Adjuvant Therapy for Gastric Carcinoma: Closing out the Century

ABSTRACT: Gastric cancer is often advanced and unresectable at diagnosis. Even when a curative resection is possible, the 5-year survival rate for patients with T2 or higher tumors is less than 50%. Survival rates are even lower if lymph node metastases are present at surgery. Many phase III trials of adjuvant therapy have been conducted around the world during the past 4 decades, but their interpretation varies in the East and West. In the West, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Thus, at present, the routine use of postoperative therapy should be discouraged. In the Orient, however, routine use of postoperative chemotherapy and/or immunotherapy is common after a surgical procedure. Further investigations that correlate treatment response with molecular markers are needed. Improved clinical trial designs, including better preoperative staging, standardized surgical techniques, inclusion of adequate numbers of patients, and the continued use of a surgery-alone control group, are essential. In addition, the incorporation of newer active agents, radiotherapy, and new strategies, such as preoperative therapy and selection of patients based on tumor biology, would result in much-needed advances. Less toxic approaches with novel mechanisms of action, such as antiangiogenesis therapy, tumor vaccines, monoclonal antibodies, and matrix metalloproteinase inhibitors, also hold promise. [ONCOLOGY 13(11):1485-1494, 1999]

Introduction

Gastric cancer is a global health problem. Although the incidence of this cancer is declining in many industrialized nations, gastric cancer remains the second most frequently diagnosed malignancy worldwide. It accounts for 9.9% of all new cancer diagnoses and is responsible for 12.1% of all cancer-related deaths.[1] In the United States, it is estimated that 21,900 cases of gastric cancer will be diagnosed in 1999 and 13,500 persons will die of this disease.[2]

Gastric cancer is often advanced and unresectable at diagnosis-a fact that contributes to its high morbidity and mortality. The stomach is a hollow organ, and the abdominal cavity is large and compliant to distention. Because of the large potential space, patients often develop symptoms only when the cancer is far advanced. Outside of Japan, an industrialized nation where gastric cancer is common, early detection of gastric cancer is not attempted.

Reports based on large German and Korean databases show that 57% to 63% of gastric cancer patients undergoing resection of the primary tumor have lymph node metastases.[3,4] In the United States, data suggest that 85% of patients enrolled in a recently completed adjuvant trial had lymph node metastases [personal communication, J. S. Macdonald, MD, November 1998].

Worldwide, large amounts of resources have been expended in the search for an effective adjuvant therapy to reduce the risk of postoperative relapse. Numerous phase III clinical trials have been published over the past few decades. The results of these trials, however, have often been disappointing or equivocal and are sometimes conflicting. Adjuvant therapy trials in western countries and Asia published between 1984 and 1997 were recently reviewed by Shimada and Ajani.[5] In this article, we review various approaches to adjuvant therapy.

Prognostic Factors

Selection of appropriate patients for adjuvant therapy is extremely important. In addition to TNM stage, recent advances in the field of molecular diagnostics will likely affect the selection of gastric cancer patients for such therapy, as well as identify new prognostic markers. Current studies correlating clinical outcomes with the status of genes, such as p53, thymidylate synthase, ERCC1, and many others, may help direct therapy for individual patients.

Based on TNM staging criteria, the depth of invasion (T), presence of lymph node metastases, and number of lymph nodes involved (N) predict the risk of relapse. This was confirmed in a large German multicenter trial published by Siewert et al in 1998.[3] The study involved 1,654 patients undergoing surgical resection of gastric tumors.

A significant survival advantage was found for the 1,182 patients (71.5%) who underwent an R0 resection (ie, no residual disease and no cancer cells at the resection margins). In addition to the depth of invasion and nodal status, the ratio between involved and removed lymph nodes proved to be an important independent prognostic factor.[3]

The prognostic importance of R0 resection, depth of invasion, nodal status, and the ratio between involved nodes and removed nodes was confirmed in a large Korean study involving 10,783 patients.[4] In this study, an R0 resection was achieved in 4.8% of patients.

The American College of Surgeons also has published a large analysis of gastric cancer patients.[6] This study was based on a tumor registry review of 25 consecutive patients from each participating institution seen in the years 1982 and 1987. Data on a total of 18,365 patients were analyzed.

