Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO

C. Kollmannsberger1,2, W. Budach3,4, M. Stahl5, N. Schleucher6, T. Hehr3, H. Wilke5, J. Schleicher7, U. Vanhoefer6, E. C. Jehle8, K. Oechsle1, T. Trarbach6, I. Boehlke1, L. Kanz1, J. T. Hartmann1 and C. Bokemeyer1,9,*

1 Department of Hematology/Oncology, 3 Department of Radiation Oncology, University of Tuebingen, Tuebingen; 2 Division of Medical Oncology, British Columbia Cancer Agency–Vancover Cancer Centre, Vancover, Canada; 4 Department of Radiation Oncology, University of Duesseldorf, Duesseldorf; 5 Department of Medical Oncology/Hematology, Kliniken Essen Mitte, Essen; 6 Department of Internal Medicine, Westdeutsches Tumorzentrum Essen, 45122 Essen; 7 Department of Hematology/Oncology, Katharinenhospital Stuttgart, Stuttgart; 8 Department of Surgery, Oberschwabenklinik, Ravensburg; 9 Department of Hematology/Oncology, University of Hamburg, Hamburg, Germany

* Correspondence to: Prof. C. Bokemeyer, M.D., Department of Hematology/Oncology, University Hospital Hamburg Eppendorf, Martinistr. 52, 20 246 Hamburg, Germany. Tel: +49-40-42 803-2960; Fax: +49-40-42 803-8054; Email: c.bokemeyer{at}uke.uni-hamburg.de


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy.

Patients and methods: Between December 2000 and October 2003, a total of 86 patients were included in both studies. Patients with completely resected gastric adenocarcinoma including a D1 or D2 lymph node dissection (LND) were eligible. Treatment consisted of two cycles of folinic acid 500 mg/m2, 5-FU 2000 mg/m2 continuous infusion over 24 h once weekly for 6 consecutive weeks, paclitaxel 175 mg/m2 in weeks 1 and 4 and cisplatin 50 mg/m2 in weeks 2 and 5 (FLPP; n=41) or two cycles of the same 5-FU/folinic acid schedule but with cisplatin 50 mg/m2 only in weeks 1, 3 and 5 (FLP; n=45). Radiation with 45 Gy plus concomitantly applied 5-FU 225 mg/m2/24 h was scheduled in between the two cycles.

Results: Patients characteristics were: D1/D2 LND FLP group 53%/42%; FLPP group 27%/68%; stage distribution: UICC stages III/IV(M0) FLP group 63% and FLPP group 66%. Median follow-up was 10 months (3–25) for FLP and 18 months (2–51) for FLPP patients. CTC grade 3/4 toxicities during the first cycle/chemoradiation/second cycle of FLP: granulocytopenia 3%/0/27%, anorexia 6%/10%/8%; diarrhea 8%/0/4%, nausea 3%/0/4%; FLPP: granulocytopenia 0/0/37%, anorexia 5%/11%/6%; diarrhea 5%/0/3, nausea 3%/8%/0%; early death in one patient due to Pneumocystis carinii pneumonia. Projected 2-year progression-free survival was 64% (95% CI 56% to 68%) for the FLP and 61% (95% CI 42% to 78%) for the FLPP group.

Conclusions: Both chemoradiation regimens appear feasible with an acceptable toxicity profile indicating that cisplatin can be added to 5-FU/FA and that even a four-drug regimen can be investigated further in prospective clinical trials in completely resected gastric cancer patients. Treatment should be given in experienced centres in order to avoid unnecessary toxicity.

