Commentary (Goldberg/O'Neil): Neoadjuvant Therapy for Gastric Cancer

Because of recent advances in each discipline we commonly recommend and deliver three modalities-chemotherapy, radiation, and surgery-in the management of localized gastrointestinal cancers in patients who are judged to be suitable candidates for aggressive therapy. After years of experimentation and some therapeutic misadventures, combination chemotherapy can now be delivered with greater safety and effectiveness. This is based in part on better antiemetics, better supportive therapies such as judicious use of granulocyte colony-stimulating factors, and more accurate models for adjusting dosages based on pharmacokinetic and pharmacodynamic profiling. The mix of technologic advances coupled with the leavening of clinical experience have made multiagent drug delivery the standard of care. Finetuning of radiation field design using computer modeling to deliver intensity- modulated radiation is a step forward that means less collateral damage to healthy organs bordering a tumor without compromising local control rates. Advances in surgical practices have also positively affected patient outcomes. The pioneers who championed these innovative approaches have made us understand the significance of identification and nerve-sparing, and appreciate the importance of the removal of an intact lymphovascular bundle, as is done with total mesorectal excision during rectal cancer surgery. Mastery of new technologies, such as laparoscopic or robot-assisted techniques, now permits tailored surgical procedures while reducing their morbidity. The ascendance of the multidisciplinary model of care in academic centers and sophisticated community practices has catalyzed the interdigitating of different disciplines to bring all applicable tools to bear on disease management in a coordinated fashion. The explosion of information available through the Internet and advocacy groups now permits patients to identify and travel to centers of excellence, where they can expect state-of-the-art care. Neoadjuvant Chemotherapy and Radiation
For 3 decades the traditional order for multidisciplinary intervention in the setting of locally advanced disease has been surgery first and, based upon the surgically determined stage of disease, postoperative adjuvant chemotherapy to reduce the likelihood of systemic disease, as well as radiation to reduce the likelihood of local recurrence. In the past decade neoadjuvant combinations of chemotherapy and radiation before surgery have been systematically tested and proven to be advantageous in specific circumstances, perhaps most notably in locally advanced breast and rectal cancers. The use of chemotherapy first provides an in vitro human chemosensitivity assay, permitting the assessment of the medical therapy's ability to shrink the breast or rectal mass. Increasingly functional imaging with positron-emission tomography (PET) and PET/computed tomography scans can be used to quantify metabolic alterations in the tumor physiology consequent to therapeutic intervention in ways that are predictive of short-term as well as longterm outcomes in individual patients. Inherent in this approach is the ability to obtain clear surgical margins after chemotherapy and radiation have reduced the size of a tumor, possibly permitting less radical resections. In fact, in the exceptional case of anal carcinoma, the need for radical surgery-the procedure of choice in the era prior to the 1970s-is limited only to patients whose disease recurs after nonsurgical therapy. It is perhaps the success of this approach in anal cancer pioneered at Wayne State University that has led to the interest in applying the tenets of neoadjuvant therapy to more and more disease settings. The issue of whether a lesser operation might be performed in gastric cancer based on response to therapy is an unresolved one. In some ways, gastric cancer is akin to colon cancer in that resection is not generally limited by the boundaries imposed by the anatomic space occupied by the organ. Indeed, in a recent report from The University of Texas M. D. Anderson Cancer Center, neoadjuvant therapy allowed an R0 resection in 78% of patients,[1] which is identical to that achieved in the Dutch Gastric Cancer Group study[2] with no neoadjuvant treatment. In general, neoadjuvant therapy has been attempted after randomized phase III trials have shown the advantages of adjuvant therapy in a particular disease setting. In gastric cancer, the Intergroup trial by Macdonald and colleagues[3] has established a standard of care in gastric cancer for postoperative chemotherapy and radiation, at least in North America. In addition, the Dutch Gastric Cancer Group trial has given us evidence that our patients will not realize a survival advantage from more extensive lymphadenectomy. In this historical setting, Drs. Chadha, Kuvshinoff, and Javle have provided a comprehensive and clearly articulated review of the appropriate literature from around the world that provides the rationale and background for neoadjuvant chemotherapy and radiation in the setting of gastric cancer. While the logic for this approach is clear, the benefits and morbidities are not yet established; the results of the phase III trials in progress that are described in this article are eagerly anticipated. Intraperitoneal Chemotherapy and Intraoperative Radiation
Two points bear further discussion. Intraperitoneal chemotherapy, while under investigation, is a method of administration that many oncologists find too daunting to manage. This is illustrated by the fact that despite randomized data favoring intraperitoneal chemotherapy over intravenous therapy in ovarian cancer, the overwhelming majority of oncologists do not employ this approach. Another potential mechanism by which to maximize local control that the authors did not discuss is intraoperative radiation. While delivery of a single high dose of radiation in the operating room requires either a dedicated machine in the operating suite or patient transport under anesthesia, there are some theoretical reasons to support interdigitation of this technique into the multidisciplinary care plan. Displacement of radiation-sensitive bowel and the use of electrons with high energy but a short activity range permit employment of a targeted additional tool in the setting of close margins. Phase III trials of this technique compared to external-beam radiation alone are lacking to date. Conclusions
There is sound logic to experimenting with delivery of multimodality preoperative therapy. If we can fine-tune our approaches over time, the possibility of curative therapy without radical surgery as is the current standard of care for squamous cell carcinoma of the anus seems possible in this setting as well. Hopefully we can harness the investigative energy generated by the experiences in randomized trials in patients with anal and esophageal cancer to enhance cure rates for patients with gastric cancer using a similar multimodality neoadjuvant approach delivered in the setting of a collaborative interdisciplinary and expert disease management team.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. 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(6):1237- 1244, 2005.
2. Bonnenkamp JJ, Hermans J, Sasako M, et al: Extended lymph node dissection for gastric cancer. N Engl J Med 340:908-914, 1999.
3. Macdonald JS, Smalley S, Benedetti J, et al: Chemotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001.