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Phase II Trial of Preoperative Chemoradiation in Patients With Localized Gastric Adenocarcinoma (RTOG 9904): Quality of Combined Modality Therapy and Pathologic Response

Jaffer A. Ajani, Kathryn Winter, Gordon S. Okawara, John H. Donohue, Peter W.T. Pisters, Christopher H. Crane, John F. Greskovich, P. Rani Anne, Jeffrey D. Bradley, Christopher Willett, Tyvin A. Rich

From the Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Radiation Therapy Oncology Group Headquarters; Thomas Jefferson University Hospital, Philadelphia, PA; McMaster University, Hamilton, Ontario, Canada; Mayo Clinic, Rochester, MN; University Hospitals, Cleveland, OH; Washington University School of Medicine, St Louis, MO; Duke University Medical Center, Durham, NC; and the University of Virginia, Charlottesville, VA

Address reprint requests to Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: Jajani{at}mdanderson.org

	ABSTRACT

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PURPOSE: Preoperative therapy for localized gastric cancer has considerable appeal. We hypothesized that, in a cooperative group setting, preoperative chemoradiotherapy would induce a 20% pathologic complete response (pathCR) rate. Combined-modality therapy quality, survival, and safety were secondary end points.

PATIENTS AND METHODS: Patients with localized gastric adenocarcinoma were eligible. A negative laparoscopic evaluation was required. Patients received two cycles of induction fluorouracil, leucovorin, and cisplatin followed by concurrent radiation and chemotherapy (infusional fluorouracil and weekly paclitaxel). Resection was attempted 5 to 6 weeks after chemoradiotherapy was completed. Quality of therapy was assessed with other end points.

RESULTS: Twenty institutions participated. Forty-nine patients were entered and 43 were assessable (12% stage IB; 37% stage II; and 52% stage III). The pathCR and R0 resection rates were 26% and 77%, respectively. At 1 year, more patients with pathCR (82%) are living than those with less than pathCR (69%). Grade 4 toxicity occurred in 21% of patients. Chemotherapy, radiotherapy, and surgery per protocol (including acceptable variations) occurred in 98%, 44%, and 63% of patients, respectively. A D2 dissection was performed in 50% of patients. Of 18 major radiotherapy variations, 17 were due to the lack of inclusion of the L3-4 vertebral interphase as prespecified.

CONCLUSION: For localized gastric cancer, preoperative chemoradiotherapy strategy achieved a pathCR rate of more than 20% in a cooperative group setting. The quality of surgery improved (50% with D2 dissection) possibly because surgery was part of this trial. With some refinements, this preoperative chemoradiotherapy strategy is poised for a randomized comparison with postoperative adjuvant chemoradiotherapy in patients with gastric cancer.

	INTRODUCTION

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The standard approach to localized gastric adenocarcinoma is to perform a limited staging followed by an attempted surgical resection. In North America and some of Europe, postoperative adjuvant chemoradiotherapy frequently is recommended to a select group of patients with curatively resected (R0) gastric cancer because postoperative adjuvant chemoradiotherapy significantly reduces the risk of relapse and prolongs survival.¹ However, this approach, as it is carried out in most hospitals, has a number of drawbacks: it lacks long-term planning of patient care from the outset and uses a fragmented approach in which decisions are made as patients are cared for sequentially by various disciplines. Theoretically, these shortcomings can be eliminated by performing multidisciplinary evaluations before any therapy is initiated. The surgeon can be instrumental in planning for effective administration of other modalities. For example, the surgical field can be defined precisely by using radio-opaque markers and a feeding jejunostomy tube can be placed for nutritional support during postoperative adjuvant chemoradiotherapy. The preoperative chemoradiotherapy strategy provides additional potential advantages because not only are multidisciplinary evaluations essential from the outset, but also the location of the primary cancer is known more precisely, which would facilitate the planning of more accurate and effective radiation fields. The preoperative approach also provides a window of observation for more advanced cancer to manifest itself before a major operation is undertaken. Other conceptual advantages of the preoperative approach have been discussed previously.^2-4

In the Intergroup trial 0116,¹ surgery was not part of the trial and quality of surgery was considered suboptimal, with the majority of patients not even having a D1 dissection and examination of at least 15 nodes. It may be possible to improve the quality of surgery by using the preoperative approach as surgery becomes the part of the trial; however, data do not exist in a cooperative group setting.

