Adjuvant Therapy for Gastric Carcinoma: Closing out the Century

This article by Yao, Shimada, and Ajani accurately describes the current state of the art of adjuvant therapy for gastric cancer. The authors’ primary conclusion and current recommendations are as follows:

1. No adjuvant treatment has definitively been shown to be superior to observation after surgery.

2. Patients who have undergone a curative surgical resection should be observed or enrolled in clinical trials.

Although concise and well defended, both realities are disappointing, given the intensive effort to improve curative therapy for this disease and the unequivocal benefit of postsurgical adjuvant therapy in other adult solid tumors, such as colon cancer and breast cancer. Yao et al raise several issues of interest that deserve special comment.

Molecular Markers Require Further Study

Genetic abnormalities in gastric cancer cells have been described. Identification of these abnormalities increases the possibility that prognosis could be more precisely defined and response to chemotherapy more accurately predicted. To better understand the biology of gastric cancer, these investigations are of substantial scientific interest and are certainly worthwhile.

The clinical utility of these molecular markers is limited at present, however, for several reasons: Definitive studies demonstrating their value have not been performed; the majority of gastric cancer patients in the United States and Europe have relatively advanced disease (with associated poor prognosis at the time of diagnosis); and currently available chemotherapeutic agents are only marginally effective.

Value of Radical Lymphadenectomy, Regional Adjuvant Approaches

The optimal extent of surgical resection that affords the greatest likelihood of long-term survival for gastric cancer patients has been debated for years. The value of more radical lymphadenectomy has been challenged by a prospective, randomized, landmark trial performed by the Dutch Gastric Cancer Group (see the authors’ reference 18). This trial documented a higher rate of complications, more postoperative deaths, longer hospital stay, and no improvement in 5-year survival in patients subjected to the more aggressive lymphadenectomy.

The authors suggest that radical lymphadenectomy should be considered, if done by an experienced surgeon. In the absence of controlled studies that provide evidence of benefit for radical lymphadenectomy, however, it seems contradictory to recommend this more aggressive (and morbid) procedure, regardless of the surgeon’s experience and technical expertise.

High rates of tumor metastases to regional lymph nodes and the peritoneal cavity have created interest in regional approaches to adjuvant therapy for gastric cancer. However, because hematogenous and lymphatic metastases are frequently present outside these body compartments, the strategies of external-beam radiation therapy and intraperitoneal chemotherapy can be questioned. In the absence of a clinical trial, these strategies should not be used in routine medical practice.

Role of Neoadjuvant Chemotherapy

Ajani et al discuss preoperative (neoadjuvant) chemotherapy as a potentially beneficial strategy in patients with gastric cancer. Although beginning systemic treatment earlier in the course of disease could improve the ability to eradicate micrometastases and downstage the primary tumor (thereby increasing the likelihood of curative surgical resection in some patients), it remains to be determined whether this approach will yield better long-term survival compared to immediate surgery. The eventual key to success may well rest on identifying more effective systemic agents based on a better understanding of the biology of this disease, rather than on determining the optimal sequence of treatment modalities.

East vs West

This article repeatedly stresses the differences in the treatment of gastric cancer in Asia compared to the West (Europe and the United States). There is no doubt that screening has led to the diagnosis of stomach cancer at an earlier stage in Japan, resulting in a much higher surgical cure rate. It is not clear, however, whether differences in the decision to use adjuvant therapy in clinical practice are based on fundamental differences between these populations with respect to the biology of malignant disease and response to therapy, or are simply due to differences in physician philosophy and patient preference.

Need for Novel Approaches

Finally, I agree with the authors’ call for less toxic approaches with novel mechanisms of action for use in gastric cancer patients in the adjuvant setting. Based primarily on preclinical studies, antiangiogenesis therapy, tumor vaccines, monoclonal antibodies, and matrix metalloproteinase inhibitors are all of significant interest. Well-conducted, controlled clinical trials will be necessary to establish whether any of these novel therapies will increase the curability of gastric cancer.