OHO-30(543-558) 11/18/02 9:25 AM Page 549 NEUROLOGICAL PARANEOPLASTIC SYNDROMES 549 Paraneoplastic cerebellar degeneration (PCD) Cancer types Breast, SCLC, ovary, Hodgkin \200 \231s disease (HD). Presentation Rapid onset and progression; usually prior to cancer diagn osis; bilateral cerebellar signs; late diplopia and dementia. Diagnosis CT \200\224cerebell ar atrophy (late); serum auto-antibodies \200\224 anti-Yo, -Tr, and -Hu. Treatment Response to anti-tumor treatment, steroids, plasma- pheresis. Cancer-associated retinopathy (CAR) Cancer types SCLC, breast, melanoma. Presentation Visua l defects i.e. blurred vision, episodic visual loss, impaired color vision; leads to progre ssive painless visual loss; usually precedes cancer diagnosis. Diagnosis Loss of acuity; sc otomata; abnormal electroretinogram; anti-retinal ab \200\231s. Treatment Corticosteroids. Lambert \200\223Eaton myasthenic syndrome (LEMS) Disorder of the neuro-muscular junction; r educed pre-synaptic calcium-dependent acetylcholine release. About 60% of patients with LEM S have underlying cancer. Cancer types SCLC (60 \200\22370%), breast, thymus, GIT cancers. Presentation Proximal muscle weakness. Diagnosis EMG \200\224normal conduction velocity wit h low-amplitude compound muscle action potential that enhance to near normal fol- lowing ex ercise. Treatment Cancer treatment, corticosteroids, plasma exchange (high response rate). Dermatomyositis/polymyositis In \202ammatory myopathies, often present prior to cancer dia gnosis. Cancer types NSCLC, SCLC, breast, ovary, GIT cancers Presentation Proximal myopathy , skin changes, other systemic fea- tures; cardiopulmonary conditions, arthralgias, retinop athy. Diagnosis Serum \200\224high CK, LDH, aldolase; muscle biopsy \200\224myo- sitis; EMG \200\223 \201brillation, insertion irritability, short polyphasic motor units. Treatment Search for and treat tumor; corticosteroids, azathioprine. OHO-30(543-558) 11/18/02 9:25 AM Page 550 PARANEOPLASTIC SYNDROMES 550 Hematological paraneoplastic syndromes Red cell disorders Erythrocytosis Common, often secondary to increased erythropoi- etin pro duction e.g. renal cell carcinoma, hepatoma. Treat with phleb- otomy if required. Haemolyti c anemia (cid:2) Autoimmune \200\224secondary to lymphoproliferative disorders (treat- ment \200\224corticosteroids). (cid:2) Micro-angiopathic \200\224secondary to vascular tumors, acute pro- myelocytic leuke mia, or widespread metastatic adenocarcinoma. Treat the tumor; replace coagulation factors; IV heparin. Red cell aplasia Seen in thymoma, CLL; rare in solid tumors. White cell disorders Autoimmune neutropenia (rare) (cid:2) Granulocytosis \200\224secondary to haemopoietic growth factor- secreting tumors (e.g. squamous cell cancers of lung, thyro id). (cid:2) Eosinophilia \200\224in patients with HD. Platelet disorders (cid:2) Thrombocytosis \200\224(>450 \227 109/L) is common and usually asymp- tomatic; in some cases may be secondary to IL-6 production. Idiopathic thrombocytopenia \200\224is associated with leukaemias and lymphomas. Coagulopathy (cid:2) Minor abnormaliti es of \201brin and \201brinogen degradation products (cid:2) are common. (cid:2) Overt disseminated intravascular coagulation is rare, associated with Acute Myelocytic Leukemia and adenocarcinomas. (cid:2) Diagnosed by triad of thrombocytopenia, abnormal prothrombin time, and hypo \201brinoginemia (cid:2) Treatment is controversial. OHO-30(543-558) 11/18/02 9:25 AM Page 551 hematological PARANEOPLASTIC SYNDROMES 551 OHO-30(543-558) 11/18/02 9:25 AM Page 552 PARANEOPLASTIC SYNDROMES 552 Dermatological paraneoplastic syndromes Pruritus Common; characteristic of HD, leukaemias, CNS tumors, NHL. Pigmentation Acanthosis nigricans Itchy brown hyperkeratotic plaques, mainly in \202exure s; may precede cancers by many years; associated with GIT tumors e.g. gastric adenocarcinom a. Vitiligo Patchy depigmentation, especially face, neck, and hands; associated with malign ant melanoma; possibility due to anti- melanoma immune response. Erythematous Necrolytic migratory erythema Exfoliative dermatitis \200\224cutaneous T-cell lymphoma. Islet cell tumor. Bullous Pemphigus Characteristic bullous lesions on skin and mucous membranes; associated w ith lymphoma, Kaposi \200\231s sarcoma, thymic tumors. Dermatitis herpetiformis Chronic, in tensely itchy vesicles over elbows, knees, and lower back; precede tumor by many years; ass ociated with lymphomas e.g. NHL of the small intestine. OHO-30(543-558) 11/18/02 9:25 AM Page 553 DERMATOLOGICAL PARANEOPLASTIC SYNDROMES 553 OHO-30(543-558) 11/18/02 9:25 AM Page 554 PARANEOPLASTIC SYNDROMES 554 Other syndromes Hypertrophic osteoarthropathy Characterized by \201nger clubbing, periosteal new bone for mation, and arthropathy. Cancer types Lung cancer, especially NSCLC. Presentation Painful, swollen joints. Diagnosis Clinical \200\224X-ray showing