A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

BACKGROUND: This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC). METHODS: Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured. RESULTS: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival. CONCLUSION: The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer.

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863.

BACKGROUND: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction. PATIENTS AND METHODS: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m(2), irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients. RESULTS: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m(2). Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m(2). These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study. CONCLUSIONS: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Therapeutic approaches to metastasis confined to the liver.

Liver metastases nearly always represent disseminated cancer, and systemic therapies are usually indicated. However, in a minority of patients--some with colorectal cancer, others with selected tumors--management of the hepatic disease may be clinically important and even curative. This review identifies unique patient subgroups and novel treatment approaches that may be indicated in patients with liver metastases.

Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565.

PURPOSE: To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. PATIENTS AND METHODS: Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dL; II-bilirubin level 1.6 to 7.0 mg/dL; and III-creatinine level 1.6 to 5.0 mg/dL with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. RESULTS: Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups or compared with historical controls. CONCLUSION: If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatinine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation.

Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a disease that is extremely difficult to manage and is increasing markedly in incidence. This presents both an opportunity and a challenge. At-risk patients can be identified and early detection of HCC is feasible. New surgical techniques and postoperative therapies, including hepatic intra-arterial radiation, may improve the outlook for some patients with resectable cancer. Unfortunately, the vast majority of patients with HCC will have unresectable cancers. Regional treatments may shrink or necrose tumors, but no clear benefit to such therapies has been demonstrated. Recent evidence suggests combination chemotherapy may help some patients, although this needs validation. Perhaps the best hope is that the further elucidation of the genetic and molecular features of HCC will lend us insight into innovative strategies to manage this difficult cancer.

Regional strategies for managing hepatocellular carcinoma.

Hepatocellular carcinoma is a common, difficult-to-treat cancer that has a variable natural history depending on patient demographics and the etiology and extent of underlying liver disease. Resection is the preferred treatment option but is only possible in the rare patient who has adequate hepatic reserve and limited-stage cancer. Systemic chemotherapy is mostly inactive. Because most patients with hepatocellular cancer succumb to hepatic failure, this is a disease that appears to be amenable to regional treatments. For this reason, numerous intratumoral, ablative techniques are available. Other routinely used regional treatment modalities include intraarterial chemotherapy, chemoembolization, Lipiodol chemoembolization, and internal radiation. However, the benefits of these interventions have been difficult to ascertain given the variable clinical course of the disease. Regional delivery may prove to be most valuable as a route for administering newer agents.

Hepatocellular carcinoma.

Early detection of hepatocellular carcinoma (HCC) is feasible, particularly in patients known to be at risk from chronic hepatitis and chronic liver disease. The optimal surveillance strategy is unknown. HCC usually presents as an incurable disease even when detected on surveillance. Surgical resection is the treatment of choice, but the coexistence of chronic liver disease and the insidious nature of HCC make it unresectable in most patients. Orthotopic liver transplantation for selected patients or ablative techniques may offer an opportunity to render patients disease-free even if the tumor is unresectable. There are numerous therapies offered to patients with unresectable HCC, including chemotherapy, hormonal therapy, and regional intra-arterial treatments. While potentially palliative, none of these approaches has been demonstrated to prolong survival in these patients. If possible, the treatment of patients with HCC should be done on clinical trials.

Transcatheter embolization for the treatment of misperfusion after hepatic artery chemoinfusion pump implantation.

