Chapters from Clinical Oncology

Transcription

1 Chapters from Clinical Oncology Lecture notes University of Szeged Faculty of Medicine Department of Oncotherapy 2012.

2 Childhood malignancies The number one cause of death in children is accidents (44%), followed by cancer (10%), congenital abnormalities (8%), homicide (5%), and heart disease (4%). Incidence of childhood cancers: - leukemias are the most common (~30%, the majority of which are ALL) followed by - CNS neoplasms(~20%) - lymphomas (~15%, Hodgkin s > NHL > Burkitt s lymphoma) - neuroblastoma (~8%), - Wilms tumor (~6%), - Sarcomas:osteosarcoma (~3%), rhabdomyosarcoma (~3%), non-rhabdomyosarcoma soft-tissue sarcomas (~3%), Ewing s sarcoma (~2%), - retinoblastoma (~2%), and others. Of pediatric CNS neoplasms, gliomas are most common (lowgrade astrocytomas ~35 50%, brainstem gliomas ~15%, malignant astrocytomas ~10%, optic pathway gliomas ~5%), followedby medulloblastoma (~20%), ependymomas (~10%), craniopharyngioma (~5 10%), and germ cell tumors (<5%). Difficulties in treatment of childhood malignancies: Late discovery, sensitive (especially radiosensitive) normal tissues, lack of compliance during therapy, psychological issues. Complex therapy of childhood malignancies follows the general rules of oncological interdisciplinary treatment approach based on the three large pillars of surgery, chemotherapy radiotherapy. The decision is based on risk groups defined strict protocols, and if the child is younger than 3 years RT should be postponed to elder age if possible. Because of potential serious late sequales such as fibrosis, organ impairment, function disturbance, retardation in bone growth, serious deformities functional-, cosmetic problems, and because of the danger of second tumor induction. (For pediatric brain tumors see brain tumor chapter) Haematological malignancies are treated according to the regularly upgraded protocols. Leukaemias Malignant disease of the white blood cells, affecting the blood, bone marrow, and lymphoid system. Clinically and pathologically, leukemia is subdivided into a variety of large groups. Acute leukemia is characterized by a rapid increase in the number of immature blood cells and needed immediate treatment, meanwhile in chronic leukemia represented by the excessive build up of relatively mature, but still abnormal, white blood cells. Symptoms and signs of the disease caused by: bone marrow infiltration: anemia (pallor, lethargy, dyspnea, murmur) decrease of platelets (bleeding, petechiae, purpura) Neutropenia (fevers and infections) Bone pain (limp, reduced walking, irritability) Extramedullary spread: Lymphadenopathy, hepatosplenomegaly, orthopnea, cough, mediastinal mass, tracheal compression, facial nerve palsy, testicular enlargement, skin lesions, gingival hypertrophy Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. The survival rates vary by age: 85% in children and 50% in adults. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia. Treatment based on chemotherapy, but special type of radiotherapy belongs to the standard treatment protocols for profilactic irradiation o the meningeal spaces, and in the case of testiculat or meningeal involvment.

