsel patients meaningfully, the cancer community has moved on to newer, more efficacious, and hopefully less toxic agents for which there is little or no experience in pregnancy. Finally, for obvious reasons, there are no untreated controls for comparison. It may be very difficult to sort out the maternal consequences (nausea, vomiting, fever, weight loss, dehydration) that might result directly from the malignancy and cause adverse pregnancy outcomes from some of the toxicities of the chemotherapeutic agents used to treat the malignancy.


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InternalMed_Harrison. Generally, toxic chemotherapy should be avoided during pregnancy, if at all possible. It should virtually never be given in the first trimester. However, a variety of single agents and combinations have been given in the second and third trimesters, without a high frequency of toxic effects to the pregnancy or the fetus, but data on safety are sparse. Maternal factors that may influence the pharmacology of chemotherapeutic agents include the 50% increase in plasma volume, altered absorption and protein binding, increased glomerular filtration rate, increased hepatic mixed function oxidase activity, and third space created by amniotic fluid. The fetus is protected from some agents by placental expression of drug efflux pumps, but decreased fetal hepatic mixed function oxidase and glucuronidation activity may prolong the half-life of agents that do cross the placenta. A database on the risks associated with individual chemotherapy agents is available on the Internet


InternalMed_Harrison

InternalMed_Harrison. and glucuronidation activity may prolong the half-life of agents that do cross the placenta. A database on the risks associated with individual chemotherapy agents is available on the Internet (http://ntp.niehs.nih.gov/ntp/ohat/cancer_chemo_preg/ chemopregnancy_monofinal_508.pdf ).


InternalMed_Harrison

InternalMed_Harrison. Optimal management strategies have not been developed based on prospective clinical trials. Management of a malignancy complicating pregnancy will be critically determined by the gestational age when the malignancy is diagnosed and the anticipated natural history of the lesion, if left untreated. On one extreme, if the malignancy is slowly progressive, the patient is near her delivery date, and waiting until delivery to begin treatment would not be anticipated to compromise maternal prognosis, then treatment could be delayed until after delivery to avoid fetal exposure to chemotherapy. If there is a greater sense of urgency to begin definitive treatment to avoid compromising maternal prognosis, and the patient is beyond 24 weeks of gestation but remote from her delivery date, then treatment (surgical, medical, or both) might be initiated during pregnancy and plans made to deliver the fetus early to avoid exposure to more chemotherapy than absolutely necessary. Finally, if the patient


InternalMed_Harrison

InternalMed_Harrison. (surgical, medical, or both) might be initiated during pregnancy and plans made to deliver the fetus early to avoid exposure to more chemotherapy than absolutely necessary. Finally, if the patient is in her first trimester and toxic chemotherapy must be initiated promptly to avoid a very poor maternal outcome, then it may be necessary to consider therapeutic abortion to avoid maternal disaster and fetal survival with injury resulting in long-term morbid sequelae. No two cases are precisely alike, and inevitably, decision making must be individualized, preferably with consultation with a multidisciplinary team including medical oncology, surgical oncology if appropriate, maternal–fetal medicine, neonatology, and anesthesia. Pregnancy appears to have little or no impact on the natural history of malignancies, despite the hormonal influences. Spread of the mother’s cancer to the fetus (so-called vertical transmission) is exceedingly rare.


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InternalMed_Harrison. The incidence of cervical cancer in pregnant women is roughly comparable to that of age-matched controls who are not pregnant. Invasive cervical cancer complicates about 0.45 in 1000 live births, and carcinoma in situ is seen in 1 in 750 pregnancies. About 1% of women diagnosed with cervical cancer are pregnant at the time of diagnosis. Early signs of cervical cancer include vaginal spotting or discharge, pain, and postcoital bleeding, which are also common features of pregnancy. Early visual changes in the cervix related to invasive cancer can be mistaken for cervical decidualization or ectropion (columnar epithelium on the cervix) due to pregnancy. Women diagnosed with cervical cancer during pregnancy report having had symptoms for 4.5 months on average.


InternalMed_Harrison

InternalMed_Harrison. Approximately 95% of all cervical cancer is caused by human papillomavirus (HPV) infections, with types 16 and 18 accounting for about 70% of cervical cancer. The rate of carriage of these serotypes is highest among women in their early twenties and can be reduced with the use of vaccination before exposure. Women generally tend to clear the infection by age 30, with the risk of cervical cancer being highest among those who fail to clear the infection. Screening is recommended at the first prenatal visit and 6 weeks postpartum. The rate of cytologic abnormalities on Pap smear in pregnant women is about 5–8% and is not much different than the rate in nonpregnant women of the same age.


InternalMed_Harrison

InternalMed_Harrison. In 2012, several sets of recommendations were published for screening for cervical cancer: one by the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP); a second by the U.S. Preventive Services Task Force (USPSTF); and a third by the American College of Obstetricians and Gynecologists (ACOG). Although the details of the recommendations for screening and management of abnormal results differ slightly among the three sets of guidelines, there is general consensus that cytology screening should start at age 21 and continue every 3 years through age 29. After age 30, cytology screening frequency may be reduced to every 5 years if accompanied by co-testing for HPV. Recommendations for management of abnormal cytology findings are complex and determined by the degree of abnormality of the cytology finding (e.g., atypical squamous cells of undetermined significance; atypical squamous cells,


InternalMed_Harrison

InternalMed_Harrison. of abnormal cytology findings are complex and determined by the degree of abnormality of the cytology finding (e.g., atypical squamous cells of undetermined significance; atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion; low-grade squamous intraepithelial lesion; or high-grade squamous intraepithelial lesion), the HPV status of the patient, the age of the patient, and whether this is the first abnormal finding or a persistent abnormality. A full discussion of all the treatment recommendations based on these factors is beyond the scope of this chapter. Some of the diagnostic procedures recommended for evaluation of nonpregnant women are contraindicated in pregnancy, and the indications for some procedures are modified in the setting of pregnancy. Suffice it to say that the evaluation of women with abnormal cervical cytology in pregnancy should be referred to knowledgeable and experienced gynecologists or gynecologic oncologists.


InternalMed_Harrison

InternalMed_Harrison. Cervical intraepithelial neoplasia is a slowly progressive lesion and has a low risk of progression to invasive cancer during pregnancy (~0.4%), and many low-grade lesions (36–70%) regress spontaneously. Accordingly, some physicians defer definitive diagnostic procedures in pregnant women until 6 weeks postpartum unless they are at high risk for invasive disease. If invasive disease is suspected and the pregnancy is between 16 and 20 weeks, a cone biopsy may be performed to make the diagnosis and may be curative for some lesions; however, the procedure may cause heavy bleeding due to the increased vasculature in the gravid cervix and increases the risk of premature rupture of membranes and preterm labor twoto threefold. Cone biopsy should not be done within 4 weeks of delivery. The only indication for therapy of cervical neoplasia in pregnant women is the documentation of invasive cancer.


InternalMed_Harrison

InternalMed_Harrison. Management of invasive disease is guided by the stage of disease, the gestational age of the fetus, and the desire of the mother to have the baby. If the disease is in early stage and the pregnancy is desired, it is safe to delay treatment regardless of gestational age until fetal maturity allows for safe delivery. Abortion followed by definitive therapy is recommended for women with advanced, but potentially curable, cancer in the first or second trimester (Chap. 117). If the disease is in an advanced stage in early pregnancy and the patient declines pregnancy termination to permit prompt definitive therapy, she must be informed of the fact that the maternal safety of delaying therapy is unproven. In women in the third trimester with advanced disease, the mother should be treated with betamethasone to accelerate fetal lung maturation and the baby should be delivered at the earliest possible gestational age followed immediately by stage-appropriate therapy. Most women with invasive


InternalMed_Harrison

InternalMed_Harrison. betamethasone to accelerate fetal lung maturation and the baby should be delivered at the earliest possible gestational age followed immediately by stage-appropriate therapy. Most women with invasive cancer have early-stage disease. If the disease is microinvasive, vaginal delivery can take place and be followed by definitive treatment, usually conization. If a lesion is visible on the cervix, delivery is best done by caesarian section and followed by radical hysterectomy.