Preoperative chemoradiotherapy was feasible in a limited multicenter trial³ and also at one institution.⁴ However, the coordination of preoperative strategy and complex staging is challenging, and for it to succeed as an experimental arm of a phase III trial, it was necessary to demonstrate its activity, quality, and feasibility in the cooperative group setting.

This study was one of the two strategies conceived of by the Gastrointestinal Cancer Intergroup. The other study, performed by the Eastern Cooperative Oncology Group (E7296), used preoperative chemotherapy (paclitaxel/cisplatin) then postoperative chemoradiotherapy (fluorouracil/leucovorin). It was believed that if both approaches proved feasible and active, it might be possible to initiate an Intergroup phase III trial comparing these two strategies.

We report on the strategy of preoperative chemoradiotherapy conducted at 20 Radiation Therapy Oncology Group (RTOG) institutions.

	PATIENTS AND METHODS

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Patient Selection and Evaluation
Patients with localized, histologically confirmed gastric or gastroesophageal adenocarcinoma were eligible. The majority of cancer was in the stomach, although the gastroesophageal junction may have been involved. As part of the staging work-up, patients underwent the following investigations: a chest radiograph, computed tomography of the abdomen (and pelvis and chest if needed), upper GI barium radiographs, esophagogastroduodenoscopy with endoscopic ultrasonography (EUS), ECG, SMA-12 serum chemistry panel, CBC, and measurement of electrolyte and carcinoembryonic antigen levels. Patients with T2-3 carcinoma with (N1) or without (N0) lymph node involvement, and patients with T1, N1 carcinoma were eligible. T stage was determined by EUS results. Laparoscopic staging and J-tube placement were performed in all patients. A multidisciplinary evaluation was required before a patient's participation in this study. Both RTOG and individual institutional review boards approved this protocol before patient entry. All patients signed an approved written informed consent form.

Patients ineligible for inclusion were those with T4, M1, or T1/N0 carcinoma, peritoneal carcinomatosis (gross or microscopic), or uncontrolled medical conditions. Patients who could not comprehend or comply with the study were also ineligible.

Study Design
Patients were to receive up to two cycles of induction chemotherapy and then chemoradiotherapy. The second induction cycle was administered if the cancer had not progressed; if it did progress, then patients commenced concurrent chemotherapy and radiotherapy. Patients were taken off protocol treatment if distant metastases developed. Clinical responses were judged using radiographic or endoscopic techniques.

If a patient had an R0 resection, no further therapy was administered. In the case of an R1 resection (microscopic residual), R2 resection (gross residual), or M1 carcinoma, patients received palliative care.

Step 1: Chemotherapy
Induction chemotherapy consisted of fluorouracil 200 mg/m²/d by continuous infusion on days 1 to 21, and cisplatin 20 mg/m²/d intravenously on days 1 to 5. Patients received therapy in the outpatient setting with standard premedications and hydration. If the patient had not experienced disease progression, then the second cycle was to be repeated 28 days after the initiation of the first cycle.

Drug doses were decreased by 20% if grade 3 nonhematologic toxicity or grade 4 hematologic toxicity occurred. Dose reduction was not done if nausea or vomiting could be better controlled. CBCs were performed weekly and serum chemistries were performed before each course.

Step 2: Chemoradiotherapy
The interval between day 1 of the last induction chemotherapy cycle and the first day of chemoradiotherapy was 28 days. Radiation fields included the entire stomach, any perigastric extension, and lymph nodes (gastric, celiac, porta hepatis, gastroduodenal, splenic-suprapancreatic, and retropancreaticoduodenal). For lesions involving the cardia or gastroesophageal junction, a 5-cm margin of esophagus was included, and for distal lesions near the gastroduodenal junction, a 5-cm margin of duodenum was included. Esophagoscopy, barium radiographs, and computed tomography were used to determine the maximum extent of disease. Fields were modified as needed to shield at least two thirds of one kidney. For proximal lesions, cardiac shielding was recommended, along with the possible use of lateral fields for a component of treatment.

Linear accelerators delivered a dose of 45 Gy (25 fractions of 1.8 Gy) during 5 weeks using at least 6-MV photons and the three-dimensional conformal radiotherapy technique. Oblique anterior and posterior fields were sometimes required to avoid overdosage of the spinal cord and right kidney.

