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Manuel Hidalgo, MD
Malignant tumors of the gastrointestinal tract comprise some of the most common and lethal malignant diseases. For the majority, radical surgical resection represents the only reasonable chance of cure. However, most gastrointestinal tumors present with either locally advanced disease or metastatic disease that is not amenable to radical surgical resection. Over the last decade, an intense clinical research effort has concentrated in the development of combined modality treatment, integrating surgery, radiation therapy, and chemotherapy in the treatment of patients with locally advanced malignant diseases of the gastrointestinal tract. Tuesday's (September 14) symposium focused on recent advances in the multimodality treatment of patients with several gastrointestinal tumors.
Esophageal Cancer
The treatment of choice for patients with squamous cell carcinoma of the esophagus is surgery, provided complete resection can be achieved. However, even in patients in which a complete resection is attained, the incidence of local and distal recurrences is too high. Over the last 10 years, several studies have evaluated the integration of chemotherapy, mainly using cisplatin and 5-fluorouracil, and radiation therapy in the management of patients with esophageal cancer.Dr. Fink from the Klinikum rechts der Isar, Munchen, reviewed data from the most recent clinical trials.[1] The neoadjuvant administration of radiation therapy has not been demonstrated to improve survival versus surgery alone in patients with resectable disease. Similarly, although the administration of presurgical chemotherapy and chemotherapy combined with radiation therapy is feasible and results in a higher number of patients having a complete resection, the results from randomized trials have not consistently demonstrated a survival benefit in patients treated with combined modality approaches versus those treated with surgery alone. Therefore, surgery remains the standard of care in patients with resectable squamous cell carcinoma of the esophagus.
In contrast, in patients with locally advanced disease at diagnosis, the standard treatment today involves administration of chemotherapy followed by chemoradiation. Whether these subjects benefit from surgical resection is still a matter of debate. It is evident from the combined modality trials that only patients who achieve a response after induction chemotherapy and radiation therapy benefit from this approach. The careful selection of patients will certainly spare a substantial number from unnecessary and toxic treatments. Several potential tools to recognize patients who might benefit form induction therapy include the analysis of different markers of response to chemotherapy and the use of newer imaging techniques such as positron emission tomography. For example, patients with high tumor levels of thymidylate synthetase, the enzyme that mediates the action of 5-fluorouracil, have lower response rates to this agent and could be potentially spared form this treatment.
Gastric Cancer
Similar to treatment of other gastrointestinal malignancies, the treatment of choice for patients with local gastric cancer is surgery. However, only patients in whom no residual tumor is left after surgery enjoy prolonged survival. Complete resection is usually achievable in 80% of patients with small tumors (T1-T2), and more than 70% can be cured. Unfortunately, 75% present with locally advanced tumors, and in this subgroup fewer than 50% of patients achieve a complete resection, with only 20%-30% experiencing long term survival.Dr. Wilke from the Kliniken Essen-Mitte, Germany, reviewed the most recent data on gastric cancer treatment. Currently, the most promising multimodality approach in patients with gastric cancer consists of preoperative chemotherapy, particularly in patients with locally advanced disease. A large number of phase II clinical trials have demonstrated this approach to be feasible and to result in a large percentage of patients who achieve complete resection, in the range of 60%-70%. One of the problems with studies performed so far is that the definition of local or locally advanced disease has been made based on clinical data and nonhomogeneous radiological staging and, therefore, the studies are very difficult to compare. In patients with nonresectable disease at laparotomy, it is clear that they should be treated with preoperative chemoradiation in an attempt to make the disease resectable. This is the only chance for prolonging survival.[2]
Pancreatic Cancer
Dr. Wagner from the Inselpital, Switzerland, discussed the current surgical approaches to patients with resectable pancreatic cancer. This patient group, however, represents no more than 20% of patients diagnosed with this disease. It seems that today, the best imaging method for pancreatic cancer staging is abdominal MRI which can delineate patients with vascular or surrounding structures.For patients with resectable disease, the surgical approach of choice today is a pyloro-preserving pancreatoduodenectomy, since this has been shown to have similar efficacy to more radical procedures and to carry fewer postoperative complications. Of interest, patients with more advanced disease that involves the peripancreatic lymph nodes benefit from more aggressive resections. One of the major factors predicting a successful operation is the number of cases performed per year in a given hospital. Patients should ideally be referred to centers with experience in the performance of this operation.