InternalMed_Harrison

InternalMed_Harrison. Breast cancer complicates approximately 1 in 3000 to 10,000 live births. About 5% of all breast cancers occur in women age 40 years or younger. Among all premenopausal women with breast cancer, 25–30% were pregnant at the time of diagnosis. It has been recognized for some time that breast cancer associated with pregnancy generally seems to have a poorer prognosis for both overall survival and progression-free survival. The definition of pregnancy-associated breast cancer (PABC) has differed in various publications, but a generally accepted definition is breast cancer diagnosed during pregnancy or within 1 year of delivery. There are likely several reasons for the observation of the poorer prognosis. Breast cancers diagnosed during pregnancy are often diagnosed at a later stage of disease and so have a poorer outcome. The late diagnosis is often due to the fact that early physical signs of the disease are missed or attributed to the changes that occur in the breast normally as a


InternalMed_Harrison

InternalMed_Harrison. and so have a poorer outcome. The late diagnosis is often due to the fact that early physical signs of the disease are missed or attributed to the changes that occur in the breast normally as a function of pregnancy. However, a discreet breast mass in a pregnant woman should never be assumed to be normal. Another reason is the more aggressive behavior of the cancer possibly related to the hormonal milieu (estrogen increases 100-fold; progesterone increases 1000-fold) of the pregnancy. However, about 70% of the breast cancers found in pregnancy are estrogen receptor– negative. About 28–58% of the tumors express HER2, a biologically more aggressive breast cancer subset. Another factor is that aggressive, definitive chemotherapy and radiation therapy are often delayed due aLower measured levels could be in part artifactual due to the increased levels of estrogen in the milieu.


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InternalMed_Harrison. to concerns about the consequences of those treatments for the fetus. Younger women with breast cancer have a higher likelihood of having mutations in BRCA1 or BRCA2.


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InternalMed_Harrison. Differences in presentation between PABC and breast cancers diagnosed in nonpregnant women are shown in Table 124e-3. About 20% of breast cancers are detected in the first trimester, 45% in the second trimester, and 35% in the third trimester. Some argue that stage for stage, the outcome is the same for breast cancer diagnosed in pregnant and nonpregnant women. Primary tumors in pregnant women are 3.5 cm on average, compared to <2 cm in nonpregnant women. A dominant mass and a nipple discharge are the most common presenting signs, and they should prompt ultrasonography and breast MRI exam (if available) followed by lumpectomy if the mass is solid and aspiration if the mass is cystic. Mammography is less reliable in pregnancy due to the increased breast density. Needle aspirates of breast masses in pregnant women are often nondiagnostic or falsely positive. Even in pregnancy, most breast masses are benign (~80% are adenoma, lobular hyperplasia, milk retention cyst, fibrocystic disease,


InternalMed_Harrison

InternalMed_Harrison. in pregnant women are often nondiagnostic or falsely positive. Even in pregnancy, most breast masses are benign (~80% are adenoma, lobular hyperplasia, milk retention cyst, fibrocystic disease, fibroadenoma, or other rarer entities).


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InternalMed_Harrison. Many studies comparing outcomes among women with PABC to those of nonpregnant women have small sample sizes, and there is considerable heterogeneity among the study results, but a formal meta-analysis including multiple adjustments and sensitivity analyses confirms the clinical impression of poorer outcomes for women with PABC. The hazard ratios were 1.44 for poorer overall survival and 1.60 for poorer disease-free survival.


InternalMed_Harrison

InternalMed_Harrison. Although having had a pregnancy is a protective factor against breast cancer in women in general, it is questionable as to whether it retains its protective effect in carriers of BRCA1 and BRCA2 mutations. Cullinane et al. (Int J Cancer 117:988, 2005) found a statistically insignificant difference (odds ratio 0.94) in breast cancer risk among BRCA1 carriers who had ever been pregnant versus those who never had a pregnancy. Stratifying the risk of breast cancer according to the number of prior pregnancies versus no pregnancies, no statistically significant protective trend was observed. For BRCA2 carriers, there was a marginally statistically significant increased risk of breast cancer among women with prior pregnancies. In an international study with more than 65,000 person-years of observation (Andrieu J: Natl Cancer Inst 98:535, 2006), there was no significant effect in either direction of pregnancy on breast cancer risk for carriers of either mutation. Staging the axillary lymph


InternalMed_Harrison

InternalMed_Harrison. (Andrieu J: Natl Cancer Inst 98:535, 2006), there was no significant effect in either direction of pregnancy on breast cancer risk for carriers of either mutation. Staging the axillary lymph nodes is currently somewhat controversial. Sentinel lymph node sampling is not straightforward in pregnant women. Blue dye has been carcinogenic in rats, and fetuses cannot be shielded from administered radionuclides. For this reason, many surgeons favor axillary node dissection to stage the nodes. Largely due to the typical delay in diagnosis, axillary nodes are more often positive in pregnant than in nonpregnant women.


InternalMed_Harrison

InternalMed_Harrison. As with other types of cancer in pregnant women, counseling following diagnosis in the first trimester should include a discussion of pregnancy termination to allow definitive therapeutic intervention at the earliest possible time without the potential for permanent injury to a surviving fetus. While definitive local surgery can safely be performed in the first trimester, radiation therapy and chemotherapy are considerably more risky. Delay in administration of systemic therapy can increase the risk of axillary spread. In the second and third trimesters, chemotherapy (particularly anthracycline-based combinations) is both safe and effective (Chap. 108). Lumpectomy followed by adjuvant chemotherapy is frequently used; fluorouracil and cyclophosphamide with either doxorubicin or epirubicin have been given without major risk to the fetus. Taxanes and gemcitabine are also beginning to be used; however, safety data are sparse. Methotrexate and other folate antagonists are to be avoided


InternalMed_Harrison

InternalMed_Harrison. have been given without major risk to the fetus. Taxanes and gemcitabine are also beginning to be used; however, safety data are sparse. Methotrexate and other folate antagonists are to be avoided because of effects on the fetal nervous system. Myelotoxic therapy is generally not administered after 33 or 34 weeks of gestation to allow 3 weeks off therapy before delivery for recovery of blood counts. Endocrine therapy and trastuzumab are unsafe during pregnancy. Experience with lapatinib is anecdotal, but no fetal malformations have been reported. Antiemetics and colony-stimulating factors are also considered safe. Women being treated into the postpartum period should not breast-feed their babies because of excretion of cancer chemotherapy agents, particularly alkylating agents, in milk.


InternalMed_Harrison

InternalMed_Harrison. Subsequent pregnancies following gestational breast cancer do not appear to influence relapse rate or overall survival. A meta-analysis found that pregnancy in breast cancer survivors was associated with a reduced the risk of dying from breast cancer by as much as 42%. This finding, however, is heavily confounded by the “healthy survivor effect”; women with more extensive or advanced disease are more likely to avoid pregnancy.


InternalMed_Harrison

InternalMed_Harrison. Speculation about melanoma occurring during pregnancy based largely on anecdotal evidence and small case series concluded that it occurred with increased frequency, was more aggressive in its natural history, and was caused in part by the hormonal changes that also produced hyperpigmentation (so-called melasma) during pregnancy. However, more complete epidemiologic data suggest that melanoma is no more frequent in pregnant women than in nonpregnant women in the same age group, that melanoma is not more aggressive during pregnancy, and that hormones seem to have little or nothing to do with the etiology. Pregnant and nonpregnant women do not differ in the location of primary tumor, depth of primary tumor, tumor ulceration, or vascular invasion.


InternalMed_Harrison

InternalMed_Harrison. Suspicious lesions should be looked for and managed definitively with excisional biopsy during pregnancy. Wide excision with sampling of regional lymph nodes is warranted. If lymph nodes are involved, the course of action is less clear. Several agents have demonstrated some activity in melanoma, but none have been used during pregnancy. Adjuvant interferon α is toxic, and its safety in pregnancy has not been documented. Agents active in advanced disease include dacarbazine, IL-2, ipilimumab (antibody to CTLA-4), and in those with BRAF mutation V600E, a BRAF kinase inhibitor. In the setting of metastatic disease, abortion may be indicated so that systemic therapy can be initiated as soon as possible (Chap. 105). Melanoma is one of the very few cancers that are well documented to metastasize transplacentally to the fetus, where it seems to have a predilection for the head and neck. It has a very grave prognosis in the offspring. Fortunately, transplacental spread is rare.


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InternalMed_Harrison. Pregnancy subsequent to the diagnosis and treatment of melanoma is not associated with an increased risk of melanoma recurrence.