Concurrent chemotherapy, in an outpatient setting, consisted of fluorouracil 300 mg/m²/d by continuous infusion through a portable pump 5 days each week commencing usually on Monday and ending on Friday; in addition, paclitaxel 45 mg/m² intravenously was administered each Monday for 5 weeks.

Step 3: Surgical Therapy
The type of operation depended on the location and extent of the primary tumor. The tumor was resected along with a luminal gastric margin of 5 cm when feasible. Also when feasible, a 2-cm duodenal margin was obtained for distal cancers and a 3-cm esophageal margin for proximal cancers. In both cases, frozen-section confirmation of a negative margin was sought. For distal cancers, a subtotal gastrectomy was considered adequate; total gastrectomy was at the discretion of the surgeon. For proximal cancers, total gastrectomy or esophagogastrectomy was performed. En bloc resection of adjacent organs was performed when their involvement was questionable. The spleen was preserved when possible. An extended nodal dissection or an anatomic D2-type lymphadenectomy was encouraged, but not required. A feeding jejunostomy tube was recommended in all patients.

Tumor Response, Toxicity Criteria, and Data Management
Upper GI barium radiographs were taken after each 28-day cycle of induction chemotherapy and just before chemoradiotherapy, and esophagogastroduodenoscopy, computed tomography of the abdomen, chest radiography, and all blood tests were repeated before surgery. Previously described criteria for response evaluation^3,4 were used. R0 resection was defined as removal of all gross tumor and histopathologic examination of proximal, distal, and circumferential margins that revealed the absence of malignant cells more than 2 mm from the edge.

Acute toxicities were evaluated by National Cancer Institute Common Toxicity Criteria version 2.0 and late radiotherapy toxicities were graded using RTOG/European Organisation for Research and Treatment of Cancert Late Radiation Morbidity Scoring Schema. Each patient was assessed at 3, 6, and 12 months, then every 6 months for 5 years, and then annually or until death.

Statistical Design and Methods
The primary hypothesis was that a 20% pathologic complete response (pathCR) rate would be achievable using this strategy in a cooperative group setting but a pathCR rate of less than 5% would not be desirable. The calculation of the sample size was based on the pathCR rate and Simon's optimal two-stage design.⁵ A pathCR rate of 5% was set as the lowest desirable rate and 20% was the targeted rate. Type I and type II errors were set at 0.05 and 0.10 respectively, such that if the true response rate was less than 5%, the probability of incorrectly accepting the treatment for further study was 5%, and if the true response rate exceeded 20%, the probability of incorrectly rejecting it for additional study was 10%. Using Simon's optimal two-stage design and the specified parameters, a maximum of 41 pathologically assessable patients were required. In the first stage, 21 patients were to be evaluated. If no more than one pathCR was observed, the study was to be terminated. However, if more than one pathCR was observed, then an additional 20 patients (second stage) were to be entered. Finally, if more than four pathCRs were observed among 41 patients, then this strategy and regimen might have been considered as the experimental arm of an intergroup phase III trial in patients with localized gastric carcinoma. It was assumed that at least 85% of patients' treatment responses would be pathologically assessed, therefore requiring a total sample size of 49. Secondary end points included in this report are treatment feasibility and toxicity. PathCR and treatment feasibility rates were calculated along with corresponding 95% CIs.

	RESULTS

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Twenty institutions participated in this trial between November 1999 and February 2004. The rate of accrual increased each year and peaked in 2003. Forty-nine patients were enrolled in the study and 43 (88%) patients were assessable. Only 13 (30%) eligible patients were accrued at large centers. Six patients were excluded from the analysis because two did not have protocol treatment and four were ineligible. The median age was 55 years (range, 34 to 80 years), and 98% of patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patient characteristics are listed in Table 1. All 43 patients were evaluated for pathologic response, safety, quality of the combined-modality therapy, feasibility, and survival.

Surgical Findings and Surgical Pathology
Seven patients did not have surgery because of progression. Of the 36 patients (83% of 43 patients treated) having an operation, 15 had a subtotal gastrectomy, 14 had a total gastrectomy, four had an esophagogastrectomy, one had a total esophagogastrectomy with colonic interposition, one had a proximal gastrectomy, and one had a palliative gastrojejunostomy. Of the 32 patients with sufficient anatomic information regarding the extent of their lymph node dissection, 16 (50%) had a D2 lymphadenectomy. An R0 resection was achieved in 27 patients (77%; 95% CI, 63% to 91%; this was 63% of the initial 43 patients).

