Corso di Oncologia Medica, AA RENAL CELL CARCINOMA

Transcription

1 Corso di Oncologia Medica, AA RENAL CELL CARCINOMA

2 RENAL CELL CARCINOMA (RCC) 90-95% of malignant renal neoplasms; notable features include: - refractoriness to cytotoxic agents; - infrequent but reproducible responses to biologic response modifiers (e.g., interferon - α and interleukin, IL - 2) - variable clinical course for pts with metastatic disease (with anecdotal reports of spontaneous regression)

3 EPIDEMIOLOGY

4 RENAL CELL CARCINOMA Epidemiology * annual incidence (in 2002, 36,000 new diagnosed cases in USA deaths); - M / F = 2 : 1; - incidence peak at yrs (but diagnosed at any age)

5 RENAL CELL CARCINOMA Incidence over time

6 RENAL CELL CARCINOMA Incidence by age

7 RISK FACTORS

8 many environmental factors investigated as possible contributing causes; - cigarette smoking (strongest association, accounting for 20-30% of cases); - obesity; - acquired cystic disease of kidney (associated with end - stage renal disease), and - tuberous sclerosis

9 most cases are sporadic, with some familial forms: - von Hippel - Lindau (VHL) syndrome, predisposing to RCC (in ~ 35% of pts and incidence in 1st degree relatives), retinal hemangioma, hemangioblastoma of spinal cord and cerebellum and pheochromocytoma - allelic loss at chr 3p = most frequent genetic alterations (97% of cases?); - deletions at 3p21-26 (where the VHL gene maps) in familial as well in sporadic cases

10 MUTATIONS IN VON HIPPEL - LINDAU GENE VHL gene maps to chr 3 above: structure of VHL gene (on chr 3); below: arrows, lines and asterisks = ifferent mutations in individual families (germline) or in individual, sporadic tumors

11 PATHOLOGY

12 RENAL CELL CARCINOMA. Pathology most RCC arise from epithelial cells of proximal tubules : - clear cell carcinoma (60%); - papillary tumors (5-15%); - chromophobic tumors (5-10%); - oncocytomas (5-10%), and - collecting or Bellini duct tumors ( 1%)

13 RENAL CELL CARCINOMA. Pathology. IV.

14 RENAL CELL CARCINOMA. Pathology. * clear cell tumors: tumor cells with clear cytoplasm and usually deletion of 3p; * papillary tumors: often bilateral and multifocal (trisomy 7 and / or 17 as most frequent markers); - chromophobic tumors: multiple chromosomal losses (no 3p deletions, quite indolent course); - oncocytomas: typical morphology with deeply eosinophilic cytoplasm (no 3p deletions or trisomy 7 or 17,?benign tumors); - Bellini duct carcinomas: very rare,?from collecting ducts of renal medulla, young pts, highly aggressive

15 CARCINOMA TYPE GROWTH PATTERN CELL OF ORIGIN CYTOGENETICS clear cell acinar or sarcomatoid proximal tubule 3p- papillary papillary or sarcomatoid proximal tubule +7, +17, -y chromophobic solid, tubular or sarcomatoid cortical collecting tubule hypodiploid oncocytic tumor nests cortical collecting tubule undetermined collecting duct papillary or sarcomatoid medullary collecting tubule undetermined

16 clear cell renal carcinoma (clear cytoplasm and deletion of 3p)

17 * papillary renal tumor associated with hereditary renal cell cancer with c - met tyrosine tinase mutations (# from VHL or TSC mutations resulting in clear cell histology)

18 oncocytoma (typical morphology of deeply eosinophilic cytoplasm)

19 RENAL CELL CARCINOMA. Pathology. * growth pattern (acinar, papillary or sarcomatoid); * degree of differentiation (G1, G2, G3)

20 CLINICAL FEATURES

21 CLINICAL PRESENTATION. Local symptoms * classic triad of hematuria, abdominal pain and flank or abdominal mass (10-20% of pts); - microscopic hematuria = consistent abnormality of urinary sediment (40% of pts, macrohematuria not usual)

22 CLINICAL PRESENTATION. Systemic symptoms * ESR, fever, weight loss and anemia in 20-55% of pts RCC called the internist s tumor because diagnosed from systemic symptoms rather than from urologic manifestations

23 CLINICAL PRESENTATION. Paraneoplastic syndromes * a spectrum of paraneoplastic syndromes associated with RCC, including: * hematologic paraneoplastic syndromes: - erythrocytosis (~ 3% of pts, from production of erythropoietin; more frequently anemia, as a sign of advanced disease) - eosinophilia, leukemoid reactions, thrombocytosis

24 CLINICAL PRESENTATION. Paraneoplastic syndromes * non hematologic paraneoplastic syndromes: - hypercalcemia (5%, from PTH - like substances and prostaglandins), galactorrhea (prolactin), hypertension (renin), feminization and masculinization (gonadotropins) and Cushing s syndrome (glucocorticoids); - non - metastatic hepatic dysfunction (Stauffer s syndrome, 15% of pts, with alkaline phosphatase, hypoalbuminemia and prolonged prothrombin time), and - acquired dysfibrinogenemia