InternalMed_Harrison

InternalMed_Harrison. (See Chap. 134) Hodgkin’s disease occurs mainly in the age range that coincides with child-bearing. However, Hodgkin’s disease is not more common in pregnant than nonpregnant women. Hodgkin’s disease is diagnosed in approximately 1 in 6000 pregnancies. It generally presents as a nontender lymph node swelling, most often in the left supraclavicular region. It may be accompanied by B symptoms (fever, night sweats, unexplained weight loss). Excisional biopsy is the preferred diagnostic procedure because fine-needle aspiration cannot reveal the architectural framework that is an essential component of Hodgkin’s disease diagnosis. The stage at presentation appears to be unaffected by pregnancy. Women diagnosed in the second and third trimester can be treated safely with combination chemotherapy, usually doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). In general, the patient in the first trimester is asymptomatic, and a woman with a desired pregnancy can be followed until the


InternalMed_Harrison

InternalMed_Harrison. usually doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). In general, the patient in the first trimester is asymptomatic, and a woman with a desired pregnancy can be followed until the second or third trimester when definitive multiagent chemotherapy can be safely given. Radiation therapy is not given during pregnancy and is not necessary for optimal management of the pregnant patient. If symptoms requiring treatment appear during the first trimester, anecdotal evidence suggests that Hodgkin’s disease symptoms can be controlled with weekly low-dose vinblastine. Such an approach has been safely used to avoid termination of pregnancy. Pregnancy does not have an adverse effect on treatment outcome.


InternalMed_Harrison

InternalMed_Harrison. Non-Hodgkin’s lymphomas are more unusual in pregnancy (approximately 0.8 per 100,000 pregnancies), but are usually tumors with an aggressive natural history, such as diffuse large B cell lymphoma, Burkitt’s lymphoma, or peripheral T cell lymphoma. Diagnosis relies on an excisional biopsy of a tumor mass, not fine-needle aspiration. Staging evaluation is generally limited to ultrasound or MRI examinations. Diagnosis in the first trimester should prompt termination of the pregnancy followed by definitive treatment with combination chemotherapy, because aggressive lymphomas are not likely to be held at bay with single-agent chemotherapy. Women diagnosed in the second or third trimesters can be treated with standard chemotherapy, such as with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The experience with rituximab in this setting is anecdotal. However, infants born of mothers who have received rituximab may have transient delay in B cell development that typically


InternalMed_Harrison

InternalMed_Harrison. (CHOP). The experience with rituximab in this setting is anecdotal. However, infants born of mothers who have received rituximab may have transient delay in B cell development that typically normalizes by 6 months. The treatment outcome is similar in lymphomas diagnosed in pregnant and nonpregnant women of the same clinical stage.


InternalMed_Harrison

InternalMed_Harrison. (See Chap. 405) Thyroid cancer, along with melanomas, brain tumors, and lymphomas, are cancers that are increasing in incidence in the general population. Thyroid cancers are rising faster among women in North America than the other increasing tumor types. The Endocrine Society has developed practice guidelines to inform the management of patients with thyroid disease during pregnancy (http://www.endocrine .org/~/media/endosociety/Files/Publications/Clinical%20Practice%20 Guidelines/Thyroid-Exec-Summ.pdf ). Thyroid nodules 1 cm or larger are approached by fine-needle aspiration. If a malignancy is diagnosed, surgery is generally recommended in the second and third trimesters. However, surgical complications appear to be twice as common when the patient is pregnant. Because the growth of thyroid tumors is often indolent, surgery can safely be postponed until after the first trimester. Patients with follicular cancer or early papillary cancer can be observed until the postpartum period.


InternalMed_Harrison

InternalMed_Harrison. tumors is often indolent, surgery can safely be postponed until after the first trimester. Patients with follicular cancer or early papillary cancer can be observed until the postpartum period. The fetal thyroid begins trapping iodine by 12 weeks of gestation and does so with very high avidity. Even small doses of radioactive iodine given during pregnancy can completely ablate the fetal thyroid with serious consequences for the fetus and should be avoided throughout pregnancy. Radioactive iodine can be safely administered after delivery. Patients with a history of thyroid cancer who become pregnant should be maintained on thyroid hormone replacement during pregnancy because of the adverse impact of maternal hypothyroidism on the fetus. Women who are breast-feeding should not be treated with radioactive iodine, and women treated with radioactive iodine should not become pregnant for 6–12 months after treatment.


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InternalMed_Harrison. The assessment of thyroid function during pregnancy is challenging because of the physiologic changes that occur during pregnancy. Women who have previously been treated for thyroid cancer are at risk of hypothyroidism. The demand for thyroid hormone increases during pregnancy, and doses to maintain normal function may increase by 30–50%. Total T4 levels are higher during pregnancy, but target therapeutic levels also increase (Table 124e-4). It is recommended that the upper and lower limits of the laboratory range be multiplied by 1.5 in the second and third trimester to establish a pregnancy-specific normal range. The target thyroid-stimulating hormone (TSH) level is <2.5 mIU/L. Source: Based on the National Health and Nutrition Examination Survey III (NHANES III) (OP Soldin et al: Ther Drug Monit 17:303, 2007).


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InternalMed_Harrison. (See Chap. 117) Gestational trophoblastic disease encompasses hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor, and assorted miscellaneous and unclassifiable trophoblastic tumors. Moles are the most common, occurring in 1 in 1500 pregnancies in the United States. The incidence is higher in Asia. In general, if the serum level of β-human chorionic gonadotropin (β-hCG) returns to normal after surgical removal (evacuation) of the mole, the illness is considered gestational trophoblastic disease. By contrast, if the β-hCG level remains elevated after mole evacuation, the patient is considered to have gestational trophoblastic neoplasia. Choriocarcinoma occurs in 1 in 25,000 pregnancies. Maternal age >45 years and prior history of molar pregnancy are risk factors. A previous molar pregnancy makes choriocarcinoma about 1000 times more likely to occur (incidence 1–2%).


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InternalMed_Harrison. Hydatidiform moles are characterized by clusters of villi with hydropic changes, trophoblastic hyperplasia, and absence of fetal blood vessels. Invasive moles are distinguished by invasion of the myometrium. Placental site trophoblastic tumors are composed mainly of cytotrophoblast cells arising at the site of placental implantation. Choriocarcinomas contain anaplastic trophoblastic tissue with both cytotrophoblast and syncytiotrophoblast features and no identifiable villi.


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InternalMed_Harrison. Moles can be partial, typically associated with fetal tissue, or complete, typically not associated with any fetal or embryonic tissue. Partial moles have a distinct molecular origin and usually are smaller tumors with less hydropic villi and considerably less potential for persistent or malignant disease. Partial moles result from fertilization of an egg by two sperm, resulting in diandric triploidy. Complete moles usually have a 46,XX genotype; 95% develop by a single male sperm fertilizing an empty egg and undergoing gene duplication (diandric diploidy); 5% develop from dispermic fertilization of an empty egg (diandric dispermy).


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InternalMed_Harrison. Women with molar gestations often present with first-trimester bleeding, disproportionately high serum β-hCG levels for menstrual age, unusually large uterine size for menstrual age, hyperemesis gravidarum, theca lutein cysts in the ovaries (due to β-hCG stimulation), and hyperthyroidism (due to cross-reactivity of β-hCG and TSH) and may develop preeclampsia before 20 weeks of menstrual age. Pelvic ultrasound imaging of complete moles shows absence of fetal parts, an enlarged echo-bright, hydropic placenta in an enlarged uterus, and enlarged multicystic ovaries. If the diagnosis is uncertain at the initial examination and the pregnancy is desired, then a serum β-hCG level should be obtained and the examination repeated in a week. If no embryo is seen within 7–10 days and the serum β-hCG is elevated, 124e-5 then this is a nonviable pregnancy that should be evacuated. Diagnosis of partial molar pregnancies can be more difficult because an embryo or fetus with visible heart motion is


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InternalMed_Harrison. is elevated, 124e-5 then this is a nonviable pregnancy that should be evacuated. Diagnosis of partial molar pregnancies can be more difficult because an embryo or fetus with visible heart motion is usually present, and the hydropic changes in the placenta, uterine enlargement, and elevations of β-hCG are not usually as dramatic. Although an embryo or fetus is present, it rarely grows normally with normal anatomy, and repeated ultrasound examinations usually make the diagnosis. Amniocentesis will also make the diagnosis by demonstration of triploidy.


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InternalMed_Harrison. Patients with molar pregnancies require prompt uterine evacuation with suction curettage, which may be complicated by very heavy bleeding. Following evacuation of complete moles, approximately 20% will result in persistent, invasive, or metastatic disease. Partial moles are considerably less likely (<5%) to result in persistent disease. Patients should be monitored with serial determinations of serum β-hCG until the values fall below the lower limit of the assay and remain low for at least 6 months. Patients should be advised not to become pregnant for at least 12 months. A variety of criteria have been used to make the diagnosis of post-molar gestational trophoblastic disease, but current consensus guidelines as adopted by the International Federation of Gynecology and Obstetrics are listed below: 1. A β-hCG level plateau of four values plus or minus 10% recorded over a 3-week duration (days 1, 7, 14, and 21) 2.


