Chemoradiotherapy for Gastrointestinal Cancers Tyvin A. Rich, MD,* Christopher Crane, MD, Joshua D. Lawson, MD, and Jerome Landry, MD

Address *Department of Radiation Oncology, University of Virginia, PO Box 800383, Charlottesville, VA 22908, USA. E-mail: [email protected] Current Oncology Reports 2005, 7:196–202 Current Science Inc. ISSN 1523-3790 Copyright © 2005 by Current Science Inc.

New combinations of chemotherapy with radiotherapy for gastrointestinal cancers are showing evidence that improved outcomes may result from toxicity profiles associated with “targeted” systemic radiosensitizing agents. These new agents are also clinically attractive owing to such factors as oral bioavailability and patient dosing schedules, making them practical and convenient compared with older intravenous administration requirements. Several new classes of radiosensitizing agents are discussed here and underscore aspects of molecular activation in tumors rather than normal tissues because of differences in pathways of metabolism or based on the process of tumorassociated angiogenesis.

Introduction Chemoradiotherapy (concurrent irradiation and chemotherapy) for gastrointestinal cancer is a well-tested clinical practice. It has largely been achieved with application of a combination of the antimetabolite 5-fluorouracil (5-FU) in differing doses and treatment schedules over the past 40 years for primary, adjuvant, and palliative irradiation. In many patients, organ preservation can be achieved because complete tumor eradication has resulted in nonsurgical management with acceptable long-term normal tissue function. In the following review are data regarding chemoradiotherapy with an oral 5-FU prodrug, capecitabine, and early clinical data with other systemic agents, oxaliplatin and bevacizumab, used with irradiation.

Oral Fluoropyrimidines The poor bioavailability of oral 5-FU coupled with the inconvenience of protracted intravenous (IV) administration with ambulatory pumps has provided a strong impetus for the development of oral fluoropyrimidines.

Elucidation of the details of metabolism of 5-FU led to the design and testing of a number of oral 5-FU prodrugs and 5-FU catabolic inhibitors (based on dihydropyrimidine dehydrogenase [DPD]) that prolong the half-life of 5-FU. Novel approaches have investigated reversible and irreversible DPD inhibitors, combination therapies, and various prodrug structures. A detailed description and comparison of these agents has been reviewed elsewhere, but briefly they include ftorafur; tegafur (UFT); a combination product consisting of ftorafur taken with a 4-fold molar excess of uracil; S-1 (ftorafur plus a DPD inhibitor plus an inhibitor of 5-FU phosphorylation); and emitefur, which combines a 5-FU prodrug with a DPD inhibitor as a single molecule. The oral agent capecitabine has been extensively evaluated for clinical activity and as a radiation sensitizer. It is a rationally designed 5-FU prodrug consisting of a fluoropyrimidine carbamate that is converted to 5-FU by the action of three enzymes: an esterase, a deaminase, and thymidine phosphorylase (TP). Higher concentrations of TP are found in many tumor types, compared with matched normal tissue [1], and it is particularly higher in excised human colon cancer [2]. This suggests that higher tumor concentrations of 5-FU might be expected due to a higher production of active drug in the tumor tissue, thereby providing a favorable target-to-normal tissue ratio for toxicity and radiosensitization. Tumor selectivity and conversion of capecitabine to active 5-FU within the tumor tissue has been confirmed in human samples, which show a 3.2-fold higher concentration of 5-FU in tumor compared with normal tissue and 21-fold higher tumor-to-plasma ratio [2]. In comparison, when IV 5-FU is administered, either by bolus or continuous infusion, the concentration of active drug in tumor is no higher than that in normal tissue [3]. When the sequence of TP was determined in 1995, it was found to be identical to tumor-associated angiogenic factor and platelet-derived endothelial cell growth factor [4], thereby endowing TP with additional activities involving angiogenesis and tumor cell apoptosis [5]. Increased intratumoral levels of TP are correlated with aggressive malignant growth and poor patient prognosis [6]. In addition, upregulation of TP occurs with taxanes, anthracyclines, gemcitabine, vinorelbine, and irradiation [7–9],

Chemoradiotherapy for Gastrointestinal Cancers • Rich et al.