BACKGROUND: The use of surgically implanted chemoinfusion pumps for the treatment of hepatic metastases from colorectal carcinoma can be complicated by intra- or extrahepatic misperfusion. This may result in suboptimal tumor exposure to the chemotherapeutic agent and injury to other gastrointestinal organs. Misperfusion can be managed by selective arterial transcatheter embolization. METHODS: Between 1989 and 1996, 16 patients with liver metastases from colorectal carcinoma and with hepatic artery chemoinfusion pump misperfusion were treated using transcatheter coil embolization. Six female and 10 male patients (age range, 34-84 years; median, 51.5 years) were identified by retrospective review of the records of the Department of Interventional Radiology. After pump placement, abnormal liver perfusion scan or methylene blue endoscopy study results prompted angiography with coil embolization. After embolization, the imaging studies were repeated and patients were monitored in the Oncology Clinic. RESULTS: Eight patients exhibited intrahepatic misperfusion (group 1) and eight extrahepatic misperfusion (group 2). Coil embolization was immediately successful in 100% of patients in group 1, with restoration of normal hepatic perfusion, and in 75% in group 2. There were no immediate procedure-related complications. Follow-up periods ranged from 1 to 23 months (median, 13.5 months). Embolization was unsuccessful for two patients (in group 2), who tolerated a modified chemotherapeutic regimen, with follow-up periods of 18.5 and 22 months. CONCLUSIONS: Transcatheter coil embolization is the therapy of choice for the management of hepatic artery chemoinfusion pump misperfusion. It is rapid, effective, and well tolerated by patients and obviates the need for additional surgical intervention.

Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.

PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.

Embolization and chemoembolization therapy for neuroendocrine tumors.

Neuroendocrine tumors, particularly those of gastrointestinal tract origin, have a predisposition for metastasizing to the liver. In such patients, the clinical course is often dominated by the hepatic disease, either because of hormone secretion or because of tumor bulk. Because the liver has a dual vascular supply and hepatic metastases derive the majority of blood from the hepatic artery, the regional delivery of chemotherapy can offer pharmacokinetic advantages over systemic administration. The hepatic artery is also a nonsurgical avenue for inducing selective metastasis ischemia by the embolization of tumor vessels. The combination of these two therapies, or chemoembolization, may provide additive benefits. Such an approach has been demonstrated to reduce tumor bulk, reduce hormone levels, and palliate the symptoms of many patients with liver-dominant neuroendocrine metastases. Embolization or chemoembolization is an appropriate modality for some patients with neuroendocrine tumors.

Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction.

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.

Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264.

PURPOSE: To characterize the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of paclitaxel in patients with abnormal liver function. PATIENTS AND METHODS: Adults with tumors appropriate for paclitaxel therapy who had abnormal liver function tests were eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL. Doses were explored in at least three patients within each cohort. Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinetics were to be studied in all patients. RESULTS: Eighty-one patients were assessable for toxicity. Patients with bilirubin levels greater than 1.5 mg/dL had substantial toxicity at all doses explored, whereas the toxicity for patients with elevated AST levels occurred at doses that ranged from 50 to 175 mg/m2 administered over 24 hours. In most patients, the DLT was myelosuppression. The pharmacokinetic data were insufficient to adequately evaluate the relationship between pharmacokinetics and toxicity in patients who received 24-hour infusions but provided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group. CONCLUSION: If paclitaxel is used for patients with elevated levels of AST or bilirubin, dose reductions are necessary, and an increase in toxicity can be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patients.

Update on hepatic intra-arterial chemotherapy.

The use of hepatic intra-arterial (HIA) chemotherapy is based on the pharmacologic principle that the regional administration of certain drugs can lead to higher drug concentrations at the site of a tumor. This has been studied most extensively in patients with liver-only colorectal metastases. Four large randomized studies have failed to demonstrate a survival advantage of regional treatment over systemic chemotherapy, although two meta-analyses confirmed an improvement in response rate and suggest a trend toward improvement in survival. Two randomized studies have shown improved survival in patients treated with HIA chemotherapy, as compared with those given supportive care, and quality of life also appears to be superior in HIA chemotherapy recipients. The treatment employed in all of the randomized studies was hindered by substantial hepatobiliary toxicity and many surgical complications. Improved surgical techniques and newer chemotherapy combinations appear to have improved phase II results with HIA therapy, leading to a randomized trial now being conducted by the Cancer and Leukemia Group B (CALGB). The role of HIA chemotherapy in adjuvant settings and in other diseases has not been as well-studied, and such uses remain appropriate only for very selected patients. Ultimately, the regional advantage gained by the HIA route may prove to be most advantageous for the delivery of newer biologic agents.

