Chusilp Charnsangavej

Preoperative Gemcitabine-Based Chemoradiation for Patients With Resectable Adenocarcinoma of the Pancreatic Head

PURPOSE We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma. PATIENTS AND METHODS Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous (IV) infusions of gemcitabine (400 mg/m(2) IV over 30 minutes) plus radiation therapy (30 Gy in 10 fractions over 2 weeks). Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery. RESULTS The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively. CONCLUSION Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets: patients likely to benefit from PD (n = 64) and those in whom surgery would be unlikely to provide clinical benefit (n = 22). Furthermore, the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer.

Targeting Vascular Endothelial Growth Factor in Advanced Carcinoid Tumor: A Random Assignment Phase II Study of Depot Octreotide With Bevacizumab and Pegylated Interferon Alfa-2b

PURPOSE Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors. PATIENTS AND METHODS Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow. RESULTS In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed. CONCLUSION Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.

Rationale for en bloc vein resection in the treatment of pancreatic adenocarcinoma adherent to the superior mesenteric-portal vein confluence

OBJECTIVE Tumor invasion of the superior mesenteric-portal vein (SMPV) confluence is often considered a contraindication to pancreaticoduodenectomy for patients with malignant tumors of the pancreas or periampullary region. The authors sought to determine whether pancreaticoduodenectomy with en bloc resection of the SMPV confluence could be safely performed and whether tumors involving the SMPV confluence were associated with pathologic parameters suggesting poor prognosis. SUMMARY BACKGROUND DATA Several centers have reported high rates of retroperitoneal margin positivity after pancreaticoduodenectomy for tumors of the pancreatic head and periampullary region. Positive-margin or incomplete resection is associated with early tumor recurrence and no survival benefit compared with palliative therapy. Tumor adherence to the lateral of posterior wall of the SMPV confluence often represents the only barrier to complete tumor resection at the time of pancreaticoduodenectomy. METHODS Data on all patients undergoing pancreaticoduodenectomy for adenocarcinoma of the pancreas or periampullary region over a 3.5-year period were entered prospectively in a pancreatic tumor database. To be considered for surgery, patients were required to fulfill the following computed tomography criteria for resectability: 1) the absence of extrapancreatic disease, 2) no tumor encasement of the superior mesenteric artery or celiac axis, and 3) a patent SMPV confluence. Tumor adherence to the superior mesenteric vein or SMPV confluence was assessed intraoperatively, and en bloc venous resection was performed when necessary to achieve complete tumor extirpation. Data on operative characteristics, morbidity, mortality, tumor size, nodal metastases, margin positivity, perineural invasion, and tumor DNA content were compared for patients who did and did not receive venous resection. RESULTS Fifty-nine patients underwent pancreaticoduodenectomy, 36 without venous resection and 23 with en bloc resection of the SMPV confluence. No differences in median hospital stay, morbidity, mortality, tumor size, margin positivity, nodal positivity, or tumor DNA content were observed between groups. CONCLUSIONS When necessary, segmental resection of the SMPV confluence may be performed safely during pancreaticoduodenectomy for periampullary malignant tumors. Tumors invading the SMPV confluence are not associated with histologic parameters suggesting a poor prognosis. Our data suggest that venous involvement is a function of tumor location rather than an indicator of aggressive tumor biology.

Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases.

CONTEXT The standard criteria used to evaluate tumor response, the Response Evaluation Criteria in Solid Tumors (RECIST), were developed to assess tumor shrinkage after cytotoxic chemotherapy and may be limited in assessing response to biologic agents, which have a cytostatic mechanism of action. OBJECTIVE To validate novel tumor response criteria based on morphologic changes observed on computed tomography (CT) in patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy regimens. DESIGN, SETTING, AND PATIENTS A total of 234 colorectal liver metastases were analyzed from 50 patients who underwent hepatic resection after preoperative chemotherapy that included bevacizumab at a comprehensive US cancer center from 2004 to 2007; date of last follow-up was March 2008. All patients underwent routine contrast-enhanced CT at the start and end of preoperative therapy. Three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. These criteria were validated with a separate cohort of 82 patients with unresectable colorectal liver metastases treated with bevacizumab-containing chemotherapy. MAIN OUTCOME MEASURES Response determined using morphologic criteria and RECIST was correlated with pathologic response in resected liver specimens and with patient survival. RESULTS Interobserver agreement for scoring morphologic changes was good among 3 radiologists (kappa, 0.68-0.78; 95% confidence interval [CI], 0.51-0.93). In resected tumor specimens, the median (interquartile range [IQR]) percentages of residual tumor cells for optimal morphologic response was 20% (10%-30%); for incomplete response, 50% (30%-60%); and no response, 70% (60%-70%; P < .001). With RECIST, the median (IQR) percentages of residual tumor cells were for partial response 30% (10%-60%); for stable disease, 50% (20%-70%); and for progressive disease, 70% (65%-70%; P = .04). Among patients who underwent hepatic resection, median overall survival was not yet reached with optimal morphologic response and 25 months (95% CI, 20.2-29.8 months) with incomplete or no morphologic response (P = .03). In the validation cohort, patients with optimal morphologic response had median overall survival of 31 months (95% CI, 26.8-35.2 months) compared with 19 months (95% CI, 14.6-23.4 months) with incomplete or no morphologic response (P = .009). RECIST did not correlate with survival in either the surgical or validation cohort. CONCLUSION Among patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy, CT-based morphologic criteria had a statistically significant association with pathologic response and overall survival.