raising the potential for enhanced tumor response with capecitabine-based chemoradiotherapy. Capecitabine has been approved in more than 50 countries, including the European Union and Canada, and is currently the only oral prodrug of 5-FU approved in the United States. Capecitabine is indicated as monotherapy for the treatment of patients with metastatic breast cancer that is resistant to both paclitaxel and an anthracyclinecontaining regimen or resistant to paclitaxel where anthracycline therapy is not indicated [10]. It is also indicated for metastatic breast cancer in combination with docetaxel after anthracycline failure. On the basis of two large phase III studies, capecitabine has also been approved as a firstline alternative to IV 5-FU/leucovorin (LV) in advanced metastatic colorectal cancer [11,12]. Most recently, capecitabine was used in the adjuvant setting and found to compare favorably with bolus 5-FU plus LV in the treatment of resected colon cancer [13]. This oral approach has thus been suggested to be part of the new standard in the adjuvant management of colon cancer. In all of these trials in which capecitabine has been compared with 5-FU/LV, higher objective responses were observed with capecitabine and were accompanied by a more manageable toxicity profile. Serious adverse events with capecitabine included higher rates of hand-foot syndrome and bilirubinemia but lower rates of neutropenia, diarrhea, stomatitis, nausea, and hospitalizations compared with 5-FU. Capecitabine has also been used in combination therapy with irinotecan or oxaliplatin with promising results in phase II studies. Phase III studies include comparisons of capecitabine plus oxaliplatin with standard 5-FU/LV/oxaliplatin (FOLFOX) and are currently in progress. Capecitabine is also being tested in combination with irinotecan in a phase III study conducted by the European Organization for Research and Treatment of Cancer (EORTC) and compared with infusional 5-FU with LV and irinotecan (FOLFIRI). The efficacy and safety of capecitabine in these combination studies provides support for its use in chemoradiotherapy. Chemoradiotherapy studies in rectal cancer using total capecitabine doses of 1650 to 1800 mg/m 2 are administered daily in divided doses in the morning and afternoon for 5 or 7 days per week during irradiation. Dunst et al. [14] reported an 81% overall response rate and downstaging in 71% of locally advanced patients with acceptable toxicity after capecitabine chemoradiotherapy. Similarly, Ngan et al. [15•] used 5-day per week capecitabine dosage of 1800 mg/m 2 /d in a phase I chemoradiotherapy study for rectal cancer. Preoperative 5-FU–based chemoradiotherapy with capecitabine in resectable rectal cancer has resulted in tumor downstaging in more than 40% of treated patients and local response rates near 80% with acceptable toxicity profiles. Capecitabine chemoradiotherapy is being evaluated in phase II and III studies in rectal cancer conducted by the Radiation Therapy Oncology Group and the National Surgical Adjuvant Breast and Bowel Project before resection. In Europe, several trials are

197

maturing with capecitabine (1650 mg/m2) and oxaliplatin given in various schedules on an intermittent or weekly basis. In summary, recent clinical trials with 5-FU–based chemoradiotherapy show that improved functional outcome in terms of downstaging and sphincter preservation and excellent survival rates can be obtained in rectal cancer patients using treatment schedules that result in prolonged exposure to 5-FU.

Platinum-based Chemoradiotherapy Oxaliplatin [trans-L-dach (1R-diaminocyclohexane) Oxaliplatin] exists as a diaminocyclohexane platinum complex. Its cytotoxic effects are mediated by DNA adducts, similar to carboplatin and cisplatin. Oxaliplatin has demonstrated efficacy in cells resistant to cisplatin and in gastrointestinal malignancies where cisplatin has been ineffective; the discrepant spectrum of action is thought to result largely from the bulky side chain of oxaliplatin, which is retained in solution. The toxicity profile of oxaliplatin also differs from that of cisplatin. Oxaliplatin is not associated with renal toxicity and has only mild hematotoxicity. Side effects are predominantly gastrointestinal (nausea, vomiting, diarrhea). Two additional unique toxicities are a cumulative but usually reversible peripheral sensory neuropathy and an acute laryngopharyngodysesthesia exacerbated by cold.

