Treatment of Early Stage Stage I Esophageal Cancer

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One of the problems with esophageal cancer has traditionally been the inability to accurately assess the stage preoperatively. Endoscopic ultrasonography, however, has revolutionized our ability to assess depth of penetration and involvement of regional lymph nodes. Additionally, the combination of CT and PET has allowed a more accurate determination of metastatic spread. These noninvasive modalities have allowed us to more accurately stage esophageal cancers before treatment is initiated. They also have increased the confidence level in determining that patients with endoscopic sonographic evidence of early-stage disease and no evidence of metastatic cancer on PET and CT of the chest and abdomen truly have localized cancer. This is important because it allows treatment to be focused on the primary tumor without concern for distant or micro-metastatic cancer. Consequently, patients with early-stage esophageal cancer, as documented by endoscopic ultrasonography, can be treated with esophagectomy for cancers in the middle esophagus (i.e., those occurring between the aortic arch and inferior pulmonary ligament) or lower esophagus (i.e., those occurring between the inferior pulmonary ligament and gastroesophageal junction [GEJ]) or combined chemotherapy and radiation therapy (chemoradiation) for cancers in the upper esophagus (those occurring between the thoracic inlet and aortic arch, <20 cm from the incisors).

At M. D. Anderson, the modality of treatment used in a particular case is determined by the tumor location and the patient's physiologic status (Figures 15-1 and 15-2). Early-stage upper esophageal cancers are treated with chemoradiation because in most cases, surgery requires a laryngectomy. For cases in which the cancer is in the middle or lower esophagus or the GEJ, surgery is typically performed because the morbidity rate is acceptable and a laryngectomy is not required (Figure 15-2). Patients who cannot tolerate surgery, however, are treated with chemoradiation or radiation therapy alone, often with curative results.

The anatomic location of esophageal cancer makes surgical resection a formidable procedure. The esophagus originates at the lower border of the cricoid cartilage and descends into the thorax posterior to the trachea, heart, and great vessels to the esophageal hiatus, where it enters the stomach through the GEJ. The vital structures and posterior location of the esophagus make radical resection of the esophagus difficult. Surgical resection requires several choices, including the type of conduit to be used, the location of the anastomosis, and the anatomic route of the conduit. At M. D. Anderson, resection of the esophagus is approached either transtho-racically from the right chest (Ivor-Lewis resection) or transabdominally (transhiatally) by blunt dissection through the hiatus without a thoracot-omy. After esophageal resection, a conduit or neoesophagus is created out of the stomach (most common), colon, or jejunum, and an anastomosis is

Figure 15-1. Algorithm for treatment of upper esophageal tumors based on physiologic status and clinical stage. PS, performance status; RT, radiation therapy.
Esophageal Cancer Stage Based Treatment
Figure 15-2. Algorithm for treatment of esophageal tumors in the middle or lower esophagus or in the gastroesophageal junction (GEJ) based on physiologic status and clinical stage. PS, performance status; RT, radiation therapy.

created with the residual esophagus in the chest or neck, using a sutured or stapled technique. The conduit is placed in the bed of the resected esophagus (posterior chest), although in some instances, if the esophagus cannot be removed, a substernal or subcutaneous route is chosen.

All esophagectomies begin with a thorough abdominal exploration for evidence of metastases. The most common sites of metastatic esophageal cancer in the abdomen are the liver and nonregional lymph nodes. In cases in which metastatic cancer is identified, surgical resection is not performed because of the short life expectancy associated with metastatic disease. After a complete abdominal exploration, the stomach is mobilized by dividing the gastrocolic ligament, short gastric vessels, and left gastric artery. The vascular supply of the gastric conduit requires that the right gastroepiploic, gastroduodenal, and common hepatic arteries be preserved. A pyloroplasty or pyloromyotomy is performed to avoid gastric stasis that can result from division of the vagus nerves during esophageal transection. Once mobilized, the gastric conduit can easily reach to the neck or chest, as needed, and is vascularly well supplied by blood from the right gastroepiploic artery, which originates from the gastroduodenal and common hepatic arteries. The celiac, perigastric, and periesophageal lymph nodes also are resected and submitted as a separate specimen.

