Onkologie 1991:14:13-20
Results of Surgery in Multimodality Therapy of Esophageal Cancer P. Selling
Summary and Key Words
Zusammenfassung und Schlüsselwörter
Results of surgical treatment for squamous cell carcinoma of the esophagus are not satisfactory. The relatively low resectability rate, extensive surgery associated with a relatively high morbidity and mortality as well as the high risk for local recurrence and distant metastases influence the unfavorable prognosis. The improvement of these risk factors has been attempted through multimodality therapy such as preoperative radiotherapy and/or chemotherapy. Even with the advantages of such a treatment plan which was documented in different phase II studies, it has not been possible to prove in ran domized studies its advantage in comparison to immediate surgery. But there is some evidence that multimodality therapy may benefit some patient groups. The definition of these groups has to be the task of future studies. Important selection criteria may be tumor size, tumor localization and response to preoperative chemo- and/or radiotherapy. Before these questions arc answered in further studies, the best treatment for non metastatic localized, esophageal carcinoma is still radical surgical resection.
Die Behandlungsergebnisse operativer Therapie des PlattenepithelKarzinoms der Speiseröhre können nicht befriedigen. Eine relativ geringe Resektabilitiitsrate. die mit dem operativen Eingriff verbun dene. nicht zu vernachlässigende Morbidität und Mortalität, sowie ein hohes Rezidiv- und Metastasierungsrisiko bestimmen die ungünstige Prognose. Diese zu verbessern wird durch multimodales Vorgehen unter Einbeziehung von Radio- und/oder Chemotherapie in den ope rativen Behandlungsplan versucht. Trotz der Vorteile eines solchen Behandlungskonzeptes, wie sie sich aus verschiedenen Phase-II-Studien ergaben, konnte die Überlegenheit einer multimodalen Therapie bei lokalisiertem, nicht metastasiertem Plattenepithel-Karzinom der Speiseröhre in randomisierten Studien bisher nicht eindeutig belegt werden. Es bestehen aber Hinweise, daß bestimmte Patientengrup pen. deren weitere Definition und Absicherung zukünftigen Untersu chungen Vorbehalten bleibt, von einem multimodalen Behandlungs konzept profitieren können. Tumorgröße, Tumorlokalisation und Ansprechen auf eine Vorbehandlung sind hierfür wichtige Kriterien. Bevor diese Fragen in weiteren Studien klar beantwortet sind, bleibt die Standardbehandlung des operablen, nicht metastasierten Oesophagus-Karzinoms nach wie vor die ausschließliche operative The rapie.
Carcinoma o f the esophagus ■Multimodality therapy ■Radiotherapy ■ Chemotherapy
Oesophagus-Karzinom ■Multimodale Therapie Bestrahlung ■Chemo therapie
Introduction
tional lymph nodes is mandatory as well as lymphadenectomy of the epigastrium including the paracardiac and coeliac lymph nodes. This is also the major prerequisite to achieving a reliable pathohistological tumor staging with a relevant prog nostic statement. The role of minimal invasive surgery by which the esophagus can be removed via a special constructed mediastinoscope, must be defined in the future. The mainte nance of food passage is best ensured by forming a gastric tube, preferably by retrosternal lifting of the stomach. Thus, in case of a tumor recurrence at the former site of the esophagus, restenosing of the gastric passage can be avoided and at the same time the conditions for postoperative radiotherapy are more favorable. The collar anastomosis is advantageous because an anastomotic leak can more easily be handled than after an intrathoracic anastomosis. Despite these operative standardizations, the surgical intervention continues to carry a considerable rate of morbidity and mortality in unselected cases, even in specialized centers.
In the past, various attempts have been made to improve the treatment of esophageal cancer. The results, so far, have been disappointing. This is due to the high rate of primarily inopera ble tumors, and the early appearance of local recurrence and distant metastases [5, 6], The extensive surgery required for esophageal cancer carries considerable morbidity and has also to be taken into consideration. New approaches toward im proving therapeutic results have to aim at further standardiza tion of treatment, improvement of surgical risk-assessment and at a combined modality concept.