Clinical efficacy The observed synergy of oxaliplatin and 5-FU has recently been partially explained. Cells from the DLD-1 human colon cancer cell line were treated with several concentrations of oxaliplatin and 5-FU. The two drugs were found by median drug effect analysis to exhibit synergy (combination index <1). This is thought to be because cells treated with oxaliplatin displayed significant downregulation of thymidy late syntha se mR NA a nd fre e thy midy late synthase, the target enzyme of 5-FU. In several human cancer types, including colorectal cancers, expression of thymidylate synthase is inversely proportional to 5-FU sensitivity [16]. The oxaliplatin-induced decrease in thymidylate synthase thus heightens cell sensitivity to 5-FU. The clinical response and benefit of oxaliplatin have been evaluated in phase II and III trials. Several prior phase II trials showed a 10% response rate and overall survival of 8 months in patients with metastatic colorectal cancer previously treated with 5-FU at an oxaliplatin dosage of 130 mg/m 2, every 3 weeks until disease progression [17]. Response rates of 12% to 24%, progression-free survival time of 4 months, and overall survival of 13 to 14 months were reported for patients with previously untreated metastatic colorectal cancer [18–20]. The benefit of oxaliplatin as a first-line therapy for advanced or metastatic colorectal cancer was established by two phase III studies [21,22]. These two phase III trials added oxaliplatin to 5-FU and LVcontaining regimens as first-line treatment for advanced or

198

Gastrointestinal Cancers

metastatic colorectal cancer. Response rates of 51% and 53% with the oxaliplatin-containing regimens and 22% and 16% with 5-FU and LV only were reported. A subsequent phase II trial examined capecitabine with oxaliplatin as a first- or second-line treatment for advanced or metastatic colorectal cancer. Response rates among previously untreated patients were similar to response rates for patients treated with continuous-infusion 5-FU, LV, and oxaliplatin [23]. More recent studies established the benefit of adding irinotecan to 5-FU and LV as a first-line therapy for metastatic colorectal cancer. This shift in primary treatment created the need for changing second-line treatment as well. A subsequent phase III trial compared single-agent oxaliplatin, bolus and infusional 5-FU, and LV, and the combination of the two (FOLFOX4) in patients with disease progression on irinotecan, bolus 5-FU, and LV. Interim results of this trial indicate a modest but significant level of activity of the FOLFOX4 regimen over either regimen alone, with a partial response rate of 9.9%. The response rates for single-agent oxaliplatin and the 5-FU/LV regimen were 1.3% and 0%, respectively [24]. A similar trial evaluated the sequencing of two regimens, each containing 5-FU and folinic acid. One regim e n c o m bi ne d t hi s w i th i r in ot e c a n, 1 8 0 m g /m 2 (FOLFIRI), and the other with oxaliplatin, 100 mg/m 2 (FOLFOX6) given over 2 hours on day 1. Patients with metastatic colorectal cancer were randomly assigned to receive either arm A or arm B until progression or unacceptable toxicity, at which time treatment was shifted to the other regimen. Overall survival in both arms was more than 20 months, with no significant sequencing benefit for either arm [25]. FOLFOX4 has been tested against 5-FU/LV alone in a phase III trial as adjuvant therapy for resected Dukes B and C colon cancer. This trial (MOSAIC) demonstrated a significant improvement in disease-free survival in patients receiving FOLFOX4 with a 23% decrease in disease relapse [26]. Based on the results of these trials and the documented safety and tolerability [27] of oxaliplatin, the United States Food and Drug Administration (FDA) approved oxaliplatin in August 2002 in combination with infusional 5FU and LV for treatment of patients with advanced colorectal cancer that progressed or relapsed after therapy with irinotecan, 5-FU, and LV. Postoperative combined-modality therapy for highrisk rectal cancer has resulted in improvement in diseasefree and overall survival over surgery alone [28]. Preoperative therapy offers the allure of possible tumor downsizing, incr ea sing the re se ctabil ity of tum or and the probability of sphincter preservation. The experience with oxaliplatin thus far has largely been in combination with 5-FU as a preoperative regimen for advanced or unresectable rectal cancers. A phase II Intergrupo Argentino para el Tratarniento de los Turnores Gastrointestinales (IATTGI) study of

