Overview on Esophageal Cancer Management Ahmed Allam A.H. Mohammed.

Ass. Lecturer, Clinical oncology and Nuclear med. Depart. Assiut

University Hospitals

Esophageal Cancer Management

•Surgery•Radiation therapy.•Chemotherapy.

Surgery:• Surgery is the mainstay of treatment for most patients with

esophageal cancer who have technically resectable disease and are medically fit.

•  Mariette and colleagues, in a series of 179 patients with stage 0 to II esophageal cancer treated with surgery alone between 1982 and 2002, observed an overall actuarial survival rate at 5 years of 59%.

• The investigators report, however, that no long-term survivors were observed among a subset of patients with locally advanced disease. Analysis of surgical pathology shows that a significant number of patients present with disease involving the regional lymph nodes and that such involvement results in a worse outcome.

• The optimum number of lymph nodes to be removed and examined at the time of resection remains unclear. Latest retrospective analysis determined the optimal no. range from 18-23.

Tis-T1

•patients with Tis and T1a disease (lymph node negative) can be considered for primary endoscopic treatment such as endoscopic mucosal resection (EMR) or ablation with, for example, argon laser.

T2-4 N+ve• Transthoracic two-stage (Ivor Lewis) surgery

involves laparotomy and coeliac lymph node dissection. Right thoracotomy is performed for mobilisation and resection and mediastinal lymphadenectomy, along with intrathoracic anastomosis.

• Transhiatal approach involves resection by an abdominal laparotomy with a cervical anastomosis.

• Total thoracic, three-stage (McKeown) surgery is as per Ivor Lewis above, but with neck exploration, dissection, and anastomosis

Milestones in Radiation Therapy •RTOG 85-01 phase III trail.• INT 0122 phase II trial.• INT 0123 (RTOG 94-05) Phase III Trial.•RTOG 92-07 phase III trial.•CROSS group phase III trail.

Randomized Patients ( n:123)

Radiation Therapy alone (n:62)64 Gy /32 fractions over 6.4

weeks

Overall Survival at 5 years 0%

Combined Modality (n:61) 50 Gy/25 fr/5 Ws+

Cisplatinum D1+ 5Fu D1-4 / W1-4-8-11

Overall Survival at 5 years: 26%

Non-randomized patients (n:69)

Combined Modality (n:61) 50 Gy/25 fr/5 Ws+

Cisplatinum D1+ 5Fu D1-4 / W1-4-8-11

Overall Survival at 5 years 14%

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

• The incidence of local failure as the first site of failure (defined as local persistence plus recurrence) was also lower in the CMT arm (47% versus 65%)

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

The Intergroup INT 0122 phase II trial

• the intergroup INT 0122 phase II trial was designed in which the chemotherapy and radiation doses delivered in the combined-modality therapy arm of RTOG 85-01 were intensified.

• The regimen was modified as follows: (1) 5-FU continuous infusion was increased from 4 to 5

days; (2) total number of chemotherapy cycles was increased

from four to five(3) three cycles of full-dose neoadjuvant 5-FU and

cisplatin were delivered before the start of combined-modality therapy

(4) radiation dose was increased from 50 to 64.8 Gy.Minsky BD, Neuberg D, Kelsen DP, et al: Final report of intergroup trial 0122 (ECOG PE-289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and highdose radiation for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 43:517-523, 1999.

•The response, local/regional control, and survival rates for INT 0122 were similar to those reported in the combined modality arm of RTOG 85-01. However, the incidence of treatment-related mortality was higher (9% v 2%).

Minsky BD, Neuberg D, Kelsen DP, et al: Final report of intergroup trial 0122 (ECOG PE-289, RTOG 90-12): Phase II trial of neoadjuvant chemotherapy plus concurrent chemotherapy and highdose radiation for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 43:517-523, 1999.

Minsky BD, Pajak T, Ginsberg RJ, et al: INT 0123 (RTOG 94-05) phase III trial of combined modality therapy for esophageal cancer: high dose (64.8 Gy) vs. standard dose (50.4 Gy) radiation therapy. J Clin Oncol  2002; 20:1167-1174

• Results: (1) For the 218 eligible patients, there was no

significant difference in median survival, 2-year survival (31% v 40%), or local/regional failure and local/regional persistence of disease (56% v 52%) between the high-dose and standard-dose arms.

