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Phase I Study of Bevacizumab Added to Fluorouracil- and Hydroxyurea-Based Concomitant Chemoradiotherapy for Poor-Prognosis Head and Neck Cancer

Tanguy Y. Seiwert, Daniel J. Haraf, Ezra E.W. Cohen, Kerstin Stenson, Mary Ellyn Witt, Allison Dekker, Masha Kocherginsky, Ralph R. Weichselbaum, Helen X. Chen, Everett E. Vokes

From the Section of Hematology/Oncology, Department of Medicine; Department of Radiation and Cellular Oncology; Section of Otorhinolaryngology, Department of Surgery; Department of Health Studies; The University of Chicago Cancer Research Center at the University of Chicago, Chicago IL; and the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Corresponding author: Everett E. Vokes, MD, Section of Hematology/Oncology, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL 60637; e-mail: evokes{at}medicine.bsd.uchicago.edu

	ABSTRACT

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Purpose We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients.

Patients and Methods Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m² (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded.

Results Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m², HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/², HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5).

Conclusion Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m² every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.

	INTRODUCTION

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With a worldwide annual incidence of more than 640,000 cases and 45,660 cases in the US in 2007, head and neck cancer (HNC) is the sixth most common cancer worldwide. As many as 30% to 40% of HNC patients die as a result of their disease. Locoregional treatment failure remains the dominant cause of disease relapse and death. Unfortunately, on tumor recurrence, treatment options in the previously radiated field are limited. Low-volume, resectable disease is best approached surgically; however, the majority of patients have unresectable disease, are medically unfit for surgery, or decline resection.¹ Even after surgery, many tumors recur quickly. There is no established standard of care, and treatment is usually palliative using chemotherapy. Active drugs include platinum, taxanes, fluorouracil (FU), methotrexate, and cetuximab. Response rates are 15% to 30%, and the median survival is 6 to 10 months.^2,3 Phase II trials suggest that multimodality treatment including reirradiation can achieve long-term survival in a minority of patients with locoregional recurrence. Long-term survival rates of 10% to 40% were reported after chemo-reirradiation.^4,5 The addition of chemotherapy targets radioresistant clones and enhances tumor cell killing.^6,7

The University of Chicago (Chicago, IL) has a longstanding interest in chemo-reirradiation. Specific regimens are based on the FHX platform, consisting of FU, hydroxyurea (HU), and concomitant radiation, to which a novel agent may be added. Multiple trials from our group,^1,8-14 the Institut Gustave-Roussy (Villejuif, France), the University of Alabama-Birmingham (Birmingham, AL), and the Radiation Therapy Oncology Group (RTOG) support the feasibility of reirradiation approaches.^5,15-19 In a previous summary analysis of reirradiation protocols, we identified that the use of surgery, triple-agent chemotherapy, and higher reirradiation dose (trimodality therapy) were independent predictors of a more favorable outcome.² The analysis included seven trials with a median survival of 11 months.² We concluded that reirradiation remains an experimental approach and that tumor radioresistance leads to poor outcomes.

One mechanism of radioresistance is increased vascular endothelial growth factor (VEGF) expression,²⁰ which occurs under hypoxic conditions²¹ and is radiation induced.²² Increased levels of VEGF were found in head and neck squamous cell carcinomas (and serum)^23,24 and seem to induce tumor growth, metastasis, and treatment failure.^25-29 In preclinical models, anti-VEGF therapies showed radiosensitizing properties, with increased oxygenation, and additive/supra-additive antitumor effects.^22,30

Anti-VEGF therapy is now available in the form of bevacizumab, a recombinant humanized, monoclonal immunoglobulin G antibody (rhuMAb-VEGF). Here, we study bevacizumab in combination with the FHX chemoradiotherapy platform⁸ in a population of poor-prognosis HNC patients.