Key words: gastric cancer, adjuvant chemoradiation, feasibility, toxicity


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Complete surgical resection remains the only curative treatment option for patients with gastric cancer. The prognosis of patients with locoregionally confined disease depends on the extent of the primary tumor and the extent of lymph node involvement. Even after complete surgical resection with negative margins (R0 resection) plus systematic lymphadenectomy of compartments 1 and 2 (D1 or D2 lymphadenectomy), many patients, particularly those with stage III and IV (M0) disease, will eventually relapse. Studies investigating the pattern of disease recurrence have not only revealed a high rate of distant failure but also a high rate of locoregional relapses even after R0 resection [1Go, 2Go]. Long-term survival is only achieved in 8%–40% of patients with locoregionally advanced disease, which makes the evaluation of adjuvant or neoadjuvant treatment options a priority for these patients [3Go]. A number of randomized studies have investigated the role of adjuvant chemotherapy, but an effective standard regimen has not yet been defined [4Go–6Go]. Recent meta-analyses suggested a modest, but statistically significant, impact of adjuvant chemotherapy. These meta-analyses, however, have to be carefully interpreted since methodological drawbacks such as the use of literature-derived patient data may have influenced their results [7Go, 8Go]. The high locoregional failure rate of up to 70% after curatively intended resection has served as the rationale for the use of adjuvant and neoadjuvant radiation therapy. While radiation as an adjunct to surgery has been shown to improve locoregional control, no significant impact on overall survival was achieved [9Go, 10Go].

US Intergroup Study 0116 was the first large randomized trial demonstrating a significant progression-free and overall survival benefit of 17% and 9% at 3 years follow-up, respectively, for patients receiving adjuvant combined chemoradiation therapy [11Go]. The chemotherapy regimen in this protocol consisted of three cycles of bolus 5-fluorouracil (FU) and folinic acid given according to the Mayo Clinic protocol. It is of interest to note that the comparison of the patterns of disease relapse in the treatment and observation groups in this study suggested that the adjuvant treatment was more effective in reducing the rate of local recurrence rather than the rate of distant metastasis. This indicates that bolus 5-FU/folinic acid did not significantly decrease the development of distant metastases. Newer regimens such as continuously infused 5-FU, folinic acid plus cisplatin (PLF), epirubicin, cisplatin plus continuously infused 5-FU (ECF) or regimens including novel agents such as paclitaxel, oxaliplatin or irinotecan, have been shown to have a substantially higher activity in metastatic disease than 5-FU/folinic acid alone, which makes them an attractive option for the use in the adjuvant setting [12Go–16Go].

In order to develop a novel regimen for adjuvant chemoradiation in patients with completely resected gastric cancer, we simultaneously performed two cooperative multicenter phase II studies investigating the combination of continuously infused 5-FU, folinic acid, and cisplatin with or without paclitaxel as chemotherapy plus radiochemotherapy with continuously infused 5-FU in these patients. The primary end point of both studies was to explore the feasibility and toxicity of the two chemotherapy regimens (either three-drug 5-FU/folinic acid/cisplatin or four-drug 5-FU/ folinic acid/cisplatin plus paclitaxel) in combination with radiochemotherapy in gastric cancer patients following complete resection with D1 or D2 lymphadenectomy. Secondary end points were the progression-free and overall survival rates.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Both studies were simultaneously opened. Centers were only permitted to participate in one of the two studies. Once decided, all participating patients had to be treated with the same regimen at that center. In order to be allowed to participate in the adjuvant study concepts, each center had to send in a joint agreement to the study office signed by the local medical oncologist, radiotherapist and surgeon. The studies were approved by the Ethics Committees of the University of Tuebingen as well as of the participating centers. Both studies were officially accredited as joint multicenter studies by the German Society of Medical Oncology (AIO), German Society of Radiation Oncology (ARO) and German Society of Surgical Oncology (ACO).

Patients
The eligibility criteria for both studies were equal and included histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction; complete resection of the tumor, defined as resection performed with curative intent and resulting in negative resection margins; classification as stage II–IV (M0) according to the 1997 staging criteria of the International Union Against Cancer; a performance status of 2 or better according to the criteria of the Eastern Cooperative Oncology Group; age 18–75 years; adequate function of major organs (indicated by a creatinine clearance of at least 60 ml/min, a hemogram within normal limits, a bilirubin concentration no more than twice above the upper limit of normal); no concurrent insufficiently treated diseases such as heart, renal or hepatic failure or uncontrolled infection; start of adjuvant treatment at latest 6 weeks after surgery; and written informed consent.

