Esophageal Cancer: Background and Clinical Evidence

Fig. 3.1
American Joint Committee on Cancer 2010 esophageal cancer staging system
 
     

      3.5 Prognostic Factors

      1. (a)
        According to SEER Data, the 5-year survival of patients with esophageal cancer is approximately 20 %, and patients with esophageal cancers with lymph node-negative disease, lymph node metastases, and systemic metastases have a 5-year survival rate of 40 %, 21 %, and 4 %, respectively.
         
      2. (b)
        Resection status, age, and histologic subtype have been prognostic for patients undergoing surgery alone [23]:
        1. (i)
          Survival data from the Intergroup 0113 trial, which randomized esophageal cancer patients to surgery or neoadjuvant cisplatin and 5-FU followed by surgery, reported 5-year survival of patients undergoing an R1 or R2 resection that was significantly inferior to those patients with an R0 resection [24].
           
        2. (ii)
          The CROSS study, which randomized patients to neoadjuvant chemoradiation followed by surgery or surgery only, showed that there was a near doubling of overall survival for patients with squamous cell carcinoma versus adenocarcinoma [25].
           
         
      3. (c)
        Tumor size has also been reported to be prognostic for both adenocarcinoma and squamous cell carcinoma:
        1. (i)
          In one series 5-year survival decreased from 77 to 23 % for patients with resected squamous cell carcinomas measuring less than 1 cm compared to those greater than 3 cm [26].
           
        2. (ii)
          Patients with adenocarcinomas greater than 2 cm have also been shown to have significantly worse 5-year survival compared to patients with tumors <2 cm [27].
           
         

      3.6 Management

      1. (a)
        Surgery alone
        1. (i)
          Surgery for esophageal cancer often involves a subtotal or total esophagectomy, via a transthoracic or transhiatal approach, with nodal dissection:
          1. (i)
            It has been suggested that exposure of the chest cavity with a transthoracic approach can facilitate a more complete resection and therefore improved disease-related outcomes.
             
          2. (ii)
            The question of optimal surgical approach was examined in a Dutch trial which randomized 220 patients to transthoracic or transhiatal resection [28]:
            1. 1.
              Although the rate of locoregional recurrence was similar between the two surgical approaches (31 % in the transthoracic arm versus 32 % in the transhiatal arm), there appeared to be improved survival at a median follow-up of 4.7 years with the transthoracic approach (40 % vs. 30 %, p = 0.012).
               
            2. 2.
              Higher rates of perioperative morbidity, pulmonary complications, and lengths of hospital stays were seen in patients undergoing resection by the transthoracic approach.
               
             
           
        2. (ii)
          Independent of surgical technique, local recurrence rates range from 32 to 45 % in randomized trials containing a surgery-alone arm (Table 3.1), providing a rationale for multimodality treatment of this malignancy.
          Table 3.1
          Comparison of surgery alone arms in randomized studies of surgery with or without preoperative chemoradiation
          Trial
          Year
          Patients, total
          Patients, surgical
          Median survival (months)
          2-year survival
          3-year survival
          Walsh et al. [60]
          1996
          110
          55
          11
          26 %
          6 %
          Urba et al. [41]
          2001
          100
          50
          18
          NA
          15 %
          Bosset et al. [38]
          1997
          282
          139
          19
          40 %
          35 %
          Kelsen et al. [36]
          1998
          440
          227
          16
          37 %
          23 %
          MRC [61]
          2002
          802
          402
          13
          34 %
          NA
          Burmeister et al. [62]
          2005
          256
          128
          19
          NA
          31 %
          Van Hagen et al. [42]
          2010
          366
          188
          24
          NA
          48 %
          Mariette et al. [39]
          2014
          195
          98
          44
          NA
          NA
           
         
      2. (b)
         Postoperative therapy
        1. (i)
          One of the advantages of adjuvant therapy is that the pathological stage of the malignancy is known; thus, patients with either early stage or metastatic disease, who may not benefit from adjuvant therapy, can be identified.
           
        2. (ii)
          Pathologic staging and knowledge of surgical findings are helpful in radiation therapy planning.
           
        3. (iii)
          Studies investigating the efficacy of adjuvant radiation therapy following surgery have not consistently demonstrated an improvement in either local control or survival:
          1. (i)
            French investigators
            1. 1.
              Randomized 221 patients with squamous cell carcinoma of the mid- to distal esophagus to either resection, with or without postoperative radiation therapy alone.
               
            2. 2.
              Irradiated patients received 45–55 Gy within 3 months of surgery [29].
               
            3. 3.
              There was no improvement in survival for patients randomized to adjuvant radiation therapy even with a reduction in local recurrence rates from 35 to 10 % [29].
               
             
          2. (ii)
            Hong Kong investigators
            1. 1.
              Evaluated the outcome of 130 patients undergoing surgery and adjuvant radiation therapy alone versus surgery only in patients undergoing curative or palliative resection [30].
               
            2. 2.
              Similar to the French trial, local recurrence was decreased (31 % vs. 15 %, p = 0.06) in the radiation group.
               