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InternalMed_Harrison. A β-hCG level plateau of four values plus or minus 10% recorded over a 3-week duration (days 1, 7, 14, and 21) 2. A β-hCG level increase of more than 10% in three values recorded over a 2-week duration (days 1, 7, and 14) 3. Persistence of detectable β-hCG for more than 6 months after molar evacuation About half of choriocarcinomas develop after a molar pregnancy, and half develop after ectopic pregnancy or, rarely, after a normal full-term pregnancy. Disease is classified as stage I if it is confined to the uterus, stage II if disease is limited to genital structures (~30% have vaginal involvement), stage III if disease has spread to the lungs but no other organs, and stage IV if disease has spread to liver, brain, or other organs.


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InternalMed_Harrison. Patients without widely metastatic disease are generally managed with single-agent methotrexate (either 30 mg/m2 IM weekly until β-hCG normalizes or 1 mg/kg IM every other day for four doses followed by leucovorin 0.1 mg/kg IV 24 h after methotrexate), which cures >90% of patients. Patients with very high β-hCG levels, presenting >4 months after a pregnancy, with brain or liver metastases, or failing to be cured by single-agent methotrexate are treated with combination chemotherapy. Etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA-CO) is the most commonly used regimen, producing long-term survival in >80% of patients. Brain metastases can usually be controlled with brain radiation therapy. The vast majority of choriocarcinomas can be cured with chemotherapy alone. Hysterectomy is reserved for women who have completed their child-bearing, women with chemotherapy-resistant disease in the uterus, and women with rare placental site


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InternalMed_Harrison. cured with chemotherapy alone. Hysterectomy is reserved for women who have completed their child-bearing, women with chemotherapy-resistant disease in the uterus, and women with rare placental site trophoblastic tumors confined to the uterus because these tumors are less reliably sensitive to chemotherapy. Women cured of trophoblastic disease who have not undergone hysterectomy do not appear to have increased risk of fetal abnormalities or maternal complications with subsequent pregnancies.


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InternalMed_Harrison. Oncology and Hematology Late Consequences of Cancer and Its Treatment Carl E. Freter, Dan L. Longo There are over 10 million American cancer survivors. The vast major-ity of these will bear some mark of their cancer and its treatment, and 125 a large proportion will experience long-term consequences including medical problems, psychosocial dysfunction, economic hardship, sexual dysfunction, and discrimination regarding employment and insurance. Many of these problems are directly related to cancer treatment. As patients survive longer from more types of malignancies, we are increasingly recognizing the biologic toll our very imperfect therapies take in terms of morbidity and mortality. The human face of these consequences of therapy confronts the cancer specialist who treats them every day. Although long-term survivors of childhood leukemias, Hodgkin’s lymphoma, and testicular cancer, as examples, have taught us much about the consequences of cancer treatment, we keep learning more as


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InternalMed_Harrison. Although long-term survivors of childhood leukemias, Hodgkin’s lymphoma, and testicular cancer, as examples, have taught us much about the consequences of cancer treatment, we keep learning more as patients survive longer with newer therapies. Newer “targeted” chemotherapy drugs have their own, often unique, long-term toxicities about which we remain in a learning process. Cancer “survivorship” clinics are increasing to expressly follow patients for long-term toxicities of cancer treatment.


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InternalMed_Harrison. The pace of developing therapies that mitigate treatment-related consequences has been slow, partly due to an understandable aversion to alter regimens that work and partly due to a lack of new, effective, less toxic therapeutic agents with less “collateral damage” to replace known agents with known toxicities. The types of damage from cancer treatment vary. Often, a final common pathway is irreparable damage to DNA. Surgery can create dysfunction, including blind gut loops with absorption problems and loss of function of removed body parts. Radiation may damage end-organ function, for example, loss of potency in prostate cancer patients, pulmonary fibrosis, and neurocognitive impairment, and may act as a direct carcinogen. Cancer chemotherapy can be a direct carcinogen and has a kaleidoscope of other toxicities discussed in this chapter. Table 125-1 lists the late effects of cancer treatment.


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InternalMed_Harrison. The first goal of therapy is to eradicate or control the malignancy. Late treatment consequences are, indeed, testimony to the increasing success of such treatment. Their occurrence sharply underlines the necessity to develop more effective therapies with less long-term morbidity and mortality. At the same time, a sense of perspective and relative risk is necessary; fear of long-term complications should not prevent the application of effective, particularly curative, cancer treatment.


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InternalMed_Harrison. Cardiovascular toxicity of cancer chemotherapeutic agents includes dysrhythmias, cardiac ischemia, cardiomyopathic congestive heart failure (CHF), pericardial disease, and peripheral vascular disease. Because these cardiac toxicities are difficult to distinguish from disease that is not associated with cancer treatment, clear etiologic implication of cancer chemotherapeutic agents may be difficult. Cardiovascular complications occurring in an unexpected clinical setting in patients who have undergone cancer therapy are often important in raising suspicion. Dose-dependent myocardial toxicity of anthracyclines with characteristic myofibrillar dropout is pathologically pathognomonic on endomyocardial biopsy. Anthracycline cardiotoxicity occurs through a root mechanism of chemical free radical damage. Fe3+doxorubicin complexes damage DNA, nuclear and cytoplasmic membranes, and mitochondria. About 5% of patients receiving >450–550 mg/m2 of doxorubicin will develop CHF. Cardiotoxicity in


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InternalMed_Harrison. damage. Fe3+doxorubicin complexes damage DNA, nuclear and cytoplasmic membranes, and mitochondria. About 5% of patients receiving >450–550 mg/m2 of doxorubicin will develop CHF. Cardiotoxicity in relation to the dose of anthracycline is clearly not a step function, but rather a continuous function, and occasional patients are seen with CHF at substantially lower doses. Advanced age, other concomitant cardiac disease, hypertension, diabetes, and thoracic radiation therapy are all important cofactors in promoting anthracycline-associated CHF. The risk of cardiac failure appears to be substantially lower when doxorubicin is administered by continuous infusion. Anthracycline-related CHF is difficult to reverse and has a mortality rate as high as 50%, making prevention crucial. Some anthracyclines such as mitoxantrone are associated with less cardiotoxicity, and continuous-infusion regimens and liposomally encapsulated doxorubicin are associated with less cardiotoxicity. Dexrazoxane, an


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InternalMed_Harrison. such as mitoxantrone are associated with less cardiotoxicity, and continuous-infusion regimens and liposomally encapsulated doxorubicin are associated with less cardiotoxicity. Dexrazoxane, an intracellular iron chelator, may limit anthracycline toxicity, but the concern of limiting chemotherapeutic efficacy has somewhat limited its use. Monitoring patients for cardiac toxicity typically involves periodic gated nuclear cardiac blood pool ejection fraction testing (multigated acquisition scan [MUGA]) or cardiac ultrasonography. More recently, cardiac magnetic resonance imaging (MRI) has been used, but MRI is not standard or widespread. Testing is performed more frequently at higher cumulative doses, with additional risk factors, and certainly for any newly developing CHF or other symptoms of cardiac dysfunction.


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InternalMed_Harrison. After anthracyclines, trastuzumab is the next most frequent cardiotoxic drug currently in use. Trastuzumab is frequently used as adjuvant breast cancer therapy, sometimes in conjunction with anthracyclines, which is believed to result in additive or possibly synergistic toxicity. In contrast to anthracyclines, cardiotoxicity is not dose-related, is usually reversible, is not associated with pathologic changes of anthracyclines on cardiac myofibrils, and has a different biochemical mechanism inhibiting intrinsic cardiac repair mechanisms. Toxicity is typically routinely monitored every three to four doses using functional cardiac testing as mentioned earlier for anthracyclines. Other cardiotoxic drugs include lapatinib, phosphoramide mustards (cyclophosphamide), ifosfamide, interleukin 2, ponatinib, imatinib, and sunitinib.


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InternalMed_Harrison. Radiation therapy that includes the heart can cause interstitial myocardial fibrosis, acute and chronic pericarditis, valvular disease, and accelerated premature atherosclerotic coronary artery disease. Repeated or high (>6000 cGy) radiation doses are associated with greater risk, as is concomitant or distant cardiotoxic cancer chemo-621 therapy exposure. Symptoms of acute pericarditis, which peaks about 9 months after treatment, include dyspnea, chest pain, and fever. Chronic constrictive pericarditis may develop 5–10 years following radiation therapy. Cardiac valvular disease includes aortic insufficiency from fibrosis or papillary muscle dysfunction resulting in mitral regurgitation. A threefold increased risk of fatal myocardial infarction is associated with mantle field radiation with accelerated coronary artery disease. Carotid radiation similarly increases the risk of embolic stroke.