Despite the large number of patients, however, the results of this analysis are not easy to interpret. This was a retrospective study that involved a large

number of heterogeneous institutions. Symptoms at presentation may have important prognostic value. Weight loss was the most common symptom, reported in 61.6% of patients. However, the presence or absence of weight loss was not correlated with clinical outcome, and the degree of weight loss was not specified. Similarly, 42% of patients who underwent surgical resection with clear margins received adjuvant chemotherapy or radiation therapy. However, patient characteristics and type of therapy given were not specified. The 5-year survival rates based on pathologic stage after resection were reported as 50%, 29%, 13%, 3% for stages I, II, III, and IV, respectively. These survival rates are significantly worse in every stage category than those reported in the German and Korean studies.

Histologic tumor type may influence patterns of failure. The liver is a frequent site of failure in intestinal-type tumors, whereas peritoneal carcinomatosis is more common with the diffuse type.[7-9] Diffuse histology is on the rise throughout the world.

Molecular Factors

Advances in molecular diagnostics have opened new avenues for predicting clinical outcome. One area of active research is the determination of p53 mutations.[10] In early-stage, T1 tumors, p53 overexpression correlates with depth of invasion and lymph node involvement.[11]

Another area of active research is the correlation of in vivo response to chemotherapy with genetic phenotype. Fluorouracil, which is the most commonly used agent for gastric cancer, targets the enzyme thymidylate synthase. Lenz et al[12] found that low thymidylate synthase messenger RNA (mRNA) expression was predictive of response and survival in patients treated with fluorouracil and cisplatin (Platinol). More recently, however, Fata et al[13] found high thymidylate synthase mRNA expression to be a predictor of favorable survival.

The excision repair cross-complementing gene (ERCC1) was studied in 33 patients treated with preoperative fluorouracil and cisplatin. In this study, ERCC1 expression correlated with response to therapy.[14] Furthermore, when thymidylate synthase and ERCC1 expression were both low, 11 (85%) of 13 patients responded to therapy; in contrast, when both thymidylate synthase and ERCC1 expression were high, only 2 (20%) of 10 patients responded.

Staging

The current National Comprehensive Cancer Network (NCCN) practice guidelines for gastric cancer recommend the following tests and examinations as the minimum preoperative work-up: history, physical examination, complete blood counts (including platelets), SMA-12, computed tomography (CT) of the abdomen, chest roentgenogram, esophagogastroduodenoscopy, and, in female patients, CT or ultrasound of the pelvis.[15]

Increasingly, laparoscopy also is being recommended prior to a major resection. The use of laparoscopy may be supported by the fact that an R0 resection cannot be performed in 30% to 40% of patients undergoing surgery. In the German study, 29.3% of the patients had M1 disease at laparotomy.[3] In these patients, median survival was less than 12 months.

At the University of Texas M. D. Anderson Cancer Center, 83 patients were enrolled in preoperative chemotherapy trials, 73% of whom underwent a curative resection. In the group who could not receive a curative resection, 55% of patients avoided nontherapeutic laparotomy because of an extensive preoperative work-up.[16]

Surgery

A number of controversies exist in the surgical management of gastric cancer. The most important of these is the extent of lymphadenectomy.

A D1 resection entails a gastrectomy with the removal of all perigastric nodes and the removal of the greater and lesser omenta. In addition to these structures, for a D2 dissection the surgeon removes the omental bursa portion of the transverse mesocolon and the nodes along the left gastric, celiac , and splenic arteries. For a D3 dissection, in addition to the standard

D2 dissection, lymph nodes in the hepatoduodenal ligament, along the superior mesenteric vein, posterior to the common hepatic artery, and on the posterior surface of the pancreatic head are also removed. A D4 dissection involves the removal of lymph nodes around the abdominal aorta, in addition to all of the structures mentioned above.

In the East, extensive lymphadenectomy (D2 through D4) is commonly practiced without excessive complications. Recently, the Japan Clinical

Oncology Group[17] conducted a randomized study of D2 dissection with or without para-aortic node dissection; these researchers reported no treatment-related deaths but a 6% rate of major complications. In the West, the extent of lymph node dissection is more controversial. Western surgeons usually do not perform D2 dissections due to the high rate of complications.

The Dutch Gastric Cancer Group randomized 711 patients with all stages of disease to either a D1 or D2 dissection. Patients who underwent a D2 resection had a higher rate of complications, more postoperative deaths, longer hospital stays, and no improvements in 5-year survival.[18] However, assuming that the ratio of involved lymph nodes to resected nodes predicts outcome, removal of more negative nodes, which occurs during an extended node dissection,[19] may improve long-term survival.

