Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.

BACKGROUND: Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination. PATIENTS AND METHODS: Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%. RESULTS: Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity. CONCLUSION: The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00720174.

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.

Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience.

BACKGROUND: Locoregionally advanced, stage IV head and neck cancer has traditionally carried a poor prognosis. We sought to assess changes in patterns of failure, prognostic factors for recurrence, and overall outcome, using two different strategies of chemoradiotherapy conducted in prospective, multi-institutional phase II trials. PATIENTS AND METHODS: Three hundred and thirty-seven stage IV patients were treated from 1989 to 1998. We compared locoregional and distant recurrence rates, overall survival and progression-free survival from two different treatment strategies: intensive induction chemotherapy followed by split-course chemoradiotherapy (type 1, n=127), or intensified, split-course, hyperfractionated multiagent chemoradiotherapy alone (type 2, n=210). Univariate and multivariate analyses of 12 chosen covariates were assessed separately for the two study types. RESULTS: The pattern of failure varied greatly between study types 1 and 2 (5-year locoregional failure of 31% and 17% for study types 1 and 2, respectively, P=0.01; 5-year distant failure rate of 13% and 22% for study types 1 and 2, P=0.03). Combined 5-year overall survival was 47% [95% confidence interval (CI) 41% to 53%) and progression-free survival was 60% (95% CI 55% to 66%). Both treatment strategies yielded similar survival rates. Poor overall survival and distant recurrence were best predicted by advanced nodal stage. Locoregional recurrence was extremely rare for patients with T0-T3 tumor stage, regardless of lymph-node stage. CONCLUSIONS: This analysis suggests that pattern of failure in primary head and neck cancer may be dependent upon treatment strategy. Randomized clinical trials of induction chemotherapy are warranted as a means to determine if a decrease in distant metastases can lead to an increase in survival rates in the setting of effective chemoradiotherapy for locoregional control. Additionally, this analysis provides impetus for randomized clinical trials of organ preservation chemoradiotherapy in sites outside the larynx and hypopharynx.

Phase II studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck cancer.

BACKGROUND: Bryostatin 1 is a marine derived macrolactone with antineoplastic activity modulated through protein kinase C, and with good activity in in vitro and in vivo models. There are few drugs that offer palliation for metastatic soft-tissue sarcoma and head and neck cancer, and drugs with new mechanisms of action warrant detailed disease specific study. PATIENTS AND METHODS: Two phase II studies for patients with incurable soft tissue sarcoma (12), or head and neck cancer (12) were conducted. Patients were treated with bryostatin, 120 mg/m2/72 hours every 2 weeks for 3 cycles prior to re-evaluation. Most patients had received prior chemotherapy. RESULTS: No patients had objective responses to therapy. Six patients had brief periods of disease stabilization. Toxicity was generally mild, with myalgia being prominent (n=8). Hyponatremia, not previously described, occurred in 5 patients. The mechanism of this toxicity was unclear. CONCLUSIONS: Bryosytatin 1 given as a single agent for advanced adult soft tissue sarcoma and head and neck cancer is inactive. Myalgia and hyponatremia were the predominant toxicities.

The spectrum of vascular lesions in the mammary skin, including angiosarcoma, after breast conservation treatment for breast cancer.

BACKGROUND: With the general acceptance of lumpectomy, axillary staging, and radiotherapy as local treatment for infiltrating breast cancer, an appreciation is evolving for the spectrum of vascular lesions that occur in the mammary skin after this treatment. Most of these lesions develop within the prior radiation field after breast conservation treatment. STUDY DESIGN: A retrospective chart and slide review was conducted, consisting of five patients with cutaneous vascular lesions after breast conservation treatment for infiltrating breast cancer. RESULTS: The latent time interval from definitive treatment of breast cancer to the clinical recognition of vascular lesions ranged from 5 to 11 years. Two patients did not have either arm or breast edema, two patients had breast edema, and the fifth patient had arm edema. Lesions arising in the irradiated mammary skin included extensive lymphangiectasia (one), atypical vascular lesions (two), and cutaneous angiosarcoma (four). CONCLUSIONS: Atypical vascular lesions at the skin margins of mastectomy may be predictive of recurrence after resection of angiosarcoma. Excision of skin from the entire radiation field may be necessary to secure local control of the chest wall in patients with cutaneous angiosarcoma after therapeutic breast radiotherapy.

Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer.

PURPOSE: To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS: Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS: The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION: T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.

Phase II trial of aminocamptothecin (9-AC/DMA) in patients with advanced squamous cell head and neck cancer.

Fourteen patients with squamous cell carcinoma of the head and neck received 9-AC/DMA infusions of 850 mg/M2/day over 72 hours. Eligibility criteria included good performance status, advanced disease incurable by conventional means, no prior treatment of metastatic disease, and measurable lesions for objective response assessment. The infusions were repeated at 21 day intervals until progression or prohibitive toxicity occurred. A median of 3 cycles (range 1-7) was given. No objective responses were observed. Median survival of the group was 6 months. Toxicity was hematologic which was modest and promptly reversible. 9-AC/DMA is inactive against this tumor type at the dose and schedule employed in this study.

A phase I-II study of concomitant chemoradiotherapy with paclitaxel (one-hour infusion), 5-fluorouracil and hydroxyurea with granulocyte colony stimulating factor support for patients with poor prognosis head and neck cancer.