	PATIENTS AND METHODS

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Eligible patients were 18 years of age or older with histologically proven HNC from two groups: (1) recurrent, previously radiated without distant disease or low-volume distant disease requiring locoregional palliation; (2) previously untreated patients, with an estimated 2-year survival less than 10% with radiation. Prior radiotherapy had to be completed at least 4 months and/or chemotherapy at least 1 month before initiating treatment, and patients had to have recovered from adverse effects (grade 0 to 1). Postoperative treatment was allowed. Anticipated life expectancy of more than 12 weeks, Eastern Cooperative Oncology Group (ECOG) performance status no higher than 2, and normal organ function were required. Exclusion criteria are listed in the legend for Figure 1. Institutional review board approval and informed consent were obtained.

View larger version (42K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Trial schema with key inclusion criteria. (B) Administration schedule for bevacizumab, fluorouracil, hydroxyurea, and radiation (BFHX; one cycle): cycle was repeated seven times (six times after complete surgery if only microscopic disease remains after surgery). Exclusion criteria included significant infection, pregnancy, brain metastasis, monoclonal antibody, hypersensitivity, other significant illnesses, prior FHX use, involvement of major vessels (invasion/encasement), hemoptysis of1 tablespoon or greater, use of anticoagulation, history of a bleeding diathesis/thrombosis, chronic aspirin/nonsteroidal anti-inflammatory drug use, surgery within 4 weeks, nonhealing wounds, uncontrolled hypertension, and significant proteinuria (> 0.5 g/24 h). HNC, head and neck cancer; ECOG, Eastern Cooperative Oncology Group; CT, computed tomography; MRI, magnetic resonance imaging; MTD, maximum-tolerated dose; G-CSF, granulocyte colony-stimulating factor; FU, fluorouracil.

All patients underwent CT-based planning with three-dimensional conformal or intensity-modulated radiotherapy. Radiation fractions were 1.8 to 2 Gy for approximately 35 treatments (seven 2-week cycles). Radiation doses to gross disease were 63 to 70 Gy and 33 to 50 Gy to the supraclavicular fossa for high-risk microscopic disease, and boosted with a field reduction to 66 to 72 Gy for gross macroscopic disease. Doses to the posterior neck were 45 to 60 Gy and 66 to 72 Gy for gross macroscopic disease. Anterior neck doses were 50 to 60 Gy. Doses to the spinal cord were limited to less than 45 Gy. If prior resection was complete, chemoradiotherapy was shortened by one cycle (radiation dose reduced accordingly). For recurrent tumors, the gross tumor plus margin, or after resection the surgical bed at risk plus margin were irradiated. Margins were defined as 1 to 1.5 cm complete volumetric expansion, with subsequent modification to avoid extension beyond the skin or spinal cord overlap.

Toxicities were assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 2.0).³¹ Dose-limiting toxicity (DLT) was assessed during all cycles. Dose escalation of bevacizumab and FU/HU were performed sequentially (Table 1). Bevacizumab dose escalation was capped at 10 mg/kg/m², FU at 800 mg/m², and HU at 1,000 mg. A modified version of the traditional dose escalation design ("Design A" by Storer)³² was employed. Cohorts of three to six patients were enrolled at each dose level. If none of the first three patients experienced DLT, accrual to the next dose level started. If one of three patients experienced DLT, three additional patients were enrolled; dose level was escalated if no more than one DLT occurred. If at least two of first three patients or at least two of six experienced DLT, the phase I portion stopped and the previous dose level was recommended as MTD. If the DLT observed were attributable to FHX, dose escalation of bevacizumab could continue and FHX dose was reduced. At the recommended dose, 18 to 20 patients were added (expanded cohort). Bevacizumab treatment was held until resolution for proteinuria (>1+), grade 3 uncontrolled hypertension or worse, grade 3 transaminase elevation or worse.

