Bethesda Handbook of Clinical Oncology, 2nd Edition

Digestive System

4

Esophageal Cancer

Gregory D. Leonard*

David P. Kelsen^†

Carmen J. Allegra^‡

*The Royal College of Physicians, Dublin, Ireland

^†Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York

^‡Network for Medical Communication and Research, Atlanta, Georgia

Esophageal cancer is the ninth most commonly occurring cancer worldwide and the sixth most common cause of cancer mortality (1). It is highly curable in its earliest stages; however, it usually presents in the advanced disease. Despite the last two decades of progress in clinical research, the median survival time for a patient with symptoms of a primary esophageal cancer is less than 18 months. Most research and controversy in the treatment of esophageal cancer currently focuses on the role of chemoradiotherapy as either adjuvant or as primary therapy for esophageal cancer.

EPIDEMIOLOGY

United States:

• Esophageal cancer was estimated to account for 1% of all malignancies and 6% of all gastrointestinal malignancies in 2003 (2). The age-adjusted incidence from 1996 to 2000 is 4.5 cases per 100,000 population (http://www.seer.cancer.gov/csr/1975_2000/).
• Approximately 13,900 new cases and 13,000 deaths were estimated for 2003.
• The median age at diagnosis is 67 years. This cancer rarely occurs in patients younger than 25 years.
• Esophageal cancer is two to four times more frequent in men than in women. Siewert type 1 tumors [adenocarcinoma (ADC)] are eight to nine times more common in men than in women.
• Rates of occurrence of esophageal cancer are approximately threefold higher among blacks than among whites.
• Squamous cell carcinoma (SCC) is more common in black men; ADC is more common in white men.
• Five-year relative survival rates were 5% from 1974 to 1976 and 13% from 1992 to 1998.

Rest of the world:

• There are approximately 500,000 cases of esophageal cancer in the world, but there is marked geographic variation. Regions with clusters of high rates include China (e.g., Linxian), Iran, France, and South Africa.
• In the 1970s, approximately 90% of esophageal cancers were SCCs. The incidence of ADCs has increased dramatically and currently accounts for approximately 60% to 70% of new cases—a rate of acceleration greater than that of any other cancer in the United States.

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ETIOLOGY

Adenocarcinoma

• Barrett esophagus
• Obesity
• Gastroesophageal reflux disease (GERD), which can be caused by obesity and might result in Barrett esophagus.

Squamous Cell Carcinoma

• Tobacco
• Alcohol
• Predisposing conditions:
• Tylosis (SCC)
• Achalasia
• Esophageal diverticula and webs (SCC)
• Plummer–Vinson syndrome
• Human papillomavirus (HPV)
• Celiac disease
• Less significant causes include environmental exposure and dietary factor.

BARRETT ESOPHAGUS

Barrett esophagus, perhaps as a result of GERD, is the most important risk factor (100 times risk increase over other factors) for ADC.

Screening recommendations (no randomized trial data for surveillance practices) are as follows:

• For no dysplasia, endoscopy every 2 to 3 years
• For low-grade dysplasia, endoscopy every 6 months for 12 months and then yearly
• For high-grade dysplasia, esophagectomy or three monthly endoscopies or photodynamic therapy (PDT).

CLINICAL PRESENTATION

The most common clinical presentations of esophageal cancer are listed in Table 4.1 and are usually related to local compression or infiltration symptoms or generalized malaise and anorexia.

TABLE 4.1. Clinical presentation of esophageal cancer

Symptoms Patients with symptoms (%) Dysphagia (solids usually before liquids) 80–96 Weight loss 42–46 Odynophagia    ≤50 Epigastric or retrosternal pain    ≤20 Cough or hoarseness    ≤5 Tracheoesophageal fistula    1–13

The classic triad for presentation of esophageal cancer is as follows:

• Asthenia
• Anorexia
• Analgesia (for dysphagia).