Subgroup analyses of the German[3] and Korean[4] databases show that D2 dissection benefited patients with stage II disease in both studies and benefited patients with stage IIIA disease in the Korean study. However, subgroup analyses are fraught with difficulties. The level of surgical expertise needed to perform an extended node dissection appears to have an impact on surgical morbidity and mortality.

An analysis by Estes et al[19] shows that operative documentation needs improvement. These investigators reviewed operative reports from more than 300 surgeons given a checklist for documentation prior to participating in a national protocol. Inadequate documentation was common. The status of the primary tumor, lymph nodes, liver, peritoneum, and omentum was not stated in 6%, 10%, 17%, 28%, and 28% of operative reports, respectively. Also, the reports often lacked sufficient information about the extent of dissection.

At present, D1 dissection should be considered the minimum resection for patients with potentially curable gastric carcinoma. Estes et al found that 54.2% patients undergoing “curative” resection of gastric cancer had a D0 dissection. This indicates that adequate resection and staging are not being practiced.[19] D2 resection, a proper oncologic surgical procedure, should be considered by experienced surgeons who frequently perform gastric cancer surgery.

Adjuvant Chemotherapy

Single Agents

Early studies of adjuvant chemotherapy for gastric cancer were performed by the Veterans Administration Surgical Oncology Study Group and the University Cooperative Surgical Group. In these early studies, patients were randomly assigned to triethylenethiophosphoramide (thiotepa) or no further treatment after surgery. Patients given chemotherapy showed no advantage with respect to overall survival.[20,21]

In 1977, Imanaga and Nakazato published the first positive results of treatment with adjuvant mitomycin (Mutamycin).[22] They pooled data from four trials performed by the Japanese Surgical Adjuvant Chemotherapy Group using various doses and schedules of mitomycin and mitomycin-containing regimens. In all four trials, surgery alone was the control arm.

In one trial, 242 patients were treated with 0.08 mg/kg of mitomycin twice weekly for 5 weeks. The mitomycin group in this trial had a superior 5-year survival rate than the 283 patients in the control group (67.8% vs 53.3%; P = .05). However, the other three trials failed to demonstrate a significant survival advantage of mitomycin (Table 1).

Investigators from Barcelona, Spain, reported the findings of a small, randomized trial of mitomycin in 1983.[23] The 70 enrolled patients received either mitomycin (20 mg/m² every 6 weeks for four courses) or placebo. The 2-year survival rate was better in the treated group than in the placebo group.

After treating an additional 63 patients with the same dose and schedule of mitomycin and attaining longer follow-up, the Barcelona researchers published their updated results in 1993.[24] Improved 5-year survival rates of 41% were reported in the treated group, compared to 26% for the surgery-only controls (P < .025; Table 1). The survival advantage continued to be significant at 10 years (39% vs 26%). However, the total number of patients treated was small (68 patients received surgery plus mitomycin), and the distribution of important prognostic factors, such as histologic type, performance status, tumor location, and type of surgical resection performed, was not stated.

These limitations, along with numerous negative trials of adjuvant mitomycin or mitomycin-based regimens, make it difficult to draw definitive conclusions.

Combination Chemotherapy

Many combination chemotherapy regimens that produced encouraging results in phase II and phase III trials of advanced gastric cancer have been tried in the adjuvant setting. However, few of these regimens have demonstrated a significant survival benefit. Table 2 summarizes selected trials of adjuvant combination chemotherapy for resected gastric carcinoma.

The Gastrointestinal Tumor Study Group published encouraging results in 1982.[25] In this randomized trial, 71 patients were assigned to receive fluorouracil (325 mg/m² intravenously on days 1 to 5 and days 36 to 40) plus semustine (methyl-CCNU; 150 mg orally on day 1) and 71 patients were assigned to surgery alone. Treatment was repeated every 10 weeks for 2 years.

The patients who received adjuvant chemotherapy showed a significant survival advantage at 5 years. However, two subsequent randomized trials, conducted by the Veterans Administration Surgical Oncology Study Group and Eastern Cooperative Oncology Group, failed to demonstrate a survival advantage for the combination of fluorouracil plus methyl-CCNU.[26,27]

The combination of fluorouracil, Adriamycin (doxorubicin), and mitomycin (FAM) was widely used for the treatment of advanced gastric cancer in the early 1980s. This combination has been studied in the adjuvant setting by the Southwest Oncology Group, European Organization for Research and Treatment of Cancer, and International Collaborative Cancer Group.[28-30] In these studies, observation after surgery was used as the control arm.