	RESULTS

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Patient Characteristics
Between July 2001 and September 2004, 43 patients were enrolled. Median follow-up for living patients is 38.7 months (range, 28.2 to 56.0 months), and 10.7 months overall. Patient characteristics are reported in Tables 2 and 3. Twenty-nine patients (67.4%) had received prior radiation (four with distant metastases), and 14 patients (32.6%) were newly diagnosed (two with distant disease): The six patients (14%) with distant disease had dominant locoregional symptoms. For patients with prior radiotherapy, the median time since radiation was 18.4 months (range, 4.2 to 362.0 months). The median previous radiation dose was 63 Gy (range, 50.4 to 81.0 Gy). Of 14 patients (32.6%) who had not received prior radiation, eight had experienced failure with prior definitive surgical treatment and had disease recurrence, two had received recent surgery within 6 weeks for the current tumor and were in need of adjuvant chemoradiotherapy for poor-prognosis residual disease, two had newly diagnosed distant metastatic disease with predominant local symptoms, and two had newly diagnosed locoregionally advanced, poor-prognosis HNC. Overall, 12 patients (28%) underwent surgical resection followed by adjuvant FHX plus bevacizumab.

Table 4 lists grade 3 to 5 related toxicities and severe unrelated toxicities. Overall, grade 3 mucositis occurred in 69.8% of patients with the highest rates in dose levels 3 (72.7%) and 4/expanded cohort (73.1%). Grade 3 radiation dermatitis was observed in 11.6%.

Three patients developed grade 3 hypertension (controlled with antihypertensives) and one patient an allergic rash in reaction to bevacizumab.

On level 1, one patient developed an upper-extremity deep vein thrombosis 14 days post-therapy. Although likely treatment related, per definition, this was not a DLT because it occurred post-therapy. During dose level 4, one patient developed a superior mesenteric vein thrombosis (DLT); bevacizumab was discontinued.

Three thrombotic events were seen, including deep vein thromboses in two patients (level 1, 3), and one stroke (expanded cohort; Table 4). Despite possible relation to treatment/bevacizumab, only one event met criteria for DLT (described further in the Discussion section). The two hemorrhages were a fatal esophageal bleed and a carotid blowout (both in the expanded cohort). Again, a relation to bevacizumab is suspected, although the later seems to relate primarily to tumor invading the carotid artery (involvement developed during treatment and was not present on enrollment). In summary, in the expanded cohort, five patients died (Table 4) from stroke, hemorrhage,² sepsis² and unknown etiology; a link to study treatment is suspected for stroke and hemorrhages (described further in the Discussion section).

Nonacute toxicities included five patients (11.6%), who developed fistulas (Table 5); histology showed underlying radionecrosis or residual tumor. Three patients did not have surgery; two patients had undergone neck dissection. An additional four patients had ulceration/wound healing complications in the treatment field without fistula formation (three postsurgery). All 11 cases were treated with debridement/resection, and, if necessary, flap repair (Table 5).

Survival
The median overall survival was 10.7 months (95% CI, 7.7 to 16.5 months). One- and 2-year survival rates were 49% and 28%, respectively. Median overall survival for patients not previously radiated (40.1 months; 95% CI, 10.4 months to undefined) was substantially higher than for patients with prior radiotherapy (9.2 months; 95% CI, 5.4 to 13.2 months; P = .0046); distant metastases were present in some patients in both groups (Table 3).

Further subgroup analysis was performed for patients with recurrent, nonmetastatic HNC undergoing reirradiation. The median survival was 10.3 months (95% CI, 5.6 months) with 1- and 2-year survival rates of 41.4% and17.2%, respectively (n = 29). Figure 2A was split into disease-specific cumulative incidence of death and competing non–disease-related incidence of death (Fig 2B). Disease-specific incidence of death at 1 and 2 years was 31.0% (95% CI, 15.2% to 48.4%) and 51.7% (95% CI, 31.7% to 68.5%), respectively. Response was assessable in 26 patients, with an overall response rate of 85% (Table A1, online only).

