Goals and Objectives. Historical Background. Historical Background. Incidence. Epidemiology 7/1/2015 ROLE OF RADIOTHERAPY IN WILMS TUMOR

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1 Goals and Objectives ROLE OF RADIOTHERAPY IN WILMS TUMOR Arnold C. Paulino, M.D. Professor of Radiation Oncology MD Anderson Cancer Center To gain an understanding of presentation and work-up of Wilms tumor To determine the role of radiotherapy in localized and metastatic Wilms tumor To gain familiarity with other pediatric renal tumors which may be treated with radiotherapy Historical Background 1814 Rance first case (Case of fungus haematodes of the kidnies) 1828 Gairdner second case (Agnes B) 1899 Max Wilms (Die Mischgeschwuelste) Historical Background Wilms tumor timeline Incidence Epidemiology 450 cases/ year in the U.S. 7 cases per million children in the U.S. Most common abdominal tumor of childhood Sex ratio 0.92:1(M:F) Median age: 3.5 years Cases per million children 1

2 Congenital Syndromes Aniridia Syndrome Presentation Chromosomal Locus WAGR Denys-Drash Beckwith- Wiedemann Aniridia, genitourinary anomalies, mental retardation Intersexual disorders, nephropathy Macroglossia, organomegaly, neonatal hypoglycemia, gigantism 11p13 11p13 11p15 Genetic Change Monoallelic deletion at chromosome 11p13 WT1 point mutation Duplication of paternal allele Incidence of Wilms Tumor > 30% > 90% < 5% Incidence: 8.4 per 1000 Wilms tumor cases Usually identified prior to Wilms (median 522 days) Risk of developing Wilms ranges from 18% to 40% Breslow N et al. Med Pediatr Oncol 1993; 21: Hemihypertrophy Incidence: 24.7 per 1000 Wilms tumor cases Most commonly involves leg Hemihypertrophy diagnosed usually 1 day after dx of Wilms Hemihypertrophy identified in only 32% of cases > 1 month prior to dx of Wilms Breslow N et al. Med Pediatr Oncol 1993; 21: Beckwith-Wiedemann Syndrome Relative risk for Wilms tumor during first 4 years of life: 816 Also have a high incidence of hepatoblastoma, neuroblastoma, adrenocortical carcinoma DeBaun MR, Tucker MA. J Pediatr 1998; 132: Genitourinary Abnormalities Other Anomalies in Wilms Tumor Patients Cryptorchidism 27.8* Hypospadias 17.8 Double collecting system 15.2 Fused kidney 3.7 Other urinary 7.3 Other genital 2.1 * per 1000 Wilms tumor cases Musculoskeletal system (clubfoot, hip anomalies) Uterine anomalies (septate uterus, unicornuate uterus)* Cardiovascular and Respiratory system (septal defects, accessory or anomalous renal vessels, coarctation of aorta) Breslow N et al. Med Pediatr Oncol 1993; 21: *Nicholson HS et al. Cancer 1996; 78:

3 Molecular Biology LOH 16q WT1 (germline deletion at 11p13) WT2 alteration at one or more loci on band 11p15 underlie development of BWS and Wilms tumor LOH 16q found in 20% of cases LOH 1p found in 10% of cases P = 0.01 Grundy P et al. Cancer Res 1994; 54: LOH 1p LOH 1p and 16 q (Stage I/II FH, NWTS-5) P = 0.08 P = 0.01 Grundy P et al. Cancer Res 1994; 54: Grundy PE et al. J Clin Oncol 2005; 23: LOH 1p and 16 q (Stage III/IV FH), NWTS-5 Clinical Presentation P = 0.04 Abdominal Mass (in an otherwise healthy child) Abdominal Pain Hematuria Hypertension Malaise Varicocoele Grundy PE et al. J Clin Oncol 2005; 23:

4 Work-Up of Abdominal Mass History Physical Examination Abdominal Ultrasound CBC Liver function, BUN, creatinine Urine catecholamines Work-up of Wilms tumor Computed tomography of abdomen and pelvis Computed tomography of chest Skeletal survey (CCSK only) Radionuclide bone scan (CCSK only) MRI of brain (CCSK and Rhabdoid tumor) Bone marrow aspiration and biopsy (CCSK only) NWTS-5 Pretreatment Evaluation Computed tomography of abdomen Differential Diagnosis Pathology Favorable Histology Stromal Epithelial Blastemal 4

