Neoadjuvant Therapy for Esophageal Cancer

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Neoadjuvant Therapy for Esophageal Cancer
Daniel Morgensztern, M.D.
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Overview

• Background
• Neoadjuvant radiotherapy
• Neoadjuvant chemotherapy
• Neoadjuvant chemoradiotherapy
• Neoadjuvant or definitive chemoradiotherapy
• The significance of pathologic CR
• Strategies to improve outcome
• Conclusions

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EpidemiologyWorldwide

• Worldwide estimates for 2000
• Eight most common cancer with 412,000 new cases
• Sixth most common cause of cancer death with
  338,000 deaths
• 2002 update
• 462,000 new cases
• 386,000 deaths

Parkin DM, Lancet Oncol 2001 2 533-543 Parkin
DM, CA Cancer J Clin. 20055574-108
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EpidemiologyUS

• US estimates for 2005
• 14,520 new cases
• 11,220 male
• 3,300 female
• 13,570 deaths

Jemal A CA Cancer J Clin. 20055510-30
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AJCC StagingT Stage
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AJCC StagingN stage
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AJCC Staging and Prognosis After Complete
Surgical Removal of the Tumor
Ezinger PC, N Engl J Med 2003 3492241-2252
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Neoadjuvant Radiotherapy

• Rationale
• Decrease tumor size with potential increase in
  resectability
• Improve local control
• Decrease the number of viable cells with possible
  minimization of intraoperative spilling
• Disadvantages
• No effect in micrometastatic disease
• Delay in definitive therapy

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Neoadjuvant RadiotherapyRandomized Trials
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Neoadjuvant RadiotherapyMeta-analysis

• Oesophageal Cancer Collaborative Group
• 5 trials including 1147 patients
• Increased 2-year survival from 30 to 34 (95 CI
  0-9)
• Increased 5-year survival from 15 to 18 (95 CI
  0-8)
• Arnott SJ, Int J Radiat Oncol Biol Phys 1998
  41 579-583
• Arnott SJ, Cochrane Database Syst Rev 2000 4
  CD001799

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Neoadjuvant chemotherapy

• Rationale
• Downstage of the disease with potential increase
  in resectability
• Improvement in local control
• Eradication of micrometastatic disease
• Pathologic evaluation of treatment response with
  possible selection of adjuvant therapy
• Disadvantages
• Delay in definitive therapy with risk of disease
  spreading
• Limited efficacy of the available
  chemotherapeutic agents

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Neoadjuvant chemotherapyRandomized Trials
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Neoadjuvant chemotherapyINT 0113 and MRC Trials
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Neoadjuvant chemotherapyMeta-analysis

• Cochrane Database 2003
• 11 Randomized trials involving 2051 patients
• Clinical relevance based on median survival and 1
  to 5 year survival
• When specific survival was not available, it was
  calculated from the published survival curves
• Pooled response rate to chemotherapy was about
  36 with 3 pCR
• No difference in survival at 1 and 2 years
• Survival advantage starts at 3 years and reaches
  statistical significance at 5 years
• Cochrane Database Syst Rev 2003 4 CD001556

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Neoadjuvant chemotherapyMAGIC Trial

• Cunningham ASCO 2005

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Neoadjuvant chemotherapyMAGIC Trial

• Overall, both median survival (24 m vs 20 m) and
  5-year OS (36 vs 23) favored neoadjuvant therapy
• On multivariate analysis, treatment effect was
  unchanged after adjustment for primary site
• Perioperative chemotherapy significantly
  increased both PFS and OS in patients with
  gastric or lower esophageal cancer

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Neoadjuvant Chemoradiotherapy

• Rationale
• Combine the benefits from both therapeutic
  modalities Downstage of the tumor facilitating
  surgical resection and eradication of
  micrometastatic disease
• Increase the number of pathologic complete
  remissions which may translate into improved
  survival
• Disadvantages
• Patients may not undergo surgery due to toxicity
  or tumor progression
• Increased post-operative mortality

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Neoadjuvant ChemoradiotherapyNon-Randomized
Trials

• 46 trials from 1981 to 1999
• 2704 patients 69 SCC, 31 Adenocarcinoma
• RT dose from 30 to 60 Gy
• Majority of studies used 5-FU and cisplatin
• Resection rate 74
• Pathologic CR 24 (32 surgical patients)
• Patterns of recurrence after surgical resection
• - Locoregional 9
• - Distant 31
• - Both 6

Geh JI, Br J Surg 2001 88338-356.
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Neoadjuvant ChemoradiotherapyRandomized Trials
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Neoadjuvant ChemoradiotherapyMeta-analyses

• Urschel J, Am J Surg 2003 185 538-543
• - Neoadjuvant chemoradiation improves 3-year
  survival, with more significant benefit in the
  concurrent studies (OR 0.45, 95 CI 0.26 to 0.79,
  p 0.005)
• - Decrease LR but not distant recurrences
• Fiorica F, Gut 200453 925-930
• - Neoadjuvant chemoradiotherapy significantly
  reduces the 3-year mortality rate (OR 0.53, 95
  CI 0.26 to 0.72, p 0.03)
• - Risk of postoperative mortality is higher in
  the neoadjuvant group ( OR 2.10, 95 CI
  1.18-3.73, p 0.01)
• Greer SE, Surgery 2005 137 172-177
• - Neoadjuvant chemoradiotherapy is associated
  with a small, non-statistically significant
  improvement in overall survival (RR of death in
  neoadjuvant group 0.86, 95 CI 0.74 to 1.01, p
  0.07)
• Malthaner RA, BMC Med 2004 2 35
• A significant difference in the risk of mortality
  at 3-years favors neoadjuvant chemoradiation (RR
  0.87, 95 CI 0.80-0.96, p 0.004)