unresectable rectal cancer added oxaliplatin, 25 mg/m 2/d by 30-minute infusion, to bolus LV, 20 mg/m 2 /d and bolus 5-FU, 375 mg/m 2/d on days 1 to 4 of weeks 1 and 5 of standard radiation, and 4 weeks after radiation. An additional dosage of oxaliplatin, 50 mg/m 2, was given in week 3. Following radiation, 5-FU and LV were given every 28 days for three cycles, with surgery performed 4 weeks after the last chemotherapy. At the time of surgery, 12 of 16 patients had complete resections with five of 12 sphincter-sparing procedures. Three of 12 had complete responses and another two of 12 had minimal microscopic residual tumor cells [29]. The Lyon R 97-03 phase I trial and subsequent Lyon R0-04 phase II trial further examined oxaliplatin regimens for advanced rectal cancer. The phase I trial used oxaliplatin, 80, 100, or 130 mg/m 2 as a 2-hour infusion on day 1 of weeks 1 and 5. 5-FU, 350 mg/m 2/d continuous infusion on days 1 to 5, and L-folinic acid, 100 mg/m2/d by IV bolus, were given on days 1 to 5 of weeks 1 and 5. The radiotherapy dosage was 45 Gy at 1.8 Gy/fraction. Of 17 total patients across three oxaliplatin doses, seven had complete responses, seven had partial responses, and the final three had minimal clinical responses. Of eight patients undergoing surgery, five of whom were originally T4, all were able to undergo complete resections. An additional patient with T4 dise ase achie ved a complete response and opted against surgery. The maximum tolerated dose was not reached in this study [30]. The subsequent phase II trial raised the radiation dose to 50 Gy delivered with a concomitant boost. Chemotherapy was given on weeks 1 and 5 and consisted of oxaliplatin, 130 mg/m2 on day 1 and 5-FU with L-folinic acid given as described previously. Surgery was performed 5 weeks after completion of radiotherapy. Patients had T3 to T4 or unfavorable T2 disease but were initially operable. All but one of the 40 total patients completed this regimen, with 16 grade 3 and 4 toxicities seen in seven patients. Every patient underwent surgery, with gross total resection possible in all patients. Twenty-six patients underwent sphincter-sparing surgery. Six patients had pathologic complete responses, with another 12 patients having only a few residual cells of uncertain vitality. Taken together, these two groups had a 45% complete or near complete response rate [31••]. One of the largest trials to date was a phase I/II trial of preoperative capecitabine, oxaliplatin, and radiotherapy to 50.4 Gy in 32 patients with locally advanced (T3/T4) or low-lying rectal cancers. Capecitabine, 825 mg/m 2 , was administered twice daily on days 1 to 14 and 22 to 35. Oxaliplatin was started at 50 mg/m2 on days 1, 8, 22, and 29 with the plan of increasing the dose by 10 mg/m 2 to a maximum of 80 mg/m2. During the phase I portion of this trial, two of six patients treated with oxaliplatin, 60 mg/ m 2 , developed dose-limiting toxicity, so the phase II portion of the trial used an oxaliplatin dose of 50 mg/m 2. At re-evaluation, only one patient was deemed inoperable.

Chemoradiotherapy for Gastrointestinal Cancers • Rich et al.

Of the remaining 31 who underwent surgery, 29 achieved negative margins, and the other two had microscopically positive margins. Nineteen percent of the patients had a pathologic complete response; another 39% had only a few residual tumor cells [32]. Another recent phase I/II trial combined raltitrexed and oxaliplatin with radiation to 50.4 Gy in patients with resectable rectal cancer. The phase I portion of this trial combined raltitrexed, 3 mg/m 2, with oxaliplatin, 65, 80, 110, and 130 mg/m 2, each given on days 1, 19, and 38. Toxicities were acceptable at all dose levels; oxaliplatin, 130 mg/m 2, was used in the phase II portion of the trial. For the phase II portion, 30 patients were enrolled; four were staged T3N0, 17 were T3N1, and nine were initially T3N2. Twenty-eight were able to undergo sphincter-sparing surgery, and 17 were either pathologic T0 or microscopic at resection. The overall rates of tumor and nodal downstaging were 67% and 77%, respectively [33]. A recent Eastern Cooperative Oncology Group (ECOG) phase I trial (E1297) examined oxaliplatin at 55, 70, and 85 mg/m 2 given on days 1, 15, and 29 combined with continuous-infusion 5-FU and radiotherapy to 50.4 Gy. There were no dose-limiting toxicities. Of 12 pathologically evaluable patients, seven (58%) had either a pathologic complete response or microscopic residual tumor cells at resection. The trend was toward improved response with higher oxaliplatin dose [34].