Phase I Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors

PURPOSE Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors. PATIENTS AND METHODS Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers. RESULTS Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endos activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed. CONCLUSION rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

PURPOSE Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function. RESULTS Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL. CONCLUSION A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.

Comparison of CT methods for determining the fat content of the liver.

OBJECTIVE The purpose of this study was to assess which of a number of methods of measuring attenuation on CT scans is best for prediction of hepatic fat content. MATERIALS AND METHODS This retrospective study was approved by our institutional review board. Consecutively registered patients who underwent liver resection for metastatic disease formed the study group. Attenuation measurements were obtained from 12 regions of interest in the liver and three in the spleen on both unenhanced and portal phase contrast-enhanced preoperative hepatic CT images. Hepatic attenuation measurements were analyzed both with and without normalization with the spleen. Normalization included both differences and ratios between hepatic and splenic attenuation values. Pathologic fat content was graded semiquantitatively as a percentage of the nonneoplastic liver parenchyma of the resected specimen. Average attenuation values of the liver were compared with pathologic fat content, as were the differences and ratios between hepatic and splenic attenuation values. Linear regression analysis was conducted on a log-log scale. RESULTS Data on 88 patients were analyzed. On unenhanced and contrast-enhanced CT images, all associations between pathologic fat content and attenuation measurements were significant (p < 0.0001). All series of R2 values for unenhanced CT scans were much higher than those for contrast-enhanced CT scans. The R2 values of liver-only measurement were higher than those of hepatic values normalized with splenic values on both unenhanced (0.646-0.649 > 0.523, 0.565) and contrast-enhanced (0.516 > 0.242, 0.344) CT. CONCLUSION Measurement of attenuation of liver only on unenhanced CT scans is best for prediction of pathologic fat content.

Selection of Patients for Resection of Hepatic Colorectal Metastases: Expert Consensus Statement