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DIAGNOSIS

• Symptoms
• Dysphagia or odynophagia
• Hematemesis
• Dyspepsia
• Hoarseness
• Dyspnea
• Anorexia.
• Signs (usually late presentation)
• Horner syndrome
• Left supraclavicular lymphadenopathy (Virchow node)
• Cachexia
• Hepatomegaly
• Bone metastases (rare but paraneoplastic hypercalcemia can occur).
• Upper gastrointestinal endoscopy
• This diagnostic procedure is the gold standard. The combination of endoscopic biopsies and brush cytology has an accuracy of greater than 90% in making a tissue diagnosis of esophageal cancer.
• Barium contrast radiography
• This diagnostic procedure can document contour and motility abnormalities and unexpected airway fistula and may be useful when the entire esophagus has not been visualized endoscopically. However, a tissue diagnosis is needed for definitive diagnosis.

PATHOLOGY

• Most newly diagnosed patients have ADC, but there are contrasting reports on their relative prognosis. Less than 1% of esophageal tumors are lymphoma, melanoma, carcinosarcoma, or small cell carcinoma.
• Fifty percent of tumors arise in the lower one-third of the esophagus, 25% arise in the upper esophagus, and 25% of tumors occur in the middle one-third of the esophagus (2).

STAGING

The American Joint Commission for Cancer (AJCC) has designated staging of cancer by TNM classification, which defines the anatomic extent of disease (3) (see Table 4.2). Of note, cervical adenopathy in tumors in the lower one-third of esophagus is M1 as opposed to N1.

TABLE 4.2. Definition of TNM and stage grouping

TNM stage: Primary tumor (T) Distant metastasis (M)    TX: Primary tumor cannot be assessed    T0: No evidence of primary tumor    Tis: Carcinoma in situ    T1: Tumor invades lamina propria or submucosa    T2: Tumor invades muscularis propria    T3: Tumor invades adventitia    T4: Tumor invades adjacent structures    MX: Distant metastasis cannot be assessed    M0: No distant metastasis    M1: Distant metastasis    Tumors of the lower thoracic esophagus    M1a: Metastasis in celiac lymph nodes    M1b: Other distant metastasis    Tumors of the midthoracic esophagus    M1a: Not applicable    M1b: Other distant metastasis    Tumors of the upper thoracic esophagus    M1a: Metastasis in cervical nodes    M1b: Other distant metastasis Regional lymph nodes (N)    N1: Regional lymph node metastasis    NX: Regional lymph nodes cannot be assessed    N0: No regional lymph node metastasis Stage Grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IIA T2 N0 M0   T3 N0 M0 Stage IIB T1 N1 M0   T2 N1 M0 Stage III T3 N1 M0   T4 Any N M0 Stage IV Any T Any N M1 Stage IVA Any T Any N M1a Stage IVB Any T Any N M1b

The Siewert classification subclassifies gastroesophageal junction tumors into three types according to their anatomic location: Type 1 are distal esophagus tumors, type II are cardia tumors, and type III are subcardia gastric tumors (4).

Staging work-up can include the following:

• Computerized tomography scan (CT) scan:CT scan of the chest and abdomen can demonstrate evidence of spread of tumor to lymph nodes or distant metastases to the liver (35%), lungs (20%), bone (9%), and adrenals (5%). CT scan may underestimate the depth of tumor invasion and peri-esophageal lymph node involvement in up to 50% of cases. Magnetic resonance imaging (MRI) provides similar results to CT.
• Endoscopic ultrasound (EUS):EUS may be helpful when metastases are not detected by CT or other imaging modalities. EUS is the optimal technique for locoregional staging. A meta-analysis demonstrated greater than 71% sensitivity in staging preoperative depth of invasion (T) and greater than 60% sensitivity for locoregional lymph nodes (N); specificity was greater than 67% and greater than 40%, respectively (5).

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• Positron emission tomography (PET):PET is useful when CT is negative for metastatic disease, and the diagnosis can change management of cancer in 20% to 25% of patients (6). Bronchoscopy is required in tumors less than 25 to 26 mm from the incisors, to exclude invasion of the posterior membranous trachea or tracheoesophageal fistula.