Surgical resection of early-stage esophageal cancers provides a 5-year cure rate of 75% because the cancer is localized to the specific area, with a low likelihood of distant metastatic spread. The operation is complex and associated with high morbidity and mortality rates if performed at a center in which surgeons are inexperienced with the procedure (one study found mortality rates of 20% at low-volume centers vs 2% at high-volume centers [Swisher et al, 2000]). For this reason, if surgical resection is chosen as the treatment modality, it is essential that the operation be performed at a high-volume center that specializes in esophageal resection to minimize the risk of surgery-related morbidity and death.

Many patients with early-stage esophageal cancers have no swallowing disorders before they undergo resection but experience difficulty swallowing after surgery. It is essential to warn patients that they may develop long-term changes in swallowing, with possible dumping syndrome, reflux, and early satiety. These symptoms improve with time but in some cases can persist for a long time.

Patients who have early-stage esophageal cancers located in the upper esophagus require laryngectomy in addition to esophagogastrectomy to attain a complete surgical resection. This disfiguring procedure leaves the patient unable to speak. Furthermore, morbidity and mortality rates (11% to 18%) are significantly higher for these patients than for those who undergo resection of tumors in the body of the esophagus. For these reasons, at M. D. Anderson, patients who have upper esophageal cancer or who cannot tolerate surgical resection are treated with concomitant chemotherapy and radiation therapy rather than surgery (50.4 Gy over 5 weeks; 1.8 Gy/fraction/day, 5 days a week, with concurrent cisplatin and 5-fluorouracil [5-FU]) or are treated with radiation therapy alone (60 Gy over 6 weeks) if they cannot tolerate chemotherapy (Figure 15-1). In cases of early-stage esophageal tumors, chemotherapy serves as a radiosensi-tizing agent to improve local control from radiation therapy. If the patient's physical condition is too weak, however, radiation therapy alone can be administered. Although chemoradiation is better than radiation therapy alone, the latter has a palliative effect and may be considered for some patients.

Treatment of Locoregionally Advanced (Stage II-IVA) Esophageal Cancer

Although early-stage esophageal cancer is curable, most patients present with locoregionally advanced esophageal cancer (TNM classification of T2-4, N1, or M1a). One reason patients present with late-stage esophageal cancer is that the distensibility of the esophagus often prevents symptoms until the tumor is quite large. Usually, obstruction of 70% or more of the esophageal lumen is required before symptoms develop. Because the average size of the tumor at presentation is greater than 4 cm (Swisher et al, 1995) and more than 1 x 109 cells are required to achieve a size of 1 cm, it is clear that locoregionally advanced cancer has already grown for a long time (2 to 12 years) before detection (Mizuno et al, 1984). In many patients with locoregionally advanced cancer, the cancer has already spread beyond regional lymph nodes to distant sites. This was demonstrated in a study from Germany (Thorban et al, 1996) in which investigators who used monoclonal antibodies to epithelial cell-associated antigens detected cancer cells in the bone marrow of more than 40% of patients undergoing esophageal resection for locoregionally advanced esophageal cancer.

Because patients with esophageal cancer so often present with advanced-stage disease, management of esophageal cancer consists of not only attempting to cure the patients but also palliating their symptoms. Symptoms of dysphagia are progressive and if left untreated lead to the inability to handle even oral secretions. These symptoms are attributable to the primary cancer and can be debilitating if not managed aggressively. Therefore, even though many patients have systemic micrometastatic spread at the time of presentation, control of the primary tumor is essential to avoid the significant problems associated with progressive esophageal obstruction. For patients with good performance status, we at M. D. Anderson have focused on an aggressive multidisciplinary approach to maximize the chance of curing the cancer and palliating the symptoms of patients with locoregionally advanced esophageal cancer. The approach in each case is based in part on the tumor location.