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Overall survival of subgroup of patients with recurrent head and neck cancer (HNC) without evidence of metastatic disease on enrollment (n = 29). Median survival was 10.3 months (95% CI, 5.6 to 13.5 months). One- and 2-year overall survival rates were 41.4% and 17.2%. (B) Cumulative incidence estimates of death resulting from disease and other causes in a subgroup of patients with recurrent HNC after prior radiotherapy without evidence of metastatic disease on enrollment (n = 29). One- and 2-year cumulative incidences of death resulting from disease were 31.0% (95% CI, 15.2% to 48.4%) and 51.7% (95% CI, 31.7%, to 68.5%).

Locoregional control rates also seem substantially higher for previously nonirradiated patients (of eight patients with locoregional recurrences, six received prior radiation).

Correlatives
Baseline VEGF levels were measured (Fig A1, online only), but no correlation with survival or response was seen.

	DISCUSSION

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Targeted therapies for solid tumors are increasingly integrated into clinical practice and may provide an incremental survival benefit with tolerable toxicity.^35-41 Examples include bevacizumab for colon³⁵ and lung cancer,³⁶ and erlotinib/cetuximab for lung,³⁷ head and neck,^3,38,41 and colorectal tumors.³⁹ Increasingly, combination approaches with radiation are being investigated, and the recent study by Bonner et al⁴¹ showed benefit when adding cetuximab to radiation. Preclinical evidence suggests that anti-VEGF therapy may act as a radiosensitizer.^22,30,42,43

In this study, we investigated the use of bevacizumab, an anti-VEGF antibody, in combination with a standard chemoradiotherapy platform (FHX) in poor-prognosis HNC patients, to determine safety, a phase II dose, and in the expanded cohort feasibility and signs of activity. The results demonstrate that bevacizumab can be integrated at doses of up to 10 mg/m² every 2 weeks with FHX chemoradiotherapy. Bevacizumab dosing is similar to use without radiation in other tumors. Cytotoxic chemotherapy needed to be capped one dose level lower than typical for FHX alone because the combination enhanced neutropenia and led to elevated liver enzymes. After the FU/HU dose reduction, this was no longer observed. Similarly, Crane et al⁴⁴ in pancreatic cancer and Sandler et al³⁶ for lung cancer reported increased neutropenia when adding bevacizumab.

In our prior experience with the FHX regimen, the addition of paclitaxel required adjustment of the FU/HU dose; this paclitaxel/FHX regimen was highly active.¹² Bevacizumab, on the other hand, may not be comparable to a cytotoxic agent because it does not have single-agent activity in HNC. The precise effect of dose reduction of FU/HU with respect to activity requires further study. Comparison across phase I/II studies performed 10 years apart is not informative. Undoubtedly, our reported regimen shows activity and comparable toxicity rates, and a randomized trial is necessary to better define efficacy and synergy.^22,30,42,43

Overall treatment was well tolerated, and no severe synergistic toxicities were observed. Possible bevacizumab-related toxicities included two DVTs, a fatal stroke, and two fatal bleeding events. The multicenter RTOG 96-10 trial, which did not use bevacizumab (79 assessable patients) reported two fatal bleeding events and six "unrelated" deaths, including three strokes, one pneumonia, one myocardial infarction, and one unknown cause of death. Furthermore, from our own institution a review of seven consecutive phase I/II trials (115 reirradiation patients) reported six hemorrhages.¹ Overall, the rate of severe complications whether related or unrelated to therapy is identical to observations in other studies in this high-risk population, and a randomized study is needed to assess bevacizumab toxicities.^1,5,8-18,45

Previously significant hematologic toxicities were reported.¹⁸ Our final dose level compares favorably, potentially as a result of frequent monitoring and intervention.