5 Relapses after Preoperative Chemotherapy According to Pathology (SIOP-9/GPOH) Histologic Subtype Epithelial predominant Stromal predominant Blastemal predominant Stage I (%) Stage II (%) Stage IIN+/III (%) Total (%) 0/7 (0) 0/1 (0) - 0/8 (0) 0/25 (0) 0/8 (0) 0/3 (0) 0/36 (0) 5/11 (45.4) 2/8 (25.0) 2/5 (40.0) 9/24 (37.5) Mixed 5/54 (9.3) 3/16 (18.8) 0/6 (0) 8/76 (10.5) Regressivechange predominant 4/52 (7.7) 1/22 (4.5) 5/23 (21.7) 10/97 (10.3) Completely necrotic 0/9 (0) 0/5 (0) 0/3 (0) 0/17 (0) North American Approach North America Immediate nephrectomy Chemotherapy +/- Radiotherapy Depending on Stage and histology Weirich A et al. Ann Oncol 2001; 12:311-9 European Approach NORTH AMERICAN (POSTOPERATIVE) EUROPEAN (PREOPERATIVE) Preoperative chemotherapy followed by nephrectomy Additional chemotherapy +/- radiotherapy according to stage and histology Diagnosis and stage known Decrease Tumor Rupture/Spillage Less Children Receiving Radiotherapy Staging System for Wilms Tumor Stage Distribution I Tumor confined to kidney and completely resected. No penetration of the renal capsule or involvement of renal sinus vessels II Tumor extends beyond kidney but completely resected. (a) penetration of renal capsule (b) invasion of renal sinus vessels III Gross or microscopic residual remains postoperatively (inoperable tumor, positive surgical margins, tumor spillage either before or during surgery, regional lymph node metastases, tumor is removed greater than one piece, penetration through peritoneal surface) IV Hematogenous or lymph node metastases outside abdomen V Bilateral Wilms tumor at onset 21% 11% 5% 20% 43% 5

6 Wilms Tumor Stage I, Favorable Histology NWTS-1 Radiotherapy not necessary for Group 1 Wilms tumor < 2 years of age There was a benefit for radiotherapy for Group 1 Wilms tumor > 2 years of age (2 yr DFS: 77% vs. 58%, p = 0.04). These pts were treated with Regimen A (AMD alone) NWTS-2 Radiotherapy not used in Group I patients. VCR was added to regimen. Randomization was 6 mos vs. 15 mos. Of AMD + VCR. 3-yr RFS was 89% and 84% respectively Wilms Tumor Stage II, Favorable Histology NWTS-3 Treatment Percent alive at 2 years AMD + VCR 98.6% AMD + VCR cgy 98.4% AMD + VCR + ADR 95.5% AMD + VCR + ADR cgy 93.5% D'Angio GJ et al. Cancer 1976, D'Angio et al. Cancer 1981 D'Angio GJ et al. Cancer 1989; 64: Wilms Tumor Stage III, Favorable Histology Spill and Local Recurrence: The Case for Radiation Therapy NWTS-3 Treatment Percent alive at 2 years AMD + VCR cgy 88.3% AMD + VCR cgy 91.0% AMD + VCR + ADR cgy 92.7% AMD + VCR + ADR cgy 93.1% Stage II Stage III No Spill RR = 1.0 RR = 1.0 Spill RR = 4.5 RR = 1.9 D'Angio GJ et al. Cancer 1989; 64: Shamberger RC et al. Ann Surg 1999; 229:292-7 SIOP-1, -5 and Tumor Rupture In SIOP-1, tumor rupture occurred in 32% of patients who had primary surgery (n =63) and in 4% who had 20 Gy preoperative RT (n=73) (p = 0.001) In SIOP-5, tumor rupture was 6% with preoperative VCR + AMD chemotherapy (n =88) and 8% with 20 Gy preoperative RT (n=76) (p=n.s.) Lemerle J et al. J Clin Oncol 1983; 1:604-9 Intraoperative Spill 135/1131 (11.9%) of unilateral Wilms tumor on AREN03B2 had intraoperative spillage of tumor 110 were secondary to the primary tumor while 20 occurred due to renal vein thrombectomy Two factors associated with intraoperative spill: tumor size > 12 cm and right laterality Gow KW et al. J Pediatr Surg 2013; 48:34-8 6