Intra-abdominal desmoplastic small round-cell tumor: expansion of the pathologic profile.

This report describes an intra-abdominal desmoplastic small round-cell tumor in a 29-year-old man that significantly differed from the classically described appearances of this unique tumor. It showed extensive papillary areas, no necrosis, and very little desmoplasia. The latter was limited, paucicellular, and present in areas separate from the papillary structures. Also, areas of back-to-back, single-cell infiltration, which mimicked lobular breast carcinoma, were present. These epithelial features suggested the diagnosis of adenocarcinoma or peculiar mesothelioma. But, the immunohistochemical features (tumor cells positive for keratin, desmin, and vimentin) were more consistent with an intra-abdominal desmoplastic small round-cell tumor. The diagnosis became clear after application of reverse transcriptase-polymerase chain reaction techniques to formalin-fixed, paraffin-embedded tissue, which showed the presence of a 100-base pair product containing the fusion junction of Ewing's sarcoma-1 exon 7 to Wilms' tumor-1 exon 8. This feature is considered unique to intra-abdominal desmoplastic small round-cell tumors. This case illustrates the less common histologic findings that can be found in intra-abdominal desmoplastic small round-cell tumor. This deviation from the classic histologic findings may be an expression of an uncommon morphologic variant and/or partially produced by the effects of prior chemotherapy. In either event, only by illustrating the various histologic appearances of intra-abdominal desmoplastic small round-cell tumor are the chances increased for the accurate diagnosis of this aggressive neoplasm with a poor prognosis.

Regional chemotherapy approaches for primary and metastatic liver tumors.

There are pharmacologic principles that make regional chemotherapy to the liver a logical treatment strategy. Patients with colorectal liver metastases and hepatocellular carcinoma would appear to be the best candidates for such an approach. Although there are many objective responses to such treatment, survival benefit has not been demonstrated, but new regimens and refined techniques appear to be improving results. Ultimately, regional delivery may be best suited for innovative treatments such as biologicals and gene therapies.

Liver transplantation for hepatocellular carcinoma: results with preoperative chemoembolization.

At the University of California, San Francisco, 17 patients who met the following criteria-hepatic tumor unresectable because of location or inadequate liver reserve, no metastases, HBsAg negative, no tumor larger than 5 cm in diameter, and no more than three tumors--were enrolled prospectively in a protocol employing preoperative chemoembolization to assess whether orthotopic liver transplantation (OLT) could cure a majority of highly selected patients with hepatocellular carcinoma (HCC). Thirteen patients had biopsy-proven HCC, 2 had the fibrolamellar variant, and 2 had radiological findings of HCC but no biopsy confirmation. Fourteen had underlying liver disease. All arteriographically apparent lesions were chemoembolized using a mixture including Gelfoam powder, doxorubicin, mitomycin-c, and cisplatin. Eight patients with poor hepatic reserve were chemoembolized when a donor organ became available, whereas 9 patients were chemoembolized and then placed on the waiting list. The only complication of chemoembolization was a gangrenous gallbladder in 1 patient. Thirteen patients underwent liver transplantation (2 patients without prior histological confirmation of carcinoma had no identifiable tumor at OLT); 3 patients developed metastases between the time of enrollment and donor organ availability and subsequently died; and 1 patient underwent a trisegmentectomy. Ten of the 11 patients with biopsy-proven HCC who underwent transplantation remain free of recurrent cancer at a median of 40 months; 1 patient died at 6 months of lymphoproliferative disease with no cancer found at autopsy. Although the role of chemoembolization is uncertain, these data show that the majority of carefully selected patients with HCC may achieve long-term survival with OLT.