Susan G. Hilsenbeck

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer

PURPOSEnTo evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy.nnnPATIENTS AND METHODSnPatients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response.nnnRESULTSnOne complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case.nnnCONCLUSIONnIrinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Phase I and pharmacokinetic trial of weekly CPT-11

PURPOSEnWe conducted a phase I and pharmacokinetic trial of CPT-11 (irinotecan) to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetic profile, and antitumor effects in patients with refractory solid malignancies.nnnPATIENTS AND METHODSnWe treated 32 patients with CPT-11 administered as a 90-minute intravenous infusion every week for 4 consecutive weeks followed by a 2-week rest period. Dose levels ranged from 50 to 180 mg/m2/wk. We determined concentrations of the lactone (active) and total (lactone plus carboxylate) forms of CPT-11 and its metabolite, SN-38, in the plasma and urine of selected patients during and after drug infusion.nnnRESULTSnGrade 4 diarrhea was the dose-limiting toxicity (DLT) at the 180-mg/m2/wk dose level. Other toxicities attributed to CPT-11 included dehydration, nausea, vomiting, and asthenia. Hematologic toxicity was mild in most patients. The terminal plasma half-life for CPT-11 (total) was 7.9 +/- 2.8 hours, for CPT-11 (lactone) 6.3 +/- 2.2 hours, for SN-38 (total) 13.0 +/- 5.8 hours, and for SN-38 (lactone) 11.5 +/- 3.8 hours. We observed significant correlations between drug dose and peak plasma concentration (Cpmax) and between drug dose and area under the concentration curve (AUC) for CPT-11, but not for SN-38.nnnCONCLUSIONnThe MTD for CPT-11 in this patient population was 150 mg/m2/wk when administered on a weekly-times-four schedule repeated every 6 weeks. At dose levels greater than 150 mg/m2/wk, diarrhea is dose-limiting.

Incidence and hospital stay for cardiac and pulmonary complications after abdominal surgery.

OBJECTIVE: Internists frequently evaluate preoperative cardiopulmonary risk and comanage cardiac and pulmonary complications, but the comparative incidence and clinical importance of these complications are not clearly delineated. This study evaluated incidence and length of stay for both cardiac and pulmonary complications after elective laparotomy.DESIGN: Nested case-control.SETTING: University-affiliated Department of Veterans Affairs Hospital.PATIENTS: Computerized registry of all 2,291 patients undergoing elective abdominal operations from 1982 to 1991.MEASUREMENT AND MAIN RESULTS: Strategy for ascertainment and verification of complications was systematic and explicit. The charts of all 116 patients identified by the registry as having complications and 412 (19%) randomly selected from 2,175 remaining patients were reviewed to verify presence or absence of cardiac or pulmonary complications, using explicit criteria and independent abstraction of pre- and postoperative components of charts. From these 528 validated cases and controls (23% of the cohort), 96 cases and 96 controls were matched by operation type and age within ten years. Hospital and intensive care unit stays were significantly longer (p<0.0001) for the cases than for the controls (24.1 vs 10.3 and 5.8 vs 1.5 days, respectively). All 19 deaths occurred among the cases. Among the cases, pulmonary complications occurred significantly more often than cardiac complications (p<0.00001) and were associated with significantly longer hospital stays (22.7 vs 10.4 days, p=0.001). Combined cardiopulmonary complications occurred among 26% of the cases. Misclassification-corrected incidence rates for the entire cohort were 9.6% (95% CI 7.2–12.0) for pulmonary and 5.7% (95% CI 3.8–7.7) for cardiac complications.CONCLUSIONS: For noncardiac surgery, previous research has focused on cardiac risk. In this study, pulmonary complications were more frequent, were associated with longer hospital stay, and occurred in combination with cardiac complications in a substantial proportion of cases. These results suggest that further research is needed to fully characterize the clinical epidemiology of postoperative cardiac and pulmonary complications and better guide preoperative risk assessment.

Time-dependence of hazard ratios for prognostic factors in primary breast cancer

Some prognostic factors, such as steroid receptors, appear strongly related to outcome in early studies with short follow-up, but as follow-up matures the relationships appear to weaken. We investigated this phenomenon for several factors (tumor size, axillary lymph nodes, S-phase fraction, estrogen receptor (ER) status, and adjuvant therapy) in a large sample of breast cancer cases (N=2,873) with up to 17 years of follow-up for disease-free survival (DFS). Subjects in the study were identified from patients who had hormone receptor assays performed in our laboratory. Analysis of DFS included fitting a multivariate Cox proportional hazards model, testing for nonproportionality, and examining diagnostic plots. The assumption of proportional hazards was violated for several factors including ER, tumor size, and S-phase fraction. For ER, the hazard ratio was initially less than 1.0, indicating a good effect on prognosis, but increased at later times to values greater than 1.0, indicating a bad effect on prognosis. In contrast, the hazard ratios for tumor size and S-phase were initially high and decreased asymptotically toward 1.0 over time. Analysis of p53 expression in a subset of cases yielded qualitatively similar results. We conclude that several standard prognostic factors (ER, tumor size, S-phase fraction) and possibly other investigational factors have important but nonproportional effects on hazard. It is likely that violation of proportional hazards is common and not limited to breast cancer. Failure to recognize violations of proportional hazards can lead to both over- and under-estimation of the effects of important prognostic factors.