3 Acute myelogenous leukemia (AML) occurs more commonly in adults than in children The five-year survival rate is 40%. Subtypes of AML include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia. AML is treated with chemotherapy. Chronic lymphocytic (CLL) and myelogenous leukemia (CML) occurs mainly in adults; A very small number of children also develop CML. One subtype is chronic monocytic leukemia. Treatment is with imatinib or other drugs. The five-year survival rate is 90%.. PEDIATRIC HODGKIN S LYMPHOMA Hodgkin s lymphoma constitutes ~6% of childhood cancers. It shares many aspects of biology and natural history with adult. Due to morbidity from RT, lower-dose RT with chemo is used to treat children. Hodgkin s lymphoma is most common among children >10 years and rare among children <4 years. Approximately 80 85% of patients present with stage I III disease, and 15 20% present with stage IV. WORKUP History (including B symptoms, pruritis, respiratory symptoms) and physical exam. Labs include CBC, LFTs, BUN/Cr, ESR. Imaging includes, CT of chest, abdomen, and pelvis, and PETCT scan Pathologic diagnosis is obtained by excisional biopsy (to study architectural changes). Bone marrow biopsy is obtained for patients with B symptoms or stage III IV. Histologic assessment is required to diagnose spleen and/or liver involvement. STAGING Ann Arbor Staging System used TREATMENT Low risk: IA, IIA favorable (no bulky disease, no extranodal disease) Chemo 2 4c ± Involved field (IF) RT Gy Intermediate risk: stage I or II (not low-risk); IIIA Chemo 2 4c ± Involved field (IF) RT Gy High risk: IIIB, IVA/B, selected IIB with adverse associated features (e.g.,bulky disease) Chemo 2 4c ± Involved field (IF) RT Gy Chemotherapy Hybrid regimens that utilize lower cumulative doses of alkylators, doxorubicin, and bleomycin are used [e.g., COPP/ABV, OEPA (males), OPPA (females), etc.]. Drugs include: cyclophosphamide (C), procarbazine (P), vincristine (O) and/or vinblastine (V), prednisone (P) or dexamethasone, doxorubicin (A) or epirubicin, bleomycin (B), dacarbazine (D), etoposide (E), methotrexate (M), and cytosine arabinoside. RADIATION Use of thermoplastic mask for immobilization for better reproducibility is recommended. Involved fields are protocol specific, but generally include the initially involved lymph node region(s). Attempts should be made to exclude as much lung, humeral head, and breast tissue as possible. For children <5 years, some consider bilateral RT to avoid growth asymmetry. However, with low doses, unilateral fields are usually appropriate. Dose prescriptions In general, the dose is Gy (protocol specific). Occasionally, a 5 Gy boost is used. Dose may be determined by response to initial chemo. COMPLICATIONS: Chemo complications include bleomycin (pulmonary fibrosis/ pneumonitis); doxorubicin (cardiomyopathy); alkylators and etoposide (AML and myelodysplasia); procarbazine (male infertility); prednisone (avascular necrosis). Complication of RT include musculoskeletal hypoplasia, sterility, hypothyroidism, radiation pneumonitis, increased risk for myocardial atherosclerotic heart disease, and increased risk of second malignancy. The rate of second malignancies is ~8 15% at 20 years. Breast cancer is the most common solid 2nd malignancy following RT.

4 WILMS TUMOR Seventy-five percent of cases present before age 5. Median age at diagnosis is 3 4, or 2.5 years for bilateral tumors (only 4 8%) of cases Signs and symptoms Tumor presents with abdominal mass, pain, hematuria, HTN, fever, and/or malaise. Calcifications are uncommon (10%) in contrast to neuroblastoma (90%). Histology Ninety percent of cases are favorable histology (FH) = no anaplastic or sarcomatous components, while 10% are unfavorable histology (anaplastic [focal vs. diffuse], clear cell sarcoma, or rhabdoid tumor). Difference between focal and diffuse anaplasia is strongly significant for stage II IV 4-year OS (90 100% vs. 4 55%). Genetics Congenital anomalies associated with Wilms tumor (~10%) include WAGR syndrome (Wilms, aniridia, genitourinary malformations, retardation due to del 11p13 and WT1 gene), Denys Drash syndrome (pseudohermaphroditism, renal mesangial sclerosis, renal failure due to WT1 gene mutation), and Beckwith Wiedemann syndrome (hemihypertrophy, macroglossia, GU abnormalities, gigantism due to 11p15 abnormality near WT2 gene). FH patients with LOH of 1p and/or 16q have poorer RFS and OS according to NWTS-5. WORKUP H&P, abdominal US, CT or MRI of primary, CXR and/or CT chest, CBC, UA, BUN/Cr, LFTs. For clear cell variant, add bone scan, MRI brain, and bone marrow aspiration and biopsy (propensity for bone, bone marrow, and brain mets). For rhabdoid variant, may add MRI of brain (because 10 15% of patients have PNET of cerebellum or pineal regions). Do not biopsy unless unresectable or bilateral. STAGING COG staging system NWTS 3 and 4 10-year OS TREATMENT: % are resectable at diagnosis. Nodes must be sampled; liver and contralateral kidney should be evaluated. Perform radical nephrectomy. Clips should be placed in residual disease. If unresectable, biopsy, and give neoadjuvant therapy resection if possible. Chemotherapy agents include vincristine (V), actinomycin (A), doxorubicin (D), cyclophosphamide (C), etoposide (E), carboplatin (P), and irinotecan (I). Actinomycin prohibited during RT! 10.8 Gy to flank Whole abdomen RT indicated if diffuse tumor spillage, pre-op or intraperitoneal tumor rupture, peritoneal tumor seeding, and cytology + ascites. Gross residual disease after surgery should receive 10 Gy boost Stage III diffuse anaplasia, I III rhabdoid: 19.8 Gy (infants 10.8 Gy) to flank. Whole abdomen RT indicated if diffuse tumor spillage, pre-op or intraperitoneal tumor rupture, peritoneal tumor seeding, and cytology + ascites. Gross residual disease after surgery should receive 10 Gy boost. COMPLICATIONS Scoliosis, kyphosis, soft-tissue hypoplasia, small bowel obstruction, iliac wing hypoplasia, liver/kidney hypoplasia, renal failure, pneumonitis, congestive heart failure (related to doxorubicin), and second malignancy. NEUROBLASTOMA Neuroblastoma is the most common extracranial solid tumor in children and the most common malignancy in infants <1-year old. The median age at diagnosis is 17 months. It arises from primitive neural crest cells of the spinal ganglion, dorsal spinal nerve roots, and adrenal medulla. Shimada Classification divides neuroblastoma into favorable (FH) and unfavorable (UH) histology based on age, amount of Schwann cell stroma, nodular vs. diffuse pattern, degree of differentiation, and mitotic index. Cytogenetic abnormalities associated with poorer prognosis