PathCR was confirmed in 11 (26%; 95% CI, 13% to 39%) of 43 patients. There was an association between per protocol/acceptable variation and pathCR (P = .02). Among the 11 patients with a pathCR, seven (64%) had treatment without major variations, whereas four (36%) had major variations. However, this need not imply that per-protocol therapy would result in a pathCR, given that primary cancer and nodes were treated with radiation therapy in most patients.

Survival
At a median follow-up of 21.6 months (range, 4.4 to 54.9 months), the median survival of 43 patients is 23.2 months and 72% of patients remain alive at 12 months (Fig 1). At the 12-month juncture, 82% of patients with pathCR are alive compared with 69% of patients with less than pathCR (Fig 2). Survival by R0 resection for patients undergoing surgery is shown in Figure 3. R0 resection resulted in a favorable overall survival.

View larger version (6K): [in this window] [in a new window]   Fig 1. Overall survival.

View larger version (8K): [in this window] [in a new window]   Fig 2. Overall survival by pathologic complete response (pathCR).

View larger version (8K): [in this window] [in a new window]   Fig 3. Overall survival by R0 resection.

Of the 36 patients having an operative procedure, 21 (59%) were surgically treated according to protocol guidelines. There were seven (19%) acceptable variations in treatment. Six patients had pathologically clear, but closer than recommended margins of resections (three with gastric margins of less than 5 cm, two with esophageal margins of less than 3 cm, and one with duodenal margin of less than 2 cm). In one patient, the surgeon did not leave surgical clips to mark the site of adherence to the pancreas. There were eight (22%) minor protocol variations, including four patients with distant metastatic disease diagnosed at operative exploration, three patients with tumor involvement of resection margin(s), and one patient who did not have an en bloc resection of a T4 gastric cancer involving the pancreas. Only 2% of patients had unacceptable protocol variations for chemotherapy administration.

Toxicities and Surgical Complications
Details of acute chemoradiotherapy-induced toxicities by Common Toxicity Criteria version 2.0 are listed in Table 2. Grade 4 toxicity was reported in 21% patients and there were no treatment-related deaths. There were only two grade 3 late radiation toxicities observed (one esophagitis and one skin), as listed in Table 3. Table 4 lists the first sites of failure and Table 5 lists all grade 3 surgical complications within 30 days of surgery.

View this table: [in this window] [in a new window]   Table 5. All Grade 3 Postoperative Complications Within 30 Days of Surgery

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

For preoperative strategy to succeed in a prospective clinical trial, we would be required to demonstrate that complex staging to include endoscopic ultrasonography and staging laparoscopy can be performed routinely outside of large cancer centers and that this approach has activity (as defined by an intermediate end point of a 20% pathCR rate). Thus, a multi-institutional cooperative group setting would be an ideal place to test this strategy. Achievement of pathCR has been associated with longer survival time than observed with less than pathCR in esophageal cancer^6,7 and gastric cancer.^3,4

The current study was conducted in a setting of a cooperative group to assess whether the proposed preoperative approach would be active and a whether a good quality of combined-modality therapy can be achieved safely. The primary end point was observation of a pathCR of at least 20% to consider the strategy viable and worthy of additional evaluation; the secondary end point was assessment of the quality and feasibility in the participating multiple institutions.

Our data demonstrate that a pathCR rate of 20% may be expected from the preoperative chemoradiotherapy approach. The 50% rate of D2 dissection is highly encouraging, and suggests that if surgery is incorporated in protocols for localized gastric cancer, its quality can be improved. We acknowledge that even though 20 institutions participated, the denominator is rather small. One might question whether the feasibility (as specifically defined in the protocol) of this complex strategy was less than expected. Feasibility of executing radiation therapy and surgery without unacceptable variations was possible in only 35% of patients. In particular, the unacceptable variations from protocol suggested radiation planning occurred in 18 (42%) of 43 patients predominantly because of the lack of incorporation of the interphase of L3-4 vertebrae. RTOG sent out a questionnaire to 18 primary radiation oncologist who deviated unacceptably from the recommendations; of these, 17 sent a response and 16 responses suggested that the treating radiation oncologists had assumed that the protocol accorded flexibility for individualization of radiation field based on tumor/nodal geography. However, the language of the protocol did not allow any flexibility and lack of inclusion of the interphase of L3-4 vertebrae was considered an unacceptable variation. On review of the deviations and additional discussions, it was concluded that some refinements in recommendations are needed that provide limited flexibility for individualization of the fields in future gastric cancer protocols. The quality and feasibility of chemotherapy in this combined modality setting was not an issue, with only 2% of unacceptable variations.