None of the trials found a significant improvement in 5-year overall survival with the FAM regimen. A subgroup analysis of the International Collaborative Cancer Group trial showed a survival advantage for patients with T3 and T4 tumors.[30] However, subgroup analyses are unreliable.

Hallissey et al of the British Stomach Cancer Group[31] conducted a three-arm study of adjuvant therapies in which patients were randomly assigned to FAM, radiotherapy, or no further treatment after surgical resection. At 5 years, there were no significant differences in survival among the three groups. Similarly, in another randomized trial, postoperative fluorouracil and doxorubicin (without mitomycin) failed to improve 5-year survival.[32]

Neri et al [33] investigated the combination of fluorouracil, leucovorin (folinic acid), and epirubicin, an anthracycline with less cardiac toxicity than doxorubicin. In a small trial of 103 patients found to have lymph node involvement at resection, 3-year survival rate was better in the chemotherapy group than in control patients who underwent surgery alone (25% vs 13%; P < .01). In this study, 75 mg/m² of epirubicin was administered on day 1, and 200 mg/m²/d of folinic acid and 450 mg/m²/d of fluorouracil were given on days 1 to 3 of a 21-day cycle. Again, the small number of patients limits the strength of these findings.

The British Stomach Cancer Group conducted a three-arm trial designed to assess intensive induction chemotherapy.[34] Patients were randomly assigned to surgery alone or surgery plus chemotherapy. All of the treated patients received fluorouracil plus mitomycin, and one-third also received cyclophosphamide (Cytoxan, Neosar), methotrexate, and vincristine during the first course. No significant differences in 5-year survival were detected among the groups.

Recently, Grau et al from Spain published a trial comparing mitomycin plus ftorafur (tegafur; an oral prodrug of fluorouracil) to mitomycin alone.[35] Between 1985 and 1996, 85 patients were randomly assigned to receive either single-agent mitomycin (10 to 20 mg/m² every 6 weeks) or the same mitomycin dose plus ftorafur (500 mg/m²/d on days 1 to 36). As shown in Table 2, the 5-year survival rate was significantly higher in patients receiving the two-drug regimen than in those given single-agent mitomycin (67% vs 44%; P = .04).

As pointed out by Bleiberg et al,[36] however, this trial can be criticized on several grounds. These include the small number of patients, an 11-year accrual time, and the lack of information about the distribution of important prognostic factors, such as tumor location and histologic type. Also, mitomycin is an inappropriate treatment control.

Mitomycin has also been combined with uracil-tegafur (UFT). Carrato et al[37] randomly assigned 157 patients with stage II and III disease to receive mitomycin (10 mg/m² every 28 days for six doses) plus UFT (300 mg/m²/d orally for 1 year) or surgery alone. After a median follow-up of 3 years, 144 patients were evaluable, and there were no differences in median survival or disease-free survival.

Adjuvant Chemoimmunotherapy

It is hoped that stimulating the immune system will control microscopic carcinoma after a curative resection. Most immunotherapy trials from eastern countries do not include a surgery-alone control group; this complicates the interpretation of their results. In western trials, the addition of immunotherapy to chemotherapy has not been shown to improve survival.

Two immunotherapy agents, levamisole (Ergamisol) and OK-432 (picibanil), have been combined with chemotherapy and studied in randomized trials. Table 3 summarizes the results of these trials.

The Italian Gastrointestinal Tumor Study Group studied the effect of adding levamisole to chemotherapy.[38] A total of 213 patients were randomly assigned to receive either no treatment after surgery; methyl-CCNU and fluorouracil; or methyl-CCNU, fluorouracil, and levamisole. The 5-year survival rate was 50% in all three groups.

In a similar three-arm trial, patients were randomly assigned to receive mitomycin, fluorouracil, and cytarabine; the same three drugs plus picibanil; or no additional treatment after resection. The number of treated patients was small, and no significant survival differences were observed.[9] However, an unplanned subgroup analysis showed a possible benefit of chemotherapy plus picibanil in patients with T2 or T3 cancers.

Adjuvant Chemoradiotherapy

Locoregional recurrence occurs in 41% of patients after curative resection of gastric cancer.[6] Studies of chemoradiotherapy have reported long-term survival in a small percentage of patients with locally advanced disease.[39]

To evaluate the effectiveness of combined-modality treatment in the adjuvant setting, an intergroup trial coordinated by the Southwest Oncology Group (INT 116) compared surgery alone vs surgery followed by chemoradiotherapy. The chemotherapy consisted of fluorouracil and folinic acid; planned radiotherapy was external-beam radiation (45 Gy). Patients randomized to treatment received one course of chemotherapy followed by concurrent chemoradiotherapy and then two additional courses of chemotherapy.

