Primary Tumor In Place Research Articles

Clinico-biological factors predicting the benefit of the LV5FU2 maintenance strategy as a first-line therapy in patients with metastatic pancreatic cancer.

Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy. We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated. Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant. Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337).

Imaging HER2-positive metastatic esophagogastric cancer with 89Zr-trastuzumab PET and 18F-FDG PET.

4068 Background: Variations in HER2 expression between primary tumor and metastases may contribute to drug resistance in HER2-positive mEG cancer. Whole body imaging with 89Zr-trastuzumab PET has a potential advantage over single site biopsies as it can non-invasively assess variations in HER2 expression and target engagement. 89Zr-trastuzumab PK, biodistribution and dosimetry in mEG cancer were previously published by our group (O’Donoghue, JNM 2018). We now present lesion level analysis of baseline 18F-FDG-PET and CT in comparison with baseline 89Zr-trastuzumab imaging. Methods: Patients with metastatic HER2-positive (IHC 3+, IHC 2+/FISH &gt; 2.0) mEG cancer and RECIST 1.1 measurable disease were consented and imaged with 89Zr-trastuzumab PET, 18F-FDG-PET and CT. All visualized lesions (maximum 5 per organ) were annotated in detail using RECIST 1.1 measurements (CT) and maximum standard uptake values (SUVmax) on 89Zr-trastuzumab and 18F-FDG PET scans. Correlation of visualized disease burden between imaging modalities with clinical and pathologic characteristics was performed. Results: 33 patients with mEG adenocarcinoma were imaged with 89Zr-trastuzumab PET, 18F-FDG-PET and CT (12% esophageal, 64% GEJ, 24% gastric). HER2 status (IHC 3+ 70%; IHC2+/FISH+ 27%, NGS 3%) was assessed from biopsy of primary (66.7%) or metastasis (33.3%). Median time from diagnosis to 89Zr-trastuzumab PET was 12.6 months. At the time of 89Zr-trastuzumab PET, 39% were treatment naive, while 61% had received prior therapy including trastuzumab (58%) and afatinib (median lines 2, range 0-6). 82% of patients had the primary tumor in place and all patients had metastatic disease at the time of enrollment with metastases to lymph nodes (70%) peritoneum (24%), liver (58%), lung (33%), and/or bone (9%). Median number of RECIST 1.1 lesions measured on baseline CT was 6 (range 1-15). PET analysis is complete in 18 of 33 patients. Median number of 89Zr-trastuzumab PET positive (SUV &gt; 3) lesions was 5.5 (range 1-11) with 5 patients having at least 1 (max 3) very intense lesion (SUV &gt; 15). Median number of 18F-FDG-PET-positive lesions was 8 (range 1-14). Three patients had at least 1 lesion positive on 89Zr-trastuzumab-PET and negative on 8F-FDG-PET (range 0-5), and 8 patients had at least 1 lesion positive on 18F-FDG-PET and negative on 89Zr-trastuzumab-PET (range 0-7). Of the total lesions identified on 89Zr-PET but not CT, 40% were in bone. Of those identified on 89Zr but not 8F-FDG-PET, 40% were in bone, and of those on 18F-FDG- but not 89Zr-PET, 6% were in bone. Conclusions: 89Zr-trastuzumab PET effectively identifies heterogeneity of HER2 expression and allows assessment of lesions throughout the whole body. Bone lesions were better identified and appeared earlier on 89Zr-trastuzumab PET compared with CT. Additional analyses including correlation of baseline HER2 heterogeneity with overall and disease-free survival will be presented. Clinical trial information: NCT02023996.

Response of Primary Renal Cell Carcinoma to Systemic Therapy

BackgroundUpfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials. ObjectiveWe investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC. Design, setting, and participantsA pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place. Outcome measurements and statistical analysisThe objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox’s models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses. Results and limitationsIn total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16–23) in patients treated with first-line therapy (any type), 28% (22–33) in those treated with first-line VEGF-targeted therapy, and 23% (19–28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5–13) and 20% (15–27) in IMDC poor- and intermediate-risk patients, respectively. ConclusionsSystemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics. Patient summaryAntiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.