25 SIGNS AND SYMPTOMS IN PATIENTS WITH RENAL CELL CANCER presenting sign or symptom % classic triad: hematuria, flank pain, flank mass hematuria 40 flank pain 40 palpable mass 25 weight loss 33 anemia 33 fever 20 hypertension 20 abnormal liver function 15 hypercalcemia 5 erythrocytosis 3 neuromyopathy 3 amyloidosis 2 ESR 55

26 CLINICAL PRESENTATION. * over the past two decades, incidental finding on a radiograph (25-40% of today s diagnoses) = earlier detection of incidental, low - stage RCC due to widespread use of radiologic cross - sectional imaging procedures (CT, ultrasound, MRI) during evaluation of other medical conditions; -the no. of incidentally discovered lowstage tumors 5 - yr survival and use of nephron - sparing surgery (partial nephrectomy)

27 DISSEMINATION AND METASTASES FROM RENAL CELL CARCINOMA * contiguous extension to renal capsule, perirenal fat, lymph nodes, renal vein, inferior vena cava and ipsilateral renal adrenal gland; * lung, bone, liver, mediastinum, CNS and thyroid = most common sites of metastases

28 DIAGNOSIS AND EVALUATION OF THE PATIENT

29 EVALUATION OF THE PATIENT. * standard evaluation of pts with suspected RC tumors includes: - ultrasonography of kidneys; - computed tomography (CT) scan of abdomen and pelvis; - chest X - ray, and - urine analysis with cytology

30 COMPUTED TOMOGRAPHY (CT) SCAN OF * = preferred modality for evaluating in: - # cysts from RCC; - renal vein and inferior vena cava invasion; - regional lymph node enlargement (due to either tumor or hyperplasia), and - liver involvement ABDOMEN AND PELVIS diagnosis and staging RCC

31 CT scan of abdomen tumors in left kidney (hypernephroma)

32 CT scan large mass from right renal cortex (due to size of this mass, tumor is palpable on physical exam)

33 EVALUATION OF THE PATIENT. Preoperative selective renal arteriography * complements CT with equivocal CT findings or (more often) when additional definition of vascular anatomy required for surgery

34 DIFFERENTIAL DIAGNOSIS

35 EVALUATION OF THE PATIENT. X. DIFFERENTIAL DIAGNOSIS * cysts; * benign neoplasms (adenoma, angiomyolipoma, oncocytoma); * inflammatory lesions (pyelonephritis or abscesses), and * other primary or metastatic malignant neoplasms (including Wilms' tumor, transitional cell carcinomas of renal pelvis, sarcoma, lymphoma, and metastatic disease, especially melanoma primaries); * all of these < common than RCC

36 STAGING AND PROGNOSIS

37 Staging renal cell carcinoma Tx = primary tumor cannot be assessed; T0 = ca. in situ; T1 = 7 cm in greatest Ø, limited to kidney T2 = > 7 cm in greatest Ø, limited to kidney T3 = extension into major veins or invasion of adrenal gland or perinephric tissues, but not beyond Gerota's fascia; T4 = invasion beyond Gerota's fascia

38 Staging renal cell carcinoma T1 = 7 cm in greatest Ø, limited to kidney

39 Staging renal cell carcinoma T2 = > 7 cm in greatest Ø, limited to kidney

40 Staging renal cell carcinoma T3 = gross extension into renal vein(s) or vena cava, below the diaphragm

41 Staging renal cell carcinoma T4 = invasion beyond Gerota's fascia

42 Regional lymph nodes (N) N0: no regional lymph node metastasis; N1: metastasis in a single regional lymph node; N2: metastasis in > 1 regional lymph node Distant metastases (M) M0: no distant metastasis M1: distant metastasis

43 AJCC stage groupings Stage I Stage II Stage III Stage IV T1, N0, M0 T2, N0, M0 T1, N1, M0 T2, N1, M0 T3a, N0 (N1), M0 T3b, N0 (N1), M0 T3c, N0 (N1), M0 T4, N0, M0 T4, N1, M0 Any T, N2, M0 Any T, any N, M1

44 KIDNEY CANCER SURVIVAL BY STAGE

45 TREATMENT

46 Localized disease

47 TREATMENT. LOCALIZED DISEASE. RADICAL NEPHRECTOMY * standard management for stage I or II and a no. of stage III disease: - en bloc removal of Gerota's fascia and its contents including kidney, ipsilateral adrenal gland and adjacent hilar lymph nodes (but role of regional lymphadenectomy still controversial)

48 TREATMENT. LOCALIZED DISEASE. II. RADICAL NEPHRECTOMY * extension into renal vein or inferior vena cava (stage III) does not preclude resection (even if cardiopulmonary bypass required); * Stauffer s syndrome (= pts with hepatic dysfunction, without metastases) also candidate to resection (hepatopathy often reversible after removal of primary)