None of the meta-analysis included Burmeisters
study, which has been recently published (Lancet
Oncol 2005) and at that time was available only
in abstract form
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The Role of Surgery after Chemoradiotherapy

• The 5-year survival for chemoradiotherapy in
  patients with unresectable locally advanced
  esophageal cancer was 26 in the RTOG 85-01 trial
  
• The subsequent INT 0123 showed a 2-year survival
  of 40 in the control standard-dose RT arm
• These results are similar to those achieved with
  surgery alone or neoadjuvant chemoratiotherapy
  followed by surgery

Cooper JS, JAMA 1999 281 1623-1627 Minsky BD, J
Clin Oncol 2002 20 1167-1174
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The Role of Surgery after Chemoradiotherapy

• FFCD 9102 Bedenne ASCO 2002 (abstract 519)
• FC X 2 RT
• Responders randomized to S or additional CRT
• S CRT
• 2-year OS 34 40 OR 0.91, p 0.56
• Median survival 17.7 m 19.3m

• No significant difference in survival
• Surgery was associated with improved local
  control
• - Decreased use of stent (13 versus 27 p
  0.005)
• - Decrease use of dilations (22 versus 32 p
  0.07)

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The Role of Surgery after Chemoradiotherapy

• GOCSG Stahl M, J Clin Oncol 2005 23 2310-2317
• FLEP X 3 ? EP 40 Gy ? surgery (89 patients)
• FLEP X 3 ? EP gt 66Gy (88 patients)
• S CRT
• 3-year OS 31.3 24.4
• Median survival 16.4 m 14.9 m
• CRT resulted in equivalent survival with
  preserved esophagus
• Surgery significantly increased local control
• Survival curves appear to spread after 3 years
  but without reaching statistical significance
• Patients responding to induction therapy appear
  to have good prognosis regardless of surgical
  intervention

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Pathologic CR

• Pathologic CR in randomized clinical trials
• Neoadjuvant chemotherapy 2.5 to 15
• Neoadjuvant chemoradiotherapy 10 to 28
• Several trials have demonstrated improved
  survival in patients achieving pCR

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Pathologic CR
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New Strategies

• Incorporation of new chemotherapy agents
• Taxanes, irinotecan, oxaliplatin
• Addition of a targeted agent
• - COX-2 inhibitors, EGFR inhibitors, bevacizumab
• Intensification of neoadjuvant therapy
• - Triplets with concomitant RT (CF taxane)
• - Triplets without RT (ECF, CF taxane)
• Induction chemotherapy followed by concomitant
  chemoratiotherapy

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Conclusions

• Surgery remains the mainstay for a curative
  approach in esophageal cancer
• Neoadjuvant RT does not appear to decrease local
  relapse or improve survival in patients with
  resectable esophageal cancer
• The role of neoadjuvant chemotherapy remains
  undefined with a small 5-year benefit obtained in
  a meta-analysis but conflicting results from two
  large randomized trials
• The impact of the MAGIC trial is unclear due to
  the small number of patients with esophageal
  cancer
• NCCN v1.2005 Preoperative chemotherapy is not
  recommended as the standard of care

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Conclusions

• Neoadjuvant chemoradiotherapy has been widely
  accepted in US despite the lack of conclusive
  evidence from phase III trials
• The confirmatory trial CALGB 9781 was terminated
  early due to poor accrual
• Benefit from trimodality therapy may be
  restricted to patients achieving significant
  response or pCR and non-responders may have worse
  outcome compared with patients treated with
  surgery only
• Small benefit observed in the 4 published
  meta-analysis may change with the inclusion of
  Burmeisters study
• Ongoing Cochrane review
• NCCN v1.2005 Although neoadjuvant
  chemoradiotherapy represents a reasonable
  approach, it remains investigational due to
  conflicting results from RCTs

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Conclusions

• Surgery following neoadjuvant chemoratiotherapy
  improves local and regional control but not
  overall survival
• Post-therapy pathologic status may be a better
  predictor for outcome than the baseline clinical
  AJCC staging system
• The pathologic status achieved with neoadjuvant
  therapy may provide an early surrogate benchmark
  to speed up comparative trials

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Conclusions

• Distant relapse continues to be a major challenge
  in patients presenting with locally advanced
  disease
• More intense chemotherapy regimens using
  third-generation agents may increase the
  eradication of micrometastatic disease
• Patients treated with induction chemotherapy may
  benefit from early evaluation of response to
  avoid unnecessary delays in surgery
• Larger randomized trials of neoadjuvant
  chemotherapy or chemoradiotherapy are needed to
  identify optimal regimens capable of producing
  higher pCR rates with acceptable toxicity