Frequency of unplanned surgery in patients with stage IV colorectal cancer receiving palliative chemotherapy with an intact primary: An analysis of SEER-Medicare.

Stage IV colorectal cancer is often treated with palliative chemotherapy with the primary tumor in place. Low rates of unplanned surgical intervention (due to obstruction or perforation) have been reported. We examined a large national dataset to determine the rate of unplanned surgical intervention in these patients. Surveillance Epidemiology and End Results-Medicare were queried for patients with metastatic colorectal cancer receiving chemotherapy (1998-2013). Patient who underwent planned surgery to the primary or metastasectomy were excluded. The primary outcome was the need for nonelective surgery. Time to surgery or death was measured. Conditional analyses were performed to determine the risk of surgical intervention at 6-month, 1-, and 2-year after diagnosis. The analytic cohort consisted of 4692 patients (median age = 75). At 24 months, 80% of the patients had died. The overall unplanned intervention rate was 12%. The probability of requiring unplanned surgery between 6 and 12 months was 8.1%; 12 and 24 months = 6.7%, and >24 months = 5.3%. Males, those with right-sided tumors, and older patients were less likely to require surgery. Patients treated with palliative chemotherapy who are not resected upfront are unlikely to require unplanned surgery. Prophylactic surgery to reduce the risk of perforation or obstruction may not be necessary.

TARIBO trial: Cytoreductive nephrectomy in metastatic renal cell carcinoma patients treated with targeted agents.

TPS4601 Background: In the cytokine era cytoreductive nephrectomy (CN) has been shown to increase survival in patients (pts) with metastatic renal cell carcinoma (mRCC). Efficacy of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib has been demonstrated. It is unclear if similar survival benefit could be achieved without CN with TKIs since most of pts enrolled into phase III trials had undergone CN. Methods: A total of 270 mRCC pts will be randomized to receiveCN followed by TKIs vs upfront TKIs without CN. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: to compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: i) to compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs; ii) Safety; iii) Exploratory analyses: evaluation of the predictive role of circulating tumor cells count and circulating tumor DNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression. Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; histological diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary tumor in place; up to three different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( &gt; or = 4 metastatic organ sites); disease suitable of metastasectomy ( &lt; 3 lesions confined at one organ site). Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. To date 10/270 pts have been enrolled. Clinical trial information: NCT02535351.

MSKCC and Heng prognostic risk assessment for synchronous metastatic renal cell carcinoma (syncmRCC) and the tumor in place treated in the targeted therapy era.

e15525 Background: SyncmRCC is heterogenous and selection for cytoreductive nephrectomy (CN) and targeted therapy is required. MSKCC and Heng models for overall survival (OS) are validated for targeted therapy. However, they were developed from predominantly metachronous mRCC patients. It is unknown how they perform in syncmRCC and if they can be used to decide about CN. Methods: Retrospective study of pretherapeutic MSKCC and Heng scores and outcome from 146 patients with syncmRCC and the primary tumor in place treated at a single institute with targeted therapy since 2006. CN was performed in patients WHO 0-1 and low metastatic burden. Results: Table: distribution of risk and OS compared to Heng et al., JCO 27:5794, 2009 . Only n=2 were favorable risk. Overall, n=117 were treated by sunitinib, others by temsirolimus or sorafenib. CN was performed in n=94 (64.3%). Among Heng poor risk 46% (n=29) were intermediate risk by MSKCC. Of Heng poor risk n=37 (58.7%) had CN with a median OS of 8.5 months; 2y OS was 18.9% and higher than for MSKCC poor risk. Of Heng intermediate risk n=57 (69.5%) underwent CN (median OS 15.5 months (1-68); 2y OS 36.8%). Conclusions: In syncmRCC MSKCC and Heng intermediate risk patients have shorter OS than previously reported for each model in the targeted therapy era. However, 25-30 % of intermediate risk patients live &gt;2 y and a potential benefit of CN may be apparent in this group. A discrepancy exists between Heng and MSKCC poor risk percentage. We speculate that the primary tumor in place may influence thrombocyte and neutrophile counts resulting in significantly more Heng poor risk among patients with MSKCC intermediate risk. Especially MSKCC poor risk carries a dismal median and 2y OS in syncmRCC. MSKCC risk assessment performs well in identifying poor risk patients unlikely to benefit from CN. [Table: see text]