            3. 3.
              Median survival, however, was significantly worse in the adjuvant group (median OS 8.7 vs. 15.2 months, p = 0.02), possibly due to morbidity associated with the large dose-per-fraction of 3.5 Gy and high overall dose of 49 Gy in patients treated with curative intent.
               
             
          3. (iii)
            Chinese investigators
            1. 1.
              Study of 549 patients that reported a near doubling of survival at 5 years for lymph node-positive patients receiving adjuvant radiation therapy versus those having surgery alone (17.6–34.1 %) [31].
               
            2. 2.
              As expected, patients with three or more involved lymph nodes had worse 5-year survival (14.4 %) compared to patients with 1–2 (30.6 %) or no lymph nodes involved (58.1 %).
               
             
           
        4. (iv)
          Results of the Intergroup 0116 study [32] support an approach of combined chemotherapy and radiation therapy following resection of gastroesophageal junction (GEJ) adenocarcinomas:
          1. (i)
            This study included patients with gastric or GEJ adenocarcinomas undergoing an R0 resection.
             
          2. (ii)
            Five hundred fifty-six patients were randomized to no adjuvant therapy versus adjuvant therapy with 5-FU and leucovorin before, during, and after radiation therapy.
             
          3. (iii)
            With a median follow-up greater than 10 years, the HR for survival was 1.32 favoring postoperative chemoradiation [33].
             
          4. (iv)
            This benefit was observed across all stages and tumor locations.
             
           
        5. (v)
          Therefore, adjuvant treatment for GEJ adenocarcinomas is advised for resected T2–T4 N0 or any node-positive patients not receiving neoadjuvant therapy.
           
         
      3. (c)
        Preoperative therapy
        1. (i)
          Preoperative treatment with either radiation or chemotherapy has a number of potential advantages:
          1. (i)
            For radiation specifically, preoperative treatment often employs smaller radiation fields with less treatment-related morbidity compared to postoperative treatment.
             
          2. (ii)
            Resection of the treated esophagus may also limit long-term complications as one of the primary tissues at risk, the esophagus itself, is removed.
             
          3. (iii)
            Neoadjuvant chemotherapy may allow for elimination of micrometastatic disease and determination of tumor chemosensitivity.
             
          4. (iv)
            Overall, an increased likelihood of resection due to downstaging and avoidance of surgery in patients with progression through treatment underscore the rationale for preoperative therapy.
             
          5. (v)
            Preoperative therapy is associted with higher rates of compliance and ability to deliver intended therapy as compared to the adjuvant setting.
             
           
        2. (ii)
          Preoperative chemotherapy
          1. (i)
            Similar to the conflicting results of adjuvant radiation therapy (described previously), the outcomes of randomized trials of preoperative chemotherapy alone have not consistently shown a survival benefit:
            1. 1.
              Medical Research Council (MRC) OEO2 trial
              1. (a)
                Largest trial including 802 patients with adenocarcinoma or squamous cell carcinoma of the esophagus randomized to cisplatin and 5-FU for two cycles prior to surgery versus surgery alone [34].
                 
              2. (b)
                Long-term follow-up at 6 years showed significantly improved 5-year overall survival in the preoperative chemotherapy arm (23 %) versus the surgery-alone (17 %) arm [35].
                 
               
            2. 2.
              Intergroup 0113 trial
              1. (a)
                Four hundred forty patients received either cisplatin with 5-FU before and following resection or resection alone.
                 
              2. (b)
                No difference in 3-year overall survival or local or distant failure was seen [24, 36].
                 
              3. (c)
                Potential caveats to this study include that only approximately 60 % of patients in either arm underwent an R0 resection, and in patients undergoing R1 resection, the only long-term survivors received adjuvant radiation therapy [24].
                 
               
            3. 3.
              MAGIC trial
              1. (a)
                Perioperative combination of epirubicin, cisplatin, and 5-FU (ECF) was evaluated [37].
                 
              2. (b)
                Although designed for patients with gastric cancer, the study eligibility was later expanded to include patients with distal esophageal and GEJ cancers, and ultimately one-fourth of patients accrued on this study had esophageal or GEJ tumors.
                 
              3. (c)
                There were no pathologic complete responders to the neoadjuvant chemotherapy component.
                 
              4. (d)
                The 5-year survival was significantly improved for patients randomized to perioperative chemotherapy (36 %) compared to patients undergoing surgery only (23 %, p = 0.009). This survival benefit was seen in all primary sites – esophageal, GEJ, or stomach.
                 