BACKGROUND: Concomitant chemoradiotherapy is an effective treatment modality for advanced head and neck cancer, but improved regimens are needed. We sought to define the toxicities, recommended phase II dose, and outcome of a combination chemotherapy regimen with concomitant hyperfractionated radiotherapy in patients with poor prognosis cancers of the head and neck, including those having received prior curative intent radiotherapy. PATIENTS AND METHODS: From 1995 until 1997, 54 patients were treated, 25 of whom had received a prior full course of radiotherapy to the head and neck. Patients were treated with 5-fluorouracil (5-FU) 600 mg/m2/day continuous infusion x 5 days (days 1-5), hydroxyurea, 500 mg p.o. bid x 11 doses (days 1-6) and paclitaxel (60-150 mg/m2) by one-hour infusion on day 2 using a dose escalation strategy. Radiotherapy was given concomitantly on days 2-6, 150 cGy bid. Each of 4-5 cycles was delivered every other week. RESULTS: The MTD of paclitaxel was 100 mg/m2. The regimen was feasible; radiotherapy was delivered at a median of 7300 cGy and 83% of patients received > or = 80% planned dose intensity. Hematological toxicity, with granulocyte colony stimulating factor, was very mild. Dose limiting toxicities were mucositis and dermatitis. Despite poor prognosis, two-year survival was 45%. CONCLUSIONS: The recommended phase II dose of this regimen is 5-FU 600 mg/m2/day x 120 hours (days 1-5), hydroxyurea 500 mg p.o. b.i.d. x 11 doses (days 1-6), paclitaxel 100 mg/m2 over one hour on day 2, and radiotherapy 150 cGy b.i.d. days 2-6. Concomitant chemotherapy and re-irradiation was feasible on this protocol and resulted in long-term survival in patients without other curative intent options.

Integration of taxanes into primary chemotherapy for squamous cell carcinoma of the head and neck: promise fulfilled?

Chemotherapy has become integrated into the treatment of head and neck cancer in not only the palliative but now also the primary setting. Organ preservation is possible using induction chemotherapy, and improved survival results have been confirmed for concomitant chemoradiotherapy. The taxanes, paclitaxel and docetaxel, appear to be as active as any other drugs in head and neck cancer. When used in combination in the induction, recurrent, or metastatic settings, response rates rival those of the standard cisplatin/5-fluorouracil regimen. At least one ongoing study will help to establish superiority of cisplatin/paclitaxel versus cisplatin/5-fluorouracil in the recurrent or metastatic setting, and another between cisplatin/5-fluorouracil and doctaxel/cisplatin/5-fluorouracil in the induction setting. Both paclitaxel and docetaxel are being extensively studied as radiosensitizers. They are relatively well tolerated and have good efficacy but have not yet been adequately studied in comparison with other regimens. In conclusion, the taxanes have significantly expanded our effective treatment options in both the primary and recurrent or metastatic settings.

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.

Swallowing function in patients with head and neck cancer prior to treatment.

OBJECTIVE: To define the site-specific swallowing dysfunctions of patients with head and neck cancer with respect to tumor site and stage by, videofluoroscopic oropharyngeal motility (OPM) study prior to initiation of treatment. DESIGN: Retrospective survey. SETTING: Academic university institution. PATIENTS: A consecutive sample of 79 patients with stage III or IV head and neck cancer without prior treatment or tracheotomy. Patients were divided into groups according to tumor site: oral cavity (n = 7), oropharynx (n = 27), larynx (n = 24), and hypopharynx (n = 10). Patients with sinonasal, nasopharyngeal, and unknown primary carcinomas served as the comparison group (n = 11). INTERVENTION: All patients underwent OPM study prior to treatment. MAIN OUTCOME MEASURES: Parameters of swallowing function, including oral impairment, pharyngeal impairment, cervical esophageal impairment, aspiration, and Swallowing Performance Status Scale (SPSS) score (a global measure of swallowing function) were extracted from the pretreatment OPM study and analyzed with reference to tumor site, T stage, and overall stage. The relations between tumor site and area or degree of dysfunction, and between stage of disease and area or degree of dysfunction were analyzed using chi2 and Fisher exact tests. RESULTS: Aspiration status, cervical esophageal impairment, and pharyngeal impairment examined as a function of disease site showed statistically significant differences between groups, with laryngeal and hypopharyngeal sites revealing the most severe dysfunctions. The SPSS score did not correlate with tumor site, T stage, or overall stage. Other OPM parameters analyzed as a function of T stage and overall stage revealed no consistent patterns. CONCLUSIONS: Hypopharyngeal and laryngeal disease sites have a high degree of pretreatment functional impairment. The SPSS score is a good global measure of swallowing dysfunction. In addition, significant site-specific dysfunctions are found when the OPM study is analyzed via its separate parameters. It is therefore critical that posttreatment function is compared with baseline pretreatment dysfunction.

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,

Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrent or advanced head and neck cancer.

5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged drug exposure, 5-FU is commonly given by continuous infusion. Eniluracil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule. Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7). 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum 5-FU and uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2 5-FU BID. One patient died of neutropenic sepsis during cycle 4. Other late cycle toxicities included diarrhea, fatigue, and mucositis. Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral 5-FU given with the DPD-inactivator eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting mucositis and dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of eniluracil and 5-FU as radiation enhancers.

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.