Outcomes associated with sunitinib alternative schedule compared to traditional schedule: a single-center experience.

e15611 Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 28 days (d) on/14 d off (traditional schedule; TS). Sunitinib is associated with several adverse events (AEs). An ideal treatment modification algorithm is not known. We sought to identify 1) common AEs, 2) alternative schedules (AS) that maintained dose intensity while decreasing AEs, and 3) the impact of AS on outcomes. Methods: Single-center retrospective review of mRCC pts performed from 1/26/06 to 3/1/11. Pts &gt; 18 years of age with mRCC who received first-line antiangiogenic therapy with sunitinib were eligible. A subset of pts were switched at first intolerable AE from TS to a 14 d/7 d, or further adjusted to 7 d /3 d, or other AS. Control group underwent standard dose reduction. Pt characteristics including demographics, disease status, laboratory data, AEs, AS, and treatment outcomes were analyzed. Results: 186 eligible pts were identified. At baseline, 87% received sunitinib 50 mg and 88% were on TS. 99 pts (53%) continued TS and 87 pts (47%) were switched to AS. Baseline characteristics were similar. Median age was 61 yrs; by MSKCC criteria 5% were good, 50% intermediate, and 45% poor prognosis. Pts had median 2 visceral mets and 42% had primary tumor in place. AEs included fatigue (47%), diarrhea (24%), and hand-foot syndrome (26%). Median time to AS was 126 d with 14 d/7 d the most common (82%). Median time on treatment was 14.9 months (mo) (95% CI:10.2 – 17.0 mo) in AS pts vs 4.2 mo (95% CI: 3.6 – 5.7 mo), respectively (p &lt; 0.0001). Median OS was 32.9 mo (95% CI:28.3-54.1 mo) vs 18.5 mo (95% CI: 10.3-21.5 mo), respectively (p = 0.0001). ECOG PS &gt; 2 (HR 3.9), elevated LDH (HR 2.04), and &gt; 2 mets (HR 1.79) were associated with decreased OS. MSKCC intermediate vs poor (HR 0.57) and AS (HR 0.54) were associated with improved OS by multivariate regression analysis (p &lt; 0.05). Conclusions: In our cohort study, AS sunitinib significantly prolonged time on treatment and was predictive of OS. Prospective investigations of alternate dosing schemas are warranted.

A single-center retrospective review of outcomes associated with sunitinib alternative schedule compared to traditional schedule.

381 Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 28 days (d) on/14 d off (traditional schedule; TS). Sunitinib is associated with several adverse events (AEs). An ideal treatment modification algorithm is not known. We sought to identify (1) common AEs, (2) alternative schedules (AS) that maintained dose intensity while decreasing AEs, and (3) the impact of AS on outcomes. Methods: Single-center retrospective review of mRCC pts performed from January 26, 2006 to March 1, 2011. Pts &gt; 18 years of age with mRCC who received first-line antiangiogenic therapy with sunitinib were eligible. A subset of pts were switched at first intolerable AE from TS to a 14 d/7 d, or further adjusted to 7 d /3 d, or other AS. Control group underwent standard dose reduction. Pt characteristics including demographics, disease status, laboratory data, AEs, AS, and treatment outcomes were analyzed. Results: 186 eligible pts were identified. At baseline, 87% received sunitinib 50 mg and 88% were on TS. 99 pts (53%) continued TS and 87 pts (47%) were switched to AS. Baseline characteristics were similar. Median age was 61 yrs; by MSKCC criteria 5% were good, 50% intermediate, and 45% poor prognosis. Pts had median 2 visceral mets and 42% had primary tumor in place. AEs included fatigue (47%), diarrhea (24%), and hand-foot syndrome (26%). Median time to AS was 126 d with 14 d/7 d the most common (82%). Median time on treatment was 14.9 months (mo) (95% CI:10.2 – 17.0 mo) in AS pts vs. 4.2 mo (95% CI: 3.6 – 5.7 mo), respectively (p &lt; 0.0001). Median OS was 32.9 mo (95% CI:28.3-54.1 mo) vs. 18.5 mo (95% CI: 10.3-21.5 mo), respectively (p = 0.0001). ECOG PS &gt; 2 (HR 3.9), elevated LDH (HR 2.04), and &gt; 2 mets (HR 1.79) were associated with decreased OS. MSKCC intermediate vs. poor (HR 0.57) and AS (HR 0.54) were associated with improved OS by multivariate regression analysis (p &lt; 0.05). Conclusions: In our cohort study, AS sunitinib significantly prolonged outcomes and was predictive of OS. Prospective investigations of alternate dosing schemas are warranted.