periosteal shadowing; bone scan \200\224increased uptake. Treatment Anti-tumor therapy, NSAIDS, corticosteroids, radiation. OHO-30(543-558) 11/18/02 9:25 AM Page 555 OTHER SYNDROMES 555 OHO-30(543-558) 11/18/02 9:25 AM Page 556 PARANEOPLASTIC SYNDROMES 556 Constitutional symptoms Fever Can be presenting feature of lymphomas, hepatomas, renal cell carcinoma; mediated by IL-1; treat with NSAIDS, corticosteroids; exclude other causes. Cachexia Very common, >10% loss of body weight is associated with poor prognosis; due to complex, multi-factorial meta bolic derange- ments; treat with enteral caloric supplements and appetite stimulants e.g. c orticosteroids, megesterol acetate. OHO-30(543-558) 11/18/02 9:25 AM Page 557 CONSTITUTIONAL SYMPTOMS 557 Further reading MacCaulay, V.M. and Smith, I.E. (1995) Paraneoplastic syndromes. Oxford Textbook of Oncology, p. 2228 \200\22353. Oxford University Press. John, W.J., Patchell, R.A., and Foon, K.A. (1994) Paraneoplastic syndromes. In Cancer \200\224Principles and Practice of Oncology (5th edn) (ed. V.T. DeVita et al) p. 239 7 \200\223422. Paraneoplastic syndromes (1997). Seminars in Oncology 24, 265 \200\223381. OHO-30(543-558) 11/18/02 9:25 AM Page 558 This page intentionally left blank OHO-31(559-570) 11/18/02 9:26 AM Page 559 Chapter 31 AIDS-related malignancies Kaposi \200\231s sarcoma 562 Non-Hodgkin \200\231s lymphoma 566 Primary CNS lymphoma 568 Ot her malignancies 570 OHO-31(559-570) 11/18/02 9:26 AM Page 560 AIDS-RELATED MALIGNANCIES 560 Patients with the acquired immune de \201ciency syndrome (AIDS) are at increased risk of d eveloping certain malignant tumors. At present four malignancies de \201ne the onset of AI DS. (cid:2) Kaposi \200\231s sarcoma (KS) (cid:2) Non-Hodgkin \200\231s lymphoma (NHL) (cid :2) Primary CNS lymphoma (cid:2) Cervical cancer Epidemiological research has identi \201e d other tumors, such as anal cancer and Hodgkin \200\231s disease, that also have an increa sed incidence in HIV-positive individuals. OHO-31(559-570) 11/18/02 9:26 AM Page 561 AIDS-RELATED MALIGNANCIES 561 OHO-31(559-570) 11/18/02 9:26 AM Page 562 AIDS-RELATED MALIGNANCIES 562 Kaposi \200\231s sarcoma (KS) Prior to the HIV epidemic, this tumor was seen in three clinical settings: (cid:2) The clas sical form affects predominantly the lower legs in men of East European or Jewish origin an d often follows an indolent course, rarely requiring any speci \201c treatment. (cid:2) An African variant, which has been endemic for many years. This can be indolent in nature or it may be more aggressive with wide- spread lymph node and visceral involvement. (cid:2) Patients receiving immunosuppressive therapy e.g. in organ trans- plant recipients. In this instance the tumor may regress when this treatment is reduced. However, the commonest form of KS in the developing world is the epidemic form associated w ith AIDS. Due to the successful treatment and prophylaxis of opportunistic infections and e ffective anti- retroviral therapy, AIDS patients are now surviving longer. Although the inc idence of KS is declining, the morbidity and mortality ascribed to KS has increased. Viscer al KS now accounts for the death of one in four HIV-positive homosexuals. KS affects male homosexuals in particular and rarely affects other groups at risk of AIDS, such as infected blood recipients and intra- venous drug abusers. In those developing AIDS in an African environ- ment, KS can be seen frequently in heterosexuals. A sexually transmi tted co-factor may play an important role in its development. Recent research has identi \201ed a virus \200\224the Kaposi \200\231s sarcoma herpes virus (KSHV), also known as huma n herpes virus 8(HHV8). DNA from this virus has been identi \201ed in KS lesions and in se men, blood, and bronchial washings from affected patients. However, its precise role in the development of KS is not yet fully understood. KS is a multi-focal tumor and new lesions occur at various cutaneous and internal organ sit es. The most likely cell of origin is mesenchymal with vascular or lymphatic cell markers a nd factor VIII antigen is often positive on immunocytochemistry staining. A diag- nostic fe ature is the intradermal proliferation of abnormal vascular structures, lined with large, s pindle-shaped endothelial cells. Frequent extravasation of red blood cells and mononuclear leukocytes occur. Recent advances have identi \201ed that AIDS KS cells produce growth factors and cytokines , for example TNF and IL6, which appear to regulate their growth. This suggests an importan t role in the patho- genesis of KS, which may hold promise for the development of future tr eatments. OHO-31(559-570) 11/18/02 9:26 AM Page 563 KAPOSI \200\231S SARCOMA 563 Presentation (cid:2) Cutaneous red purple multiple lesions (cid:2) Flat, then progress to plaques, nodul es, with oedema (cid:2) Site \200\224upper body, face, legs (cid:2) Diagnosis \200\224skin biopsy (cid:2) Systemic lesions \200\224presents with lung, GI tract \200\224pain, dyspnoea, haemoptysis, bowel obstruction \200\224diagnosis by endoscopy Staging Important prognostic factors relate not only to disease extent but to the patient \200\231s immune status and KS can occur as an early and late feature in AIDS patients. The Aids Clinical Trials Group (ACTG) has developed a staging classi \201cation. Treatment There is currently no cure for KS. Therefore, the primary goal of treat- ment is to prolong life, while maintaining quality. The treatment should be tailored to the form of the disease. Localized treatment options include: (cid:2) Camou \202age with cosmetics (c id:2) Cryotherapy and laser, especially if lesions are <1 cm diameter Intra-lesional chemot herapy with vinblastine or interferon (cid:2) (cid:2) Radiotherapy KS is responsive to radiation treatment. A 70% response rate, equal to intra-lesional chemotherapy, can be achieved with single fraction doses of 8 Gy. This can be repeated if there is recurrence or insuf \201cient regression. Palatal lesions can also be irradiated using iridium wire molds. Systemic treatment is required if there is widespread cutaneous or visceral involvement. Im munotherapy using interferon is most Table 31.1 ACTG guidelines Good prognosis \200\224all of Poor prognosis \200\224any of Tumor Skin only lymph nodes and or minimal oral disease Oedema/ulceration, extensive oral disease, visceral KS Immunological CD4 >200 CD4 <200 Symptoms Nil, Karnofsky >70 Opportunistic infection or thrush, B symptoms, Karnofsky <70, other HIV-related illnesses OHO-31(559-570) 11/18/02 9:26 AM Page 564 AIDS-RELATED MALIGNANCIES 564 effective if the CD4 count is >200. This form of treatment results in less bone marrow supp ression. The high doses required often result in fever, night sweats, and lethargy. If the CD4 count is below 200, treat- ment with vincristine and bleomycin can achieve response rat es of 50 \200\22360%. Side-effects include some degree of bone marrow suppres- sion, dose-r elated pulmonary \201brosis (in the case of bleomycin), and a peripheral neuropathy (with vincristine). The addition of doxorubicin may result in signi \201cant bone marrow suppre ssion and alopecia. Recent developments have led to liposomally packaged preparations that enable selective dis tribution to and retention in tumors, reduc- ing uptake in unwanted sites such as the bone marrow. Response rates of 80% have been observed. Several new treatments are also being res earched in clinical trials, including taxol, beta HCG, trans-retinoic acid, and anti-angiog enic agents such as thalidomide. Table 31.2 Treatment options for KS Local intervention Systemic intervention Cryotherapy/laser esp <1 cm Interferon \200\224if CD4 >200 Radiotherapy \200\2248 GY single fraction Vincristine 2 mg and bleomycin 30 units every 3 weeks Liposomal doxorubicin 20 mg/m2 every 3 weeks Intra-lesional chemotherapy Liposomal daunorubicin 40 mg/m2 every 2 weeks Brachytherapy \200\224palate OHO-31(559-570) 11/18/02 9:26 AM Page 565 KAPOSI \200\231S SARCOMA 565 OHO-31(559-570) 11/18/02 9:26 AM Page 566 AIDS-RELATED MALIGNANCIES 566 Non-Hodgkin \200\231s lymphoma The second most common malignancy to affect those with AIDS. Almost half of these will alre ady have a prior AIDS-de \201ning illness. Unlike KS, its incidence is 3% within all risk groups \200\224one hundred times higher than in the general population. NHL also has a high er incidence in other congenitally and iatrogenically immune-suppressed individuals. A viral co-factor \200\224the Epstein \200\223Barr virus (EBV) \200\224is closely linked to the development of lymphoma in AIDS. EBV proteins can be demonstrated in 50% of lymphomas in nodal or extra-nodal sites. It is thought that in the immune-de \201cient host the prol iferation of EBV- infected cells may proceed unchecked. Oncogenic alterations, e.g. p53 and C-myc, have also been identi \201ed. 90% of HIV-related NHLS are of B-cell origin and are commonly high-grade. The most common sub- types are immunoblastic, centroblastic, lymphobl astic, and Burkitt- like lymphoma. Presentation (cid:2) At advanced stage (cid:2) Usually involves marrow and CNS (extra-nodal) (cid:2) Fre quently B symptoms (cid:2) Differential diagnosis TB, CMV (cid:2) Gland biopsy essential Investigations \200\224chest X-ray, CT head, abdomen, pelvis (cid:2) \200\224bone marrow biopsy \200\224LDH level \200\224lumbar puncture (cid:2) Poor prognosis \200\224median survival 6 months \200\22450% die from opportunistic infections \200\22450% die from lymphoma Prognosis Poor prognostic factors include: (cid:2) Absolute CD4 count <200 ul (cid:2) Prior AIDS-de \201ning diagnosis (cid:2) Karnofsky performance score <70 (cid:2) Extra-nodal di sease including bone marrow (cid:2) Raised LDH Immunoblastic subtype (cid:2) OHO-31(559-570) 