Emerging Strategies with Oxaliplatin-based Chemoradiotherapy Building upon the encouraging pathologic responses observed with preoperative radiation and oxaliplatinbased chemotherapy, the RTOG is conducting a randomized phase II trial comparing preoperative radiation with capecitabine (850 mg/m 2 twice daily) and oxaliplatin (60 mg/m2 weekly) with a regimen of preoperative radiation, capecitabine (600 mg/m 2 orally twice a day) and irinotecan, 50 mg/m 2 IV days 1, 8, 15, and 22 in patients with T3 and T4 rectal cancers. The study endpoints are pathologic complete response, toxicity, and patterns of failure. A European phase II trial (CORE trial) is evaluating preoperative radiation (45 Gy) with capecitabine and weekly oxaliplatin in patients with T3 and T4 rectal cancers with the primary endpoint of pathologic complete response. ECOG is developing a phase II trial of preoperative radiation, capecitabine, oxaliplatin (50 mg/m 2/wk), and bevacizumab (5 mg/ kg every 2 weeks) in patients with T3 and T4 rectal tumors with the primary endpoint also being pathologic complete response. All of the aforementioned strategies evaluate the ability of oxaliplatin-based regimens to increase tumor kill when combined with preoperative radiation. Such strategies may one day result in identifying a subset of patients who may not require surgical resection. In summary, oxaliplatin, like cisplatin, has significant radiosensitizer properties. Unlike cisplatin, however, oxali-

199

platin also has significant activity against colorectal cancers. Trials to date have shown potentially promising results for preoperative combined-modality treatment with oxaliplatin-containing regimens. We may be moving toward preoperative therapy for many rectal cancer patients, and this trend may result in increased local control and a benefit in terms of sphincter preservation. Oxaliplatin-containing regimens have been well tolerated, with a trend toward improved pathologic complete response at surgery. These results require substantiation by phase III trials.

Angiogenesis inhibitors as radiation sensitizers Vascular endothelial growth factor (VEGF) is a highly conserved glycoprotein that functions as a specific regulator of developmental, physiologic, and neoplastic angiogenesis (reviewed in [35,36]). VEGF produces a number of biologic effects, including endothelial cell mitogenesis and migration, induction of proteinases leading to remodeling of the extracellular matrix, increased vascular permeability, and m a inte n an ce of su rv i val f or ne w ly f or m e d bl oo d vessels (reviewed in [34]). The possibility that anti-VEGF therapy could increase the response to radiotherapy has been investigated in several laboratories. In vivo studies using tumor growth delay [37,38] and tumor cure endpoints [39] have shown that response to radiotherapy can be increased in tumors derived from radioresistant cell lines by using agents that prevent VEGF signaling. The results in these studies were counterintuitive to many investigators because it was predicted that damage to endothelial cells and, consequently, the tumor blood supply, would decrease oxygenation and lead to hypoxia, which correlates with radioresistance [40]. Speculation about the mechanism of increased radiosensitivity has included the possibility that endothelial cells are sensitized to radiotherapy when the VEGF pathway is blocked and that tumor vascular physiology is actually improved with anti-VEGF therapy, leading to a reduction in the number of hypoxic cells. When mice bearing a variety of tumors generated from human tumor cell lines were irradiated with and without the infusion of a monoclonal antibody to human VEGF, enhanced tumor growth delay was observed. In addition, VEGF expression was enhanced by radiation. Further in vitro studies suggested that the enhanced cytotoxicity of the combination was due to the potentiation of endothelial cell death rather than direct tumor cell cytotoxicity [37]. These results suggest that VEGF is protective of endothelial cells exposed to the stress imposed by ionizing radiation and that depriving the endothelial cell of this survival signal results in increased sensitivity of radiation [38]. More recently, animal studies using tumor growth delay [39] and tumor eradication endpoints [40] showed that response to therapy can be improved in radioresistant tumors derived by using agents that prevent VEGF signaling, again suggesting that the therapeutic target is the endothelial cell rather than the tumor cell.