A recent US Food and Drug Administration notification (Http://fda.gov/medwatch/safety/2007/Avastin_DHCP_TEF_FINAL_April2007.pdf) of bronchoesophageal fistula formation in patients with lung cancer treated with bevacizumab and concurrent chemoradiotherapy is of concern. Usually a rare complication, two events (one fatal) were observed in patients with small-cell lung cancer. Furthermore, in the pancreatic cancer study by Crane et al,⁴⁴ an increased risk of ulceration and bleeding was reported if the tumor involved the bowel wall. We reviewed all patients and identified five fistulas (11.6%) and four ulcerations/tissue necrosis events without fistulization (9.3%; Table 4B). The direct causality is not clear. Taken together, the rate of fistula formation/tissue necrosis is substantial (20.9%). These complications were not limited to patients with prior surgery.

In 10 recently published studies by various groups, only three cases of fistula formation were reported.¹² We caution, though, that reporting is not standardized and may not be complete. As a case in point, we rereviewed one of our larger reirradiation trials¹⁴ and identified two fistulas in 34 patients within 1 year that were not previously reported. In this study, though, both were associated with extensive prior surgery.

The rate, timing and severity of the fistulas reported with the bevacizumab/FHX regimen is of concern. One may speculate that the addition of bevacizumab interferes with tissue repair. Nevertheless, in contrast to the severity of fistula formation in lung cancer patients, in our HNC population surgical repair was readily achieved.

Further experience with the bevacizumab/FHX regimen in the non-reirradiation setting (trial partly completed) may provide additional insight. Furthermore data from trials combining small molecule VEGF receptor 2 (VEFGR2) inhibitors with radiation are forthcoming (eg, vandetanib).

Preclinical radiobiology experiments lend strong support to the addition of bevacizumab/antiangiogenic agents to radiation.^22,30,42,43 Despite the expectations that anti-VEGF therapies may cause hypoxia and radioresistance, studies demonstrate the opposite with increased oxygenation, and additive/supra-additive antitumor efficacy.^22,30 One of several possible explanations is that anti-VEGF therapy leads to "normalization" of blood flow in tumors, decreases interstitial fluid pressures, and increases delivery of oxygen/drugs.⁴⁶ Normalization, though, is transient, lasting less than 3-4 days, and may not fully explain the observed complexities in tumor behavior.

A clinical study of neoadjuvant rectal cancer treatment by Willett et al⁴⁷ showed that bevacizumab (5 mg/m² every 2 weeks) used in combination with FU/radiation in six patients indeed led to normalization of interstitial fluid pressures.^36,44 In a follow-up report, five additional patients were enrolled at an increased dose of 10 mg/m².⁴⁸ Two DLTs (diarrhea, colitis) limited enrollment, although responses were noted.

To date, the only larger clinical series of bevacizumab with chemoradiotherapy (capecitabine/radiation) as a primary treatment was reported by Crane et al⁴⁴ in the definitive treatment of pancreatic cancer. In this study, the combination was tolerated and preliminary results were favorable.⁴⁴ Bowel ulceration and associated bleeding were seen in the radiation field if tumor involved the bowel wall, and such patients were subsequently excluded.

Our study represents the second larger series integrating bevacizumab with chemoradiotherapy and the first application in HNC. Long-term survival was observed with the bevacizumab/FHX regimen in a minority of HNC patients comparable to previous reports. Given the poor-risk patient population, overall, the results support further examination in a phase II study. In particular the observed locoregional control with a reversal in the failure pattern (distal > locoregional) and the cumulative incidence of cancer related mortality of 51% at 2 years are noteworthy and compare favorably with prior experiences. Subgroup analysis based on prior radiation indicates higher median survival/locoregional control in radiation-naïve patients. Inclusion of patients with distant metastases limits comparison with other recent studies showing favorable outcomes with reirradiation (paclitaxel/FHX, paclitaxel, FU, gemcitabine, radiation [TFGX],^12,14 RTOG 99-11¹⁹ with 2-year survival rates of approximately 25% to 30%). Of note, these trials used hyperfractionated split-course radiation, which may improve efficacy and is frequently favored for recurrent disease. It is not clear at this point whether the addition of bevacizumab could lessen the need for altered-fractionation radiotherapy or improve its efficacy. In this phase I study once-daily radiation without paclitaxel was used because of concerns for toxicity on the basis of preclinical evidence suggesting additive/synergistic effects.^22,30