TREATMENT

Surgery

• Surgery alone remains a standard treatment for esophageal cancer with resectable local or locoregional disease. In 1993, surgery was used as a component of treatment in 34% of patients. Surgery alone was used in 18% of patients (7).
• Recent improvements in staging techniques and patient selection have improved surgical morbidity and mortality. Operative mortality rates are now less than 5%. Surgical expertise is a major contributor to survival, with better outcomes in high-volume centers. Resection is possible in approximately 50% of patients (8). Five-year survival in patients with surgical resection is 5% to 25%.
• Surgical principles include a wide resection of the primary tumor by aiming for an R0 resection (no residual tumor), including more than 5-cm resection margins plus regional lymphadenectomy. Intraoperative frozen section can assess for residual disease, which, if present, is considered an R1 (microscopic tumor) or R2 (macroscopic tumor) resection.
• In general, patients with cervical carcinoma of the esophagus are not considered candidates for surgical resection; chemoradiation is favored in these patients.

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• Surgical approaches include the following:
• Transthoracic resection:En bloc esophagectomy requires laparotomy and thoracotomy, for example, total thoracic or transthoracic (Lewis) procedures. A three-field lymph node dissection (extended lymphadenectomy) includes superior mediastinum and cervical lymphadenectomy. It is the treatment of choice in Japan but is associated with increased toxicity and has a questionable survival advantage.
• Transhiatal esophagectomy:This includes laparotomy and cervical anastomosis. This technique avoids thoracotomy.

Chemoradiotherapy (Combined-modality Approach)

Although no large prospective randomized trials have directly compared primary chemoradiation with surgery, definitive chemoradiation for locoregional carcinoma of the esophagus is considered to be an alternative to surgery.

• Interest in chemoradiotherapy is based on the Radiation Therapy Oncology Group (RTOG) 85-01 trial (9) that demonstrated a survival advantage (14 versus 9 months median survival and 27% versus 0% 5-year survival) in favor of chemoradiotherapy over radiotherapy alone in inoperable patients (see Table 4.3). A number of randomized trials of chemoradiotherapy versus radiotherapy alone have failed to duplicate the results of RTOG 85-01; however, a recent Cochrane review has confirmed the superiority of chemoradiotherapy versus radiotherapy in fit, motivated patients (10).
• Chemoradiotherapy is now the standard of care for patients with unresectable esophageal cancer or an alternative to surgery for patients with resectable cancers.

TABLE 4.3. Radiation Therapy Oncology Group (RTOG) 85-01 trial of chemoradiotherapy versus radiotherapy alone in esophageal cancer

Number of patients Histology Treatment Median survival 5-Year survival p-value SCC, squamous cell carcinoma; ADC, adenocarcinoma; 5-FU, 5-fluorouracil; Gy, Gray of radiation; fx, fraction of radiation. From Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA 1999;281:1623–1627, with permission. 121 SCC = 88% ADC = 12% Cisplatin 75 mg/m2 d 1 5-FU 1,000 mg/m2/d d 1–4 50 Gy of radiation wk 1, 5 Cisplatin/5-FU wk 8, 11 versus 64 Gy of radiation 2Gy/fx 14.1 mo vs. 9.3 mo 27% vs. 0% 0.0001

Chemoradiotherapy as Definitive Therapy in Resectable Cancer

Upper thoracic esophageal (above the aortic arch) tumors and T4 or N1 tumors are usually considered unresectable.

• The outcomes of chemoradiotherapy in RTOG 85-01 were comparable to those found in surgical therapy (11). Results from the randomized trials of preoperative chemoradiotherapy have demonstrated pathological complete response rates of greater than 25% and are associated with an improved survival.
• Trials that used surgery after chemoradiotherapy in patients who responded and higher doses of radiation for patients who did not respond failed to show a benefit for the group receiving surgery.