11/18/02 9:26 AM Page 567 NON-HODGKIN \200\231S LYMPHOMA 567 Treatment Systemic treatment with chemotherapy is usually the only available curative treat ment. However, if the disease is truly localized, radio- therapy can result in long-term co ntrol and is invaluable for the palli- ation of local symptoms. The standard treatment for more advanced disease is combination chemotherapy. CHOP (cycloph osphamide, doxorubicin, vincristine, prednisolone) is a typical chemotherapy regimen, given every three weeks. More intensive schedules can be used, but due to increased toxicity are often not well tolerated. In those at high risk of meningeal involvement, concomitant intr athecal chemotherapy of methotrexate and cytarabine is also used. Recent studies suggest that more aggressive chemotherapy regimens result in an overall decr ease in survival due to toxicity-related compli- cations. Modi \201ed schedules including a 75% dose reduction may pro- duce similar response and overall survival rates. Those who a chieve a complete response with chemotherapy have a survival bene \201t ranging from 6 \200\22320 months. OHO-31(559-570) 11/18/02 9:26 AM Page 568 AIDS-RELATED MALIGNANCIES 568 Primary CNS lymphoma Primary CNS lymphoma (PCNSL) affects 2 \200\2236% of HIV-positive individuals. It is usuall y a late manifestation of AIDS and the patients commonly have other serious opportunistic i nfections. The histology is similar to AIDS-related NHL, except almost all cases are associ ated with EBV. Patients often present with epileptic seizures, hemiparesis, or severe heada ches. A CT or MRI is the investigation of choice. However, the scan appearances may be indi stinguishable from cere- bral toxoplasmosis and, for this reason, patients are often treate d initially with a trial of toxoplasmosis treatment. A histological diagno- sis is ideal bu t not often possible. Treatment involves whole-brain radiotherapy in combination with steroids and, sometimes, in trathecal chemotherapy. There is little evidence to support the use of systemic chemotherap y. In good per- formance status patients, the median survival is 12 months. If no treatment is given, the survival rate falls signi \201cantly to just a few months. Patients usually die from the late complications of AIDS. OHO-31(559-570) 11/18/02 9:26 AM Page 569 PRIMARY CNS LYMPHOMA 569 OHO-31(559-570) 11/18/02 9:26 AM Page 570 AIDS-RELATED MALIGNANCIES 570 Other malignancies Hodgkin \200\231s disease has an increased incidence in HIV-positive patients \200\2245 \200\2239 times higher than the general population. It is seen more commonly in patients wh ere transmission of HIV has been by intra- venous drug use. The disease is often advanced a t the time of presenta- tion. Standard chemotherapy is with ABVD (adriamycin, bleomycin, vi nblastine, dacarbazine). The median survival with chemotherapy is 12 months. Cervical cancer in HIV-positive females became an AIDS-de \201ning diagnosis in 1993. Its increased prevalence may be because both HIV virus and the human papillomavirus (HPV) are s exually trans- missible. It is advisable to screen this group more frequently, (every 6 \200\22312 months). Anal cancer is related to both HIV and HPV. It has an increased prevalence in homosexual me n practicing anal intercourse. However, the risk is higher for those who are also HIV-posit ive. OHO-32(571-582) 11/18/02 9:27 AM Page 571 Part 5 Emergencies in oncology 32 Spinal cord compression 573 33 Bone marrow suppression 583 34 Superior vena cava obstruc tion 591 35 Raised intra-cranial pressure 599 36 Stridor 605 37 Acute blood loss 611 38 Gas trointestinal obstruction 619 39 Biochemical crises 625 OHO-32(571-582) 11/18/02 9:27 AM Page 572 This page intentionally left blank OHO-32(571-582) 11/18/02 9:27 AM Page 573 Chapter 32 Spinal cord compression Presentation 575 Symptoms 577 Examination 578 Investigations 579 Management 580 General adv ice 582 OHO-32(571-582) 11/18/02 9:27 AM Page 574 SPINAL CORD COMPRESSION 574 Spinal cord compression is a medical emergency. Treatment must begin within hours, not days . OHO-32(571-582) 11/18/02 9:27 AM Page 575 PRESENTATION 575 Presentation (cid:2) Bone involvement from cancer \200\224breast \200\224prostate \200\224lung \200\224myeloma \200\224lymphoma all common \200\224thyroid \200\224kidney \200\224bladder \200\224bowel \200\224melanoma all less common Initial presentation of malignancy \200\224prostate, breast, myeloma. (cid:2) (cid:2) Crush fracture or tumor extension common. (cid:2) Occasional direct extension from retroperitoneal, mediastinal tumors e.g. lymphoma. (cid:2) Occasional extra-dural compression in absence of bone involve- ment. (cid:2) Occasional intra-medullary metastases. (cid:2) 66% of cases occur in the thoracic c ord. OHO-32(571-582) 11/18/02 9:27 AM Page 576 576 SPINAL CORD COMPRESSION Table 32.1 Spinal cord compression syndromes Complete compression