Interim data were reviewed by the trial’s data monitoring committee and the National Cancer Institute; investigators were advised to continue accrual. Accrual was completed in November 1998, with over 600 patients randomized.[personal communication, J. S. MacDonald,MD, November 1998] The results of this trial, which are expected in late 2000, should help define the role of postoperative chemoradiotherapy.

Intraperitoneal Chemotherapy

As the peritoneum and omentum are common sites of metastases in patients with gastric carcinoma, intraperitoneal chemotherapy has been investigated in an attempt to improve locoregional control. Table 4 summarizes selected trials of intraperitoneal chemotherapy.

Schiessel et al conducted a trial of intraperitoneal cisplatin with systemic thiosulfate vs surgery alone. The treatment group did no better than the control group.[40] Sautner et al also studied postoperative intraperitoneal cisplatin.[41] Compared with surgery alone, postoperative intraperitoneal treatment failed to confer a survival advantage. However, these two trials were not true tests of adjuvant intraperitoneal chemotherapy because both in-cluded patients with stage IV or gross residual disease.

In an attempt to develop a method of delivering sustained-release mitomycin intraperitoneally, Hagiwara et al combined this drug with activated charcoal.[42] Patients with gastric carcinomas who were undergoing resection were randomly assigned to receive or not to receive 50 mg of carbon-adsorbed mitomycin intraperitoneally prior to closure of the surgical incision. Although the number of patients in this study was small (24 in the treatment group and 25 in the control group), the 2-year survival rate was significantly higher in the mitomycin group than in the control group (69% vs 27%; P < .005).

The Austrian Working Group for Surgical Oncology performed a study to confirm these promising results.[43] These investigators randomly assigned 91 patients to receive 50 mg of mitomycin bound to a solution of 375 mg of carbon adsorbens or no additional therapy after surgery. The trial had to be closed after a relatively short median follow-up period because of increased postoperative morbidity and mortality in the chemotherapy group without evidence of improved survival.

Yu et al[44] in Korea studied the administration of combination intraperitoneal chemotherapy in the early postoperative period. They randomized 248 patients with clinical stage II or III gastric to receive surgery alone or surgery plus 10 mg/m² of intraperitoneal mitomycin on day 1, followed by 700 mg/m²/d of intraperitoneal fluorouracil on days 2 to 5.

An analysis of 5-year survival rates in the study population as a whole failed to show a significant improvement among patients who received intraperitoneal chemotherapy, compared with those who received surgery alone (39% vs 30%; P = .219). In a subgroup of patients with stage III cancer, a statistically significant difference in 5-year survival rates was noted between the intraperitoneal treatment and control groups (49.1% vs 18.4%; P = .011). Once again, however, analyses of subgroups are difficult to interpret.

At present, early postoperative intraperitoneal chemotherapy cannot be recommended outside of the context of a clinical trial. Better chemotherapeutic agents are needed.

Continuous Hyperthermic Peritoneal Perfusion

Continuous hyperthermic peritoneal perfusion (CHPP) is performed immediately before or after closure of the abdomen during exploratory laparotomy. This technique was designed to favorably alter the distribution and kinetics of agents used in intraperitoneal chemotherapy.[45] During CHPP, a preheated perfusate containing chemotherapeutic agent(s) is used to bath the peritoneal cavity. The intraperitoneal temperature is maintained at a desired level (eg, 42 °C) for about 45 minutes with the use of a heat exchanger and a pump. A number of randomized trials of adjuvant CHPP have been performed in Japan (Table 5).

Hamazoe et al[46] randomly assigned 82 patients to surgery alone or CHPP with 10 µg/mL of mitomycin. No significant difference in 5-year survival was found. However, a trend toward fewer peritoneal recurrences in the CHPP group was observed.

In a larger randomized trial targeting patients with T3 disease, 171 assessable patients received systemic mitomycin and UFT. In addition to this systemic therapy, 78 patients received CHPP with 80 to 100 mg/m² of mitomycin in 8 to 10 L of fluid. The 5-year survival rate did not differ significantly between the groups.[47]

Continuous hyperthermic peritoneal perfusion of the combination of mitomycin and cisplatin also has been studied. Fujimura et al[48] randomly assigned patients to receive CHPP, continuous normothermic peritoneal perfusion (CNPP), or surgery alone. For both CHPP and CNPP, cisplatin (300 mg/kg; 10.1 µg/mL maximal concentration) and mitomycin (30 mg/kg; 1 µg/mL maximal concentration) were administered in 10 L of fluid.