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• A better determinant of the role of surgery after chemoradiotherapy is evident from two recent trials:
• In the first trial, patients with locally advanced but resectable tumors were treated with chemoradiotherapy, and patients with at least a partial response were randomized to continued chemoradiotherapy or surgery (12). There was no difference in overall survival (19.3 versus 17.7 months, respectively), but early mortality and duration of hospital stay were less in the chemoradiotherapy-only arm.
• The second trial randomized patients with locally advanced tumors to either definitive chemoradiotherapy or chemoradiotherapy (lower doses of radiation) and surgery (13). There was no significant difference in survival outcomes (15 versus 16 months, respectively) between the two groups of patients. There was improved survival in a subgroup of patients receiving surgery because they did not respond to chemoradiotherapy.
• No prospective randomized trial has compared chemoradiation to surgery alone in resectable tumors.
• Local recurrence rates, however, remain greater than 45%.
• Radiation dose escalation has not proved to be beneficial. A recent trial examining this approach was closed after an interim analysis indicated that there would be no advantage with higher doses of radiation.

Preoperative Chemoradiotherapy (Trimodality Approach)

• The rationale for preoperative chemoradiotherapy was first studied by Leichman et al. in 21 patients with SCC. Patients were treated with 3,000 cGy of radiation and with two cycles of concurrent 5-fluorouracil (5-FU) and cisplatin (14). An additional 2,000 cGy of radiation was given postoperatively when residual tumor was seen at surgery. The pathologically complete response was 37% with a median survival of 18 months.
• Eight prospective randomized phase III trials (two reported in abstract form) have addressed the issue of whether preoperative chemoradiotherapy offers any benefit over surgery alone (11). Much debate exists about the interpretation of these trials (see Table 4.4). Only Walsh et al. have demonstrated significant benefits in median survival (16 versus 11 months; p= 0.01) and 3-year survival (32% versus 6%; p = 0.01) of patients receiving preoperative chemoradiotherapy (15). However, limitations of this trial include poor surgical outcome, small numbers of patients studied, and the fact that all patients had ADC.

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• Other trials failed to duplicate these results, although many showed nonsignificant median survival benefits, disease-free survival benefits, and, overall, showed a trend toward an improvement in outcome when preoperative chemoradiotherapy was added.
• Use of new chemotherapeutic agents such as paclitaxel and irinotecan have shown promise.

TABLE 4.4. Randomized phase III trials of trimodality therapy compared to surgery

Study Number of evaluable patients Histology 3-Year survival trimodality therapy vs. surgery SCC, squamous cell carcinoma; ADC, adenocarcinoma; NA, not available. a 2 × 2 factorial design; b 5-year survival; c median follow-up of 55 mo; d median survival. Nygaard (16) 88 SCC 17% vs. 9%a Apintop (17) 69 SCC 24% vs. 10%b Le Prise (18) 86 SCC 19% vs. 14% Walsh (15) 113 ADC 32% vs. 6% Bosset (19) 282 SCC 30% vs. 31%c Urba (20) 100 SCC 25% ADC 75% 30% vs. 16% Burmeister (21) 505 SCC 29% ADC 61% 21.7 mo vs. 18.5 mod Lee (22) 102 NA 28.2 mo vs. 27.3 mod

Postoperative Chemoradiotherapy

• There are fewdata on the use of postoperative chemoradiotherapy in esophageal cancer.
• A recent trial found a statistically significant survival advantage for postoperative chemoradiotherapy compared to surgery alone in gastroesophageal and gastric cancers (see Table 4.5) (23). On the basis of these data, adjuvant chemoradiotherapy has been recommended for ADC tumors of the lower esophagus. It is possible that the survival benefit associated with the use of chemoradiotherapy results from reductions in local recurrences and thus compensates for inadequate surgery (only 10% of patients had the recommended D2 resection).

TABLE 4.5. Intergroup-116 trial of adjuvant chemoradiotherapy versus surgery alone in gastric or gastroesophageal adenocarcinomas

Number of patients Surgery Treatment Median survival 3-Year survival p-value 5-FU, 5-fluorouracil; LV, leucovorin. a Two further courses of chemotherapy were given 1 mo apart after radiation. Additional 5-FU 400 mg/m2 and LV 20 mg/m2 were given on the first 4 d and the last 3 d of radiotherapy. 556 D0 54% Surgery followed by 36 mo 50% 0.005 D1 36% 5-FU 425 mg/m2/d d 1–5 vs. vs. D2 10% LV 20 mg/m2/d d 1–5a 27 mths 41% 4,500 cGy radiation d28,180 cGy/d 5 d/wk for 5 wk vs. surgery alone

Radiation Therapy

• Radiation therapy alone is generally considered palliative and is used in patients who are unable to tolerate chemoradiotherapy.

