Esophageal Cancer and Combined modality Treatment

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Esophageal Cancer and Combined modality Treatment

• Aruna Kommareddy, M.D.
• Fellow, Washington University School of Medicine

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Epidemiology

• Around 13,200 cases each year
• About 12,500 deaths each year
• Before 1980
• SCC seen in association with tobacco and alcohol
  abuse was the most common form
• Only15 of all cases were adenocarcinoma

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Changing trends

• Recently adeno-carcinoma associated with
  Barretts metaplasia and seen almost exclusively
  in middle-aged Caucasian men with GERD has become
  the most predominant form.
• In 1994 60 of all esophageal cancers were
  adenocarcinoma.
• Reasons for this change are not known.

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Current AJCC 2002 staging
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Regional nodes

• Cervical Esophagus Scalene, Internal jugular,
  Upper and lower cervical, Peri-esophageal,
  Supraclavicular
• Intra-thoracic esophagus Upper peri-esophageal,
  Sub carinal, Lower peri-esophageal, mediastinal
  nodes
• Gastro-esophageal junction Lower esophageal,
  diaphramatic, para-cardial, left gastric and
  celiac

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Treatment

• Surgical resection is the standard treatment for
  early esophageal cancer ie Stages I, II and most
  cases of III
• During the past decade, outcomes with surgery
  have improved resulting in a better 5 year
  survival due to
• Better staging techniques
• Increased rate of curative resection
• A decreased rate of postoperative death
• However, the proportion of patients who
  survive for five years remains low
• 30 to 50 - stage I
• 15 to 30 - stage IIA
• 5 to 15 stage IIB

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Types of esophagectomies

• Transhiatal
• Exposure is provided by an upper midline
  laparotomy and a left neck incision.
• The thoracic esophagus is bluntly dissected, and
  a cervical anastomosis created thoracotomy is
  not required.
• Drawbacks inability to perform a full thoracic
  lymphadenectomy, and lack of visualization of the
  midthoracic dissection.

• Transthoracic
• The Ivor Lewis esophagectomy combines a
  laparotomy with right thoracotomy, and produces
  an intrathoracic anastomosis.
• This technique permits direct visualization of
  the thoracic esophagus, and allows the surgeon to
  perform a limited lymphadenectomy.
• However formal dissection of lymph nodes is not
  performed

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Types of esophagectomies

• Three field lymphadenectomy
• Widely practiced in Japan
• En bloc resection of esophagus, azygous vein,
  thoracic duct, lateral pleural surfaces, part of
  pericardium
• Dissection of cervical, mediastinal and upper
  abdominal nodes with RPLD performed
• Two field lymphadenectomy
• En Bloc resection of esophagus, azygous vein,
  thoracic duct along with lateral pleural surfaces
  and part of pericardium and mediastinal nodes and
  dissection of upper abdominal nodes with RPLD
  performed

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Hulscher et al

• Perioperative morbidity was higher after TTE
• No significant difference in in-hospital
  mortality (P0.45)
• After a median follow-up of 4.7 years
• 70 of patients died post THE and 60 after TTE
  (P0.12)
• Median overall and disease-free survival did not
  differ statistically between the groups.
• However there was a trend towards improved
  long-term survival at 5 years with the TTE.

Transthoracic Esophagectomy(TTE) N114 Included
2 field lymphadenectomy
220 patients Adeno Ca
Randomize
Transhiatal Esophagectomy (THE) N106
NEJM 2003
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Patterns of disease recurrence post surgery

• In one study 108 patients had a curative
  resection for SCC of the thoracic esophagus.
• At a median follow-up of 20 months
• Recurrence 52
• Mainly extrathoracic recurrence 41
• Mainly intrathoracic recurrence 25

Br J Surg 1996 Jan83(1)107-11
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Neoadjuvant /adjuvant therapy

• Neo-adjuvant Chemotherapy
• Neo-adjuvant Radiation
• Neo-adjuvant Chemo-Radiation
• Adjuvant Chemotherapy
• Adjuvant Radiation
• Adjuvant chemoradiation

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Why Neoadjuvant/Adjuvant therapy

• In most cases esophageal cancer is a systemic
  disease at diagnosis.
• Surgery alone is curative in a small group of
  patients.
• Patterns of recurrence suggest both local and
  systemic failure.
• Disadvantages Only 50 of patients respond to
  treatment
• Delay in surgery
• Possibility of selecting drug resistant clones