Single-center multidisciplinary management of patients with colorectal cancer and resectable synchronous liver metastases improves outcomes

Management of patients with synchronous liver metastasis (SLM) is complex and the surgical decision process should be based on a comprehensive oncological strategy. The aim of the study was to compare outcome of single-center management of patients with colorectal cancer (CRC) and resectable SLM to those of referred patients for liver resection only after removal of their primary tumor (PT). Between 2000 and 2007, 47 patients with CRC and SLM underwent resection of both the PT and metastases under our care (unicentric) and 32 were referred after resection of their PT. The two groups were comparable for demographics, PT and metastatic disease data. In unicentric group, 23% received upfront chemotherapy with the PT in place, 53% had a combined CRC and SLM resection, 11% had a two-stage hepatectomy with resection of the primary during the first stage and 36% underwent delayed hepatectomy. The number of surgical interventions, the delay between diagnosis and liver resection (9 vs. 5 months, P < 0.001), the median number of cycles of chemotherapy before hepatectomy (12 vs. 6 months, P < 0.001) were significantly higher in the referred group. Postoperative morbidity was significantly higher in the referred group (75 vs. 47%, P = 0.023). The median follow-up was 43 months. OS and DFS were not significantly different between the two groups. Although the survival benefit is not proven, single-center management of patients with CRC and resectable SLM reduces the number of interventions, the number of cycles of chemotherapy and postoperative morbidity.

Current Treatment Considerations in Metastatic Renal Cell Carcinoma

In general, debulking neprhectomy is still considered for metastatic RCC patients with primary tumor in place, assuming good performance status. Initial systemic therapy should consider high-dose IL-2 for the highly select patient. One reason for initial consideration of this therapy is the less certain risk/benefit profile if employed after targeted therapy. Notably, due to its potential toxicity and emergence of new effective and more tolerable drugs, IL-2 has become a less favorable and subsequently a less utilized therapeutic tool in the current era. Otherwise, VEGF-targeted therapy is the treatment of choice, preferably on a clinical trial. Off trial, sunitinib has long been favored but pazopanib is gaining more use for tolerance pending the comparative trial. Continued VEGF targeting is favored by these authors given the underlying biology of RCC and the prospective clinical data, noting no direct comparison of mTOR and VEGF agents has yet occurred. Maintaining patient dose is critical and requires optimal supportive care and appreciation/early intervention for toxicity. Predictive biomarkers are desperately needed, and enrollment on clinical trials remains a priority to optimize patient outcome.

Schedule modifications and treatment outcomes for sunitinib-related adverse events.