The Operative Procedures
A standardization of operative techniques in treating esopha geal cancer has largely been achieved. As a rule, this means total esophagectomy. Compared to blunt dissection of the esophagus, transthoracic operation has not only the advantage of being carried out under sight but also permits a clear determination of the operability of the tumor and standardized lymphadenectomy. In this case, posterior mediastinectomy with removal of the paraesophageal, paratracheal and bifurca-
Reduction of the Operative Risk
Since only few patients suffering from esophageal cancer can be cured by surgical measures, the question arises whether
Downloaded by: Nagoya University 133.6.82.173 - 1/11/2019 10:41:34 PM
Section of Surgical Oncology, Department of Surgery, University of Heidelberg
14
Schlag
extensive surgical procedures should be employed in general or whether a more individualized risk-assessment can be car ried out in the treatment. For palliation, the indication for surgery should be made restrictively. A palliative restoration of the food passage may be achieved by nonsurgical, endosco pic or radiotherapeutic procedures as well. Bypass operations are hardly necessary and are nowadays no longer indicated for palliation. However, the palliative esophageal resection may be advantageous for selected patients in good general condi tion. The indication for operation is also critical when the tumor is located in the proximal third of the esophagus and the safe distance obtainable by surgery is insufficient. To ensure this by a more mutilating intervention such as esophagolaryngcctomy is not only critical but even questionable, taking the therapeutic benefit, operative risk and curability into conside ration. Generally, the operative risk and therapeutic benefit have to be weighed carefully even in case of potentially curative resection, because many of the patients are multimorbid. Numerous attempts have been made to improve the surgical criteria for operability. Besides analyzing the nutri tional status of the patient, increasing attention is attached to scores which help to assess the pulmonary and cardiac risk. Our own and others’ practical experiences show, however, that the predictive value of these parameters is still not satis factory [2, 14, 24].
The Concept of Multiiiiodalitv Therapy The concept of multimodal therapy is directed to increase the rate of resectability by a tumor-specific pretreatment and to decrease local or systemic recurrence and therapy, thereby improving the patient’s prognosis. Preoperative treatment procedures mostly used are radio therapy and cytotoxic chemotherapy. Both methods aim at reducing the tumor mass by devitalizing the tumor cells and thus improving the resectability. These methods are also expected to decrease intraopera tive tumor cell propagation. Further, systemic cytostatic treatment has the theoretical advantage that existing micrometastases can be destroyed and the therapeutic efficacy can be measured by the remis sion rate of the primary tumor. This offers the possibility of initiating a more rationale postoperative adjuvant therapy. There are currently four major approaches to the use of combined modality therapy for patients with localized esophageal cancers: Preoperative radiotherapy followed by a planned surgical procedure, preoperative chemotherapy
followed by an operation, or chemo- and radiotherapy with or without an operative treatment. Recent results of these different strategics should be analyzed in the following.
Preoperative Radiotherapy
The major theoretic advantage of radiotherapy before a plan ned surgical procedure is to increase resection rates and to devitalize tumor cells in order to avoid intraoperative tumor cell spillage. We investigated the possibility of preoperative radiotherapy in the treatment of esophageal cancer in the course of an EORTC trial (GI 7062). It was a randomized study in which surgery after preoperative radiotherapy with 32 Gy was compared with surgery alone. The results were recently reported in detail [7], In this multicenter study, about 100 patients were randomly allotted to each individual therapy group. Unfortunately, the preoperative radiotherapy did not as expected - influence the resectability of squamous carci noma of the esophagus. Also the preoperative radiotherapy did not prolong the duration of the disease-free interval nor the survival time of the patients. Only the absence of local recurrences was slightly improved by preoperative radiother apy. Except the EORTC-trial only two other prospective randomized studies involving radiotherapy before surgery have been reported (Table 1). Launois et al. [15] treated 124 patients with either radiation (40 Gy) followed by surgery or surgery alone. There were also no statistical differences in the percentage of patients who underwent surgery. Neither resec tability rate (76% versus 70%) nor the 5 year survival (9.5% versus 11.5%) was influenced by preoperative radiation. On the other hand, Huang [8] treated 160 patients with 40 Gy before surgery or with surgery alone. Five year survival was significantly improved in the radiotherapy-arm (45% versus 25%). But this still remains the only prospective study demon strating a positive effect of preoperative radiation, and should therefore not be recommended at this time as a routine procedure. Perhaps in a group of selected patients with local ized tumors, who respond well to radiation, preoperative radiotherapy may be beneficial. Tumors in the cervical and upper thoracic region, which are better cured by radiation alone are also more amenable to the combined approach.