Upper esophageal cancers are relatively rare. The histologic subtype in this region is usually squamous cell carcinoma. Surgical resection in this group of patients is associated with increased morbidity, and lymph node involvement is common (Vigneswaran et al, 1994). The cancers can be treated with surgery, chemotherapy, or radiation therapy depending on the clinical disease stage and the patient's status. For patients with locore-gionally advanced cervical esophageal cancers that require laryngectomy in addition to esophagogastrectomy for complete resection, the 2-year survival rate is only 20% even with radical surgery. Because chemoradiation offers similar survival rates without the disability created by radical surgery, concurrent chemotherapy and radiation therapy is used at M. D. Anderson to treat patients with cancer of the cervical esophagus (50.4 Gy over 6 weeks, 1.8 Gy/fraction/day, with concurrent cisplatin and 5-FU) (Figure 15-1).

Locoregionally advanced esophageal cancer in the middle or lower esophagus or the GEJ is treated aggressively at M. D. Anderson, with preoperative chemoradiation and surgical resection, in patients with good performance status (Figure 15-2). Middle esophageal tumors are near the tracheobronchial tree and are associated with direct extension into the membranous portion of the trachea, aorta, or azygos vein. Injury to the posterior membranous wall or mediastinal vessels by blunt dissection during transhiatal resection can lead to catastrophic results (Orringer et al, 1993). Because of these risks, all patients who are considered for surgical resection in this anatomic region should undergo pre-operative bronchoscopy to rule out extension into the tracheobronchial tree. Lower esophageal tumors are most commonly adenocarcinoma and are amenable to surgery, chemotherapy, and radiation therapy. The presence of large celiac lymph nodes is associated with decreased overall survival rates.

The treatment of locoregionally advanced esophageal cancers with surgery alone or chemoradiation alone is associated with a 5-year survival rate of only 20%. This is due in large part to locoregional and distant recurrences from microscopic disease remaining at the completion of therapy. In attempts to improve these outcomes, investigational therapies at our institution have involved the combination of all 3 modalities, with neoadjuvant (preoperative) concurrent chemotherapy and radiation therapy followed by surgery (50.4 Gy over 6 weeks, 1.8 Gy/fraction/day with concurrent cisplatin and 5-FU). Postoperative chemotherapy and radiation therapy regimens have been poorly tolerated compared with preoperative regimens and have shown no survival advantages over surgery alone (Ajani et al, 1990). At M. D. Anderson, we therefore have focused on neoadjuvant chemotherapy and radiation therapy. These aggressive approaches have resulted in the pathologic downstaging of disease in a subset of patients with locoregionally advanced esophageal carcinoma. Careful coordination of gastrointestinal oncology care, radiation therapy, and surgery have led to low treatment-related morbidity rates.

Our studies have confirmed that the subset of patients with the best outcomes comprises patients who have a pathologic complete response to neoadjuvant therapy (Swisher et al, 1996). In an attempt to increase the number of patients who respond to neoadjuvant therapy, at M. D. Anderson, we have evaluated the role of additional paclitaxel- or irinote-can-based chemotherapy administered prior to concurrent chemoradia-tion and surgery (Ajani et al, 2001). This novel 3-step approach allows additional chemotherapy to be given without dose-limiting chemoradia-tion toxicity. A preliminary review of this 3-step approach has demonstrated an encouraging overall survival rate, which was higher than expected (3-year survival rate, 65%). This is especially encouraging because these results were obtained with a low morbidity rate in a population in which 87% of patients were shown by endoscopic ultrasonogra-phy to have advanced tumor extending through the esophageal wall (T classification of T3). Whether these encouraging results can be repeated at centers whose surgeons are less experienced with esophageal cancer remains to be determined.

The treatment of locoregionally advanced esophageal cancers in patients with poor performance status, regardless of the esophageal location of the cancer, is less encouraging because aggressive multimodality approaches are often associated with much higher treatment-related morbidity and mortality rates. Patients who are physiologically unfit for surgery often cannot tolerate aggressive chemoradiation regimens either. Alternative treatment modalities focus on palliation (usually of dyspha-gia) as their main goal. The prognosis in cases of esophageal cancer treated with radiation therapy alone is poor (Okawa et al, 1989). Nevertheless, significant palliation can be achieved in a large number of patients. At the University of California at San Francisco, the symptoms of 60% of patients improved for longer than 2 months (Wara et al, 1976). In these critically ill patients, 2 months of palliation may be all that is required. The addition of other modalities, such as intraluminal brachytherapy, laser therapy, and endoesophageal stent placement, can offer additional help (Simsek et al, 1996). If treatment worsens the quality of life, it should be abandoned in favor of a completely palliative approach focusing on alleviation of dys-phagia and pain. Some patients with poor physiologic status cannot tolerate concurrent chemoradiation and should be treated with palliative radiation therapy with or without endoscopic stent placement. Our current chemoradiation regimens are often not selective enough for the tumor and many times cannot be tolerated by patients with poor performance status.