e15115 Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 4 wk on, 2 wk off (4/2) schedule. Sunitinib is associated with several adverse events (AEs). An ideal dose modification algorithm is not known. We sought to identify 1) commonly occurring AEs, 2) schedule modifications (SM) that maintained dose intensity while decreasing AEs, and 3) the impact of SM on 6 mo follow-up (f/u). Methods: Retrospective review of mRCC pts in an outpatient clinic was performed from 1/1/08 to 5/31/09. Pts ≥ 18 years of age with clear cell mRCC on sunitinib therapy with ≥ 6 mo f/u were eligible. At first intolerable AE, pts were switched from a 4/2 schedule to a 2/1 schedule, or further adjusted to a 7 day on/3 day off or other schedule. Pt characteristics including demographics, disease status, laboratory data, AEs, SMs and treatment outcomes were analyzed. Results: 74 eligible pts were identified; preliminary data from 31 pts are presented. Median age was 66 yrs; 23% had prior systemic therapy; 32% were good, 48% intermediate and 20% poor prognosis by MSKCC criteria. Pts had median 2 visceral mets and 49% had primary tumor in place. At baseline, all pts received sunitinib 50 mg daily on schedules shown in the Table. AEs included fatigue (51%), diarrhea (35%), hand-foot syndrome (32%), and mucositis (29%). Dose intensity was maintained in 81% of pts at 6 mo f/u. SM were common (Table). For the 25 pts initiated on a 4/2 schedule, 7 discontinued for PD and 3 for toxicity at 6 mo. All 6 pts initiated on a 2/1 schedule continued on sunitinib at 6 mo at the original dose intensity and schedule, whereas 13 of 15 remaining pts initiated on a 4/2 schedule had switched to an alternate schedule (p=0.0005, 95% CI 0.0752-0.830). Median treatment duration (MTD) was 10 mo for all pts. At last available f/u, 29% of pts continue on sunitinib therapy with MTD of 15.3 mo, and 89% of pts are on an alternate dosing schedule. Conclusions: In this group of pts, sunitinib SM maintained high dose intensity and did not appear to adversely impact outcome. Prospective investigations of alternate sunitinib dosing schemas may be warranted. (%) Sunitinib Schedule 4/2 2/1 7/3 alt 7/4 Other Baseline 100 77 19 3 1 6-mo follow-up 68 10 48 29 13 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Pfizer Bayer, Genentech, Pfizer

Commentary on Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma: Thomas AA, Rini BI, Lane BR, Garcia J, Dreicer R, Klein EA, Novick AC, Campbell SC, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH

We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection. A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks-on and followed by 2 weeks-off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated. Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patient experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease, and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease, and 10 (53%) with disease progression. At a median follow-up of 6 months (range 1–15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3–4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity. Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection.

Response of the Primary Tumor to Neoadjuvant Sunitinib in Patients With Advanced Renal Cell Carcinoma

We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection. A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks on followed by 2 weeks off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated. Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patients experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease and 10 (53%) with disease progression. At a median followup of 6 months (range 1 to 15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3-4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity. Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection.

Von Hippel-Lindau gene mutation status is associated with a dichotomous response in primary and metastatic tumors in patients receiving bevacizumab and erlotinib for metastatic renal cell carcinoma

15522 Background: A single arm phase II study is underway evaluating the safety and clinical benefit of presurgical bevacizumab and erlotinib in the management of patients with untreated conventional renal cell carcinoma (RCC). It is not known how the presence or absence of von Hippel Lindau (VHL) mutations affect the response to therapy in the primary or metastatic site, and whether VHL mutational status is predictive for either. Methods: Patients enrolled had conventional RCC, measurable metastatic disease, a primary tumor in place, no prior systemic therapy, a PS of 0 or 1 and no brain metastases. A total of 35 patients were enrolled as of January 8, 2007. Patients were treated with bevacizumab for 4 cycles and erlotinib for 8 weeks, and underwent cytoreductive nephrectomy at week 10 (4 weeks after the last dose of bevacizumab). A VHL gene mutation and methylation analysis was completed on nephrectomy specimens from the first 18 evaluable patients. Patients were grouped according to the presence or absence of functional VHL gene inactivation (mutation and/or methylation). Two-sample T-test and Fisher’s exact test were performed. Results: Ten patients (55%) demonstrated either VHL mutation or methylation ( table 1 ). Patients with no VHL gene inactivation demonstrated more robust primary tumor shrinkage, but did not demonstrate partial responses (PRs). Table 1 . Conclusions: These findings, although preliminary, suggest a dichotomous response in the primary and metastatic disease sites according to VHL functional status. Ongoing evaluation of new treatment strategies using antivascular/targeted agents in RCC may benefit from molecular stratification. [Table: see text] No significant financial relationships to disclose.