200

Gastrointestinal Cancers

Hypoxia has been investigated using in vivo noninvasive intratumoral oxygen measurements. Tumor oxygenation initially decreased and then increased in tumorbearing mice exposed to hormone therapy, chemotherapy, and a monoclonal antibody against the VEGF receptor-2 (R-2) [41]. The effect of tumor oxygenation on tumor response to anti-VEGF therapy was then investigated. Human tumor xenografts were irradiated with and without an infusion of a VEGF neutralizing antibody. Interstitial fluid pressure decreased and oxygenation increased or remained the same after antibody administration. An increase in tumor growth delay was seen under normal and hypoxic conditions, suggesting that the neutralization of VEGF compensated for the resistance due to hypoxia in this model [42]. Clearly, more work needs to be done to clarify the mechanisms of apparent improved cytotoxic effect with the addition of bevacizumab to radiotherapy.

Clinical Trials Incorporating Anti-VEGF Therapy in Gastrointestinal Tumors Bevacizumab is a humanized monoclonal antibody to VEGF-α that effectively prevents its binding to its receptors, VEGF-R1 and VEGF-R2. Bevacizumab has been approved by the FDA for use in patients with metastatic colon cancer receiving front-line 5-FU–based chemotherapy based on randomized data showing improved response, progression-free survival, and overall survival [43]. Results from other clinical trials of bevacizumab in combination with chemotherapy have shown promising activity in many other tumor types, including pancreatic cancer [44]. After early clinical studies in many tumor types appeared promising, the drug became available for study with radiotherapy in clinical trials. The only published article evaluating bevacizumab in combination with chemoradiotherapy suggests enhanced response to chemoradiotherapy. In that study, patients with locally advanced rectal cancer were given standard preoperative chemoradiotherapy with bevacizumab (5 mg/kg, starting 2 weeks before radiation) followed by surgery [45]. Five of six (83%) patients had only microscopic residual disease on thorough histologic evaluation, which can be compared with 192 of 431 (45%) patients who had this degree of response after treatment at The University of Texas M. D. Anderson Cancer Center with a similar neoadjuvant chemoradiotherapy approach (without bevacizumab) [46]. A series of correlative studies that accompanied the trial was carefully designed to test preclinical observations and the hypothesis that antiangiogenic therapy “normalizes” tumor vascular physiology by the reduction in permeability and elimination of immature and ine fficient blood vessels [47]. Functional magnetic resonance imaging, CT, positron emission tomography, and endoscopic assessment of response with biopsies and measurements of interstitial pressure were performed before the first dose of bevacizumab and before

the initiation of radiotherapy 2 weeks later. Vascular permeability, interstitial pressure, microvessel density, and tumor blood flow decreased 2 weeks after the first dose of bevacizumab in the majority of six patients’ tumors [45]. Tumor hypoxia was not measured, but the decrease in blood flow may have meant that the efficiency of oxygen delivery by the tumor vasculature improved, leading to a reduction in hypoxia. These correlative studies are consistent with preclinical data from these investigators and suggest that anti-VEGF therapy may lead to improved vascular physiology in the tumor [47], which theoretically would lead to more efficient drug delivery to the tumor, reduced hypoxia, and improved tumor response. However, the relationship of these results to the responses seen in these six patients is not clear. The only other study to evaluate this antibody with radiation is a phase I study in locally advanced, unresectable pancreatic cancer. Initiated in November 2002, this trial is evaluating capecitabine, bevacizumab, and radiotherapy in locally advanced unresectable pancreatic cancer. The trial has reached full accrual (48 patients). Twelve patients were treated at each of four dose levels of bevacizumab (2.5, 5.0, 7.5, and 10.0 mg/kg IV every 2 weeks) with radiotherapy (50.4 Gy in 5.5 weeks treating the primary tumor and gross adenopathy) and capecitabine administered continuously with radiotherapy (650 mg/m2 to 825 mg/m 2 orally twice daily continuously throughout radiotherapy). Patients with stable or responding disease have been offered maintenance bevacizumab (5 mg/kg IV every 2 weeks) until progression. Only two of 42 evaluable patients (4.7%) have had grade 3 gastrointestinal toxicity occurring during chemoradiotherapy, and only one patient had grade 3 hematologic toxicity. Dose adjustment of capecitabine for grade 2 gastrointestinal toxicity was common, in 16 of 42 (38%) patients but was sufficient to avoid more severe events [48••]. For the latter patients on the study, capecitabine has been omitted on the weekends and the grade 2 gastrointestinal toxicity is much lower (one of six patients at 825 mg/m 2 Monday through Friday). Encouraging activity (six of 12 patients receiving the 5-mg/kg dose achieving partial responses) [48••] has stimulated the development of RTOG P04-11, a phase II study evaluating capecitabine-based chemoradiotherapy in combination with bevacizumab. Because three greater than grade 3 duodenal bleeding episodes have occurred in patients with tumors involving the duodenal wall, these patients are not eligible for this trial. The American College of Surgical Oncology Group has proposed a phase II study (ACOSOG Z5041) that will incorporate bevacizumab and gemcitabine before surgery, and capecitabine, radiotherapy, and bevacizumab after surgery. These trials will further eva luate the value of the addition of bevacizumab combined with radiotherapy in the treatment of pancreatic cancer patients with resectable and locally advanced unresectable pancreatic cancer.