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InternalMed_Harrison. Therapy for chemotherapeutic/radiation-induced cardiovascular disease is essentially the same as therapy for disease not associated with cancer treatment. Discontinuation of the offending agent is the first step. Diuretics, fluid and sodium restriction, and antiarrhythmic agents are often useful for acute symptoms. Afterload reduction with angiotensin-converting enzyme (ACE) inhibitors or, in some cases, β-adrenergic blockers (carvedilol) often is of significant benefit, and digitalis may be helpful as well. A hybrid discipline of “cardio-oncology” has been developing in clinics to expressly follow chemotherapy-treated patients for cardiotoxicity. The goals are early intervention using more sensitive techniques, management of cardiotoxicity before it becomes symptomatic, and using clinical trials to identify cardioprotective strategies.


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InternalMed_Harrison. Bleomycin generates activated free radical oxygen species and causes pneumonitis associated with a radiographic or interstitial ground-glass appearance diffusely throughout both lungs, often worse in the lower lobes. A nonproductive cough with or without fever may be an early sign. This toxicity is dose-related and dose-limiting. The diffusion capacity of the lungs for carbon dioxide (DLCO) is a sensitive measure of toxicity and recovery, and a baseline value is generally obtained for future comparison prior to bleomycin therapy. Additive or synergistic risk factors include age, prior lung disease, and concomitant use of other chemotherapy, lung irradiation, and high concentrations of inspired oxygen. Other chemotherapeutic agents notable for pulmonary toxicity include mitomycin, nitrosoureas, doxorubicin with radiation, gemcitabine combined with weekly docetaxel, methotrexate, and fludarabine. High-dose alkylating agents, cyclophosphamide, ifosfamide, and melphalan are frequently


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InternalMed_Harrison. doxorubicin with radiation, gemcitabine combined with weekly docetaxel, methotrexate, and fludarabine. High-dose alkylating agents, cyclophosphamide, ifosfamide, and melphalan are frequently used in the hematopoietic stem cell transplant setting, often with whole-body radiation. This therapy may result in severe pulmonary fibrosis and/or pulmonary venoocclusive disease.


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InternalMed_Harrison. Risk factors for radiation pneumonitis include advanced age, poor performance status, preexisting compromised pulmonary function, and radiation volume and dose. The dose “threshold” is thought to be in the range of 5 to 20 Gy. Hypoxemia and dyspnea on exertion are characteristic. Fine, high-pitched “Velcro rales” may be an accompanying physical finding, and fever, cough, and pleuritic chest pain are common symptoms. The DLCO is the most sensitive measure of pulmonary functional impairment, and ground-glass infiltrates often correspond with relatively sharp edges to the irradiated volume, although the pneumonitis may progress beyond the field and even occasionally involve the contralateral unirradiated lung. Late Consequences of Cancer and Its Treatment processing. There is no clear mechanistic explanation for its cause and no clearly effective therapy. This entity is justifiably attracting more


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InternalMed_Harrison. Chemotherapyand radiation-induced pneumonitis is generally very corticosteroid responsive, except in the case of nitrosoureas. Prednisone 1 mg/kg is often used to control acute symptoms and pulmonary dysfunction with a generally slow taper. Prolonged glucocorticoid therapy requires gastrointestinal protection with proton pump inhibitors, management of hyperglycemia, heightened infection management, and treatment of steroid-induced osteoporosis. Antibiotics, bronchodilators, oxygen in only necessary doses, and diuretics may all play an important role in management of pneumonitis, and consultation with a pulmonologist should be routinely undertaken. Amifostine has been studied as a pulmonary radioprotectant, with inconclusive results, and is associated with skin rash, fatigue, and nausea; hence, it is not considered standard therapy at this time. Transforming growth factor β (TGF-β) is believed to be a major inducer of radiation fibrosis and represents a therapeutic target for


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InternalMed_Harrison. nausea; hence, it is not considered standard therapy at this time. Transforming growth factor β (TGF-β) is believed to be a major inducer of radiation fibrosis and represents a therapeutic target for development of anti-TGF-β therapies.


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InternalMed_Harrison. Chemotherapyand radiation-induced neurologic dysfunction is unfortunately increasing in both incidence and severity as a result of improved supportive care leading to more aggressive regimens and longer cancer survivorship allowing the development of late toxicity. Direct effects on myelin, glial cells, and neurons have all been implicated, with alterations in cellular cytoskeleton, axonal transport, and cellular metabolism as mechanisms.


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InternalMed_Harrison. Vinca alkaloids produce a characteristic “stocking-glove” neuropathy with numbness and tingling advancing to loss of motor function, which is highly dose related. Distal sensorimotor polyneuropathy prominently involves loss of deep tendon reflexes with initially loss of pain and temperature sensation, followed by proprioceptive and vibratory loss. This requires careful patient history and physical examination by experienced oncologists to decide when the drug must be stopped due to toxicity. Milder toxicity often slowly completely resolves. Vinca alkaloids may sometimes be associated with jaw claudication, autonomic neuropathy, ileus, cranial nerve palsies, and, in severe cases, encephalopathy, seizures, and coma. Cisplatin is associated with sensorimotor neuropathy and hearing loss, especially at doses >400 mg/m2, requiring audiometry in patients with preexisting hearing compromise. Carboplatin is often substituted in such cases given its lesser effect on hearing.


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InternalMed_Harrison. Many of the agents that target kinase enzymes in tumor cells and 5-fluorouracil congeners produce dysesthesias and painful hands and feet known as hand-foot syndrome or palmar-plantar erythrodysesthesia. Symptoms usually abate when the agent is stopped.


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InternalMed_Harrison. Neurocognitive dysfunction has been well described in childhood survivors of acute lymphoblastic leukemia (ALL) treatment, including intrathecal methotrexate or cytosine arabinoside in conjunction with prophylactic cranial irradiation. Methotrexate alone may cause acute leukoencephalopathy characterized by somnolence and confusion that is often reversible. Acute toxicity is dose related, especially at doses >3 g/m2, with younger patients being at greater risk. Subacute methotrexate toxicity occurs weeks after therapy and is often ameliorated with glucocorticoid therapy. Chronic methotrexate toxicity (leukoencephalopathy) develops months or years after treatment and is characterized clinically as progressive loss of cognitive function and focal neurologic signs, which are irreversible, promoted by synchronous or metachronous radiation therapy, and more pronounced at a younger age.


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InternalMed_Harrison. Neurocognitive decline following chemotherapy alone occurs notably in breast cancer patients receiving adjuvant chemotherapy; this has been referred to as “chemo brain.” It is clinically associated with impaired memory, learning, attention, and speed of information attention and clearly needs to be studied to develop effective therapy or prophylaxis. Many cancer patients experience intrusive or debilitating concerns about cancer recurrence following successful therapy. In addition, these patients may experience job, insurance, stress, relationship, financial, and sexual difficulties. Oncologists need to ask about and address these issues explicitly with patients and provide appropriate counseling or support systems. Suicidal ideation and suicide have an increased incidence in cancer patients and survivors.


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InternalMed_Harrison. Acute radiation central nervous system (CNS) toxicity occurs within weeks; is characterized by nausea, drowsiness, hypersomnia, and ataxia; and is most often associated with recovery. Early delayed toxicity occurring weeks to 3 months following therapy is associated with similar symptoms as acute toxicity and is pathologically associated with reversible demyelination. Chronic, late radiation injury occurs 9 months to up to 10 years following therapy. Focal necrosis is a common pathologic finding, and glucocorticoid therapy may be helpful. Diffuse radiation injury is associated with global CNS neurologic dysfunction and diffuse white matter changes on computed tomography (CT) or MRI. Pathologically, small vessel changes are prominent. Glucocorticoids may be symptomatically useful but do not alter the course. Necrotizing encephalopathy is the most severe form of radiation injury and almost always is associated with chemotherapy, notably methotrexate.


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InternalMed_Harrison. Cranial radiation may also be associated with an array of endocrine abnormalities with disruption of normal pituitary/hypothalamic axis function, and a high index of suspicion needs to be maintained to identify and treat this toxicity. Radiation-associated spinal cord injury (myelopathy) is highly dose-dependent and rarely occurs with modern radiation therapy. An early, self-limited form involving electric sensations down the spine on neck flexion (Lhermitte’s sign) is seen 6–12 weeks after treatment and generally resolves over weeks. Peripheral nerve toxicity is quite rare owing to relative radiation resistance.


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InternalMed_Harrison. Long-term hepatic damage from standard chemotherapy regimens is rare. Long-term methotrexate or high-dose chemotherapy alone or with radiation therapy, for example, in preparative regimens for bone marrow transplantation, may result in venoocclusive disease of the liver. This potentially lethal complication classically presents with anicteric ascites, elevated alkaline phosphatase, and hepatosplenomegaly. Pathologically, there is venous congestion, epithelial cell proliferation, and hepatocyte atrophy progressing to frank fibrosis. Frequent monitoring of liver function tests during any chemotherapy is necessary to avoid both idiosyncratic and expected toxicities. Certain nucleoside drugs have been associated with hepatic dysfunction; however, this complication is rare in oncology.