5 include LOH 1p, N-myc protooncogene amplification, diploid tumors (DNA index 1), and increased telomerase activity. The high spontaneous regression rate led to overdiagnosis of clinically insignificant disease. Neuroblastoma most commonly arises in the adrenal gland, followed by the abdomen and thorax. Sixty percent of patients <1 year present with localized disease, while 70% of patients >1 year present with metastases. Signs classically include the blueberry muffin sign (nontender blue skin nodules), raccoon eyes (orbital mets with proptosis and bruising), and opsoclonus-myoclonus-truncal ataxia (a paraneoplastic syndrome of myoclonic jerking and random eye movements that is associated with early stage and may persist after cure). WORKUP H & P, Labs include urine catecholamines vanillylmandelic acid, and homovanillic acid), CBC, BUN/Cr, and LFTs Imaging includes CT/MRI of primary, MIBG scan, and CT chest. The primary is calcified on X-ray in 80 90% of cases (vs. 5 10% in Wilms ). Biopsy of the primary or involved nodes. All patients should have a bilateral bone marrow biopsy and aspirate. TREATMENT Low risk: Surgery and observation if GTR. If STR, unresectable, or recurrence after GTR: chemo for 6 12 weeks. Chemo regimens consist of carboplatin,. Unresectable tumors may require pre-op chemo to convert them to resectable status If PR to chemo - second look surgery. If viable residual disease present: RT to primary + 2 cm margin (1.5/24 Gy). Radiation controversial in intermediate-risk disease High risk: High-dose chemo (same drugs often with ifosfamideand cisplatin) attempt maximal safe resection. After surgery:high-dose chemo and ABMT. All patients then get RT (1.8/21.6 Gy) to the postchemo presurgical extent of tumor +2 cm margin + cis-retinoic acid for 6 months. If available, IORT may be used at the time of operation, although this is not standard-of-care. RHABDOMYOSARCOMA Rhabdomyosarcoma accounts for ~3% of childhood cancers. The most common primary sites are the head and neck [40% = parameningeal (25%), orbit (9%), nonparameningeal sites (6%)], genitourinary tract (30%), extremity (15%), and trunk (15%). Most cases are sporadic, but predisposing conditions include Li-Fraumeni syndrome (germline p53 mutation), neurofibromatosis type 1, and Beckwith Wiedemann syndrome (more commonly associated with Wilms tumor). The classic histologic subtypes include: embryonal (60 70%), alveolar (20 40%), botyroid (10%), undifferentiated (5%), and spindle cell (<5%). Embryonal tumors, typically arise in the orbit, head and neck, or the genitourinary tract. Botyroid tumors arise in the vagina, bladder, nasopharynx, and biliary tract. Spindle cell tumors are most frequently observed in the paratesticular site. Alveolar tumors most commonly arise in the extremity, trunk, or retroperitoneum of adolescents. Positive prognostic histologic subtypes include botyroid (95% OS) and spindle cell (88% OS). Embryonal is an intermediate prognostic subtype (OS 66%). Poor prognostic subtypes include alveolar (OS 54%) and undifferentiated (OS 40%). WORKUP H&P: EUA may be needed. Cystoscopy should be performed for GU sites. Labs include CBC, LFTs, BUN/Cr, LDH. Imaging includes CT/MRI of primary, CT of chest and abdomen, bone scan. Bone marrow biopsy. Treatment All patients require multimodality therapy consisting of surgery (if possible) followed by chemo ±RT. Treatment is based on stage, group, and primary site. Chemotherapy agents include VCR, AMD, CY, topotecan, and irinotecan. VA = VCR/AMD. VAC = VCR/AMD/CY. VTC = VCR/topotecan/CY. VCPT = VCR/ irinotecan. RT for Low risk at