Sensory level just below level of lesion Loss of all sensory modalities \200\224may be variable at onset Bilateral upper motor neuron weakness below lesion Bladder and bowel dysfunction Anterior compression Partial loss of pain and temperature below lesion Bilateral upper motor neuron weakness below lesion Bladder and bowel dysfunction Posterior compression Loss of vibration and position below lesion Relative sparing of pain, temperature, and touch Band of dysthaesia at level of lesion Lateral compression (Brown \200\223S quard syndrome) Contralateral loss of pain and temperature (touch relatively spared) Ipsilateral loss of vibration and position Ipsilateral upper motor neuron weakness OHO-32(571-582) 11/18/02 9:27 AM Page 577 SYMPTOMS 577 Symptoms Pain, characteristically with a nerve root or \200\230girdle \200\231 distribution, exacer bated by coughing or straining and not relieved by bed rest frequently precedes neurologica l symptoms or signs. Any patient with cancer who develops severe back pain with a root dist ribution should be considered at risk of spinal cord compression and urgently investigated. Weakness of the legs (and arms if the lesion is high in the spine), retention, dribbling, o r incontinence of urine or feces, and constipa- tion, may occur and are late symptoms. Cauda equina syndrome The spinal cord ends at the level of L1 or L2. Tumors below this leve l may produce cauda equina compression with sciatic pain (often bi- lateral), bladder dysfu nction with retention and over \202ow inconti- nence, impotence, sacral (saddle) anesthesi a, loss of anal sphincter tone, and weakness and wasting of the gluteal muscles. The sympto ms may be unclear and the diagnosis dif \201cult to make without MRI. OHO-32(571-582) 11/18/02 9:27 AM Page 578 SPINAL CORD COMPRESSION 578 Examination The following may be present: (cid:2) Visible or palpable gibbus at the site of a wedged or collapsed verte- bra (cid:2) Pain and tenderness on palpation or percussion of the vertebra over the site of compression (cid:2) Band of hyperaesthesia at the level of the lesion (cid:2) Sensory and motor loss (w ith defects of power and sensation) at and below the level of the lesion The lesion may be partial or complete and the nature of the defect may depend on the portio n of the cord compressed. In a patient pre- senting with spinal cord compression without a history of malig- nancy, the examination and investigations should also be directed towards excluding an underlying malignancy. OHO-32(571-582) 11/18/02 9:27 AM Page 579 INVESTIGATIONS 579 Investigations (cid:2) Plain X-rays may demonstrate destruction and/or collapse of a ver- tebra. Changes a re sometimes more subtle e.g. loss of a vertebral pedicle. Paravertebral masses may sometim es also be shown. In 15 \200\22320% of cases, plain \201lms show no abnormality. (cid:2) MRI scanning is the investigation of choice. It will demonstrate the site and exten t of the lesion and presence of multiple lesions in ver- tebrae and in the spinal canal. It is particularly useful in cases of cauda equina syndrome. (cid:2) MRI has largely superseded myelography. Where MRI is not avail- able, myelography w ill show the anatomical location of a spinal cord lesion and whether a block is complete or not. However, if a complete block is present the upper limit of a lesion may not be demons trated without cisternal myelography. (cid:2) CT scanning may provide useful information if MRI is not avail- able. Simultanous m yelography may enhance the usefulness of the investigation. It will demonstrate an abnormal ity within a de \201ned region of the cord but is not an ideal primary investigation if th e site of compression cannot be accurately predicted from clinical and plain radiograph \201ndings. If radiotherapy or surgery is proposed, it is useful to ask the radio- logist to mark the l evel(s) of the lesion(s) on the patient \200\231s skin, to aid localization. OHO-32(571-582) 11/18/02 9:27 AM Page 580 SPINAL CORD COMPRESSION 580 Management Speed is of the essence in the management of spinal cord compression since the degree of re covery is dependent on the pre-treatment status. Fewer than 10% of patients with establishe d paraplegia from metasta- tic disease walk again. If spinal cord compression is suspected, dexamethasone 16 \200\22320 mg should be given imm ediately. This relieves peritumoural oedema. Awaiting radiological con \201rmation of spin al cord compression before starting steroids is almost never warranted. If neurological imp rove- ment occurs, the steroid dose may be reduced to the lowest that will maintain that im provement. If immediate surgery is not contem- plated, neurological status should be assess ed at least daily so that deterioration may be detected early and surgical intervention con sidered. For patients able to walk or whose paresis responds to steroids, radiotherapy is as success