Survival rates at 3 years were 68% in the CHPP group, 51% in the CNPP group, and 23% in the surgery-alone group (P < .01). The small number of patients (18 to 22 patients per treatment arm) in this trial and the lack of supporting data from other trials point to the need for larger confirmatory trials.

Preoperative Therapy

The strategy of administering chemotherapy prior to surgery (ie, preoperative therapy) may allow for downstaging and more frequent R0 resections. Ineffective therapy may be stopped early, thereby minimizing unnecessary toxicity. In trials of preoperative therapy, accurate pretreatment staging with endoscopic ultrasound and laporoscopy is essential, as treatment may downstage the tumor, making valid postoperative comparison of preoperatively treated patients with control groups impossible.

Several phase II studies of preoperative therapy have been conducted in previously untreated patients. Ajani et al reported on separate phase II trials of different regimens. In the first trial, three courses of etoposide, Adriamycin, and Platinol (EAP) were administered before surgery, and two additional courses were given after surgery if the patient responded.[49] In another trial, two courses of etoposide, fluorouracil, and Platinol (EFP) were given before surgery, and three courses were given after surgery.[50] Leichman et al[51] administered the combination of fluorouracil, leucovorin, and cisplatin preoperatively and intraperitoneal floxuridine (FUDR) with systemic cisplatin postoperatively. Kelsen[52] administered three cycles of fluorouracil, Adriamycin, and methotrexate (FAMTX) before surgery; after surgery, patients received intraperitoneal fluorouracil and cisplatin with concurrent systemic fluorouracil.

These trials show that preoperative therapy is feasible. The regimens used have resulted in downstaging, and the rate of R0 resection have been acceptable. The 2-year survival rates in these trials were approximately 40%. A large, multicenter, randomized, phase III trial is needed to define the role of preoperative therapy in gastric cancer.

Current Recommendations

Over the past few decades, numerous trials of adjuvant therapy have been conducted worldwide in an attempt to improve the survival and cure rates of patients undergoing an R0 resection. A few of these trials have shown improvements in survival. However, these trials universally suffer from the problems of small sample size and unplanned subgroup analysis. No adjuvant treatment has definitively shown superiority to observation alone after surgery. Furthermore, side effects and decreased quality of life are common with adjuvant chemotherapy.

In the West, patients who have undergone a curative resection with negative margins and have no evidence of residual disease should be observed or enrolled in clinical trials.[15] This recommendation often is unacceptable in the Orient, where physicians’ philosophies and patients’ expectations differ; as a result, most patients in the East ultimately receive some form of adjuvant therapy.

Future Directions

Success in the field of adjuvant therapy for gastric cancer still eludes us. The strategy of postoperative therapy is sound, but current therapies are ineffective. A similar dilemma plagues the treatment of advanced disease: Median survival of patients with advanced gastric cancer remains below 10 months despite reports of response rates of 40% to 60% with many chemotherapeutic regimens.

The 4- to 6-week delay that often occurs between surgery and the initiation of adjuvant therapy is another disadvantage of this approach. Micrometastases may grow during this interval, and resistant clones may emerge. New agents and new therapeutic approaches are needed.

Patients at high risk of relapse should be encouraged to participate in controlled clinical trials. Adequate sample size and the inclusion of an appropriate control group are essential. The expected absolute risk reduction with adjuvant therapy is small. (If the risk of relapse is 50% and adjuvant therapy reduces this risk by 30%, a 15% benefit will be observed.) In the West, since no adjuvant treatment has proved to be better than surgery alone, patients who receive no therapy after surgery would constitute the proper control group.

Preoperative (neoadjuvant) therapy is another strategy worthy of further investigation. Randomized trials of this approach are needed in the United States. Coupling the use of preoperative therapy with selection of patients based on molecular characteristics of their tumors may give investigators a powerful tool for customizing treatment.

Advances in the development of antiangiogenic agents, matrix metalloproteinase inhibitors, tumor vaccines, and antibody therapy may allow for the use of less toxic therapy during periods when cytotoxic therapy is undesirable. Finally, novel combinations of existing therapeutic modalities will be an area of intense interest in the early 21st century.

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