Surgery and pathology reports were reviewed to confirm the completeness of the resection and to verify the extent of the lymphadenectomy. If the extent of the lymphdenectomy performed was unclear from the operative report, at least 15 and 25 removed lymph nodes were required for classification as a D1 and D2 lymphadenectomy, respectively. All patients who were considered at review to have undergone less than a D1 lymphadenectomy and had already started protocol treatment were included in the analysis.

All patients underwent CT scans of the chest and abdomen prior to the start of adjuvant therapy in order to rule out metastatic disease. In addition, a history and physical examination, a complete blood count and serum chemistry including liver and kidney function tests, a creatinine clearance, an electrocardiogram, and an audiogram were obtained. For radiation planning, a renal scintigraphy with 99mTechnetium-MAG3 was required for all patients.

Treatment (Figure 1)
Chemotherapy regimens
Regimen A (FLPP) consisted of 5-FU administered weekly at a dose of 2000 mg/m2 as a 24-h continuous infusion preceded by 500 mg/m2 folic acid as a 2-h infusion. Paclitaxel was administered at a dose of 175 mg/m2 on days 1 and 22 as a 3-h infusion and cisplatin 50 mg/m2 was added on days 8 and 29 [14Go]. All patients received dexamethasone 20 mg and ranitidine 300 mg as well as diphenhydramine 50 mg 30 min prior to paclitaxel in order to avoid hypersensitivity reactions.

Regimen B (FLP) consisted of 5-FU administered weekly at a dose of 2000 mg/m2 as a 24-h continuous infusion preceded by 500 mg/m2 folic acid as a 2-h infusion. Cisplatin 50 mg/m2 was added on days 1, 15 and 29 [17Go].

Chemotherapy was given once weekly for a total of 6 weeks followed by 2 weeks rest in both treatment groups. This period was defined as one chemotherapy cycle. The first cycle of chemotherapy was given before chemoradiation and the second cycle started 2 weeks after the end of radiation. All patients received adequate antiemetic pre-medication prior to chemotherapy. A permanent venous access was implanted in all patients in order to facilitate the continuous 5-FU application. Portable single use 24-h infusion pumps were used for the ambulatory application of 5-FU. All patients were treated on an outpatient basis. Dose reductions of 5-FU±cisplatin/paclitaxel were planned for grade ≥2 hematological toxicity and for grade ≥2 non-hematological toxicity including nausea/vomiting, diarrhea, mucositis, anorexia, neurotoxicity, nephrotoxicity and ototoxicity. Dose reductions for grade 2 toxicities were intended for safety reasons.

Chemoradiation
Chemoradiation started 2 weeks after the last chemotherapy application and consisted of 45 Gy radiation at 1.8 Gy/day 5 days per week for 5 weeks and a total of 25 fractions. 5-FU was administered concomitantly as a continuous infusion over 24 h at a dose of 225 mg/m2 on all radiation days. An oral 5-HT3 antagonist was recommended for all patients during chemoradiation, and patients with residual gastric tissue received a proton pump inhibitor. CT-based 3D-radiotherapy treatment planning and irradiation with ≥6 MV photons was mandatory. The clinical target volume (CTV) included the regional lymph nodes, the anastomosis region and a minimum 4-cm safety margin around the former tumor along all mucosal cavity walls. Regional lymph nodes included the perigastric, the celiac axis, the local pre-vertebral para-aortic, the hepatoduodenal and pancreaticoduodenal lymph nodes as well as the nodes along the splenic artery to the splenic hilus and along the hepatic artery to the hepatic hilus. To define the extent of the CTV along the (residual gastric/esophageal/duodenal) mucosal cavity, all available information regarding the initial localization of the tumor in the stomach including pathology reports, endoscopic findings, preoperative CT imaging, barium roentgenography, and in some instances, surgical clips were used. In case of a proximal T3 lesion, the medial half of the left diaphragm was integrated into the CTV. The pre-vertebral located part of the para-aortic lymph nodes was included into the CTV, starting at the diaphragm down to the middle of the third lumbar vertebra. However, in very proximally and very distally located tumors the cranial and caudal extent of the CTV was modified to achieve a minimum 4-cm safety margin at all mucosal sites (see above). To compensate for set-up errors and organ movements, the CTV was blown up three-dimensionally by 12 mm in order to get the planning treatment volume (PTV). Kidneys, liver, spinal cord and heart were considered organs at risk (OR) for the radiotherapy planning procedure and were contoured without safety margin. The following dose volume restrictions at the OR were taken into account: spinal cord <47.5 Gy (<1.9 Gy single dose); heart <40 Gy to <30% of the ventricle volume; kidneys <12 Gy to <37.5% of the functional volume of both kidneys taken together (separately tested function); liver <30 Gy to <60%. The dose planning to the PTV and OR were performed according to the ICRU 50 and ICRU 62 guidelines. If the intended dose in the PTV could not be delivered without exceeding the dose volume restrictions at the OR, the extent of the CTV was reduced at the regional lymph nodes most distant from the documented tumor involvement, and the margin between CTV and PTV was decreased at some parts of the CTV in favor of OR. Although ventro-dorsally opposing fields were allowed in the study, in the vast majority of patients, radiotherapy was delivered by a four-field technique.