7 Local Recurrence Risk Factors (NWTS-1) Local Recurrence Risk Factors (NWTS-2) Delay Favorable Histology Unfavorable Histology P-value < 10 days 13/220 (6%) 2/29 (7%) 0.25 > 10 days 2/53 (4%) 6/15 (40%) Factor Unfavorable histology Field size too small Delay > 10 days from surgery Intraabdominal Relapse No Intraabdominal Relapse P-value 6/10 (60%) 25/249 (10%) /10 (40%) 17/249 (59%) /10 (80%) 91/249 (37%) Tefft M et al. Int J Radiat Oncol Biol Phys 1980; 6:663-7 Thomas PRM et al. J Clin Oncol 1984; 2: RT Treatment Delay Final pathology and stage needed within a few days to determine if child needs RT Need time to do simulation Younger children may need anesthesia Simulating all children with renal masses seem to be inappropriate RT Treatment Delay (NWTS-3 & 4) Total of 1226 children with Stage II-IV FH children received flank or abdominal RT Mean RT delay: 10.9 days (median: 9 days) 59% had RT delay between 8 to 12 days 8-year flank/abdominal recurrence rates were 1.9/4.8% for delay < 10 days and 1.2/5.3% for delay > 10 days (p = n.s.) Kalapurakal JA et al. Int J Radiat Oncol Biol Phys 2003; 57:495-9 Pulmonary Lesions and RT St. Jude Study (+ lung mets on CT only) Chest X-ray has traditionally been used to stage patients CT scan better in detecting nodules Not all nodules are metastatic Wilms tumor although lungs are most common site of metastasis DIFFERENTIAL DIAGNOSIS Wilms tumor metastasis Atelectasis Round pneumonia Intrapulmonary Lymph Node Histoplasma capsulatum Hamartoma Pseudotumor 11/124 (9%) of Wilms tumor pts had negative CXR and positive chest CT Treated according to local stage (I.e. no lung RT) 4/11 (36%) relapsed all pulmonary Wilimas JA et al. J Clin Oncol 1988; 6:

8 Interobserver Variability NWTS-3 (+ lung mets on CT only) CT scan Relapses Deaths Reviewer 1 Reviewer 2 Reviewer 3 CXR Present Absent Present Absent Present Absent Present Absent N N(r) % RFS N (d) % Survival Lung RT No RT P =.95 P =.63 Wilimas JA et al. J Clin Oncol 1997; 15: Green DM et al. J Clin Oncol 1991; 9: NWTS-3 and 4 Update N N (relapsed) 4-yr EFS N (died) 4-yr OS RT % 6 91% No RT % 5 85% P =.23 P=.41 UKW2 Study (No Lung XRT) 31/141 children (22%) had positive CT but negative CXR Pulmonary Relapse CT positive 4/31 (13%) CT negative 8/110 (7.3%) p = n.s. Meisel JA et al. Int J Radiat Oncol Biol Phys 1999; 44: Owens CM et al. J Clin Oncol 2002; 20: UKW2 Study (No Lung XRT) Lung Mets (NWTS-4 and -5) Stage I, N = 55 Lung Mets at Diagnosis Pulmonary Relapse Chest X ray positive CT only P-value CT positive 3/7 (43%) CT negative 5/48 (10%) Stage I pts. treated with VCR chemo only P = 0.02 Male (%) Age at dx (mos) Tumor weight (grams) All favorable histology without other sites of distant metastasis 417 pts (NWTS-4 with 165 and NWTS-5 with 252 pts) Owens CM et al. J Clin Oncol 2002; 20:

9 CT Only Lung Mets (NWTS-4 and -5) SIOP Study Chemotherapy Actinomycin-D and Vincristine Actinomycin-D Vincristine and Doxorubicin No. of pts 2 year RFS (%) 5 year RFS (%) P-value children with Stage IV Wilms tumor and pulmonary metastasis All diagnosed by chest radiograph. CT scan of chest not required Radiotherapy Whole Lung Radiotherapy No Whole Lung Radiotherapy No. of pts 2 year RFS (%) 5 year RFS (%) P-value 0.38 Received 6 weeks of preoperative AMD (1.5 micrograms/kg), VCR (1.5 mg/m 2 ) and ADR (50 mg/m 2 ) SIOP Study SIOP Study Maintenance chemo (5 courses of AMD and VCR) 26 of 36 children did not receive pulmonary RT 5-year recurrence-free survival: 83% de Kraker J et al. J Clin Oncol 1990; 8: Current COG Guidelines Pulmonary XRT (1200 cgy in 8 fractions) at 6 weeks post chemotherapy can be omitted if all are satisfied Complete response in lungs after 3-drug chemotherapy No LOH 1p AND 16q No extrapulmonary metastasis Favorable histology AREN0533 Lung Metastasis From Feb to 2013, 391 Stage IV FH pts enrolled of which 279 had isolated lung mets 163 of 279 (58%) did not achieve pulmonary CR and received WLI and Regimen M 3-year EFS and OS were 88% and 92% (compared to historical standard, p =0.0001) Dix DB et al J Clin Oncol 32:5s, 2014 (suppl; abstr 10001) 9

10 No Adjuvant Therapy Dana Farber Cancer Institute/Children s Hospital Boston pilot study Cassady tumor (age < 24 months with Stage I, unilateral, small (total tumor/kidney weight < 550 g), FH) N = 8, 5-year survival without adjuvant chemotherapy 100%, 5-year event-free survival 88% NWTS-5 No Adjuvant Therapy 75 children < 24 mos with Stage I FH, < 550 g Wilms tumor treated with nephrectomy alone 3 children developed a metachronous tumor yrs and 8 relapsed at years after diagnosis Relapse at lung (n=5), abdomen (n=3) 2-year survival: 100%, disease-free survival 86.5% Larsen E et al. Cancer 1990; 66:264-6 Green DM et al. J Clin Oncol 2001; 19: Survival for Favorable Histology Wilms Tumor Relapse- Free Survival Overall Survival Stage I, FH 92% 98% Stage II, FH 85% 96% Stage III, FH 90% 95% Stage IV, FH 80% 90% Stage V, FH 65% 78% NCI PDQ Summary Current COG Guidelines Stage Chemotherapy Radiotherapy Stage I, FH, age < 2 years with tumor and kidney weight < 550 grams Stage I and II, FH with no LOH 1p and 16q Stage I and II, FH with LOH at 1p and 16q Stage III, FH with no LOH at 1p and 16q Stage III, FH with LOH at 1p and 16q Stage IV, FH with no LOH at 1p and 16q Stage IV, FH with LOH at 1p and 16q None VCR and AMD (Regimen EE4A) VCR, AMD and DOX (regimen DD4A) VCR, AMD and DOX (Regimen DD4A) VCR, AMD, DOX, CPM, VP16 (Regimen M) VCR, AMD and DOX (Regimen DD4A) VCR, AMD, DOX, CPM, VP-16 (Regimen M) None None None Abdominal/Flank RT Abdominal/Flank RT Abdominal/Flank RT if Local Stage III Lung XRT if Lung Mets not CR Abdominal/Flank RT if Local Stage III Lung XRT if Lung Mets COG RT Guidelines for FH Wilms Tumor Disease Extent RT Volume Dose Hilar lymph nodes/ Gross or microscopic residual confined to flank/ Local spill Para-aortic lymph nodes Peritoneal seeding, Preoperative peritoneal rupture, Diffuse operative spill Tumor bed, crossing midline to include entire vertebral bodies Include bilateral paraaortic chains Whole abdomen 1080 cgy/ 6 fx 1080 cgy/ 6 fx 1050 cgy/ 7 fx COG RT Guidelines for Metastasis Disease site RT Field RT Dose Liver Involved portion cgy/11 fx cm margin Lung, age > 18mos Bilateral lung 1200 cgy/8 fx Lung, age < 18 mos Bilateral lung if no 900 cgy/ 6 fx response to chemo Lymph nodes (Gross Involved nodes 1980 cgy/ 11 fx tumor, not resected) Brain Whole brain +/- boost 2160 cgy/ 17 fx (WB) 1080 cgy/6 fx (boost) if < 16 yrs 3060 cgy/ 17 fx (WB, if > 16 yrs) Bone Lesion + 3 cm margin 2520 cgy/14 fx (< 16 yrs) 3060 cgy/17 fx (> 16 yrs) 10