InternalMed_Harrison

InternalMed_Harrison. Certain nucleoside drugs have been associated with hepatic dysfunction; however, this complication is rare in oncology. Hepatic radiation damage depends on dose, volume, fractionation, preexisting liver disease, and synchronous or metachronous chemotherapy. In general, radiation doses to the liver >1500 cGy can produce hepatic dysfunction with a steep dose-injury curve. Radiation-induced liver disease closely mimics hepatic venoocclusive disease.


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InternalMed_Harrison. Cisplatin produces reversible decrements in renal function, but may also produce severe irreversible toxicity in the presence of renal disease and may predispose to accentuated damage with subsequent renal insults. Cyclophosphamide and ifosfamide, as prodrugs primarily activated in the liver, have cleavage products (acrolein) that can produce hemorrhagic cystitis. This can be prevented with the free radical scavenger MESNA (mercaptoethane sulfonate), which is required for ifosfamide administration. Hemorrhagic cystitis caused by these agents may predispose to bladder cancer.


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InternalMed_Harrison. Alkylating agents are associated with the highest rates of male and female infertility, which is directly dependent on age, dose, and duration of treatment. The age at treatment is an important determinant of fertility outcome, with prepubertal patients having the highest tolerance. Ovarian failure is age related, and females who resume menses after treatment are still at increased risk for premature menopause. Males generally have reversible azoospermia during lower intensity alkylator chemotherapy, and long-term infertility is associated with doses of cyclophosphamide >9 g/m2 and with high-intensity therapy, such as that used in hematopoietic stem cell transplantation. Males undergoing potentially sterilizing chemotherapy should be offered sperm banking. Gonadotropin-releasing hormone (GnRH) analogs remain experimental to preserve ovarian function. Assisted reproductive technologies can be helpful to couples with chemotherapy-induced infertility.


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InternalMed_Harrison. Testicles and ovaries in prepubertal patients are less sensitive to radiation damage; spermatogenesis is affected by low doses of radiation, and complete azoospermia occurs at 600–700 cGy. Leydig cell dysfunction, in contrast, occurs at <2000 cGy, and hence, endocrine function is lost at much higher radiation doses than spermatogenesis. Erectile dysfunction occurs in up to 80% of men treated with external-beam radiation therapy for prostate cancer. Sildenafil may be useful in reversing erectile dysfunction. Ovarian function damage with radiation is age related and occurs at doses of 150–500 cGy. Premature induction of menopause can have serious medical and psychological sequelae. Hormone replacement therapy is often contraindicated (as in estrogen receptor–positive breast cancer). Attention must be paid to maintenance of bone mass with calcium and vitamin D supplements and oral bisphosphonates, and bone mass should be monitored using bone density determinations. Paroxetine, clonidine,


InternalMed_Harrison

InternalMed_Harrison. must be paid to maintenance of bone mass with calcium and vitamin D supplements and oral bisphosphonates, and bone mass should be monitored using bone density determinations. Paroxetine, clonidine, pregabalin, and other drugs may be useful in symptomatically controlling hot flashes.


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InternalMed_Harrison. Long-term survivors of childhood cancer (e.g., ALL) who have received cranial radiation may have altered leptin biology and growth hormone deficiency, leading to obesity and reduced strength, exercise tolerance, and bone density. Radiation therapy to the neck (e.g., in Hodgkin’s lymphoma) may lead to hypothyroidism, Graves’ disease, thyroiditis, and thyroid malignancies. Thyroid-stimulating hormone (TSH) is followed routinely in such patients to prevent hypothyroidism, and to suppress persistently elevated levels of TSH which may cause or drive thyroid cancer. Cataracts may be caused by glucocorticoids, depending on duration and dose; radiation therapy; and uncommonly tamoxifen. Orbital radiation therapy may cause blindness. Radiation therapy can produce xerostomia (dry mouth), with an attendant increase in caries and poor dentition. Taste and appetite may be suppressed. Bisphosphonate use may result in osteonecrosis of the jaw.


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InternalMed_Harrison. Up to 40% of patients treated with bleomycin may develop Raynaud’s phenomenon as a result of an unknown mechanism.


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InternalMed_Harrison. Second malignancies in patients cured of cancer are a major cause of death, and treated cancer patients must be monitored for their occurrence. The induction of second malignancies is governed by the complex interplay of a number of factors including age, gender, environmental exposures, genetic susceptibility, and cancer treatment itself. In a number of settings, the events leading to the primary cancer themselves increase the risk of second malignancies. Patients with lung cancer are at increased risk of esophageal and head and neck cancers, and vice versa, due to shared risk factors including alcohol and tobacco abuse. Indeed, the risk of developing a second primary head and neck, esophageal, or lung cancer is also increased in these patients. Patients with breast cancer are at increased risk of breast cancer in the opposite breast. Patients with Hodgkin’s lymphoma are at risk for nonHodgkin’s lymphomas. Genetic cancer syndromes (e.g., multiple endocrine neoplasia or Li-Fraumeni,


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InternalMed_Harrison. risk of breast cancer in the opposite breast. Patients with Hodgkin’s lymphoma are at risk for nonHodgkin’s lymphomas. Genetic cancer syndromes (e.g., multiple endocrine neoplasia or Li-Fraumeni, Lynch’s, Cowden’s, and Gardner’s syndromes) are examples of genetically based second malignancies of specific types. Cancer treatment itself does not appear to be responsible for the risk of these secondary malignancies. Deficient DNA repair can greatly increase the risk of cancers from DNA-damaging agents, as in ataxia-telangiectasia. Importantly, the risk of treatment-related second malignancies is at least additive and often synergistic with combined chemotherapy and radiation therapy, and hence for such combined-therapy treatment approaches, it is important to establish the necessity of each in the treatment program. All of these patients require special surveillance or, in some cases, prophylactic surgery as part of appropriate treatment and follow-up.


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InternalMed_Harrison. Chemotherapy is significantly associated with two fatal second malignancies, acute leukemia and myelodysplastic syndromes. Two types of leukemia have been described; in patients treated with alkylating agents, acute myeloid leukemia is associated with deletions in chromosome 5 or 7. The lifetime risk is about 1–5%, is increased by radiation therapy, and increases with age. The incidence of these leukemias peaks at 4–6 years, with risk returning close to baseline at 10 years. The other type of acute myeloid leukemia is related to therapy with topoisomerase inhibitors, is associated with chromosome 10q23 trans-locations, has an incidence of <1%, and generally occurs 1.5–3 years after treatment. Both of these acute myeloid leukemias are refractory to treatment and have a high mortality. The development of myelodysplastic syndromes is increased following chemotherapy, and these are often associated with leukemic progression and a dismal prognosis.


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InternalMed_Harrison. Patients receiving radiation have an increasing and lifelong risk of second malignancies that is 1–2% in the second decade following treatment but increases to >25% after 25 years. These malignancies include cancers of the thyroid and breast, sarcomas, and CNS cancers, which often tend to be aggressive and have a poor prognosis. An example of organ-, age-, and sex-dependent radiation-induced secondary malignancy is breast cancer, in which the risk is small with radiation in women under age 30 but increases about 20-fold over baseline in women over 30. A 25-year-old woman treated with mantle radiation for Hodgkin’s lymphoma has a 29% actuarial risk of developing breast cancer by age 55.