Prior approval of the treatment plan for radiotherapy by the radiation-oncology coordinator (W.B.) was required at least for the radiation plan of the first patients treated at each participating center prior to the initiation of radiotherapy. Treatment fields, dosimetry, surgery and pathology reports, and preoperative tumor imaging were submitted for review before the start of treatment. Radiation plans that were not approved because of the risk of toxic effects on critical organs or the failure to treat the appropriate target volumes were corrected prior to the start of radiation.

Follow-up of patients
Follow-up of both groups was obtained at 3-month intervals for 2 years, then at 6-month intervals for 3 years, and yearly thereafter with a physical examination, a complete blood count, liver-function testing, chest radiography and CT scanning as clinically indicated. The site and date of the first relapse and the date of death, if the patient died, were recorded.

Study end points
Primary objectives of both studies were the determination of the feasibility and toxicity of the combined adjuvant treatment. In order to detect even infrequently occurring toxicities, accrual of 40 patients in each of the two treatment groups was planned. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Secondary end points included the progression-free and overall survival rates. Progression-free survival time, follow-up duration and overall survival time were calculated from the start of treatment to the date of disease progression or the date of the last evaluation or death, respectively. Survival curves were estimated by the method of Kaplan–Meier [18Go]. All statistics was performed using SAS software (SAS Institute, Cary, NC, version 6.11).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 86 patients with adenocarcinoma of the stomach and a median age of 54 years (range 25–73 years) were enrolled in the two study groups. Forty-one patients were treated with FLPP and 45 with FLP. All but 5% of patients in each group underwent a systematic lymphadenectomy. The median number of resected nodes in all patients with a D1 resection was 16 (range 6–30) and 29 (range 15–73) in the D2 group. Patient characteristics are given in Table 1.


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Table 1. Patient characteristics

 
5-FU/leucovorin/cisplatin (FLP) study
In the FLP group, 24 patients (53%) had undergone a D1 lymphadenectomy and 19 (42%) a D2 lymphadenectomy. The median number of resected nodes was 20 (range 6–48). Twenty-eight patients (62%) had UICC stage III/IV (M0) disease. In two patients UICC stage had to be reclassified after the start of therapy to a stage IB disease.

Toxicity according to CTC criteria is given in Tables 2a5a as the worst toxicity per patient during each part of the study. The most common toxicities were hematological and gastrointestinal side-effects. Almost all patients had grade 1/2 anemia prior to the start of therapy due to the malignant disease and extensive surgery. The frequency of hematological grade 1/2 toxicities, particularly leucocytopenia and thrombocytopenia, increased from the pre-radiation chemotherapy cycle 1 to the post-radiation cycle 2. Severe grade 3/4 hematological toxicity was rarely observed during the first cycle of chemotherapy and during the chemoradiation period, but leucocytopenia CTC grades 3/4 was substantially more frequent in the second chemotherapy cycle. Severe thrombocytopenia was uncommon. Neutropenic infections CTC grade 3/4 occurred in less than 5% of patients and most often in the second cycle of chemotherapy.