11 Radiotherapy Fields (Stage IV) 3 year old girl with focal anaplastic Wilms tumor of right kidney with microscopic margin, positive paraaortic node and pulmonary metastasis 1050 cgy in 7 fractions to R hemiabdomen and 1200 cgy in 8 fractions to bilateral lungs Radiotherapy Fields (Stage IV) 2 year old boy with favorable histology Wilms tumor of R kidney (capsular penetration only) and pulmonary metastases Had residual pulmonary mets after 6 weeks of chemotherapy 1200 cgy in 8 fractions to bilateral lungs Radiotherapy Fields (Stage III) 4 year old female with favorable histology Wilms tumor and diffuse spillage of tumor during left nephrectomy. Three positive paraaotic lymph nodes with negative margin of resection Patient received 1050 cgy in 7 fractions to the whole abdomen Bilateral Wilms Tumor Synchronous Metachronous NWTS-1 33/606 (5.4%) 20/606 (3.3%) NWTS-2 and 3 145/3300 (4.4%) St. Jude 29/328 (8.8%) 7/328 (2.1%) SIOP 1, 2, 5 42/1043 (4.0%) 25/1043 (2.4%) Synchronous Bilateral Wilms Tumor Synchronous Bilateral Wilms Tumor NWTS-2 and 3 Montgomery BT et al. J Urol 1991; 146:514-8 SIOP 1,2,5 Coppes MJ et al. J Clin Oncol 1989; 7:310-5 St. Jude Paulino AC et al. Int J Radiat Oncol Biol Phys 1996; 36:541-8 SURVIVAL 2 years 5 years 10 years 83% 73% 70% NA NA 69% 81% 74% NA Chemotherapy (AMD, VCR, DOX) Partial Nephrectomy Chemotherapy +/- Radiotherapy (XRT given to positive margin, positive lymph node, unfavorable histology) 11

12 Metachronous Bilateral Wilms Tumor Relapsed Wilms Tumor Review of 108 cases from 30 studies from and 10-year overall survivals were 49.1% and 47.2% More than 95% of contralateral tumors occur within 60 months (median 23.1 months) Better survival with contralateral tumors appearing > 18 months from initial ipsilateral tumor (10 yr survival 55.2% vs. 39.6%) Paulino AC et al. Cancer 1998; 82: Grundy et al. NWTS-2 and -3 Dome et al. St. Jude Children s Hospital Groot-Loonen et al. UKCCSG WT-1 Study Paulino et al. University of Iowa Tannous et al. CCG-4921/POG-9945 HRisk N Survival 3 years 5 years % NA 54 NA 21% (prior to 1984) 64% (after 1984) 71 24% NA 21 38% 33% 66 52% NA Predictors of Relapse in Stage III FH Wilms Tumor Relapsed Wilms (3-yr post-rfs > 40%) Kaplan-Meier curves for (A) event-free and (B) overall survival for local stage III favorable-histology Wilms tumor by microscopic disease, nonmetastatic only. Favorable histology tumors with relapse 1. Only in lungs 2. In abdomen when RT not used 3. Originally Stage I 4. Treated with only 2 drugs 5. Recurred 12 or more months after initial diagnosis Ehrlich P F et al. JCO 2013;31: Grundy P et al. J Clin Oncol 1989; 7: Patterns of Failure: NWTS-2 and 3 Anaplastic Wilms Tumor Site Frequency Lung only 58% Abdomen +/- lung 29% Other 13% Unfavorable histology found in 4 to 5% of NWTS and SIOP studies Uncommon in infants, but found in about 10% of patients > 5 years of age Anaplasia refers to significant enlargement of nuclei in stromal, blastemal or epithelial components to at least 3X, hyperchromatism of enlarged nuclei and multiple mitotic figures Grundy PE et al. J Clin Oncol 1989; 7:

13 Anaplastic Wilms Tumor Anaplastic Wilms Tumor Faria P et al. Am J Surg Pathol 1996; 20: Faria P et al. Am J Surg Pathol 1996; 20: Anaplastic Wilms Tumor Anaplastic Wilms Tumor (NWTS-5) In NWTS-4, Stage I AH pts were treated with AMD and VCR and had 2-yr overall survival estimates of 85.5% to 93.3% depending on AMD administration regimen Stage II to IV AH pts were treated with AMD, VCR and DOX and had 4-yr overall survival rate of 27.1% without CPM and 52.2% with CPM (p = 0.04) Dome JS et al. J Clin Oncol 2006; 24: Anaplastic Wilms Tumor (NWTS-5) RT Dose in Anaplastic Wilms Tumor Stage I 4-yr EFS: 69.5% 4-yr OS: 82.6% 4-yr EFS/OS Stage II: 82.6% Stage III: 64.7% Stage IV: 33.3% Dose (Gy) N No. of Tumor Bed Relapses 4-Year Tumor Bed Relapse-free Survival (%) > Dome JS et al. J Clin Oncol 2006; 24: p=0.56, Green DM et al. J Clin Oncol 1994; 12:

14 Survival for Anaplastic Wilms Tumor Clear Cell Sarcoma of Kidney Relapse-Free Overall Survival Survival Stage I, FA/DA 69% 83% Stage II, FA 80% 80% Stage II, DA 83% 82% Stage III, FA 71-88% % Stage III, DA 46-65% 53-67% Stage IV, FA 61% 72% Stage IV, DA 31-33% 33-44% Stage V, FA/DA 44% 55% NCI PDQ Summary First reported by Kidd in cases each year in the US (4-5% of all renal tumors) 2:1 M:F ratio 29% lymph node mets at presentation Most common site of recurrence is bone and lung, followed by abdomen and brain Argani P et al. Am J Surg Pathol 2000; 24:4-18 Clear Cell Sarcoma (NWTS-4) Clear cell Sarcoma of Kidney N 8-yr RFS 8-yr OS NWTS % 83.0% NWTS % 66.9% Seibel NL et al. J Clin Oncol 2004; 22: Seibel NL et al. J Clin Oncol 2004; 22: RT Dose in Clear Cell Sarcoma Rhabdoid Tumor Dose (Gy) N No. of Tumor Bed Relapses 4-Year Tumor Bed Relapse-free Survival (%) > % of all renal tumors 80% < 2 years old 1.5:1 M:F ratio Characterized by INI-1 gene mutation Association with primary intracranial mass or brain metastasis Worst prognosis for renal tumors p=0.56, Green DM et al. J Clin Oncol 1994; 12:

15 Rhabdoid Tumor RT Dose in Rhabdoid Tumor In NWTS-5, children received 10.8 Gy Many of these children are infants In the UKCCSG Second Wilms tumor study, dose used was 30 Gy with vincristine, actinomycin and doxorubicin 2-and 4-year EFS (UKCCSG) was 36%* Optimal dose not known Tomlinson GE et al. J Clin Oncol 2005; 23: *Mitchell C et al. Br J Cancer 2000; 83:602-8 Rhabdoid Tumor Current COG Guidelines Stage Chemotherapy Radiotherapy Stage I-III, FA Stage I, DA VCR, AMD and DOX (Regimen DD4A) Abdominal/Flank RT Stage IV, FA Stage II-IV, DA (with no measurable disease) Stage IV, CCSK Stage I-IV, RTK Stage IV, DA (with measurable disease) Stage I-III CCSK VCR,AMD, DOX, CPM, VP16, CARBO (Regimen UH-1) VCR, AMD, DOX, CPM, VP16, CARBO, IRINOTECAN VCR, AMD, DOX, CPM, VP16 (Regimen I) Abdominal/Flank RT Lung RT if lung mets Abdominal/Flank RT Lung RT if lung mets Abdominal/Flank RT except Stage I CCSK Tomlinson GE et al. J Clin Oncol 2005; 23: Current COG Guidelines Conclusions Stage Stage I, CCSK Stage I-III, FA Stage I-II, DA Stage II-III, CCSK RTK, < 1 year old Stage III DA RTK, > 1 year old FA, DA, CCSK, RTK Radiotherapy Dose No RT 10.8 Gy in 6 fractions Abdominal/Flank RT 19.8 Gy in 11 fractions Abdominal/Flank RT 12 Gy in 8 fractions Lung Mets Current survival rates for most children with Wilms tumor are excellent Successive trials have reduced the number of children who will require radiotherapy for Wilms tumor Tumors with LOH 1p AND 16q have a worse prognosis and are currently being treated with more aggressive therapy 15

16 Conclusions It is unclear whether whole lung irradiation improves outcome in the setting of CT positive only disease 16