Chemoradiotherapy for Gastrointestinal Cancers • Rich et al.

Conclusions The combination of irradiation and chemotherapy continues to be a mainstay in the treatment of gastrointestinal malignancies, and especially now with the emergence of new systemic agents with radiosensitizing properties. The understanding of the utility of these combinations has been clinically driven, and for all the agents currently being enthusiastically evaluated there are preclinical data that support their use. The preclinical and clinical data so far indicate that these combinations are safe, but continued vigilance in the clinical area is necessary to fully understand the potential risks of these treatments. The modest improvements in outcome regarding tumor downstaging and local control appear to justify the continued evaluation of these new chemotherapeutic and biologic agents in combination with irradiation.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

2.

3. 4.

5.

6.

7. 8.

9.

10.

11.

Miwa M, Ura M, Nishida M, et al.: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998, 34:1274–1281. Schuller J, Cassidy J, Dumont E, et al.: Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000, 45:291–297. Kovach JS, Beart RW Jr: Cellular pharmacology of fluorinated pyrimidines in vivo in man. Invest New Drugs 1989, 7:13–25. Moghaddam A, Zhang HT, Fan TP, et al.: Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci U S A 1995, 92:998–1002. Kitazono M, Takebayashi Y, Ishitsuka K, et al.: Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase. Biochem Biophys Res Commun 1998, 253:797–803. Takebayashi Y, Akiyama S, Akiba S, et al.: Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996, 88:1110–1117. Ishitsuka H: Capecitabine: preclinical pharmacology studies. Invest New Drugs 2000, 18:343–354. Sawada N, Ishikawa T, Fukase Y, et al.: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998, 4:1013–1019. Kurosumi M, Tabei T, Suemasu K, et al.: Enhancement of immunohistochemical reactivity for thymidine phosphorylase in breast carcinoma cells after administration of docetaxel as a neoadjuvant chemotherapy in advanced breast cancer patients. Oncol Rep 2000, 7:945–948. Blum JL: The role of capecitabine, an oral, enzymatically activated fluoropyrimidine, in the treatment of metastatic breast cancer. Oncologist 2001, 6:56–64. Van Cutsem E, Twelves C, Cassidy J, et al.: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001, 19:4097–4106.

12.

201

Hoff PM, Ansari R, Batist G, et al.: Comparison of oral Capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001, 19:2282–2292. 13. Cassidy J, Scheithauer W, McKendrick H, et al.: Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): efficacy results of a phase III trial. J Clin Oncol 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004, 22:14S. 14. Dunst J, Reese T, Hoff P, et al.: Capecitabine combined with radiotherapy as neoadjuvant treatment of locally advanced rectal cancer [abstract]. Proc ASCO 2003, 22:1113. 15.• Ngan SYK, Michael M, Mackay J, et al.: A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br J Cancer, 2004, 91:1019–1024. One of several studies showing equivalence of capecitabine to infusional 5-FU when combined with irradiation. 16. Yeh K, Cheng A, Wan J, et al.: Down-regulation of thymidylate synthase expression and its steady-state mRNA by oxaliplatin in colon cancer cells. Anticancer Drugs 2004, 15:371–376. 17. Machover D, Diaz-Rubio E, et al.: Two consecutive phase II studies of Oxaliplatin(L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996, 7:95–98. 18. Diaz-Rubio E, Sastre J, et al.: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol 1998, 9:105–108. 19. Becouarn Y, Rougier P: Clinical efficacy of oxaliplatin monotherapy: phase II trials in advanced colorectal cancer. Semin Oncol 1998, 25:23–31. 20. Becouarn Y, Ychou M, Ducreux M, et al.: Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. J Clin Oncol 1998, 16:2739–2744. 21. Giacchetti S, Perpoint B, Zidani R, et al.: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000, 18:136–147. 22. de Gramont A, Figer A, Seymour M, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000, 18:2938–2947. 23. Borner MM, Dietrich D, Stupp R, et al.: Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 2002, 20:1759–1766. 24. Rothenberg M, Oza A, Bigelow R, et al.: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003, 21:2059–2069. 25. Tournigard C, Andre T, Achille E, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004, 22:229–237. 26. de Gramont A: Multicenter international randomized phase III study of 5FU/LV ± oxaliplatin in the adjuvant treatment of colon cancer. Sanofi-Synthelabo Report No: CSR_BDY-EFC3313EN-E01; 2003. 27. Ramanathan R, Clark J, Kemeny N, et al.: Safety and toxicity analysis of oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer. J Clin Oncol 2003, 21:2904–2911. 28. Blackstock AW, Hess S, Chaney S, Tepper JE: Oxaliplatin: in vitro evidence of its radiosensitizing activity—pre-clinical observations relevant to clinical trials [abstract]. Int J Radiat Oncol Biol Phys 1999, 45:253–254. 29. Carraro S, Roca E, Cartelli C, et al.: Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: a phase II IATTGI study. Int J Radiat Oncol Biol Phys 2002, 54:397–402.