Table 1: Prospective studies of preoperative radiotherapy in esophageal cancer
Huang(1986)
Gignoux(1987)
Radiation dose (Gy)
r 124
Results of Surgery in Multimodality Therapy of Esophageal Cancer P. Selling
Summary and Key Words
Zusammenfassung und Schlüsselwörter
Results of surgical treatment for squamous cell carcinoma of the esophagus are not satisfactory. The relatively low resectability rate, extensive surgery associated with a relatively high morbidity and mortality as well as the high risk for local recurrence and distant metastases influence the unfavorable prognosis. The improvement of these risk factors has been attempted through multimodality therapy such as preoperative radiotherapy and/or chemotherapy. Even with the advantages of such a treatment plan which was documented in different phase II studies, it has not been possible to prove in ran domized studies its advantage in comparison to immediate surgery. But there is some evidence that multimodality therapy may benefit some patient groups. The definition of these groups has to be the task of future studies. Important selection criteria may be tumor size, tumor localization and response to preoperative chemo- and/or radiotherapy. Before these questions arc answered in further studies, the best treatment for non metastatic localized, esophageal carcinoma is still radical surgical resection.
Die Behandlungsergebnisse operativer Therapie des PlattenepithelKarzinoms der Speiseröhre können nicht befriedigen. Eine relativ geringe Resektabilitiitsrate. die mit dem operativen Eingriff verbun dene. nicht zu vernachlässigende Morbidität und Mortalität, sowie ein hohes Rezidiv- und Metastasierungsrisiko bestimmen die ungünstige Prognose. Diese zu verbessern wird durch multimodales Vorgehen unter Einbeziehung von Radio- und/oder Chemotherapie in den ope rativen Behandlungsplan versucht. Trotz der Vorteile eines solchen Behandlungskonzeptes, wie sie sich aus verschiedenen Phase-II-Studien ergaben, konnte die Überlegenheit einer multimodalen Therapie bei lokalisiertem, nicht metastasiertem Plattenepithel-Karzinom der Speiseröhre in randomisierten Studien bisher nicht eindeutig belegt werden. Es bestehen aber Hinweise, daß bestimmte Patientengrup pen. deren weitere Definition und Absicherung zukünftigen Untersu chungen Vorbehalten bleibt, von einem multimodalen Behandlungs konzept profitieren können. Tumorgröße, Tumorlokalisation und Ansprechen auf eine Vorbehandlung sind hierfür wichtige Kriterien. Bevor diese Fragen in weiteren Studien klar beantwortet sind, bleibt die Standardbehandlung des operablen, nicht metastasierten Oesophagus-Karzinoms nach wie vor die ausschließliche operative The rapie.
Carcinoma o f the esophagus ■Multimodality therapy ■Radiotherapy ■ Chemotherapy
Oesophagus-Karzinom ■Multimodale Therapie Bestrahlung ■Chemo therapie
Introduction
tional lymph nodes is mandatory as well as lymphadenectomy of the epigastrium including the paracardiac and coeliac lymph nodes. This is also the major prerequisite to achieving a reliable pathohistological tumor staging with a relevant prog nostic statement. The role of minimal invasive surgery by which the esophagus can be removed via a special constructed mediastinoscope, must be defined in the future. The mainte nance of food passage is best ensured by forming a gastric tube, preferably by retrosternal lifting of the stomach. Thus, in case of a tumor recurrence at the former site of the esophagus, restenosing of the gastric passage can be avoided and at the same time the conditions for postoperative radiotherapy are more favorable. The collar anastomosis is advantageous because an anastomotic leak can more easily be handled than after an intrathoracic anastomosis. Despite these operative standardizations, the surgical intervention continues to carry a considerable rate of morbidity and mortality in unselected cases, even in specialized centers.
In the past, various attempts have been made to improve the treatment of esophageal cancer. The results, so far, have been disappointing. This is due to the high rate of primarily inopera ble tumors, and the early appearance of local recurrence and distant metastases [5, 6], The extensive surgery required for esophageal cancer carries considerable morbidity and has also to be taken into consideration. New approaches toward im proving therapeutic results have to aim at further standardiza tion of treatment, improvement of surgical risk-assessment and at a combined modality concept.