49 TREATMENT. LOCALIZED DISEASE. PARTIAL NEPHRECTOMY (NEPHRON - SPARING SURGERY) * via open or laparoscopic approach: - in pts with only one kidney (depending on size and location of tumor); - in pts with bilateral tumors (with radical nephrectomy on opposite site); - in pts with small tumors (and normal contralateral kidney)

50 TREATMENT. LOCALIZED DISEASE. IV. ADJUVANT THERAPY * no role for adjuvant chemotherapy, immunotherapy and radiotherapy (even in pts with poor prognosis)

51 Advanced disease

52 * overall, advanced RCC follow an unpredictable, often protracted clinical course (~ 10% of pts with metastases do not progress after 1 yr) = best to document progression before considering potentially toxic treatment approaches

53 TREATMENT. ADVANCED DISEASE. IV. * limited role for surgery; * nephrectomy: - to alleviate pain or hemorrhage of primary tumor; - not indicate to induce tumor regression (< 1% of pts) or to sensitivity to cytotoxic therapy; * occasionally, long - term survival in pts relapsed after nephrectomy in a solitary, removable site

54 TREATMENT. ADVANCED DISEASE. * interferon - α (IFN - α) and interleukin - 2 (IL-2) produce short regressions in 10-20% of pts; - IL - 2 approved from observation of durable complete remission in a small % of pts; -IFN-α as adjuvant after cytoreductive therapy?

55 HISTORICAL EXPERIENCE WITH SYSTEMIC THERAPY FOR METASTATIC RCC

56 TREATMENT. ADVANCED DISEASE. * new cytokines and biological agents under investigation; - promising results from an inhibitor of vascular endothelial growth factor (VEGF)

57 BACKGROUND FOR ANTI - ANGIOGENETIC THERAPY IN CLEAR CELL RENAL CARCINOMA (RCC) * in most sporadic clear - cell RCC tumors, von Hippel - Lindau (VHL) suppressor gene inactivation VEGF overexpression anti - angiogenetic agents expected to be effective in these pts

58 Cancer progression

59 ANGIOGENESIS NEOVASCULARIZATION * = new capillary formation from preexisting postcapillary vessels to supply O 2 and nutrients to tumor; * essential for tumor growth (> 1-2 mm 3 ) and metastasis (continuity with existing vasculature and easier entering into circulation)

60 EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR /(VEGF) ON ANGIOGENESIS * specific endothelial cell mitogen and inducer of angiogenesis; - high levels in many tumors (= major role in tumour angiogenesis)

61 ENDOTHELIAL CELL ACTIVATION receptor dimerization phosphorylation dimeric VEGF ligand p85 PLCg ligand binding adapter molecule binding ras GRB2 SOS downstream signaling events Nucleus * VEGF molecule dimers bind to VEGFRs on vascular and lymphatic endothelial cells; - VEGF - VEGFRs binding receptor dimerization activation and signal transduction cell proliferation

62 BLOCKING INITIAL ANGIOGENESIS * anti - VEGF monoclonal antibodies (bevacizumab) * small tyrosine kinase inhibitors (sorafenib, sunitinib)

63 BEVACIZUMAB (ANTI-VEGF MoAb) IN METASTATIC RENAL CELL CANCER (Yang et al NEJM, 2003) R A N D O M vs placebo (38 pts) LD bevacizumab (3 mg / kg / 2 wks) (35 pts) vs HD bevacizumab (10 mg / kg / 2 wks) (37 pts) * interim analysis: highly significant increase in TTP in HD bevacizumab arm (HR = 2.3; p = 0,001); * the study was prematurely stopped

64 BEVACIZUMAB IN METASTATIC RCC Disease free survival Yang et al NEJM 2003

65 CHANGES IN TUMOR BURDEN OVER TIME FOR METASTATIC RENAL CELL CARCINOMA TREATED WITH BEVACIZUMAB (A) high - dose bevacizumab; (B) low - dose bevacizumab; (C) placebo; - high - dose bevacizumab treatment associated with significant reduction in tumor burden (at 5 and 13 weeks) compared with either low - dose bevacizumab or placebo Elaraj DM et al J Immunotherapy 27: , 2004

66 BEVACIZUMAB IN METASTATIC RCC A) pretreatment assessment ( lymph - node metastases); B) two yrs later (treatment stopped during partial response); C) tumor relapse 6 mos thereafter; D) 2nd partial response 3 mos after therapy restarted (ongoing > 18 mos) Yang et al NEJM 2003

67 BEVACIZUMAB IN METASTATIC RCC Overall survival no significant differences among treatment groups Yang et al NEJM 2003

68 SUNITINIB VS IFN - α IN METASTATIC RCC Motzer RJ et al NEJM 356:115; 2007

69 KAPLAN - MEIER ESTIMATES OF PROGRESSION - FREE SURVIVAL (INDEPENDENT CENTRAL REVIEW)