ful as surgery and is therefore the treatment of choice. Radiation is usually delivered via a single posterior \201eld, which should extend one or two vertebrae above and below the com- pressing lesion. Typical doses include 8 Gy in a single fraction, 20 Gy in 4 \200\223 5 fractions, or 30 Gy in 10 fractions. Some prefer longer fraction- ation regimes for patie nts with hormone-responsive tumors (breast, prostate) that are newly diagnosed as metastati c. Radiation-induced oedema may exacerbate symptoms: be prepared to increase the dose of steroids again during radiotherapy. Indications for surgery include: (cid:2) Acute-onset paraplegia (cid:2) Fracture dislocation (cid:2) Failure to respond to s teroids (cid:2) Tumors known to be radio-resistant or when spinal cord com- pression progresses during, or recurs after, irradiation (cid:2) No histological proof of malignancy Patients with spinal instability, retropulsed b one fragments, or com- plete collapse of a vertebra with myelopathy do not bene \201t from radiotherapy alone. Since complete surgical clearance of tumor is not likely to be attempt ed or achieved, post-operative radiotherapy is usually necessary. Patients with established paraplegia are extremely unlikely to recover after either surgery or radiotherapy. No treatment may there- fore be appropriate, unless persistent pain is it self an indication for active intervention. OHO-32(571-582) 11/18/02 9:27 AM Page 581 MANAGEMENT 581 The overall condition and prognosis should also determine how active management should be. For example, complex spinal surgery, involving weeks or months of hospitalization, is inapp ropriate for someone whose underlying disease carries a very poor prognosis. Chemotherapy has no role in the management of acute spinal cord compression. OHO-32(571-582) 11/18/02 9:27 AM Page 582 SPINAL CORD COMPRESSION 582 General advice Early involvement of a physiotherapist and occupational therapist will ensure optimal rehab ilitation and remobilization. Discharge plans should be made as early as a realistic estima te of likely \201nal function is possible. Bear in mind the risk of deep venous thrombosi s and pres- sure sores in those patients who remain paraplegic. The prognosis for cancer patients who develop spinal cord compres- sion is poor \200\2248 \200\2239 months for those who are ambulant after treatment and only one month for those wh o are not. OHO-33(583-590) 11/18/02 9:30 AM Page 583 Chapter 33 Bone marrow suppression Introduction 584 Causes of bone marrow failure 586 Pancytopenia in the cancer patient 587 M anagement of fever in a neutropenic patient 588 Thrombocytopenia in the cancer patient 589 Red cell transfusions in cancer patients 590 OHO-33(583-590) 11/18/02 9:30 AM Page 584 BONE MARROW SUPPRESSION 584 Introduction The major dose-limiting toxicity of cancer chemotherapy is bone marrow suppression, comprom ising the potential for cure in many patients with chemotherapy malignancies. The ability t o cope with myelosuppression and its consequent morbidity is integral to an oncologist \200 \231s skills and requires a thorough understanding of haemo- poiesis and the bone marrow re sponse to different chemotherapies. Manipulation of myelosuppression kinetics with haemopoi etic growth factors is a new and exciting development in cancer treatment and, with the adv ent of stem cell technology, the dose intensity of can- cer chemotherapy is being taken to previously unheard of limits. The bone marrow is a complex organ system responsible for haemopoiesis. In adults it is pre dominantly situated in the vertebrae, sternum, ribs, skull, and proximal long bones. A sing le early stem cell is thought to be the progenitor for all blood cells, producing a lymphoi d stem cell and a mixed myeloid progenitor cell that then undergo fur- ther differentiation before being released as formed elements into the peripheral circulation. Between 1010 and 1012 cells are produced by the bone marrow every hour in a carefully controlled manner. Bo ne mar- row failure usually produces a pancytopaenia. Since red blood cells survive about 120 days, platelets about 8 days, and neutrophils appro ximately 1 \200\2232 days, early problems relate mainly to neutropenia and trombocytopenia. Therapeutic interventions in cancer patients producing bone marrow compromise include cyto - toxic chemotherapy, bone marrow transplantation, and wide- \201eld irradiation. Normal healthy bone marrow is capable of supplying the peripheral blood with mature cells f or 7 \200\22310 days after precursor cell damage by cytotoxic agents; drug effects tend to manifest between days 7 and 14. This time-frame is variable, with different drugs producing different neutrophil and platelet suppression pro \201les depending on precursor populati ons affected. Myelosuppression related to chemotherapy can be graded using de \201ned crit eria \200\224a process