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InternalMed_Harrison. Treatment of breast cancer with tamoxifen for 5 years or longer is associated with a 1–2% risk of endometrial cancer. Surveillance is generally effective at finding these cancers at an early stage. The risk of mortality from tamoxifen-induced endometrial cancer is low compared to the benefit of tamoxifen as adjuvant therapy for breast cancer. Immunosuppressive therapy, as used in allogeneic bone marrow transplantation, particularly with T cell depletion using antithymocyte globulin or other means, increases the risk of Epstein Barr virus–associated Late Consequences of Cancer and Its Treatment Pediatric cancers Majority have at least one late effect 30% with moderate/severe problems Cardiovascular: radiation, anthracyclines Lungs: radiation Skeletal abnormalities: radiation Psychological, cognitive, and sexual problems Second neoplasms significant cause of death


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InternalMed_Harrison. Hodgkin’s lymphoma Thyroid dysfunction: radiation Premature coronary artery disease: radiation Gonadal dysfunction: chemotherapy Postsplenectomy sepsis Myelodysplasia Acute myeloid leukemia Non-Hodgkin’s lymphomas Breast cancer, lung cancer, and melanoma Fatigue, psychological and sexual problems Peripheral neuropathy Acute leukemia Second malignancies: hematologic, solid tumors Neuropsychiatric dysfunction Subnormal growth Thyroid abnormalities Infertility Graft-versus-host disease (allogeneic transplant) Psychosexual dysfunction. Head and neck cancer Poor dentition, dry mouth, poor nutrition: radiation Breast cancer Tamoxifen: endometrial cancer, blood clots Aromatase inhibitors: osteoporosis, arthritis Cardiomyopathy: anthracycline ± radiation, trastuzumab Acute leukemia Hormone deficiency symptoms: hot flashes, vaginal dryness, dyspareunia Psychosocial dysfunction “Chemo brain”


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InternalMed_Harrison. Testicular cancer Raynaud’s phenomenon Renal dysfunction Pulmonary dysfunction Retrograde ejaculation: surgery 15% sexual dysfunction Colon cancer Major risk is second colon cance. Quality of life high in survivors Prostate cancer Impotence Urinary incontinence (0–15%) Chronic proctitis, prostatitis/cystitis: radiation B cell lymphoproliferative disorder. The incidence at 10 years after T cell depletion is 9–12%. Discontinuing immunosuppressive therapy, if possible, is often associated with complete disease regression.


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InternalMed_Harrison. All former cancer patients should be followed indefinitely. This is most often done by oncologists, but demographic changes suggest that more primary care physicians will need to be trained in the follow-up of treated cancer patients in remission. Cancer patients need to be educated about signs and symptoms of recurrence and potentially adverse effects related to therapy. Localized pain or palpable abnormality in a previously radiated field should prompt radiographic evaluation. Screening tests, when available and validated, should be used on a routine and regular basis (e.g., mammography and Pap smear), particularly in patients receiving radiation to specific organs. Annual mammography should start no later than 10 years after breast radiation. Patients receiving radiation fields encompassing thyroid tissue should have regular thyroid exams and TSH testing. Patients treated with alkylating agents or topoisomerase inhibitors should have a complete blood count every 6–12 months, and


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InternalMed_Harrison. thyroid tissue should have regular thyroid exams and TSH testing. Patients treated with alkylating agents or topoisomerase inhibitors should have a complete blood count every 6–12 months, and cytopenias, abnormal cells on peripheral smear, or macrocytosis should be evaluated with bone marrow biopsy and aspirate, to include cytogenetics, flow cytometry, or fluorescence in situ hybridization (FISH) studies as appropriate.


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InternalMed_Harrison. As the population of cancer survivors lives longer and grows, cancer survivorship has become an increasingly recognized subject, and the Institute of Medicine and National Research Council have published a monograph entitled From Cancer Patient to Cancer Survivor: Lost in Transition. The monograph proposes a plan that would inform clinicians caring for cancer survivors in complete detail of their previous treatments, complications thereof, signs and symptoms of late effects, and recommended screening and follow-up procedures. Table 125-2 lists long-term treatment effects by cancer type.


InternalMed_Harrison

InternalMed_Harrison. Clearly, the challenge for the future is to combine chemotherapy, targeted agents, biologic therapies, radiation, and surgery to produce better outcomes with less toxicity, including late effects of therapy. This is easily said but less easily accomplished. As treatment becomes more effective in new patient populations (ovarian, bladder, anal, and laryngeal cancers, for example), we will expect to discover new populations at risk for late effects. These populations will need to be followed carefully, so that such effects are recognized and treated. Cancer survivors represent an underused resource for prevention studies. Childhood cancer survivors, especially, suffer multiple chronic health impairments. The incidence of these late treatment consequences appears to have no plateau with age, throwing in stark relief the necessity of close monitoring and therapies with fewer late consequences of treatment. John W. Adamson


InternalMed_Harrison

InternalMed_Harrison. John W. Adamson Anemias associated with normocytic and normochromic red cells and an inappropriately low reticulocyte response (reticulocyte index <2–2.5) are hypoproliferative anemias. This category includes early iron deficiency (before hypochromic microcytic red cells develop), acute and chronic inflammation (including many malignancies), renal disease, hypometabolic states such as protein malnutrition and endocrine deficiencies, and anemias from marrow damage. Marrow damage states are discussed in Chap. 130. Hypoproliferative anemias are the most common anemias, and in the clinic, iron deficiency anemia is the most common of these followed by the anemia of inflammation. The anemia of inflammation, similar to iron deficiency, is related in part to abnormal iron metabolism. The anemias associated with renal disease, inflammation, cancer, and hypometabolic states are characterized by a suboptimal erythro poietin response to the anemia.


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InternalMed_Harrison. Internal iron exchange. Normally 80% of iron passing through the plasma transferrin pool is recycled from senescent red Iron is a critical element in the function of all cells, although the amount of iron required by individual tissues varies during development. At the same time, the body must protect itself from free iron, which is highly toxic in that it participates in chemical reactions that generate free radicals such as singlet O2 or OH-. Consequently, elaborate mechanisms have evolved that allow iron to be made available for physiologic functions while at the same time conserving this element and handling it in such a way that toxicity is avoided.


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InternalMed_Harrison. The major role of iron in mammals is to carry O2 as part of hemoglobin. O2 is also bound by myoglobin in muscle. Iron is a critical element in iron-containing enzymes, including the cytochrome system in mitochondria. Iron distribution in the body is shown in Table 126-1. Without iron, cells lose their capacity for electron transport and energy metabolism. In erythroid cells, hemoglobin synthesis is impaired, resulting in anemia and reduced O2 delivery to tissue.


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InternalMed_Harrison. Figure 126-1 outlines the major pathways of internal iron exchange in humans. Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin, the iron transport protein. Transferrin is a bilobed glycoprotein with two iron binding sites. Transferrin that carries iron exists in two forms—monoferric (one iron atom) or diferric (two iron atoms). The turnover (half-clearance time) of transferrin-bound iron is very rapid—typically 60–90 min. Because almost all of the iron transported by transferrin is delivered to the erythroid marrow, the clearance time of transferrin-bound iron from the circulation is affected most by the plasma iron level and the erythroid marrow activity. When erythropoiesis is markedly stimulated, the pool of erythroid cells requiring iron increases and the clearance time of iron from the circulation decreases. The half-clearance time of iron in


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InternalMed_Harrison. Iron Content, mg cells. Absorption of approximately 1 mg/d is required from the diet in men, and 1.4 mg/d in women to maintain homeostasis. As long as transferrin saturation is maintained between 20 and 60% and erythropoiesis is not increased, use of iron stores is not required. However, in the event of blood loss, dietary iron deficiency, or inadequate iron absorption, up to 40 mg/d of iron can be mobilized from stores. RE, reticuloendothelial. the presence of iron deficiency is as short as 10–15 min. With suppression of erythropoiesis, the plasma iron level typically increases and the half-clearance time may be prolonged to several hours. Normally, the iron bound to transferrin turns over 6–8 times per day. Assuming a normal plasma iron level of 80–100 μg/dL, the amount of iron passing through the transferrin pool is 20–24 mg/d.


InternalMed_Harrison

InternalMed_Harrison. The iron-transferrin complex circulates in the plasma until it interacts with specific transferrin receptors on the surface of marrow erythroid cells. Diferric transferrin has the highest affinity for transferrin receptors; apotransferrin (not carrying iron) has very little affinity. Although transferrin receptors are found on cells in many tissues within the body—and all cells at some time during development will display transferrin receptors—the cell having the greatest number of receptors (300,000–400,000/cell) is the developing erythroblast.


InternalMed_Harrison

InternalMed_Harrison. Once the iron-bearing transferrin interacts with its receptor, the complex is internalized via clathrin-coated pits and transported to an acidic endosome, where the iron is released at the low pH. The iron is then made available for heme synthesis while the transferrin-receptor complex is recycled to the surface of the cell, where the bulk of the transferrin is released back into circulation and the transferrin receptor reanchors into the cell membrane. At this point a certain amount of the transferrin receptor protein may be released into circulation and can be measured as soluble transferrin receptor protein. Within the erythroid cell, iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin. This mechanism of iron exchange also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells where the iron can be incorporated into heme-containing enzymes or stored. The iron


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InternalMed_Harrison. also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells where the iron can be incorporated into heme-containing enzymes or stored. The iron incorporated into hemoglobin subsequently enters the circulation as new red cells are released from the bone marrow. The iron is then part of the red cell mass and will not become available for reutilization until the red cell dies.