The Operative Procedures
A standardization of operative techniques in treating esopha geal cancer has largely been achieved. As a rule, this means total esophagectomy. Compared to blunt dissection of the esophagus, transthoracic operation has not only the advantage of being carried out under sight but also permits a clear determination of the operability of the tumor and standardized lymphadenectomy. In this case, posterior mediastinectomy with removal of the paraesophageal, paratracheal and bifurca-
Reduction of the Operative Risk
Since only few patients suffering from esophageal cancer can be cured by surgical measures, the question arises whether
Downloaded by: Nagoya University 133.6.82.173 - 1/11/2019 10:41:34 PM
Section of Surgical Oncology, Department of Surgery, University of Heidelberg
14
Schlag
extensive surgical procedures should be employed in general or whether a more individualized risk-assessment can be car ried out in the treatment. For palliation, the indication for surgery should be made restrictively. A palliative restoration of the food passage may be achieved by nonsurgical, endosco pic or radiotherapeutic procedures as well. Bypass operations are hardly necessary and are nowadays no longer indicated for palliation. However, the palliative esophageal resection may be advantageous for selected patients in good general condi tion. The indication for operation is also critical when the tumor is located in the proximal third of the esophagus and the safe distance obtainable by surgery is insufficient. To ensure this by a more mutilating intervention such as esophagolaryngcctomy is not only critical but even questionable, taking the therapeutic benefit, operative risk and curability into conside ration. Generally, the operative risk and therapeutic benefit have to be weighed carefully even in case of potentially curative resection, because many of the patients are multimorbid. Numerous attempts have been made to improve the surgical criteria for operability. Besides analyzing the nutri tional status of the patient, increasing attention is attached to scores which help to assess the pulmonary and cardiac risk. Our own and others’ practical experiences show, however, that the predictive value of these parameters is still not satis factory [2, 14, 24].
The Concept of Multiiiiodalitv Therapy The concept of multimodal therapy is directed to increase the rate of resectability by a tumor-specific pretreatment and to decrease local or systemic recurrence and therapy, thereby improving the patient’s prognosis. Preoperative treatment procedures mostly used are radio therapy and cytotoxic chemotherapy. Both methods aim at reducing the tumor mass by devitalizing the tumor cells and thus improving the resectability. These methods are also expected to decrease intraopera tive tumor cell propagation. Further, systemic cytostatic treatment has the theoretical advantage that existing micrometastases can be destroyed and the therapeutic efficacy can be measured by the remis sion rate of the primary tumor. This offers the possibility of initiating a more rationale postoperative adjuvant therapy. There are currently four major approaches to the use of combined modality therapy for patients with localized esophageal cancers: Preoperative radiotherapy followed by a planned surgical procedure, preoperative chemotherapy
followed by an operation, or chemo- and radiotherapy with or without an operative treatment. Recent results of these different strategics should be analyzed in the following.
Preoperative Radiotherapy
The major theoretic advantage of radiotherapy before a plan ned surgical procedure is to increase resection rates and to devitalize tumor cells in order to avoid intraoperative tumor cell spillage. We investigated the possibility of preoperative radiotherapy in the treatment of esophageal cancer in the course of an EORTC trial (GI 7062). It was a randomized study in which surgery after preoperative radiotherapy with 32 Gy was compared with surgery alone. The results were recently reported in detail [7], In this multicenter study, about 100 patients were randomly allotted to each individual therapy group. Unfortunately, the preoperative radiotherapy did not as expected - influence the resectability of squamous carci noma of the esophagus. Also the preoperative radiotherapy did not prolong the duration of the disease-free interval nor the survival time of the patients. Only the absence of local recurrences was slightly improved by preoperative radiother apy. Except the EORTC-trial only two other prospective randomized studies involving radiotherapy before surgery have been reported (Table 1). Launois et al. [15] treated 124 patients with either radiation (40 Gy) followed by surgery or surgery alone. There were also no statistical differences in the percentage of patients who underwent surgery. Neither resec tability rate (76% versus 70%) nor the 5 year survival (9.5% versus 11.5%) was influenced by preoperative radiation. On the other hand, Huang [8] treated 160 patients with 40 Gy before surgery or with surgery alone. Five year survival was significantly improved in the radiotherapy-arm (45% versus 25%). But this still remains the only prospective study demon strating a positive effect of preoperative radiation, and should therefore not be recommended at this time as a routine procedure. Perhaps in a group of selected patients with local ized tumors, who respond well to radiation, preoperative radiotherapy may be beneficial. Tumors in the cervical and upper thoracic region, which are better cured by radiation alone are also more amenable to the combined approach.
Table 1: Prospective studies of preoperative radiotherapy in esophageal cancer
Huang(1986)
Gignoux(1987)
Radiation dose (Gy)
r 124