Investigation of taxol as a potential radiation sensitizer

Background. The authors evaluated the effects of taxol, a microtubular inhibitor, as a possible radiation sensitizer on the human leukemic cell line (HL‐60). Taxol acts as a mitotic inhibitor, blocking cells in the G2M‐phase of the cell cycle. The differential radiation sensitivity of cells in various phases of the cell cycle has been well recognized. This study was focused on the possible interaction between radiation and a microtubular inhibitor, taxol, in regard to its ability to synchronize cells at the G2M‐phase of cell cycle and, thereby, enhance the radiation sensitivity of the cells.

The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth

The acquired ability of tamoxifen to stimulate tumor growth has been suggested as one mechanism for the development of treatment failure in breast cancer. We have reported that tamoxifen-stimulated MCF-7 breast tumors in nude mice display reduced tamoxifen levels as compared with tamoxifen-inhibited tumors and an altered metabolite profile with isomerization oftrans-4-hydroxytamoxifen to a weak antiestrogen and the production of metabolite E, an estrogenic metabolite. To investigate further the importance of tamoxifen metabolism in this model, we quantified levels of tamoxifen and major metabolites in tamoxifen-stimulated as compared with tamoxifen-inhibited MCF-7 tumors growing in nude mice and employed tamoxifen analogs resistant to metabolism. Tamoxifen-stimulated tumors have a relative abundance ofcis-4-hydroxytamoxifen and metabolite E. However, in vivo treatment of mice carrying tamoxifen-stimulated tumors with fixed-ring nonisomerizable tamoxifen analogs or with nafoxidine, a nonsteroidal antiestrogen with a different structure, nonetheless resulted in tumor growth stimulation. Tumors were also stimulated by a deoxytamoxifen analog resistant to conversion to metabolite E. Growth of tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182, 780, suggesting the need for clinical trials of this drug in patients with tamoxifen resistance. Growth of tamoxifen-stimulated tumors was further stimulated by estrogen replenishment, and this estrogen stimulation could be blocked by tamoxifen indicating that tamoxifen has both agonist and antagonist properties in these tumors. This study suggests that tamoxifen-stimulated tumor growth in this model is not due to isomerization or metabolism of tamoxifen to less antiestrogenic or more estrogenic metabolities. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties, resulting in tumor growth stimulation over time, remain to be defined.

Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q.

Deletions of chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280–286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the chromosome in which genes responsible for specific abnormal phenotypes are located. Am. J. Med. Genet. 85:455–462, 1999.

Why do so many prognostic factors fail to pan out

SummaryAlthough there can be many reasons that one study fails to confirm the results of another, the consequences of data exploration and the potential for spuriously significant results are often overlooked. A series of simulation experiments were designed to mimic the characteristics of relapse-free survival data that might be encountered in a prognostic factor study of node-negative breast cancer patients. Each simulated dataset of 500 or 250 cases was divided into a training set, used to select the “best” prognostic factor cutpoint, and a validation set, used to confirm the cutpoint. Testing multiple cutpoints markedly increased the risk of making a Type I error. The power to detect even small true differences was substantial, and increased as the number of cutpoints increased. Regardless of the number of cutpoints tested on the training sets, the Type I error rate on an independent validation data set was quite stable and the power of the validation set to detect true differences was not related to the number of cutpoints. Validation power closely approximated that predicted for a simple two group comparison. It is therefore recommended that exploratory analyses of prognostic factors formally employ some method of adjusting for increased Type I errors, such as independent validation sets, ad hoc adjustment factors, or other statistical methods of estimating the true risk.

Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53.

We have used an in vivo tumor model to evaluate the consequences of p53 tumor suppressor protein deficiency in a tissue-specific context. By breeding MMTV-ras transgenic mice, which are highly susceptible to the development of mammary and salivary tumors, with p53(-/-) mice, we generated three classes of animals which contained the MMTV-ras transgene but differed in their p53 functional status (ras/p53(+/+), ras/p53(+/-), or ras/p53(-/-)). ras/p53(-/-) mice developed tumors more rapidly than animals of the other two genotypes; however, the distribution of tumors was unexpectedly altered. Whereas the most frequently observed tumors in ras/p53(+/+) and ras/p53(+/-) mice were of mammary origin, ras/p53(-/-) mice developed primarily salivary tumors. In addition, the mammary and salivary tumors from ras/p53(-/-) mice consistently exhibited a number of unfavorable characteristics, including higher histologic grades, increased growth rates, and extensive genomic instability and heterogeneity, relative to tumors from ras/p53(+/+) mice. Interestingly, the increased growth rates of ras/p53(-/-) tumors appear to be due to impaired cell cycle regulation rather than decreased apoptosis, suggesting that p53-mediated tumor suppression can occur independent of its role in apoptosis.

Hsp27 overexpression inhibits doxorubicin–induced apoptosis in human breast cancer cells

Previously we demonstrated that heat shock protein 27 (hsp27) overexpression confers resistance to the chemotherapeutic agent doxorubicin in MDA–MB–231 breast cancer cells. Since induction of apoptosis is one underlying mechanism of chemotherapeutic drug action, we investigated the effect of hsp27 overexpression on doxorubicin–induced apoptosis, finding that hsp27 protects MDA–MB–231 cells from apoptosis. We also examined expression of the doxorubicin target, topoisomerase II (topo II), in control and hsp27–overexpressing stable transfectants, as topo II expression is important for both drug sensitivity and the initiation of apoptosis by doxorubicin. The relative levels of both topo IIα and β were higher in the controls than the hsp27–overexpressing clones, suggesting that the apoptotic protective effect of hsp27 overexpression in MDA–MB–231 cells is associated with altered topo II expression.abstract