202

30.

Gastrointestinal Cancers

Freyer G, Bossard N, Romestaing P, et al.: Addition of oxaliplatin to continuous fluorouracil, L-folinic acid, and concomitant radiotherapy in rectal cancer: the Lyon R 97-03 phase I trial. J Clin Oncol 2001, 19:2433–2438. 31.•• Gérard J, Chapet O, Nemoz C, et al.: Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 phase II trial. J Clin Oncol 2003, 21:1119–1124. One of several dose-seeking studies with oxaliplatin plus irradiation and showing acceptable clinical activity. 32. Rödel C, Grabenbauer G, Papadopoulos T, et al.: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 2003, 21:3098–3104. 33. Gambacorta MA, Valentini V, Coco C, et al.: Chemoradiation with raltitrexed and Oxaliplatin in preoperative treatment of stage II-III resectable rectal cancer: phase I and II studies. Int J Radiat Oncol Biol Phys 2004, 60:139–148. 34. Landry JC, Rosenthal D, Spitz F, et al.: ECOG 1297: a phase I study of preoperative radiation therapy (RT) with concurrent protracted continuous infusion 5-FU and dose escalating Oxaliplatin followed by surgery, adjuvant 5-FU, and Leucovorin for locally advanced (T3/4) rectal adenocarcinoma [abstract]. Int J Radiat Oncol Biol Phys 2003, 57:S17. 35. Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004, 25:581–611. 36. Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002, 20:4368–4380. 37. 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 1999, 59:3374–3378. 38. Geng L, Donnelly E, McMahon G, et al.: Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 2001, 61:2413–2419.

39.

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 2001, 61:39–44. 40. Elkind M, Swain R, Alescio T, et al.: Oxygen, nitrogen, recovery, and radiation therapy. In Cellular Radiation Oncology. Baltimore: Williams & Wilkins; 1965. 41. Hansen-Algenstaedt N, Stoll BR, Padera TP, et al.: Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy. Cancer Res 2000, 60:4556–4560. 42. Lee CG, Heijn M, di Tomaso E, et al.: Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000, 60:5565–5570. 43. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342. 44. Kindler H, Friberg G, Stadler D, et al.: Bevacizumab plus gemcitabine is an active combination in patients with advanced pancreatic cancer: interim results of an ongoing phase II trial from the University of Chicago Phase II Consortium [abstract]. Proc ASCO 2004, 23:86. 45. 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 2004, 10:145–147. 46. Bonnen M, Crane C, Vauthey J-N, et al.: Long-term results using local excision after preoperative chemoradiation among selected T3 rectal cancer patients. Int J Radiat Oncol Biol Phys 2004, 60:1098–1105. 47. Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001, 7:987–989. 48.•• Crane C, Ellis L, O'Reilly M, et al.: RhuMab VEGF (bevacizumab) with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer: an active, well tolerated regimen. Int J Radiat Oncol Biol Phys 2004, 60:S149. An important study investigating the use of bevacizumab with chemoradiotherapy.