Surgical margin status has been shown to be important in long-term outcomes following resection of colorectal liver metastases. Multiple studies have shown that a negative resection margin decreases local recurrence rates and improves survival.1,62 In a study by Scheele et al.,63 the median survival of patients who underwent an R1 or R2 resection was only 14 months compared with 44 months for those who underwent an R0 resection. In a more recent study by Choti et al.,1 patients who had a positive microscopic resection margin had a median survival of only 24 months compared with 46 months for patients with a negative surgical margin. In this study, positive surgical margin status was associated with a 3.5 increase in relative risk of disease-specific death. Similarly, Pawlik et al.62 reported that a positive resection margin was associated with a significantly higher risk of surgical margin recurrence and decreased overall survival. Given the importance of a clear surgical margin, the question then arises as to what constitutes a minimally acceptable negative microscopic margin. Several earlier series concerning liver resection for hepatic colorectal metastases have reported that one should attain at least a 1-cm margin,64,65 and if not possible, this should be a relative contraindication to surgery.66 Cady et al.65 reported that a surgical margin less than 1 cm was associated with a significantly shorter disease-free survival. As a result, many centers adopted the “1-cm rule” as a minimal margin to obtain at the time of hepatic resection.67,68 These findings, however, have not been corroborated in multivariate regression analyses adjusted for other confounding risk factors.62 In fact, other investigators62,69 more recently reported that the actual width of the surgical margin has no effect on survival as long as the margin is microscopically negative. Altendorf-Hofmann and Scheele69 noted that while patients with a microscopically positive margin had a worse prognosis compared with patients who had a microscopically negative margin, survival was not associated with the width of the negative surgical margin. Similarly, Pawlik et al.62 noted that the width of a negative surgical margin did not affect survival, recurrence risk, or site of recurrence following hepatic resection of colorectal metastases. In this study, patients with a positive surgical margin had a higher overall risk of recurrence (51%) compared with patients who had a negative surgical margin (40%); however, patients with a negative margin—regardless of the width of the surgical margin—had similar overall recurrence rates. The 5-year survival rate was 17% for patients with a positive surgical margin compared with 64% for patients with a negative surgical margin. The width of the surgical margin did not significantly affect survival in patients with negative margins.62 In the past, resection of hepatic colorectal metastases was not attempted in patients who had more than three or four metastases, hilar adenopathy, metastases within 1 cm of major vessels such as the vena cava or main hepatic veins, or extrahepatic disease. Earlier studies that established certain clinicopathologic factors as being contraindications for surgery have subsequently been criticized on both clinical and methodologic grounds. Methodologically, these studies were problematic because only a small number of patients who actually met all the “exclusion” criteria were included in the analyses. Additionally, most early studies reported only univariate or log-rank analyses while failing to control for competing risk factors. Clinically, data are problematic because many of these early studies were carried out prior to the era when new, more active chemotherapy agents, as well as new techniques such as portal vein embolization (PVE) and radiofrequency ablation, were available. More recent studies demonstrate that patients with “traditional” adverse clinicopathologic factors can achieve long-term survival following hepatic resection and therefore should not be excluded from surgical consideration. This has therefore precipitated a shift in the definition of resectability from criteria based on the characteristics of the metastatic disease (tumor number, size, etc.) to new criteria based on whether a complete (margin-negative) resection of the liver lesion can be performed. Currently, hepatic colorectal metastases should be defined as resectable when it is anticipated that disease can be completely resected, two adjacent liver segments can be spared, adequate vascular inflow and outflow and biliary drainage can be preserved, and the volume of the liver remaining after resection (i.e., the “future liver remnant”) will be adequate (at least 20% of the total estimated liver volume).21,70 This definition of resectability represents a paradigm shift. Instead of resectability being defined by what is removed, decisions regarding resectability should now focus on what will remain following resection. Concern for the future liver remnant is particularly pertinent during preoperative evaluation of patients for an extended hepatectomy (resection of ≥ five liver segments), as some patients may be excluded from the benefit of a potentially curative resection because the anticipated liver remnant may be too small. In general, 20% of the total liver volume appears to be the minimum safe volume that can be left following extended resection in patients with normal underlying liver. CT or MRI can now provide an accurate, reproducible method for preoperatively measuring the volume of the future liver remnant.70 To avoid operating on patients with low-volume future liver remnants, any patient who fails to show compensatory hypertrophy as a result of tumor growth and who has a future liver remnant of less than 20% should be considered for PVE to induce hypertrophy of the contralateral liver lobe.71 Another factor that has almost universally been well accepted as a contraindication to liver resection is the presence of extrahepatic disease. In Adson’s38 initial report in 1984, he noted that no patient with extrahepatic disease survived beyond 5 years. As such, extrahepatic disease has long been regarded as an absolute exclusion criteria for hepatic resection. The advent of more effective systemic chemotherapy agents, as well as improvements in imaging modalities to more accurately identify the true extent of extrahepatic disease, has prompted some investigators to advocate for surgical resection for patients with extrahepatic disease. Elias et al.72 have reported that the 5-year survival rates following hepatectomy for hepatic colorectal metastases and simultaneous resection of extrahepatic disease with curative intent was 29%. As such, the presence of extrahepatic disease should not be considered an absolute contraindication to hepatic resection. However, patients with extrahepatic disease must be selected carefully. In general, resection should only be considered following documentation of stable/responsive disease after treatment with systemic chemotherapy in situations where complete (margin-negative) resection is feasible. Management of patients with simultaneous intra- and extrahepatic disease involves complex clinical decision making and therefore should be carried out in a multidisciplinary setting. Consensus Statement: 1. In patients undergoing liver resection for hepatic colorectal metastases, a positive surgical margin is associated with a higher local recurrence and worse overall survival and should be avoided whenever possible. 2. While a wide (> 1-cm) resection margin should remain the goal when performing a liver resection, an anticipated margin of less than 1 cm should not be used as an exclusion criterion for resection. 3. Assessment of resectability of hepatic colorectal metastases should focus on the ability to obtain a complete resection (negative margins). 4. The feasibility of hepatic resection should also be based on three criteria related to the remaining liver following resection: (1) the ability to preserve two contiguous hepatic segments, (2) preservation of adequate vascular inflow and outflow as well as biliary drainage, and (3) the ability to preserve adequate future liver remnant (> 20% in a healthy liver). 5. The presence of extrahepatic disease should no longer be considered an absolute contraindication to hepatic resection provided the patient is carefully selected and a complete (margin-negative) resection of both intra- and extrahepatic disease is feasible.

Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms☆

A prospective diagnostic study was designed to determine the ability of thin-section contrast-enhanced computed tomography (CT) to predict the resectability of malignant neoplasms of the pancreatic head. Patients with a presumed resectable pancreatic neoplasm referred during a 21-month period were studied with abdominal CT performed at 1.5-mm section thickness and 5-mm slice interval during the bolus phase of intravenous contrast enhancement. CT criteria for resectability included the absence of extrapancreatic disease, no evidence of arterial encasement, and a patent superior mesenteric-portal venous confluence. Of 145 patients evaluated, 42 were considered to have resectable tumors by CT criteria, and 37 (88%) underwent potentially curative pancreaticoduodenectomy. Six patients were found to have a microscopically positive retroperitoneal resection margin; no patient had a grossly positive resection margin. Five (12%) of 42 patients were found at laparotomy to have unresectable, locally advanced or metastatic tumors. Thin-section contrast-enhanced CT is an essential component of the preoperative evaluation for pancreaticoduodenectomy and can prevent needles laparotomy in most patients with locally advanced or metastatic disease.

Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators

Experience with preoperative therapy for other cancers has led to an assumption that borderline resectable pancreatic cancers can be converted to resectable cancers with preoperative therapy. In this study, the authors sought to determine the rate at which neoadjuvant therapy is associated with a reduction in the size or stage of borderline resectable tumors.