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Table 2a. Hematological toxicity CTC grade 1/2 FLP regimen

 

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Table 5a. Non-hematological toxicity CTC grade 3/4 FLP regimen

 
The major CTC grade 3/4 non-hematological toxicities were alopecia, nausea, vomiting, diarrhea, as well as anorexia (see Table 5a). One patient developed CTC grade 3 hand–foot syndrome. Severe neurotoxicity was not observed. There was no significant difference in toxicity between patients with a D1 and D2 lymphadenectomy. Treatment was stopped early due to toxicity in 12 (26%) patients. Three patients (6%) relapsed during treatment. Seven patients (15%) refused part of their treatment for personal reasons in the absence of grade 3/4 toxicity. Dose reductions and/or treatment delays were performed in an additional four patients (9%), mostly for neutropenia CTC grade 2/3 and gastrointestinal side-effects grade 2/3. No dose reduction had to be performed for neurotoxicity or renal failure.

Median follow-up was 10 (range 3–25) months. Two-year relapse-free and overall survival rates were 64% (95% CI 49% to 80%) and 79% (95% CI 62% to 97%), respectively. Eight patients relapsed and seven patients died of their disease.

5-FU/leucovorin/cisplatin/paclitaxel (FLPP) study
Eleven (27%) and 28 (68%) patients had had a D1 and D2 lymphadenectomy. The median number of resected nodes was 26 (range 6–73). Thirty patients (66%) presented with UICC stage III/IV (M0) disease. One patient had to be reclassified after the start of therapy to a stage IB disease.

Toxicity according to CTC criteria for the FLPP group is given in Tables 2b5b as the worst toxicity per patient during each part of the study. Again, the most common toxicities were hematological and gastrointestinal side-effects and the frequency of hematological grade 1/2 and 3/4 toxicities, particularly leucocytopenia and thrombocytopenia, increased from the pre-radiation chemotherapy cycle 1 to the post-radiation cycle 2. Severe thrombocytopenia was uncommon and neutropenic infections CTC grade 3/4 occurred in less than 5% of patients. There was one therapy-related death (2%) in the FLPP group due to CTC grade 4 granulocytopenia and subsequent Pneumocystis carinii pneumonia after the first day of the first cycle of chemotherapy with 5-FU/folinic acid and paclitaxel.


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Table 2b. Hematological toxicity CTC grade 1/2 FLPP regimen

 

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Table 5b. Non-hematological toxicity CTC grade 3/4 FLPP regimen

 
As with the FLP regimen, the major CTC grade 3/4 non-hematological toxicities were alopecia, nausea, vomiting, diarrhea, as well as anorexia (see Table 5b). No severe neurotoxicity was observed. There was no significant difference in toxicity between patients with a D1 and D2 lymphadenectomy in each of the two patient groups.

Treatment was stopped early due to toxicity in five patients (12%). Two patients (5%) in the FLPP group refused part of their treatment for personal reasons in the absence of grade 3/4 toxicity. Dose reductions and/or treatment delays were performed in an additional seven FLPP patients (17%), mostly for neutropenia CTC grade 2/3 and gastrointestinal side-effects grade 2/3, but no dose reduction had to be performed for neurotoxicity or renal failure.