Recently Vermorken et al³ reported on palliative doublet chemotherapy with cetuximab that yielded an overall survival of 10.1 months. Randomized trials of reirradiation and palliative chemotherapy are ongoing and will help define usefulness of both approaches.

Furthermore, surrogate markers may help predict response and subpopulations that benefit. Our study does not provide evidence that baseline VEGF levels are useful prognostic or predictive markers. Other recent studies in HNC have found a potential role for VEGF,^24,49 and tissue-based markers may be an alternative.⁵⁰

On the basis of the results of this trial, we initiated a follow-up randomized phase II trial comparing the addition of bevacizumab to FHX versus FHX alone in a better prognosis, treatment-naive patient population.

In conclusion, bevacizumab at a dose of 10 mg/m² can be integrated with FHX chemoradiotherapy and shows activity. Bevacizumab-related toxicities namely thrombosis and hemorrhage, as well as serious complications during and after reirradiation treatment were observed, but do not seem to be more frequent than in previous reirradiation reports. On the other hand, the elevated rate of fistula formation and tissue necrosis will require careful monitoring in future trials.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Everett E. Vokes, Genentech (C) Stock Ownership: None Honoraria: Ezra E.W. Cohen, Genentech; Everett E. Vokes, Genentech Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Daniel J. Haraf, Helen X. Chen, Everett E. Vokes

Administrative support: Tanguy Y. Seiwert, Daniel J. Haraf, Ezra E.W. Cohen, Kerstin Stenson, Mary Ellyn Witt, Allison Dekker, Helen X. Chen, Everett E. Vokes

Provision of study materials or patients: Tanguy Y. Seiwert, Daniel J. Haraf, Ezra E.W. Cohen, Kerstin Stenson, Mary Ellyn Witt, Allison Dekker, Everett E. Vokes

Collection and assembly of data: Tanguy Y. Seiwert, Ezra E.W. Cohen, Kerstin Stenson, Mary Ellyn Witt, Allison Dekker, Everett E. Vokes

Data analysis and interpretation: Tanguy Y. Seiwert, Daniel J. Haraf, Ezra E.W. Cohen, Masha Kocherginsky, Ralph R. Weichselbaum, Everett E. Vokes

Manuscript writing: Tanguy Y. Seiwert, Ezra E.W. Cohen, Masha Kocherginsky, Ralph R. Weichselbaum, Helen X. Chen, Everett E. Vokes

Final approval of manuscript: Tanguy Y. Seiwert, Ezra E.W. Cohen, Kerstin Stenson, Masha Kocherginsky, Ralph R. Weichselbaum, Helen X. Chen, Everett E. Vokes

	Appendix

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View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Vascular endothelial growth factor (VEGF) plasma levels. Baseline mean VEGF levels (n = 37) were 202.1 ± 30.4 pg/mL (SEM); median was 165.3 pg/mL. There was no correlation of VEGF baseline levels with survival (Pearson r = –0.1) or response.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Follow-up randomized phase II trial schema.

	ACKNOWLEDGMENTS

 
We thank Theodore Karrison for statistical analysis and Cindy Badja for data management. We also thank David Gustin, who passed away unexpectedly, for his cheerful and caring demeanor, which is sorely missed by our patients and us.