The acute and long-term toxicity in the current study is considered acceptable. There was no grade 5 toxicity and 21% developed grade 4 toxicity. Late radiation-induced toxicity was observed in approximately 5% of patients.

In this study, we included induction chemotherapy before chemoradiotherapy was administered. Preoperative induction chemotherapy may be complimentary to preoperative chemoradiotherapy because it could reduce the bulk of the primary cancer (as well as treat micrometastatic cancer), making chemoradiotherapy more effective. Preoperative chemotherapy has been shown recently to prolong overall survival and disease-free survival.⁸

In conclusion, a complex preoperative strategy requiring EUS and laparoscopy as part of initial staging, followed by induction chemotherapy and chemoradiotherapy, can be performed in a cooperative group setting and results in a pathCR rate of more than 20%. Quality of chemotherapy was excellent and that of surgery was intriguingly high, with 50% of patients having a D2 dissection. To avoid unacceptable radiotherapy variations, it would be necessary to allow some flexibility for individualized administration of radiation therapy; in addition, enhanced communications and improved familiarity with protocol guidelines are recommended. The results also reconfirm that patients achieving a pathCR live longer than those achieving less than pathCR. Therefore, with some guideline refinements, the preoperative chemoradiotherapy strategy is poised for a comparison with postoperative chemoradiotherapy in patients with localized gastric cancer.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Jaffer A. Ajani, Gordon S. Okawara, John H. Donohue, Peter W.T. Pisters, Tyvin A. Rich Administrative support: Jaffer A. Ajani, Kathryn Winter, Peter W.T. Pisters, Christopher Willett, Tyvin A. Rich Provision of study materials or patients: Jaffer A. Ajani, John H. Donohue, Peter W.T. Pisters, Christopher H. Crane, John F. Greskovich, P. Rani Anne, Jeffrey D. Bradley Collection and assembly of data: Kathryn Winter Data analysis and interpretation: Jaffer A. Ajani, Kathryn Winter, Gordon S. Okawara, John H. Donohue Manuscript writing: Jaffer A. Ajani, Kathryn Winter, Gordon S. Okawara, John H. Donohue, Christopher H. Crane, John F. Greskovich, Jeffrey D. Bradley, Christopher Willett Final approval of manuscript: Jaffer A. Ajani

 

	NOTES

 
Supported by Radiation Therapy Oncology Group (RTOG) U10 Grants No. CA21661, CCOP U10 CA37422, and Stat U10 CA32115 from the National Cancer Institute (NCI). This manuscript's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Macdonald JS, Smalley S, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001[Abstract/Free Full Text]

2. Ajani JA, Mansfield PF, Lynch PM, et al: Enhanced staging and all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. J Clin Oncol 17:2403-2411, 1999[Abstract/Free Full Text]

3. Ajani JA, Mansfield P, Janjan N, et al: Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 22:2774-2780, 2004[Abstract/Free Full Text]

4. Ajani JA, Mansfield PF, Crane CH, et al: Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: Degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 23:1237-1244, 2005[Abstract/Free Full Text]

5. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline]

6. Berger AC, Farma J, Scott WJ, et al: Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330-4337, 2005[Abstract/Free Full Text]

7. Rohatgi P, Swisher SG, Correa AM, et al: Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer 104:2365-2372, 2005[CrossRef][Medline]

8. Allum W, Cunningham D, Weeden S: Perioperative chemotherapy in operable gastric and lower oesophageal cancer: A randomized, controlled trial (the MAGIC trial, ISRCTN 9379371). Proc Am Soc Clin Oncol 22:249, 2003 (abstr 998)

Submitted March 7, 2006; accepted June 26, 2006.

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