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InternalMed_Harrison. 626 In a normal individual, the average red cell life span is 120 days. Thus, 0.8–1% of red cells are replaced each day. At the end of its life span, the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system, and the red cell undergoes phagocytosis. Once within the RE cell, the ingested hemoglobin is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin. It is the efficient and highly conserved recycling of iron from senescent red cells that supports steady-state (and even mildly accelerated) erythropoiesis. Because each milliliter of red cells contains 1 mg of elemental iron, the amount of iron needed to replace those red cells lost through senescence amounts to 20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes from the diet. Normally, an adult


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InternalMed_Harrison. cells lost through senescence amounts to 20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes from the diet. Normally, an adult male will need to absorb at least 1 mg of elemental iron daily to meet needs, while females in the childbearing years will need to absorb an average of 1.4 mg/d. However, to achieve a maximum proliferative erythroid marrow response to anemia, additional iron must be available. With markedly stimulated erythropoiesis, demands for iron are increased by as much as sixto eightfold. With extravascular hemolytic anemia, the rate of red cell destruction is increased, but the iron recovered from the red cells is efficiently reutilized for hemoglobin synthesis. In contrast, with intra-vascular hemolysis or blood loss anemia, the rate of red cell production is limited by the amount of iron that can be mobilized from stores. Typically, the rate of mobilization under these circumstances will not support


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InternalMed_Harrison. blood loss anemia, the rate of red cell production is limited by the amount of iron that can be mobilized from stores. Typically, the rate of mobilization under these circumstances will not support red cell production more than 2.5 times normal. If the delivery of iron to the stimulated marrow is suboptimal, the marrow’s proliferative response is blunted, and hemoglobin synthesis is impaired. The result is a hypoproliferative marrow accompanied by microcytic, hypochromic anemia. Whereas blood loss or hemolysis places a demand on the iron supply, inflammatory conditions interfere with iron release from stores and can result in a rapid decrease in the serum iron (see below).


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InternalMed_Harrison. The balance of iron in humans is tightly controlled and designed to conserve iron for reutilization. There is no regulated excretory pathway for iron, and the only mechanisms by which iron is lost are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epithelial cells from the skin, gut, and genitourinary tract. Normally, the only route by which iron comes into the body is via absorption from food or from medicinal iron taken orally. Iron may also enter the body through red cell transfusions or injection of iron complexes. The margin between the amount of iron available for absorption and the requirement for iron in growing infants and the adult female is narrow; this accounts for the great prevalence of iron deficiency worldwide—currently estimated at one-half billion people.


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InternalMed_Harrison. The amount of iron required from the diet to replace losses averages approximately 10% of body iron content a year in men and 15% in women of childbearing age. Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories). Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed. In the United States, the average iron intake in an adult male is 15 mg/d with 6% absorption; for the average female, the daily intake is 11 mg/d with 12% absorption. An individual with iron deficiency can increase iron absorption to approximately 20% of the iron present in a meat-containing diet but only 5–10% of the iron in a vegetarian diet. As a result, one-third of the female population in the United States has virtually no iron stores. Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by


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InternalMed_Harrison. population in the United States has virtually no iron stores. Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by approximately 50%. When ionizable iron salts are given together with food, the amount of iron absorbed is reduced. When the percentage of iron absorbed from individual food items is compared with the percentage for an equivalent amount of ferrous salt, iron in vegetables is only about one-twentieth as available, egg iron one-eighth, liver iron one-half, and heme iron one-half to two-thirds.


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InternalMed_Harrison. Infants, children, and adolescents may be unable to maintain normal iron balance because of the demands of body growth and lower dietary intake of iron. During the last two trimesters of pregnancy, daily iron requirements increase to 5–6 mg, and iron supplements are strongly recommended for pregnant women in developed countries.


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InternalMed_Harrison. Iron absorption takes place largely in the proximal small intestine and is a carefully regulated process. For absorption, iron must be taken up by the luminal cell. That process is facilitated by the acidic contents of the stomach, which maintains the iron in solution. At the brush border of the absorptive cell, the ferric iron is converted to the ferrous form by a ferrireductase. Transport across the membrane is accomplished by divalent metal transporter type 1 (DMT-1, also known as natural resistance macrophage-associated protein type 2 [Nramp 2] or DCT-1). DMT-1 is a general cation transporter. Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin. The function of ferroportin is negatively regulated by hepcidin, the principal iron regulatory hormone. In the process of release, iron interacts with another ferroxidase, hephaestin,


InternalMed_Harrison

InternalMed_Harrison. ferroportin. The function of ferroportin is negatively regulated by hepcidin, the principal iron regulatory hormone. In the process of release, iron interacts with another ferroxidase, hephaestin, which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.


InternalMed_Harrison

InternalMed_Harrison. Iron absorption is influenced by a number of physiologic states. Erythroid hyperplasia stimulates iron absorption even in the face of normal or increased iron stores, and hepcidin levels are inappropriately low. Thus, patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. The molecular mechanism underlying this relationship is not known. Over time, this may lead to iron overload and tissue damage. In iron deficiency, hepcidin levels are also low and iron is much more efficiently absorbed; the contrary is true in states of secondary iron overload. The normal individual can reduce iron absorption in situations of excessive intake or medicinal iron intake; however, while the percentage of iron absorbed goes down, the absolute amount goes up. This accounts for the acute iron toxicity occasionally seen when children ingest large numbers of iron tablets. Under these circumstances, the amount of iron absorbed exceeds the


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InternalMed_Harrison. amount goes up. This accounts for the acute iron toxicity occasionally seen when children ingest large numbers of iron tablets. Under these circumstances, the amount of iron absorbed exceeds the transferrin binding capacity of the plasma, resulting in free iron that affects critical organs such as cardiac muscle cells.


InternalMed_Harrison

InternalMed_Harrison. Iron deficiency is one of the most prevalent forms of malnutri tion. Globally, 50% of anemia is attributable to iron deficiency and accounts for approximately 841,000 deaths annually worldwide. Africa and parts of Asia bear 71% of the global mortality burden; North America represents only 1.4% of the total morbidity and mortality associated with iron deficiency.


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InternalMed_Harrison. The progression to iron deficiency can be divided into three stages (Fig. 126-2). The first stage is negative iron balance, in which the demands for (or losses of) iron exceed the body’s ability to absorb iron from the diet. This stage results from a number of physiologic mechanisms, including blood loss, pregnancy (in which the demands for red cell production by the fetus outstrip the mother’s ability to provide iron), rapid growth spurts in the adolescent, or inadequate dietary iron intake. Blood loss in excess of 10–20 mL of red cells per day is greater than the amount of iron that the gut can absorb from a normal diet. Under these circumstances, the iron deficit must be made up by mobilization of iron from RE storage sites. During this period, iron stores—reflected by the serum ferritin level or the appearance of stain-able iron on bone marrow aspirations—decrease. As long as iron stores are present and can be mobilized, the serum iron, total iron-binding capacity (TIBC), and red


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InternalMed_Harrison. level or the appearance of stain-able iron on bone marrow aspirations—decrease. As long as iron stores are present and can be mobilized, the serum iron, total iron-binding capacity (TIBC), and red cell protoporphyrin levels remain within normal limits. At this stage, red cell morphology and indices are normal.


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InternalMed_Harrison. When iron stores become depleted, the serum iron begins to fall. Gradually, the TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron stores are absent when the serum ferritin level is <15 μg/L. As long as the serum iron remains within the normal


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InternalMed_Harrison. FIGURE 126-2 Laboratory studies in the evolution of iron deficiency. Measurements of marrow iron stores, serum ferritin, and total iron-binding capacity (TIBC) are sensitive to early iron-store depletion. Iron-deficient erythropoiesis is recognized from additional abnormalities in the serum iron (SI), percent transferrin saturation, the pattern of marrow sideroblasts, and the red blood cell (RBC) protoporphyrin level. Patients with iron-deficiency anemia demonstrate all the same abnormalities plus hypochromic microcytic anemia. (From RS Hillman, CA Finch: The Red Cell Manual, 7th ed. Philadelphia, F.A.Davis and Co., 1996, with permission.) range, hemoglobin synthesis is unaffected despite the dwindling iron stores. Once the transferrin saturation falls to 15–20%, hemoglobin synthesis becomes impaired. This is a period of iron-deficient erythropoiesis. Careful evaluation of the peripheral blood smear reveals the first appearance of microcytic cells, and if the laboratory technology is


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InternalMed_Harrison. impaired. This is a period of iron-deficient erythropoiesis. Careful evaluation of the peripheral blood smear reveals the first appearance of microcytic cells, and if the laboratory technology is available, one finds hypochromic reticulocytes in circulation. Gradually, the hemoglobin and hematocrit begin to fall, reflecting iron-deficiency anemia. The transferrin saturation at this point is 10–15%.