An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas.

BACKGROUND: To determine efficacy and safety of bevacizumab, a recombinant humanized antibody against vascular endothelial growth factor (VEGF), in the treatment of metastatic or locally advanced angiosarcoma and epithelioid hemangioendotheliomas. PATIENTS AND METHODS: In this single-arm phase II trial, 32 patients were enrolled and they received bevacizumab 15 mg/kg IV infusion in 21-day cycles. Patients had disease that was deemed not surgically resectable, Eastern Cooperative Oncology Group (ECOG) performance status of ≤1, adequate organ function and had not received any radiation treatment in the last 28 days. RESULTS: Of the 30 patients evaluated for efficacy and toxic effect, four (two angiosarcoma and two epithelioid hemangioendothelioma; 17%) had a partial response. Fifteen patients (11 angiosarcoma and 4 epithelioid hemangioendothelioma; 50%) showed stable disease with a mean time to progression of 26 weeks. Bevacizumab was well tolerated with only one grade 4 adverse event. Expected known toxic effects of the drug were manageable. CONCLUSION: Bevacizumab is an effective and well-tolerated treatment for metastatic or locally advanced angiosarcoma and epithelioid hemangioendotheliomas. Further phase III studies of bevacizumab in combination with other chemotherapeutic agents and/or radiation treatment are warranted.

Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels.

BACKGROUND: We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity. PATIENTS AND METHODS: Stages III-IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy. RESULTS: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027). CONCLUSIONS: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.

Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors.

We sought to define risk factors predisposing breast cancer and lymphoma patients to cardiac and pulmonary toxicity when undergoing high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR). Additionally, we evaluated in depth the predictive value of the ejection fraction measured prior to HDC in determining cardiac toxicity. In this retrospective analysis, 24 variables were examined in 138 patients undergoing HDC and ASCR from 1990 until 1995. Logistic regression models were used to model the probability of experiencing cardiac and pulmonary toxicity as a function of the 24 prognostic covariates. Cardiac toxicity occurred in 12% of patients and pulmonary toxicity in 24% of patients. Bivariate analyses showed that patients with lymphoma (as opposed to breast cancer) and those with a higher cardiac risk factor score were more likely to experience cardiac toxicity. Multivariate logistic regression models predicted lymphoma and older age to be risk factors for cardiac toxicity. History of an abnormal ejection fraction and higher doses of anthracyclines prior to HDC may also contribute to cardiac toxicity. Pulmonary toxicity occurred more commonly in lymphoma than breast cancer patients, likely due to the busulfan used in the HDC regimen. No other risk factors for pulmonary toxicity were identified. We conclude that older patients with lymphoma should be carefully evaluated prior to being accepted for HDC programs. Older patients with breast cancer may tolerate this procedure well. There is a trend towards cardiac toxicity in patients with a past history of low ejection fraction, although seemingly poor cardiac risk patients may fare well with HDC if carefully selected with the aid of a thorough cardiac evaluation.

Paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant radiation therapy for poor-prognosis head and neck cancer.

A series of phase I and phase II studies investigating multiagent concomitant chemoradiotherapy in patients with poor-prognosis head and neck cancer have been conducted at the University of Chicago. Drug combinations initially included 5-fluorouracil (5-FU) and hydroxyurea, with the more recent addition of cisplatin; in the most recent trial, paclitaxel was substituted for cisplatin. The primary end point of these trials was definition of maximum tolerated doses in combination with radiation therapy. All radiation therapy was given concomitantly with chemotherapy on an every-other-week schedule (total dose,

Oral chemotherapy in head and neck cancer.

Chemotherapy plays an important role in the palliative treatment of head and neck cancer and in the neoadjuvant setting for larynx preservation. Together with concomitant radiotherapy, chemotherapy is also important for the curative and palliative therapy of unresectable head and neck cancer. Although issues relating to anatomical and pharmacological constraints exist, new orally administered drugs, as well as oral substitutes for the currently utilised intravenous drugs, would be extremely desirable in each of these situations. Of the oral fluorinated pyrimidines, tegafur/uracil (UFT) alone produced a complete response rate of 19%, and combination therapy of tegafur/uracil or tegafur with cisplatin or carboplatin has produced response rates comparable to those seen with intravenous fluorouracil (5-FU) plus cisplatin or carboplatin. An initial dose-finding study of 5-FU plus eniluracil indicates that further studies are warranted. The ribonuclease reductase inhibitor hydroxycarbamide (hydroxyurea) has been extensively studied in combination with 5-FU and radiotherapy (the FHX regimen) in patients with head and neck cancer, with high rates of local control. Improvement in locoregional and distant control rates may occur when FHX is combined with additional systemically active agents (cisplatin then paclitaxel) and hyperfractionated radiotherapy is used. Good candidate drugs for head and neck cancer include BMS-182751, an oral platinum complex, and capecitabine and S-1, other oral fluoropyrimidines. In addition, methotrexate and cyclophosphamide both have some activity in head and neck cancer and deserve further investigation.