useful in clinical trials and in judging risk in dose-intensive ther apy. OHO-33(583-590) 11/18/02 9:30 AM Page 585 INTRODUCTION 585 Table 33.1 NCIC \200\223CTG expanded common toxicity criteria Toxicity grade 0 1 2 3 4 Hb g/dl Platelets \227 109/l WNL 7.5 \200\223normal WBC \227 109/l Granulocytes WNL 10.0 \200\223normal 8.0 \200\2239.9 6.5 \200\2237.9 <6.5 50.0 \200\22374.9 25.0 \200\22349.9 <25.0 \211 4.0 \211 2.0 \211 2.0 3.0 \200\2233.9 2.0 \200\2232.9 1.0 \200\2231.9 <1.0 1.5 \200\2231.9 1.0 \200\2231.4 0.5 \200\2230.9 <0.5 Lymphocytes 1.5 \200\2231.9 1.0 \200\2231.4 0.5 \200\2230.9 <0.5 OHO-33(583-590) 11/18/02 9:30 AM Page 586 BONE MARROW SUPPRESSION 586 Causes of bone marrow failure (cid:2) Depletion of anatomical and physiological elements e.g. myelo- \201brosis, myelodysplasia Intrinsic stem cell/precursor cell failure e.g. aplastic anemi a, paroxysmal nocturnal haemoglobinuria Iatrogenic e.g. chemotherapy, irradiation (cid:2) B one marrow in \201ltration e.g. malignancy (cid:2) Peripheral consumption e.g. hyperspleni sm (cid:2) Autoimmune diseases e.g. systemic lupus erythematosis (cid:2) Vitamin de \201ci ency e.g. megaloblastic anemia (cid:2) (cid:2) OHO-33(583-590) 11/18/02 9:30 AM Page 587 PANCYTOPENIA IN THE CANCER PATIENT 587 Pancytopenia in the cancer patient (cid:2) Neutropenia \200\224life-threatening bacterial infections (cid:2) Associated with \200\224poor nutrition \200\224mucosal barrier defects \200\224abnormal host colonization (cid:2) Qualitative and quantitative defects (cid:2) Defects in chemotaxis, neutrophil degr anulation Table 33.2 Most common micro-organisms in neutropenic patients Gram-negative bacilli Gram-positive bacilli Fungi E. coli Staphylococcus aureus Candida spp Klebsiella spp Staphylococcus epidermidis Aspergillus spp Enterobacter spp Streptococcus pneumoniae Mucorales Proteus spp Viridans streptococci P. aeroginosa Enterococci Corynebacterium OHO-33(583-590) 11/18/02 9:30 AM Page 588 BONE MARROW SUPPRESSION 588 Management of fever in a neutropenic patient Fever is common in patients with cancer. Although commonly caused by infection it can also be related to underlying malignancy, blood product transfusion, and pyrogenic medications. Careful evaluation of fever in a neutropenic patient should not take long. Untreated sep- s is in a neutropenic patient can be rapidly fatal. Generally, antibiotics are administered a fter the following simple investigations: (cid:2) Blood cultures (peripheral and central, i f line in situ) (cid:2) Sputum culture (cid:2) Urine analysis and culture (cid:2) Chest X-r ay (cid:2) Swabs from Hickman line exit site (cid:2) Careful physical examination Treatment should then be instituted, with empirical antibiotic therapy, particularly if the patient is toxic or haemodynamically compromised. The widespread adoption of this approach has redu ced the mortality of neutropenic sepsis to less than 10%. Careful observation of the febrile response to antibiotics, coupled with body \202uid cul ture results, will determine adjustment of anti- biotic therapy over the next few days. If the fever is unremitting at 48 hours, or there is any clinical deterioration, an empirical change of antibiotics to a second-line antibiotic regime should be performed. Failure to resolve the fever within 5 days may suggest other oppor- tunistic infections suc h as fungi or parasites such as Pneumocystis carinii. Careful consideration of these diagno ses, in close consultation with a microbiologist, is required before initiation of speci \201c treat- ments, such as amphotericin B, for these infections, since the therapies thems elves are potentially toxic. Often, resolution of neutropenia results in resolution of refractory fever. This process ca n be accelerated by the use of haemopoietic growth factors. OHO-33(583-590) 11/18/02 9:30 AM Page 589 THROMBOCYTOPENIA IN THE CANCER PATIENT 589 Thrombocytopenia in the cancer patient Thrombocytopenia is commonplace in patients receiving cytotoxic chemotherapy. The trigger l evel to transfuse platelets is not always absolute. Spontaneous bleeding is unlikely if pla telets are >20 \227 109/l, but the risk of traumatic bleeding is greater if <40 \227 109/ l. Most clini- cians would transfuse when platelets are <10 \227 109/l. However, if there is active bleeding, many clinicians would transfuse if <50 \227 109/l. Careful consideration of the patient \200\231s vascular status, clotting status, and diseas e risks (e.g. gastric carcinoma) will determine the threshold for transfusion in an individ ual patient. Cross-matching is not required since patients generally receive random, pooled , donor platelets. Some patients may become refractory after repeated transfusions and HLA-matched platelets s hould be used. Four units of fresh platelets, (doubled if platelets greater than three days old), should raise the count to >24 \200\22340 \227 109/l in an