               
            4. 4.
              Results of the phase III studies of preoperative chemotherapy are summarized in Table 3.2.
              Table 3.2
              Results of preoperative chemotherapy vs. surgery-alone phase III trials
              Study
              Median F/U (years)
              Path
              Arms
              Number of patients
              pCR
              2-year
              survival
              Survival difference
              OEO2 [34, 35]
              MRC
              6.0
              SCC+
              adeno
              5-FU-CDDP/surg
              surg
              400
              402
              4 %
              –
              43 %
              34 %
              p = 0.004
              Kelsen et al. [36]
              Intergroup
              4.6
              SCC+
              adeno
              5-FU-CDDP/surg
              surg
              213
              227
              2.5 %
              –
              23 % (3 years)
              26 % (3 years)
              NS
              Cunningham et al. [37]
              MRC
              4.0
              Adeno
              EPI-CDDP-5-FU/surg
              surg
              250
              253
              0 %
              –
              36 %
              23 %
              p = 0.009
              SCC squamous cell carcinoma, Adeno adenocarcinoma, EPI epirubicin, 5-FU 5-fluorouracil, CDDP cisplatin, pCR pathologic complete response, NS not significant
               
             
           
        3. (iii)
          Preoperative chemoradiation:
          1. (i)
            Preoperative radiation in addition to chemotherapy has been investigated given the limited complete pathological response rate of the primary tumor and discrepancy in survival outcomes with chemotherapy alone:
            1. 1.
              EORTC (European Organisation for Research and Treatment of Cancer) trial:
              1. (a)
                Randomized 282 patients with squamous cell carcinoma.
                 
              2. (b)
                Demonstrated a median survival of 18.6 months with or without neoadjuvant chemoradiation, albeit with improvement in disease-free survival and cancer-related deaths with the use of neoadjuvant therapy [38].
                 
              3. (c)
                In this study, cisplatin alone was administered concurrently with 37 Gy in a split course at 3.7 Gy per fraction.
                 
              4. (d)
                Postoperative mortality was worse in the patients randomized to preoperative chemoradiation (12 %) versus surgery alone (4 %). This has been hypothesized to be due to the increased fraction size and may potentially account for the lack of overall survival benefit seen [38].
                 
               
            2. 2.
              FFCD (La Fédération Francophone de Cancérologie Digestive) 9901 trial:
              1. (a)
                Randomized 195 patients with clinically staged I–II squamous cell or adenocarcinoma.
                 
              2. (b)
                Stopped early due to crossing a prespecified boundary for futility in terms of improved survival [39].
                 
              3. (c)
                Although the pathologic complete response rate (33.3 %) was high, there was no difference in R0 resection rate of 93.8 % in the chemoradiation group versus 92.1 % in the surgery group.
                 
              4. (d)
                Postoperative mortality was significantly worse with neoadjuvant treatment (11.1 % vs. 3.4 %), with a 3-year overall survival of 47.5 % in the neoadjuvant group compared to 53 % with surgery alone, potentially negating any treatment-related survival benefit.
                 
               
            3. 3.
              CALGB (Cancer and Leukemia Group B) 9781 trial:
              1. (a)
                Randomized 56 patients to 50.4 Gy with concurrent cisplatin/5-FU and surgery or surgery only.
                 
              2. (b)
                The 5-year overall survival was 16 % in the surgery-alone arm compared to 39 % with neoadjuvant chemoradiation [40].
                 
               
            4. 4.
              University of Michigan:
              1. (a)
                One hundred patients with either adenocarcinoma or squamous cell carcinoma.
                 
              2. (b)
                Three-year survival was improved from 16 to 30 % with the addition of preoperative radiation with 5-FU, cisplatin, and vinblastine to surgery alone, although this did not reach statistical significance [41].
                 
               
            5. 5.
              CROSS (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study):
              1. (a)
                Largest study of combined modality therapy, randomizing 368 patients to 41.4 Gy with weekly paclitaxel (50 mg/m2) and carboplatin (AUC = 2) followed by surgery versus resection alone [42].
                 
              2. (b)
                Pathologic complete response was seen in 47/161 patients (29 %) of the chemoradiation group.
                 
              3. (c)
                148/161 of neoadjuvantly treated patients (92 %) underwent R0 resection versus 69 % in the surgery-alone group. Similarly, locoregional failure rates were significantly lower in the chemoradiation group versus the surgery-alone group (22 vs. 38 %, p < 0.0001) [25].
                 
              4. (d)
                With a median follow-up of 84.1 months in surviving patients, an overall survival benefit to neoadjuvant chemoradiation (median 48.6 vs. 24 months) was reported [25]. This benefit was greater in patients with squamous cell carcinoma (median survival 81.6 months vs. 21.1 months), as compared to adenocarcinoma (median survival 43.2 vs. 27.1 months).
                 
              5. (e)
                Preoperative chemoradiation did not increase the toxicity of surgery as in hospital mortality was 4 % in each group, and rates of anastomotic leak (30 % vs 22 %) and mediastinitis (6 % vs. 3 %) were worse in the surgery-alone group [42].
                 
               
            6. 6.
              Table 3.3 summarizes the results of the prospective phase III randomized trials evaluating the role of preoperative chemoradiation.
              Table 3.3
              Results of preoperative combined chemoradiation vs. surgery-alone phase III trials
              Study
              Median F/U (years)
              Path
              Arms
              Number of patients
              pCR
              3-year survival
              Survival difference
              Urba et al. [41]
              Michigan
              8.2
              SCC+
              adeno
              5-FU-CDDP-Vinb/45 Gy/surg
              surg
              50
              50
              28 %
              –
              30 %
              16 %
              p = 0.15
              Bosset et al. [38]
              EORTC
              4.6
              SCC

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              Oct 18, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Esophageal Cancer: Background and Clinical Evidence

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