Median follow-up was 18 (range 2–51) months for the FLPP group. Two-year relapse-free survival was 61% (95% CI 42% to 78%) and overall survival was 77% (95% CI 61% to 94%). A total of 13 patients relapsed and seven patients died of their disease.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The main aim of the two current studies was to investigate the feasibility and toxicity of a three and a four-drug chemotherapy regimen in combination with radiochemotherapy in gastric cancer patients after extensive surgery including a D1 or D2 lymphadenectomy. The most important factor for the failure to identify active adjuvant chemotherapy regimens in the past may have been the lack of effective regimens [19Go]. Newer regimens have shown much higher response rates in the metastatic setting [13Go]. In addition, Bajetta et al. [20Go] showed a statistically significant advantage for patients with more than six metastatic lymph nodes following adjuvant 5-FU/cisplatin-based chemotherapy compared with patients without adjuvant therapy, indicating that adjuvant chemotherapy using newer chemotherapy regimens may be beneficial for certain subgroups of patients with locally advanced disease. Ajani et al. [21Go] recently demonstrated the feasibility of a similar treatment strategy consisting of 5-FU/cisplatin-based chemotherapy in combination with radiochemotherapy as neoadjuvant treatment. Promising results with a median survival of 33 months were reported. The rationale for the use of folinic acid, 5-FU given as a 24-h continuous infusion plus cisplatin in our study was based on the results of the EORTC 4095 trial, a randomized phase II study that demonstrated a 39% response rate for this combination in patients with metastatic disease. The combination of 5-FU/folinic acid/cisplatin plus paclitaxel has shown an acceptable toxicity profile and high response rates of 45% and 58%, including 10%–13% complete remissions in two consecutive studies performed in patients with metastatic gastric cancer by our study group [14Go, 22Go]. Favorable results were also reported by a US and a Korean phase II study [23Go, 24Go].

The toxicity of the combinations of a 24-h continuous infusion of high-dose 5-FU/folinic acid/ cisplatin both with and without paclitaxel used as adjuvant chemotherapy in combination with radiochemotherapy in our trial appeared acceptable and the treatment could be administered on an outpatient basis. In the INT 0116 study, 17% of patients were taken off study due to unacceptable toxicity and 8% declined further therapy. In the FLP group, treatment was stopped early due to toxic effects in 26% of patients and 15% of patients refused part of their treatment for personal reasons in the absence of significant measurable toxicity or due to toxicity that did not exceed CTC grade 2. This comparatively high rate of early treatment stops probably reflects the experience of the participating centers in the FLP study. The two studies were the first studies of adjuvant chemoradiation in gastric cancer in Germany. Accordingly, most centers did not have prior experience with adjuvant chemoradiation. While most FLPP patients were treated at a few large centers, which rapidly gained experience, the FLP regimen was used by the majority of the participating, and in particular the smaller, centers with only few patients. The majority of the early treatment terminations in the FLP group were due to hematological toxicity and in most cases treatment was stopped even before all the various protocol recommendations for dose modifications and use of growth factors were utilized. Interestingly, in the FLPP group only 12% of patients were taken off study due to toxicity and 5% of patients refused further treatment in the absence of significant toxicity despite the addition of a third drug. This indicates the importance of the center's treatment experience and adjuvant combined chemoradiation for gastric cancer should therefore only be administered at centers with a large number of patients treated. The use of growth factors, if indicated, should be recommended to maintain dose intensity and lower the risk for infections.

One patient in the FLPP study died of chemotherapy induced grade 4 neutropenia and subsequent Pneumocystits carinii pneumonia after having received only the first day of the first cycle of chemotherapy. Pneumocystis carinii pneumonias usually occur in chronically and severely immunosuppressed patients and are rarely observed after chemotherapy for solid malignancies. In addition, it is unusual that granulocytopenia CTC grade 4 develops after the very first day of chemotherapy. It can be speculated whether an additional affection of the immune system, such as chronic viral infection, may have contributed to the development of this pneumonia but we were unable to obtain further blood samples from this patient for further tests.

Toxicity particularly increased during the second cycle of chemotherapy in our studies whereas the first cycle of chemotherapy and the radiochemotherapy part were well tolerated. Most patients had grade 1 and 2 anemia even prior to the start of adjuvant therapy. Grade 3/4 hematological toxicity mainly consisted of leucocytopenia, but the frequency of neutropenic infections was very low.