	NOTES

 
Supported by National Institutes of Health Grant No. N01 CM-622201, the University of Chicago Cancer Research Center, and the Valda and Robert Svendsen Foundation.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Salama JK, Vokes EE, Chmura SJ, et al: Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 64:382-391, 2006[Medline]

2. Forastiere A, Koch W, Trotti A, et al: Head and neck cancer. N Engl J Med 345:1890-1900, 2001[Free Full Text]

3. Vermorken J, Mesia R, Vega V, et al: Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy: Results of a randomized phase III (Extreme) study. J Clin Oncol 25:XXX, 2007 (suppl; abstr 6091)

4. Stevens KR, Jr., Britsch A, Moss WT: High-dose reirradiation of head and neck cancer with curative intent. Int J Radiat Oncol Biol Phys 29:687-698, 1994[Medline]

5. Spencer SA, Harris J, Wheeler RH, et al: RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 51:1299-1304, 2001[CrossRef][Medline]

6. Weichselbaum RR, Beckett MA, Schwartz JL, et al: Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy. Int J Radiat Oncol Biol Phys 15:575-579, 1988[Medline]

7. Vokes E, Beckett M, Karrison T, et al: The interaction of 5-fluorouracil hydroxyurea and radiation in two human head and neck cancer cell lines. Oncology 49:454-460, 1992[Medline]

8. Vokes EE, Panje WR, Schilsky RL, et al: Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: A phase I-II study. J Clin Oncol 7:761-768, 1989[Abstract]

9. Haraf DJ, Weichselbaum RR, Vokes EE: Re-irradiation with concomitant chemotherapy of unresectable recurrent head and neck cancer: A potentially curable disease. Ann Oncol 7:913-918, 1996[Abstract/Free Full Text]

10. Brockstein B, Haraf DJ, Stenson K, et al: Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck. J Clin Oncol 16:735-744, 1998[Abstract]

11. Vokes EE, Haraf DJ, Mick R, et al: Intensified concomitant chemoradiotherapy with and without filgrastim for poor-prognosis head and neck cancer. J Clin Oncol 12:2351-2359, 1994[Abstract/Free Full Text]

12. Brockstein B, Haraf DJ, Stenson K, et al: 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. Ann Oncol 11:721-728, 2000[Abstract/Free Full Text]

13. Salama JK, Haraf DJ, Stenson K, et al: Phase I study of concomitant chemoradiotherapy with irinotecan, 5-FU, and hydroxyurea for patients with advanced and/or recurrent head and neck cancer. Cancer J 11:140-146, 2005[Medline]

14. Milano MT, Haraf DJ, Stenson KM, et al: Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, gemcitabine, and twice-daily radiation in patients with poor-prognosis cancer of the head and neck. Clin Cancer Res 10:4922-4932, 2004[Abstract/Free Full Text]

15. De Crevoisier R, Domenge C, Wibault P, et al: Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma. Cancer 91:2071-2076, 2001[CrossRef][Medline]

16. De Crevoisier R, Bourhis J, Domenge C, et al: Full-dose reirradiation for unresectable head and neck carcinoma: Experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 16:3556-3562, 1998[Abstract]

17. Spencer SA, Wheeler RH, Peters GE, et al: Concomitant chemotherapy and reirradiation as management for recurrent cancer of the head and neck. Am J Clin Oncol 22:1-5, 1999[CrossRef][Medline]

18. Spencer SA, Harris J, Wheeler RH, et al: Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck [Epub ahead of print August 31, 2007]

19. Horwitz EM, Harris J, Langer CJ, et al: Phase II study of paclitaxel and cisplatin in combination with split course concomitant hyperfractionated re-irradiation in patients with recurrent squamous cell cancer of the head and neck: Results of RTOG 99-11. Int J Radiat Oncol Biol Phys 63:S72–S73, 2005 (suppl)

20. Loncaster JA, Cooper RA, Logue JP, et al: Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J Cancer 83:620-625, 2000[CrossRef][Medline]