6 week 3 (36 Gy for N0 or 41.4 Gy for N1), higher risk: RT (50.4 Gy except for orbit which is 45 Gy). EWING S SARCOMA Approximately 200 cases per year in the U.S. Put this on its own bullet Ewing s sarcoma is the second most common bone cancer of children (osteosarcoma is #1). Boys are affected more than girls (1.5 2:1). The median age at presentation is 14 years (usually 8 25 years). Ewing s sarcoma is rare in African Americans and Asians. Ewing s sarcoma commonly presents in the lower extremity (femur 15 20%, more common than tibia or fibula 5 10%), pelvis (20 30%), upper extremity (humerus 5 10%), ribs (9 13%), and spine (6 8%) % percent of patients present with localized disease; 20 25% have metastases to lung, bone, or bone marrow. Nearly all patients have micromets at diagnosis, so all need chemotherapy. Ewing s family of tumors includes Ewing s sarcoma (bone 87%), extraosseous Ewing s sarcoma (8%), peripheral PNET (5%), and Askin s tumor (PNET of chest wall). More than 90% of patients have t(11;22) [or t(21;22)] involving the EWS gene on chromosome 22. The c-myc protooncogene is frequently expressed in Ewing s (whereas n- myc is often amplified in neuroblastoma). Diagnosis X-rays of the primary frequently show a moth-eaten lesion in the diaphysis. Lytic lesions are more common than blastic, and onion-skinning may be present for subperiosteal lesions. CT and/or MRI of primary, bone scan, CT chest, ±PET scan. Biopsy the lesion and obtain a bone marrow biopsy. TREATMENT Induction chemo (VDC(A) alternating with IE) 48 weeks + local treatment (surgery or RT) at week 12 with concurrent multiagent VDC chemo often given adjuvant chemo. Response rate to initial chemo is up to 90%. Chemo agents = vincristine (V), doxorubicin (D), cyclophosphamide (C), actinomycin-d (A), ifosfamide (I), and etoposide (E). Current Euro- Ewing 99 trial: VIDE chemo q3 week 6c + local therapy at week 18 + VAI or VAC chemo 8c or busulfan melphalan. Limb-salvage surgery is preferred over amputation. Post-op RT is given for gross residual disease (55.8 Gy) or + microscopic margins (45 Gy) RETINOBLASTOMA Retinoblastoma (RB) is the most common intraocular tumor of childhood. Ninety-five percent of cases occur in children <5 years. The RB1 tumor suppressor gene on chromosome 13 causes RB only when both alleles are hit. Forty percent of patients have a germline mutation of RB1; 60% of cases are sporadic. Although autosomal recessive, RB is inherited in an autosomal dominant pattern due to penetrance approaching 100%. Up to 25 40% of cases are familial in that the affected gene is inherited, but only 10% have a + family history of RB. Genetic counseling should be given to all patients with RB and siblings should be examined % of cases are unilateral (mostly sporadic) and 20 35% are bilateral (mostly due to germline mutations). In the developing world, patients present with proptosis, orbital mass, or mets. In the US, the most common presentation is leukocoria, strabismus, painful glaucoma, irritability, failure to eat, and low-grade fever. spread: continguous spread through the choroid/sclera/orbit; extension along the optic nerve into the brain; invasion of subarachnoid space/leptomeninges via CSF; hematogenous spread to bone, liver, and spleen; and lymphatic spread from the conjunctiva.i Diagnosis external ocular examination, slit lamp bimicroscopy, and biocular indirect ophthalmoscopy (often under anesthesia for mapping).

7 Imaging: Fluorescein angiography, bilateral US (A&B mode), and MRI. Bone scan and/or lumbar puncture for symptoms or suspected metastatic disease. Treatment Laser therapy, Chemotherapy, (agents include vincristine, carboplatin, and etoposide. Focal therapy options include: EBRT (46-50 Gy) with special retinoblastoma technique. Enucleation if the tumor is massive or if the eye is unlikely to have useful vision after treatment.