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Neoadjuvant chemotherapy

• Several phase II and III randomized studies have
  been conducted.
• Kok et al studied 160 patients with SCC
• Chemo Cisplatin(80mg/m2) and Etoposide 100mg/m2
  days 1-5 (2-4 cycles) followed by transhiatal
  esophagectomy.
• Evaluation after 2 cycles.
• Responders 2 additional cycles
• Non responders surgery
• Median survival18.5 Vs 11 months(P0.002)

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Neoadjuvant chemotherapy Kelsen et al

• After 55.4 months, there were no sig differences
  between the two groups
• Median survival
• Combination 14.9 months
• Surgery alone16.1 months (P0.53)
• One year survival
• Combination 59
• Surgery alone60
• Two Year survival
• Combination 35
• Surgery alone37

Immediate surgery N227

• Randomize
• N440
• Adeno squamous

Chemotherapy surgery N213 Cisplatin 100 mg/M2
day 1 5 FU1000mg/m2/ddays1-5 Pre op 3 cycles q 4
weeks Surgery 2-4 weeks after chemo Post op chemo
for 2 cycles
NEJM 12/98
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Neoadjuvant chemotherapy Kelsen et al

• The addition of chemotherapy did not appear to
  increase the morbidity or mortality associated
  with surgery.
• There were no differences in survival between
  patients with squamous-cell carcinoma and those
  with adenocarcinoma.
• Weight loss was a significant predictor of poor
  outcome (P0.03).
• With the addition of chemotherapy, there was no
  significant change in the rate of recurrence at
  locoregional or distant sites or DFS .

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Neoadjuvant chemotherapy Girling et al

• Median survival
• Combination 16.8 months
• Surgery alone13.3 months .
• Two Year survival
• Combination 43
• Surgery alone34
• Over all survival
• Better in combined modality arm
• Hazard ratio 0.79 95 CI 0.67-0.93 p0.004)
• DFS
• Better in combined modality arm (P0.0014)

Surgery N402
Immediate surgery
Cisplatin and 5 FU Pre op 2 cycles q 3 weeks

• Chemotherapy surgery
• N400

Two 4-day cycles, 3 weeks apart, of cisplatin 80
mg/m(2) by infusion over 4 h plus fluorouracil
1000 mg/m(2) daily by continuous infusion for 4
days followed by surgical resection. Clinicians
could choose to give preoperative radiotherapy
to all their patients irrespective of
randomization.
Lancet 359 (2002), pp. 17271733
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Neo-adjuvant Radiation alone

• A meta-analysis of 1147 patients from five
  randomized trials showed no survival benefit.
• Based on existing trials, there is no clear
  evidence that preoperative radiotherapy improves
  the survival of patients with potentially
  resectable esophageal cancer.

Int J Radiat Oncol Biol Phys 1998 141(3)579-83
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Neoadjuvant therapy Chemo-radiationPhase II
Studies
Comprehensive text book of Thoracic Oncology,
Williams Wilkins
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Surgery alone Vs Combined modality therapy. Phase
III study
Median Survival 11m 1 yr survival 44 2 yr
survival 26 3 yr survival 6
Surgery N55
Randomize N113 Adeno
Cis/5FU XRT Surgery N58
Median Survival 16m 1 yr survival 52 2 yr
survival37 3 yr survival 32
Two courses of chemotherapy in weeks 1 and 6 5
FU 15 mg per kg daily for five days Cisplatin, 75
mg per square m2 on day 7 Radiotherapy, 40 Gy,
administered in 15 fractions over a 3-week
period, beginning concurrently with the first
course of chemotherapy.
Walsh et al NEJM
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Walsh et al

• At the time of surgery
• 42 of patients treated with preoperative
  multimodal therapy who could be evaluated had
  positive nodes or metastases versus
• 82 of patients who underwent surgery alone
  (Plt0.001).
• 25 of patients who underwent surgery after
  multimodal therapy had complete responses, as
  determined pathologically.

NEJM Vol 335462-467
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Walsh et al

• KaplanMeier Plot of Survival of Patients with
  Esophageal Adenocarcinoma, According to the
  Intention-to-Treat Analysis.