Similar to INT 0116, gastrointestinal side-effects were the most common non-hematological toxicities in our studies, but overall grade 3/4 gastrointestinal toxicities appeared to be less frequent than in INT 0116. This may be due to the different 5-FU schedule used in our protocol with 5-FU given as a 24-h continuous infusion once weekly, which has been shown to be less toxic than the Mayo regimen [25Go]. In addition, improved radiation techniques, in particular the use of 3D radiation treatment planning resulting in four or more field techniques in the majority of patients compared with simple AP–PA portals in the INT 0116 trial, and the application of 5-FU as continuous infusion during radiotherapy as well as improved supportive measures, may all have contributed to the apparently better tolerability. Similar conclusions have been drawn by other recent studies [26Go, 27Go]. Weight loss and anorexia represent particular problems in this patient group. Adjuvant chemoradiation may further aggravate this problem and thus, all patients should be monitored for their nutritional status. Nutritional support, as well as regular consultation with a dietitian, should be offeredGo.



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Figure 1. Treatment plan. RTx, radiation therapy; CTx, chemotherapy.

 
Since toxicity increased substantially during the second cycle chemotherapy, one may hypothesize that a change of schedule of the protocol, e.g. two cycles of chemotherapy followed by radiation therapy, may influence toxicity and the results. This remains to be investigated in future studies.

While the optimal extent of lymph-node dissection in gastric cancer (D1 versus D2) is still controversial, systematic lymphadenectomy is generally recommended [28Go, 29Go]. It has not yet been investigated whether toxicity may be higher in patients after D2 lymphadenectomy with their more extensive abdominal trauma. Our results suggest that a D2 lymphadenectomy did not substantially increase the toxicity of a subsequently administered more aggressive adjuvant chemoradiation protocol.

In conclusion, we have shown that a 5-FU/folinic acid/cisplatin-based chemotherapy regimen, even plus paclitaxel in combination with radiochemotherapy, can be applied with acceptable toxicity in the adjuvant setting in patients with gastric cancer after complete resection including a D1 or D2 lymphadenectomy. The 2-year relapse-free survival and 2-year overall survival rates in the present phase II study for both groups are very encouraging considering the locoregionally advanced stage of the patients enrolled, but require phase III confirmation.


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Table 3a. Hematological toxicity CTC grade 3/4 FLP regimen

 

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Table 4a. Non-hematological toxicity CTC grade 1/2 FLP regimen

 

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Table 3b. Hematological toxicity CTC grade 3/4 FLPP regimen

 

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Table 4b. Non-hematological toxicity CTC grade 1/2 FLPP regimen

 

    Acknowledgements
 
These data were in part presented at the 40th Annual Meeting of the American Society of Clinical Oncology in New Orleans, 5–8 June 2004. This study was supported by grant AKF 55-0-0 of the AKF program of the University of Tuebingen. We are indebted to Dr Sharlene Gill, British Columbia Cancer Agency, for proofreading the manuscript.

Additional participating centers were: Städtisches Klinikum Oldenburg (H. J. Illiger, B. Metzner); Klinik am Eichert, Göppingen (G. Becker); Klinikum Landshut (B. Moritzberger); Klinikum Villingen-Schwenningen (W. Brugger); Brüderkrankenhaus St. Josef, Paderborn (H. Leber); Universitätsklinik Bonn (Y. Ko); Onkologische Schwerpunktpraxis Leer (L. Müller); Onkologische Praxis Rehling (D. Hempel); Städtisches Krankenhaus Hildesheim (B. Sievers); Dr. Horst-Schmidt-Kliniken GmbH, Wiesbaden (N. Frickhofen); Kliniken St. Antonius, Wuppertal (M. Sandmann); Krankenhaus St. Elisabeth und St. Barbara, Halle (B. Opitz); Kreiskrankenhaus Aurich (W. Langer); Onkologische Schwerpunktpraxis Mülheim, (J. Schröder); Städtische Kliniken Esslingen/Strahlentherapie Ruit (R. Eckert); Kreiskrankenhaus Sigmaringen (G. Kaefer).

Received for publication January 20, 2005. Revision received April 8, 2005. Accepted for publication April 11, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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