adult. Although frequentl y part of the differential diagnosis of refractoriness, HLA allo-immunization is only one o f many causes. Others include the presence of: (cid:2) Anti-platelet antibodies (cid:2) Dis seminated intravascular coagulation (cid:2) Concomitant drugs e.g. septrin (cid:2) Hyperspl enism OHO-33(583-590) 11/18/02 9:30 AM Page 590 BONE MARROW SUPPRESSION 590 Red cell transfusions in cancer patients A low hemoglobin in a patient with cancer is also common and requires careful diagnostic ev aluation. Elimination of obvious causes such as bleeding from a gastrointestinal malignancy are important before repeated red cell transfusions are given. A one-unit blood transfusio n should raise the hemoglobin by approximately 1 g/dl. Transfusion may reduce the platelet count, so platelet transfusion may be required before or after blood transfusion. Red cell transfusion should be based on clinical criteria rather than absolute trigger valu es. The use of erythropoietin to maintain haemo- globin values in patients with cancer, on or off treatment, is unproven. OHO-34(591-598) 11/18/02 9:31 AM Page 591 Chapter 34 Superior vena cava obstruction Etiology 592 Clinical features 593 Differential diagnoses 594 Investigations 595 Treatment 596 Prognosis 597 OHO-34(591-598) 11/18/02 9:31 AM Page 592 SUPERIOR VENA CAVA OBSTRUCTION 592 Etiology The superior vena cava can be obstructed by: (cid:2) External compression (primary tumor or lymph nodes) (cid:2) Thrombus (secondary to compression; also IV catheters) (cid:2) Combin ation of above In cancer patients the commonest cause is external compression by either a p rimary tumor in the right paratracheal region or a second- ary tumor in the paratracheal ly mph nodes. Lung cancer is the commonest tumor to cause superior vena cava obstruction (SVCO), but any tumor spreading to the mediastinal nodes (especially lymphomas) may do so. Other causes inc lude rup- tured thoracic aortic aneurysm and trauma. OHO-34(591-598) 11/18/02 9:31 AM Page 593 CLINICAL FEATURES 593 Clinical features Symptoms: (cid:2) Swelling of the neck, face, and arms, especially in the morning (cid:2) Headache (c id:2) Visual disturbance SVCO itself does not impair respiration but it is commonly asso- ciated with dyspnoea due t o tracheal or bronchial obstruction/ compression Examination: (cid:2) Fixed engorgement of external and internal jugular veins (cid:2) Collateral veins o ver anterior and lateral chest wall (which drain down) (cid:2) Papilloedema (late feature) OHO-34(591-598) 11/18/02 9:31 AM Page 594 SUPERIOR VENA CAVA OBSTRUCTION 594 Differential diagnoses Heart failure dependent oedema. Tamponade Characteristic symptoms/signs and CXR appearances . External jugular vein compression No facial oedema; no collaterals; usually supraclavicul ar fossa nodes. Jugular veins pulsating not \201xed; other cardiac signs; OHO-34(591-598) 11/18/02 9:31 AM Page 595 INVESTIGATIONS 595 Investigations The clinical diagnosis of SVCO is usually obvious and investigation should be aimed at esta blishing the cause, especially if there is no pre- existing diagnosis of malignancy. Unless the patient has very severe and life-threatening symptoms (e.g. associated stridor) treatm ent should not start until a clear diagnosis (including pathology if possi- ble) has been m ade. Chest x-ray usually shows a right paratracheal mass or other indica- tions of lung can cer or mediastinal lymphadenopathy. It is rarely normal. CT thorax is required only if CXR \201ndings are equivocal or if indicat- ed for the normal investigation of the underlying tumor. Venogram is needed if there is no obvious mass causing external com- pression, or i f thrombolysis or stent insertion are planned. FNA cytology samples should be taken from, f or example, cervical lymphadenopathy. Bronchoscopy is essential if the clinical picture and CXR suggest lung cancer and a histopathological diagnosis is not yet obtained. Mediastinal biopsy (mediastinoscopy, mediastinotomy, mini- thoracotomy, or directed-needle biopsy) is essential if a pathological diagnosis has not been established any other way. There is an i ncreased risk of hemorrhage from these procedures in patients with SVCO, but this is small in experienced hands. OHO-34(591-598) 11/18/02 9:31 AM Page 596 SUPERIOR VENA CAVA OBSTRUCTION 596 Treatment In the majority of cases the treatment is that of the underlying cause and it is important to establish a clear diagnosis (including pathology) before starting. It is unusual for the symptoms to be so severe as to require emergency treatment (unless there is coincident tra cheal com- pression) and the gradual development of collateral circulation means that sympt oms often stabilize. (cid:2) Treatment choices for commonest underlying tumors include: \200\224Small cell lung cancer: chemotherapy (unless physical state very poor); radiotherapy (at relapse following chemotherapy).