Preoperative Radiotherapy:

• No randomized trials of preoperative single-modality radiotherapy have demonstrated a survival benefit in patients.

Postoperative Radiotherapy:

• Similarly, there is no benefit of single-modality postoperative radiotherapy in patients.

Chemotherapy

• Single-agent chemotherapy demonstrates response rates of 15% to 25%. Combination chemotherapy response rates are 25% to 45%, but this has not definitively improved survival in advanced disease states.
• Cisplatin with 5-FU is the most frequently used regimen for both combined-modality therapy in locoregional disease and systemic therapy for palliation.
• SCC may be more sensitive to chemotherapy, but there is no difference in long-term outcome between SCC and ADC.
• New chemotherapeutic agents have demonstrated encouraging response rates (see Table 4.6).

TABLE 4.6. New Chemotherapeutic Agents in Esophageal Cancer

Chemotherapy Dose ranges Combination chemotherapy Response rates (%) 5-FU, 5-fluorouracil. a Some trials included radiation therapy. Paclitaxel 50–200 mg/m2 Cisplatin 26–100a Carboplatin Etoposide Docetaxel 60–100 mg/m2 Cisplatin 18–24 5-FU Irinotecan 65–125 mg/m2 Cisplatin 22–58 5-FU Oxaliplatin 85–130 mg/m2 5-FU 48–81 Epirubicin Capecitabine Capecitabine 1,000–1,250 mg/m2 Epirubicin 54 5-FU Cisplatin Oxaliplatin

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Preoperative (Neoadjuvant) Chemotherapy

• The poor survival, even for patients with clinically localized carcinoma of the esophagus, suggests that occult metastases are present at diagnosis, thereby providing the impetus to add systemic therapy early during patient management.
• In the two largest trials examining preoperative chemotherapy, the Intergroup (INT 0113) trial (24) showed no survival benefit, whereas the Medical Research Council (MRC) trial (25) demonstrated a 3-month median survival advantage for chemotherapy over surgery alone (see Table 4.7). The following differences in the two studies may have contributed to their different outcomes:
• Chemotherapy was of longer duration and was with higher doses in INT 0113. This therapy may have been detrimental by delaying access to surgery and causing more toxicity.
• Surgery was performed in only 80% of the patients in the chemotherapy arm in INT 0113 compared to 92% in the MRC trial. Outcome for surgery alone was poor in the MRC trial, thereby possibly exaggerating the benefits of chemotherapy.
• Radiation therapy off protocol (equally distributed between treatment arms) was available in the MRC trial.
• A larger sample size in the MRC trial may have facilitated detection of a statistically significant result.

TABLE 4.7. Comparison of the Two Largest Preoperative Chemotherapy Trials

Intergroup 0113 Medical Research Council (MRC) ADC, adenocarcinoma; SCC, squamous cell carcinoma; CT, chemotherapy; 5-FU, 5-fluorouracil. Patient number 467 802 Histology ADC = 54%, SCC = 46% ADC = 66%, SCC = 31% Treatment Cisplatin 100 mg/m2 D1 Cisplatin 80 mg/m2 D1 5-FU 1,000 mg/m2/d d 1–5 5-FU 1,000 mg/m2/d d 1–4 for q4wk × 3 followed by surgery vs. surgery alone For q3wk × 2 followed by surgery vs. surgery alone Postoperative CT to patients with stable disease or response to preoperative CT Three further cycles but with cisplatin 75 mg/m2 Resectability 80% CT + surgery 92% CT + surgery 96% surgery alone 97% surgery alone Median survival 14.9 mo CT + surgery 16.8 mo CT + surgery 16.1 mo surgery alone 13.3 mo surgery alone

Postoperative Chemotherapy

• Most trials of postoperative chemotherapy also involved preoperative chemotherapy.
• As with preoperative chemotherapy, there is renewed interest in this approach on the basis of the MRC data, although it has yet to be adopted as a standard approach
• A recent trial assessed the use of perioperative epirubicin, cisplatin, and 5-FU (ECF) chemotherapy or surgery alone in esophagogastric cancer. In 503 patients, 15% had esophagogastric cancer and 11% had esophageal cancer. Adjuvant chemotherapy increased progression-free survival and resectability rates and showed a trend toward improved survival (p= 0.06) (26).