A phase I clinical trial of MVA expressing 5T4 and high-dose interleukin-2 (IL-2) for metastatic renal cell carcinoma

12500 Background: Metastatic renal cell carcinoma (RCC) is an immune responsive tumor. 5T4 is a tumor antigen expressed on the cell surface of clear cell and papillary RCC. We sought to evaluate the safety and immunologic effects of vaccination with modified vaccinia virus Ankara (MVA) expressing 5T4 followed by IL-2 in patients with advanced RCC. Methods: A single dose Phase I clinical trial was conducted in patients with metastatic RCC and who were eligible for high-dose IL-2. Vaccination was given every three weeks by intramuscular injection and was followed immediately by standard high-dose bolus IL-2 (600,000 IU/kg) after the second and third vaccinations. The regimen could be repeated if there was no evidence of disease progression. Peripheral blood and serum was collected before treatment and every three weeks for analysis. Routine blood counts, chemistry, and pituitary functions were monitored. Anti-5T4 antibody titers were determined by ELISA assay and 5T4-specific T cell responses were monitored by interferon-γ ELISPOT assay using overlapping peptides. Results: 25 patients with RCC are being sequentially enrolled. There have been no serious vaccine-related adverse events although typical Grade 3 IL-2 related toxicity has been seen in all patients. To date, all patients tested have developed an increase in 5T4-specific antibody titers following three initial vaccinations. T cell assays are currently in progress. Seven patients have completed the trial through at least one course of treatment (mean age 62.3 years). Of these 7, one patient who presented with a primary tumor in place and synchronous metastatic disease had an objective complete response of all metastatic disease and underwent a post-treatment nephrectomy; the primary tumor demonstrated highly necrotic tumor. Two additional patients have had stable disease and are receiving booster vaccinations every three months. Conclusions: These results demonstrate that local vaccination with an MVA virus expressing 5T4 administered in combination with high-dose IL-2 is safe and induces 5T4-specific antibodies in all patients. Additional T cell responses and clinical follow-up will be presented. The use of MVA-5T4 and IL-2 appears to be a promising approach for the treatment of advanced RCC. [Table: see text]

Outgrowth of human liver metastases after resection of the primary colorectal tumor: A shift in the balance between apoptosis and proliferation

Rapid outgrowth of metastases after removal of the primary tumor has been described in several mouse models. Loss of primary tumor-induced inhibition of angiogenesis in the metastases has been suggested as the underlying cause. Accordingly, we recently demonstrated that vascular density in human colorectal liver metastases increases after primary tumor resection. Here, we investigate whether this increase in vascular density has, in its turn, effects on the tumor growth of the liver metastases. We analyzed tumor growth in synchronous liver metastases from patients with the primary tumor in place, in synchronous metastases from patients with the primary tumor resected and in metachronous metastases. Tumor growth was studied by assessing the percentage of cells undergoing apoptosis by activated caspase-3 staining, and the percentage of proliferating cells by Ki-67 staining. While the percentage of proliferating cells within the metastases showed a modest increase after primary tumor resection, a significant decrease in the percentage of apoptotic cells was observed. Taken together, an increased net tumor growth of the metastases occurred after primary tumor resection. This acceleration of tumor growth could be confirmed by studying biopsies taken from the same patient before and after tumor resection. Our data show that in human cancer patients, a primary tumor may inhibit the growth of its liver metastases.

Interferon alpha 2b as Medical Selection for Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma: A Consecutive Study

ObjectiveUp to 25% of the patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nephrectomy and interferon alpha-2b (IFN-α) will progress rapidly at metastatic sites and undergo needless surgery for an asymptomatic primary. We reversed the timing of surgery and immunotherapy and evaluated the role of initial IFN-α as selection for nephrectomy. Patients and methodsSixteen patients with mRCC and the primary in-situ received initial IFN-α for 8 weeks (2 weeks 5×3×106IU/wk; 2 weeks 5×6×106IU/wk; 2 weeks 5×9×106IU/wk and 2 weeks 3×9×106IU/wk). Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by IFN-α maintenance at 3×9×106IU/wk. Patients were evaluated with regard to age, sex, metastatic sites, morbidity, response, nephrectomy rate, time to progression and survival. ResultsThirteen patients received 2 months of preoperative IFN-α; 3 stopped during the 2 months period due to progressive disease (PD). Eight patients developed either a PR (n=3) or SD (n=5) at metastatic sites and underwent nephrectomy. Survival at 1 year is 50% (4/8 patients). Median progression-free survival was 6 months (3–17 months).Two of the 3 patients with PR developed a CR after 2 months maintenance following surgery. Eight patients with PD did not undergo surgery and had a median survival of 4 months (range 1–8 months). ConclusionsAbsence of progression at metastatic sites following IFN-α with the primary tumor in place may be used as selection for nephrectomy in patients with an intermediate prognosis. Currently, a randomized study is underway to assess the role of initial versus delayed nephrectomy in combination with IFN-α with regard to morbidity and survival.