Treatment of Metastatic (Stage IVB) Esophageal Cancer

Noninvasive studies are quite helpful in identifying patients with meta-static disease. At presentation, 25% of patients with esophageal cancer have metastatic cancer. At autopsy, the most frequent locations of metastatic cancer, in decreasing order of incidence, are the lymph nodes (73%), lung (52%), liver (42%), adrenal glands (20%), bronchus (17%), and bone (14%) (Anderson and Lad, 1982). The presence of metastatic cancer is the worst prognostic factor in terms of long-term survival (Table 15-1). The median survival time of patients with metastatic esophageal cancer is less than 7 months. Because of this short survival, surgical resection is seldom performed, even for palliative purposes, in patients with metastat-ic cancer.

Metastatic esophageal cancer (M classification of M1b) is seldom cured, although systemic treatment with chemotherapy may allow some palliative and short-term survival benefits and should be considered for patients with good performance status (Figures 15-1 and 15-2). Patients whose disease is symptomatic may also require palliative treatment for the primary tumor. Palliation can be accomplished with radiation therapy, endoscopic stent placement, or both in most patients (Raijman et al, 1998). Advances in chemotherapy, radiation therapy, and endoscopic stents have allowed palliation of obstruction without the need to resort to surgical bypass. These advances have allowed improvements in the quality of life for patients with metastatic esophageal cancer, although long-term survival rates have not been markedly changed.

Metastatic esophageal cancer that is symptomatic (i.e., obstruction) can be treated with radiation therapy alone (30 Gy over 2 weeks) or in combination with chemotherapy. The placement of expandable metal stents with Silastic coverings can also palliate dysphagia in patients with metastatic esophageal cancer (Raijman et al, 1998). The endoscope is used to localize the obstructing tumor. A contrast agent is then injected sub-mucosally to delineate the cephalad and caudad extension of cancer, and a wire is passed through the obstruction under direct endoscopic observation. The esophagoscope is then removed, and an expandable wire stent (diameter, 18 mm; length, 10 or 15 cm) with Silastic covering is placed under fluoroscopic guidance. Expandable metal stents with Silastic coverings can also be used to palliate tracheoesophageal fistulas and avoid the need for high-risk surgery in patients with a limited life expectancy.

Asymptomatic metastatic esophageal cancer in patients with good performance status can be treated with chemotherapy alone. A standard regimen given at M. D. Anderson is cisplatin 100 mg/m2 intravenous piggyback (IVPB) over 1 to 3 hours on day 1 and 5-FU 1,000 mg/m2/day administered by continuous infusion on days 1 to 5. The cycle is repeated every 4 weeks, and response is evaluated after 2 cycles. An alternative regimen is cisplatin 15 mg/m2/day IVPB over 1 hour on days 1 to 5, 5-FU 750 mg/m2/day as a continuous infusion on days 1 to 5, and paclitaxel 175mg/m2 IVPB over 3 hours. This alternative regimen is repeated every 4 weeks and can be evaluated for response after 2 cycles. In both of these strategies, the emphasis is on palliation, and a lack of response or worsening physiologic status is a reason to stop therapy. Other supportive agents to consider are agents that stimulate erythropoiesis and granulopoiesis.

Conclusions

Even though the overall survival rates are still low for patients with esophageal cancer, significant improvements have been made in reducing the morbidity and mortality rates associated with treatment. Treatment should be tailored to the anatomic site of the cancer, clinical stage, and the patient's physiologic status. Early-stage esophageal cancer can be cured in a large percentage of patients with surgery alone or with chemoradiation in those unable to tolerate surgery. Locoregionally advanced esophageal

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