21. Hockel M, Vaupel P: Biological consequences of tumor hypoxia. Semin Oncol 28:36-41, 2001[Medline]

22. Gorski DH, Beckett MA, Jaskowiak NT, et al: Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59:3374-3378, 1999[Abstract/Free Full Text]

23. Riedel F, Gotte K, Schwalb J, et al: Serum levels of vascular endothelial growth factor in patients with head and neck cancer. Eur Arch Otorhinolaryngol 257:332-336, 2000[CrossRef][Medline]

24. Allen C, Duffy S, Teknos T, et al: Nuclear factor-kappaB-related serum factors as longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma. Clin Cancer Res 13:3182-3190, 2007[Abstract/Free Full Text]

25. Shemirani B, Crowe DL: Head and neck squamous cell carcinoma lines produce biologically active angiogenic factors. Oral Oncol 36:61-66, 2000[CrossRef][Medline]

26. DeFatta RJ, Nathan CA, De Benedetti A: Antisense RNA to eIF4E suppresses oncogenic properties of a head and neck squamous cell carcinoma cell line. Laryngoscope 110:928-933, 2000[CrossRef][Medline]

27. Smith BD, Smith GL, Carter D, et al: Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 18:2046-2052, 2000[Abstract/Free Full Text]

28. Folkman J: Seminars in Medicine of the Beth Israel Hospital, Boston: Clinical applications of research on angiogenesis N Engl J Med 333:1757-1763, 1995[Free Full Text]

29. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4-6, 1990[Free Full Text]

30. Wachsberger P, Burd R, Dicker AP: Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: Exploring mechanisms of interaction. Clin Cancer Res 9:1957-1971, 2003[Abstract/Free Full Text]

31. National Cancer Institute: Investigator's handbook: A manual for participants in clinical trials of investigational agents sponsored by the Division of Cancer Treatment National Cancer Institute. http://ctep.cancer.gov/handbook/

32. Storer BE: Design and analysis of phase I clinical trials. Biometrics 45:925-937, 1989[CrossRef][Medline]

33. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

34. Gooley TA, Leisenring W, Crowley J, et al: Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Stat Med 18:695-706, 1999[CrossRef][Medline]

35. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

36. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006[Abstract/Free Full Text]

37. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005[Abstract/Free Full Text]

38. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005[Abstract/Free Full Text]

39. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004[Abstract/Free Full Text]

40. Garcia JA, Rini BI: Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin 57:112-125, 2007[Abstract/Free Full Text]

41. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006[Abstract/Free Full Text]

42. Winkler F, Kozin SV, Tong RT, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553-563, 2004[Medline]

43. Kozin SV, Boucher Y, Hicklin DJ, et al: Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 61:39-44, 2001[Abstract/Free Full Text]

44. Crane CH, Ellis LM, Abbruzzese JL, et al: Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol 24:1145-1151, 2006[Abstract/Free Full Text]

45. Kramer NM, Horwitz EM, Cheng J, et al: Toxicity and outcome analysis of patients with recurrent head and neck cancer treated with hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy from two prospective phase I and II studies. Head Neck 27:406-414, 2005[CrossRef][Medline]

46. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005[Abstract/Free Full Text]

47. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004[CrossRef][Medline]

48. Willett CG, Boucher Y, Duda DG, et al: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23:8136-8139, 2005[Free Full Text]

49. Druzgal CH, Chen Z, Yeh NT, et al: A pilot study of longitudinal serum cytokine and angiogenesis factor levels as markers of therapeutic response and survival in patients with head and neck squamous cell carcinoma. Head Neck 27:771-784, 2005[CrossRef][Medline]

50. Seiwert TY, Davis DW, Yan D, et al: pKDR/KDR ratio predicts response in a phase I/II pharmacodynamic study of erlotinib and bevacizumab for recurrent or metastatic head and neck cancer (HNC). J Clin Oncol 25: 2007 (online-only abstr 6021)

Submitted June 20, 2007; accepted December 13, 2007.

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