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Palliation

• Palliative options can be split into local or systemic options.
• Local therapies include external beam and brachytherapy radiation. This approach can palliate dysphagia in approximately 80% of patients. PDT has also been approved by the U. S. Food and Drug Administration (FDA) for this indication. For rapid palliation, laser or balloon dilatation and stenting is recommended. The placement of a gastrostomy or jejunostomy tube may improve the patient's nutritional status.
• The systemic chemotherapy options in esophageal cancer are improving (Table 4.6). However, no trial has identified a reference regimen specific to esophageal cancer.
• Cisplatin combined with 5-FU is the most commonly used regimen, but this did not demonstrate a statistically significant benefit over cisplatin alone when tested in a randomized trial of patients with advanced SCC of the esophagus (27).
• Most data on chemotherapy in advanced esophageal cancer are extrapolated from trials in gastric cancer that often include gastroesophageal tumors. In Europe, ECF is frequently used because of its superior survival compared to 5-FU, doxorubicin, and methotrexate (FAMTX) in advanced esophagogastric cancer (28).
• A recent trial in metastatic or unresectable gastric and gastroesophageal cancer evaluated docetaxel, cisplatin, and 5-FU (DCF) and cisplatin and 5-fluorouracil (CF). Time to disease progression improved from 3.7 months to 5.2 months (hazard ratio 1.704), and median overall survival improved from 8.5 months to 10.2 months (p= 0.0053) in patients receiving DCF compared to those receiving CF (29).

DISTRIBUTION, TREATMENT, AND SURVIVAL FOR ESOPHAGEAL CANCER BY STAGE IN THE UNITED STATES

The distribution, treatment, and survival in patients with esophageal cancer according to stage in the United States are given in Table 4.8.

TABLE 4.8. Stage, Distribution, Treatment and Survival of Esophageal Cancers in the United States

Stage Distribution (%) Treatment 5-Year relative survival rates (%) ADC, adenocarcinoma; GE, gastroesophageal; 5-FU, 5-fluorouracil. Localized (I + II) 25 Surgery 27 Chemoradiotherapy if surgery not possible Adjuvant chemoradiotherapy indicated for GE or lower esophageal ADC tumors Regional (III) 28 Surgery if possible (e.g., T3 N0 lesions) 13 Definitive chemoradiotherapy Neoadjuvant chemoradiotherapy followed by surgery Adjuvant chemoradiotherapy indicated for GE or lower esophageal ADC tumors Distant (IV) 25 Best supportive care/palliation 2 Local: Radiation therapy or brachytherapy Intraluminal intubation or dilatation Laser or endocoagulation Photodynamic therapy Chemotherapy: Cisplatin 100 mg/m2 i.v. d 1 q21d 5-FU 1,000 mg/m2 i.v. d 1–5 continuous q21d treatment until progression or intolerable toxicity Or Epirubicin 50 mg/m2 i.v. d 1 q21d Cisplatin 60 mg/m2 i.v. d 1 q21d 5-FU 200 mg/m2/d i.v. continuous infusion treatment for maximum of 6 mo

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FOLLOW-UP FOR PATIENTS WITH LOCOREGIONAL DISEASE

There is no standard surveillance scheme.

• History and physical examination, complete blood count (CBC), urea, electrolytes, and liver function tests are recommended every 4 months for 1 year, every 6 months for 2 years, and then annually (http://www.nccn.org).
• Chest radiograph should be obtained as indicated.
• CT scans of the chest/abdomen should be obtained as clinically indicated.
• Upper gastrointestinal endoscopy should be performed as clinically indicated.

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