(2) 11 treatment-related deaths occurred in the high-dose arm compared with two in the standard-dose arm, seven of the 11 deaths occurred in patients who had received 50.4 Gy or less.The higher radiation dose did not increase survival or

local/regional control. Although there was a higher treatment-related mortality rate in the patients assigned to the high-dose radiation arm, it did not seem to be related to the higher radiation dose. The standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy

RTOG 92-07 trial• 75 patients with squamous cell cancers (92%)

or adenocarcinomas (8%) of the thoracic esophagus received the RTOG 85-01 CMT regimen (5-FU/cisplatin/50 Gy) followed by a boost during cycle 3 of chemotherapy high dose rate intraluminal brachytherapy.

• High dose rate brachytherapy was delivered in weekly fractions of 5 Gy during weeks 8, 9, and 10, Following the development of several fistulas, the fraction delivered at week 10 was discontinued

• The complete response rate was 73%, with a median follow-up of only 11 months, local failure as the first site of failure was 27%.

• Acute toxicity included 58% grade 3, 26% grade 4, and 8% grade 5 (treatment-related death). The cumulative incidence of fistula was 18%/year and the crude incidence was 14%. Of the six treatment-related fistulas, three were fatal.

• Given the significant toxicity this treatment approach should be used with caution.

CROSS phase III trail.

•366 patients with resectable Sq. cell and Adenocarcinoma of esophagus and GEJ,

•T2-3 N+M0•Randomized arms inculde (1)surgery alone(2)Pre-operative RTH 41.4 Gy/ 23 Fr +

Carboplatin (AUC 2) and paclitaxil (50 mg/m2) weekly + Surgery.

Van Hagen P et al., properative chemoradiation for esophogeal or junctional cancer. NEJM 2012 May 31, 366:2074

•More ptns in combined modality arm had – ve margin R0 resection (92 Vs 69 %)

•pCR was achieved in 29% in CMT arm•Median OS was higher in CMT than

surgery alone ( 49.9 Vs 24 months)•5 years OS was higher in CMT ( 47 Vs

34%)

Van Hagen P et al., properative chemoradiation for esophogeal or junctional cancer. NEJM 2012 May 31, 366:2074

Milestones in Chemotherapy

•Most studies of preoperative chemotherapy are based on combinations that contain cisplatin, which seems to be modestly tolerated but does not increase postoperative mortality. Overall response rates using these combinations range from 25 to 50%. However, no definite conclusions can be derived from these studies because of conflicting results

• Kelsen et al. (Intergroup 0113): 440 patients. Randomized neoadjuvant chemotherapy (3 cycles cisplatin, 5-FU), surgery 2 -4 weeks after 3rd cycles followed by 2 cycles post-op(213 ptns ) compared to surgery alone (227 ptns )

• Median survival was 15 months Vs 16 months , 2 years survival rate was 35 % Vs 37 % , There was no difference in overall survival (OS), 20% at 5 years, for either histologic subtype. Preoperative chemotherapy did not improve the rate of curative resection, and virtually no pCRs were observed.

• MRC in UK : 802 ptns , 2 cycles of 5-FU, cisplatin (400)+ S Vs S alone (402) Median survival was 16.8 months Vs 13.3 months . Tumor histology and tumor site did not influence the effect of chemotherapy. 

• MAGIC in Gastric Ca but 25 % of the ptn are GE junction or distal esophageal adenocarcinoma : 503 ptns , pre and post operative Epirubcin, cisplatin, 5-FU (250 ptns ) Vs surgery alone (253 ptns ). Median survival 24 months Vs 20 months Five-year OS was improved by 13% (36% vs 23%; P < .001) in the chemotherapy group. There was no improvement in the rate of curative resection with preoperative chemotherapy, and no pathologic complete responses were observed.

• FFCD/FNLC 9703 (French trial) : 219 patients including GE junction and gastric cancer 2-3 preoperative and 2-3 post operative cisplatin, 5-FU shows 14% in 5 years over survival.

Role of Adjuvant chemotherapy :• Postoperative adjuvant chemotherapy has been

compared with surgery alone, and no OS benefit was seen in 3 phase III randomized studies or meta-analyses.

• Japanese trials of preoperative and postoperative chemotherapy in esophageal squamous cancer have reached often conflicting and inconsistent conclusions. Recent data from a Japanese trial showed a 10% survival benefit at 3 years (P = .003) after treatment with S-1 (an oral form of 5FU) in 1059 patients with resected gastric cancer. Such data provide an evidence base for treating resected esophageal cancer (pN1) in the adjuvant setting, but S-1 is not as effective in Western populations.

Vincent Van Gogh, Dutch impressionist, Starry night

S

Tell me and I forget, teach me and I may remember, involve me and I learn. - Benjamin Franklin