A multicenter phase II study of irinotecan (CPT), cisplatin (CIS), and bevacizumab (BEV) in patients with unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma

4025 Background: BEV is an anti-VEGF-monoclonal antibody that improves survival in colorectal cancer. CPT/CIS is an active combination in the treatment of gastric and GEJ cancers with a median time to tumor progression(TTP) of 4.5 months. We performed this study to evaluate the efficacy and safety of the combination of CPT, CIS, and BEV in the treatment of gastric and GEJ cancers. Methods: Patients with previously untreated metastatic gastric and GEJ adenocarcinomas are eligible. The primary endpoint is to improve median TTP to 7.5 months. Response, survival, and safety are secondary endpoints. Evaluable or measurable disease was required. Patients received BEV 15mg/kg on day 1, CPT 65mg/m2 and CIS 30mg/m2 on days 1 and 8, every 21 days. Response is assessed by RECIST criteria, and CTCv 3.0 was used for toxicity assessment. Results: We have enrolled 24 patients with the following characteristics: median age 55(range 25–67), KPS 80%(70–90%), Male:Female 19:5. We have observed only 3 patients with progression at a median follow up of 3.4 months. The progression free survival at 3 months is 89%(95%CI: 81–100%), and at 6 months, is 76%(52–100%). Median TTP has not been reached. In 16 patients with measurable disease, we have observed 12 confirmed partial responses(75%, 95%CI:47–92%), 3 minor responses(15–29% reduction) and 1 stable disease. The combination therapy has been well tolerated, without an increase in CPT/CIS related toxicity: i.e. grade 3/4 neutropenia, nausea/vomiting, or diarrhea in 8% of patients. However, thromboembolic events were seen in 25% of patients(95%CI:11–45%): 4 patients with asymptomatic pulmonary embolism and 2 patients with deep vein thrombosis. Of 20 patients with their primary tumor in place, 2 patients had a gastric perforation, and another had a near perforation. There was no significant bleeding or toxicity related death. Conclusions: The combination of CPT/CIS/BEV appears active in gastric and GEJ cancers. Though preliminary, the high rates of response and disease control are noteworthy. The combination appears safe, although thromboembolic phenomenon are concerning. Accrual continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma

The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

The role of initial immunotherapy as selection for nephrectomy in patients with metastatic renal cell carcinoma and the primary tumor in situ.

A prospective pilot study in patients with metastatic renal cell cancer and the primary in situ to assess the feasibility of immunotherapy prior to nephrectomy and to evaluate the rationale for a future randomized trial to define the role of response to upfront immunotherapy as selection for cytoreductive surgery. Sixteen patients with synchronous multiple metastases were treated with the primary tumor in place and were evaluated with regard to age, sex, sites of extrarenal disease, morbidity, response, nephrectomy rate, time to progression and overall survival. Immunotherapy consisted of 2 courses low-dose IL-2 4MIU/m(2), subcutaneous GM-CSF 2.5 microg/kg and interferon-alpha (IFN-alpha) 5MU flat on day 1-13 and 22-34. Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by a third and fourth course. No response was seen in the primary tumors. With regard to extrarenal sites SD was noted in nine cases, PR in two and progressive disease (PD) in five. Eleven patients underwent nephrectomy. No surgical complete response (CR) could be achieved. All patients with PD died after a median overall survival of 3 months versus 11.5 months (range 4-22) in those who underwent nephrectomy. Four patients are still alive at 10, 12, 18 and 19 months. Median duration of response was 6 months (range 2-10). One patient with SD following nephrectomy developed CR after two additional cycles, which is currently maintained for >10 months. Absence of progression at metastatic sites following immunotherapy may be used as a selection for nephrectomy in this selected group. Non-responding patients can be spared from surgery. A randomized study is needed to assess the timing of nephrectomy in combination with immunotherapy with regard to morbidity, overall survival and quality of life.