Oncogenic osteomalacia as a harbinger of recurrent osteosarcoma.

Discussion. Oncogenic osteomalacia is a rare paraneoplastic syndrome of skeletal demineralization from renal phosphate loss. Patients with this disorder have the characteristic clinical, laboratory, and radiographic findings of hyperphosphaturic osteomalacia. Although the pathophysiology has not yet been clearly delineated, a humoral factor produced by the tumor is suspected to be the cause.Purpose. We report the first case of oncogenic osteomalacia that improved with chemotherapy, discuss this paraneoplastic syndrome, and review the medical literature regarding its etiology.

Oral 5-FU alternatives for the treatment of head and neck cancer.

The common clinical presentations of head and neck cancer include early (stage I or II) disease, locally or regionally advanced (stage III or IV, M0) disease, and recurrent or metastatic disease (< 5% of patients). Patients with stage I-II disease are usually cured following surgery or radiotherapy; those with more advanced disease, however, will benefit from chemotherapy--either as induction treatment to avoid surgery and preserve the larynx, or as simultaneous chemoradiotherapy for patients with locoregionally advanced disease; patients presenting with metastatic disease and those with recurrent disease receive chemotherapy as the primary treatment modality. The clinical experience with oral chemotherapy in head and neck cancer patients is limited, partly because of the anatomic location of the disease and complications of local treatment. At the University of Chicago, several regimens that include oral chemotherapy have been studied, including infusional 5-fluorouracil/oral hydroxyurea/radiotherapy, and eniluracil/oral 5-FU/radiotherapy. These trials and others assessing oral agents in the treatment of patients with head and neck cancer will be discussed.

Phase II and pharmacodynamic studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal and colorectal cancer.

Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms DNA adducts via the reactive pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al, Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractory colorectal cancer (14 patients, 13 with liver metastases) to determine efficacy in each disease and to correlate safety and tolerance of the drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either tumor type. The primary toxicity of PZDH was myelosuppression with neutropenia (absolute neutrophil count, < 1000/microl) and thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum chloride or blood pH levels. The colorectal patients experienced significantly more thrombocytopenia than did the renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow reserve or that colorectal patients with liver metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytopenia. Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested.

Tumor cell contamination of bone marrow harvest products: clinical consequences in a cohort of advanced-stage breast cancer patients undergoing high-dose chemotherapy.

Patients undergoing high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) may have tumor cells inadvertently infused if their stem cell product is tumor contaminated. We used an immunocytochemical (ICC) method to analyze 31 histologically negative bone marrow (BM) specimens taken from women with advanced-stage breast cancer at the time of BM harvest before HDC. All 31 patients were treated on one of three consecutive HDC protocols and received BM or BM and peripheral stem cells (PSC) as ASCR. Six of 26 evaluable patients had ICC-detectable contaminating tumor cells in their BM harvests. These 6 patients had a trend toward decreased overall survival compared with those patients without ICC-detectable tumor cells (17 months median versus 25+ months, p = 0.11, log rank test for those patients achieving complete response, CR, from HDC). The sites of relapse in the ICC-positive and ICC-negative groups were not notably different when analyzed for new sites versus previous sites of disease. Therefore, our retrospective analysis of a small cohort of patients suggests that the infusion of tumor cells in breast cancer patients undergoing HDC may confer a poor prognosis. Relapse patterns however suggest failure both in new sites and in sites of previous disease. Additional studies in expanded patient populations are needed to explore further the role of tumor cell infusion in ASCR and the possible clinical benefits of tumor cell removal procedures.

High-dose chemotherapy with autologous stem cell rescue for breast cancer: yesterday, today and tomorrow.

Metastatic breast cancer remains incurable by conventional means and is the second leading cause of all cancer deaths in women in the United States. Laboratory and clinical studies have shown chemotherapy dose intensity may be important in breast cancer therapy, and therefore clinical trials have been investigating high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) for the past decade. Initial Phase I trials in heavily pretreated patients demonstrated good response rates but short survival times. The next generation of trials used HDC as initial treatment for metastatic breast cancer and showed improved results. Most recently, patients receive HDC after "induction" chemotherapy to minimize tumor burden prior to HDC. Results from these most recent trials are encouraging, with complete remissions (CR) achievable in at least half of patients and long-term survivors noted. An ongoing randomized trial of HDC versus conventional chemotherapy should answer whether HDC is superior to conventional chemotherapy for metastatic breast cancer. Based on encouraging data from a preliminary trial, two ongoing randomized trials are comparing HDC versus conventional chemotherapy in high-risk primary breast cancer. Technological improvements, better supportive care and experience have all contributed to decrease the morbidity and mortality of this procedure. Additionally, hospitalizations have become shorter and costs may be decreasing. This review will discuss the issues pertinent to this modality in the past and present, including chemotherapy regimens, stem cell technology and related issues, outcomes, ongoing trials and future directions for consideration.