The most appropriated treatment once surgery is completed remains a matter of controversy. While early randomized trials demonstrated a survival benefit from postoperative chemotherapy and radiation therapy, the most recent randomized trials have failed to prove this. It will be interesting to see the results of current trials in which patients with resectable diseases are being treated with preoperative chemoradiation, similar to the studies conducted in patients with esophageal and gastric cancer. In addition, because the great majority of patients present with either locally advanced or metastatic disease, new treatment modalities are urgently needed in these patient subgroups.[3]
Colorectal Carcinoma
A substantial number of studies performed during the last 10 years have established the efficacy of adjuvant chemotherapy in patients with resectable colon cancer. Currently, the most widely used regimen consists of a combination of 5-fluorouracil and leucovorin for 6 months. Most recently, the use of immunotherapy, either as an autologous vaccine or as monoclonal antibodies, have also shown promising results.Dr. Ducreux from the Institute Gustave Roussy, France, presented data on the efficacy of chemotherapy administered as an intrahepatic artery infusion and systemic chemotherapy in patients with completely resected liver metastases. As compared to the standard approach of resection alone, patients with metastatic colon cancer and resectable liver metastases benefit from postoperative chemotherapy. Furthermore, preoperative 5-fluorouracil in combination with leucovorin and oxaliplatin resulted in a significant downstaging of patients with nonoperable colon cancer with liver metastases.[4]
For patients with rectal cancer, the discussion focused on the use of radiation therapy in patients with either resectable or advanced-recurrent rectal cancer. Dr. Pahlman from Uppasala University, Sweden, showed data demonstrating that when radiotherapy is administered in combination with surgery, preoperative radiation therapy achieved better results.[5] However, this study analyzed the role of radiation therapy without the use of chemotherapy. The most widely used adjuvant regimen in patients rectal cancer consists of postoperative chemotherapy and radiotherapy, and therefore, the better results obtained with preoperative radiotherapy will need to be demonstrated in the context of chemoradiation. For patients with tumors that cannot be resected, Dr. Tveit from the Ullevaal University Hospital in Oslo, Norway, discussed the potential therapeutic alternatives, including radiation therapy, intraoperative radiation therapy, surgery, and chemotherapy. In general, these patients should be managed with a combination of preoperative radiation therapy and aggressive surgery. Although the role of chemotherapy is not yet defined for this subset of patients, it is likely that chemotherapy will also contribute to improved results.[6]
Summary - Clinical Implications
- Surgery remains the mainstay of treatment of patients with malignant gastrointestinal tumors
- Patients with locally advanced squamous cell carcinoma of the esophagus benefit from the addition of combined treatment with radiotherapy and chemotherapy
- Patients with pancreatic cancer that has metastasized to peripancreatic lymph nodes benefit from aggressive radical resection
- After liver metastasis resection, patients with colon cancer should receive adjuvant therapy
References
- Fink U. Esophageal cancer-Who benefits from neoadjuvant chemotherapy. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 856.
- Wilke H. Gastric cancer-How to improve results with a multimodality approach. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 857.
- Wagner M, Kulli C, Buchler MW. Pancreatic cancer-Can we do better. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 858.
- Ducreux M. Multimodal treatment in colon cancer: Recent advances and future prospects. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 859.
- Pahlman L. Preoperative radiotherapy is better than postoperative in rectal cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 860.
- Tveit KM. A big bullet for a big tumor?-Locally advanced rectal cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 861.
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