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Surgery alone Vs Combined modality
therapy.Bossett et al

• Median follow-up of 55.2 months
• Median survival
• Surgery alone18.6 months
• Combination 18.6 months
• Combined Modality
• Longer disease-free survival (P 0.003)
• Longer interval free of local disease (P 0.01)
• Lower rate of cancer-related deaths (P 0.002)
• Higher frequency of curative resection (P
  0.017)
• More post-op deaths (P 0.012

Surgery N139
Randomize N282 SCC T1N1,T2N0,T2N1,T3N0
Cis XRT Surgery N143
Cisplatin 80 mg/m2 0-2 days before XRT q weekly x
2. XRT 37 Gy over 2 weeks
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Disease free survivalBossett et al
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Urba et al
Median survival17.6m 3 yr survival 16
Surgery N50
Randomize N100 Adeno 75 SCC 25
Cis/5FU/Vindesine XRT Surgery N50
Median survival 16.9m 3yr survival30 (P
0.15)
Cisplatin 20 mg/m2/d on days 1 through 5 and 17
through 21, 5FU 300 mg/m2/d on days 1 through 21,
and vinblastine 1 mg/m2/d on days 1 through 4 and
17 through 20. XRT 1.5-Gy fractions twice
daily, Mon through Fri over 21 days, to a total
dose of 45 Gy. Transhiatal esophagectomy was
performed around day 42. Staging CT head, chest
abd, endoscopy, barium swallow, bone scan .
J Thorac Cardiovasc Surg 1997 Aug114(2)205-9
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Urba et al

• Survival by pathologic response to chemoradiation

• 28 of patients were histologic complete
  responders.
• Patients with complete histologic response
• Median survival 49.7m
• 1-year survival 86
• 3-year survival64
• Patients with residual disease in the resected
  specimen
• Median survival 12m
• 1-year survival 52
• 3-year survival 19 (P .01).

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Neoadjuvant therapy Chemo-radiationPhase III
Studies
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Peri op mortality, combined modality Vs surgery
alone
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3 Year survival combined modality Vs Surgery alone
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Adjuvant Radiation Vs chemotherapy
5 yr survival 44
Radiation
Randomize Post Surgery N258
Cis/Vindesinex2
5 yr survival 42 No difference in time to
recurrence or sites of recurrence
Radiotherapy (50 Gy) 2 courses of chemotherapy
consisting of cisplatin (50 mg/m2) and vindesine
(3 mg/m2) following curative resection
Chest 1993 Jul104(1)203-7
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Adjuvant Chemotherapy
5 yr survival 44.9
Surgery N100
Randomize N205
Surgery Cis/Vindesinex2 N105
5 yr survival 48.1 No significant differences
in survival were detected between the two
groups, even with lymph node stratification
Transthoracic esophagectomy with lymphadenectomy
Cisplatin (70 mg/m2) and Vindesine (3 mg/m2)
J Thorac Cardiovasc Surg 1997 Aug114(2)205-9
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Adjuvant Chemotherapy

• In another study with 242 patients randomized to
  receive no further therapy or cisplatin and 5 FU
  as adjuvant therapy
• Estimated 5 yr DFS 58 Vs 46 P(0.05)
• Overall survival no significant difference
• Node neg 77 Vs 82(P0.3)
• Node pos 35 Vs 53 (P0.06)
• Role of post op adjuvant chemotherapy currently
  undefined

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Adjuvant Radiation

• Surgery (119 patients) was compared with surgical
  treatment followed by radiation therapy (102
  patients).
• All patients had a curative esophageal resection.
  
• Radiation therapy 45 to 55 Grays
• Overall Postoperative radiation therapy did not
  improve survival
• However, there were significantly fewer local
  recurrences in patients receiving radiation
  therapy as compared with those not receiving
  radiation therapy.In a subset analyses benefit
  was limited to patients with negative lymph nodes
  (Decreased local failure from 35 to 10)

Surg Gynecol Obstet 1991 Aug173(2)123-30
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Not candidates for surgery

• Radiation alone
• Combination chemoradiation

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Chemoradiation Vs Radiation Herscovic et al
Median follow up 5 yrs for all pts Median
Survival 9.3m 5 yr 0
Radiation 64Gy N62
Randomize
Cis/5 FUx4 Radiation 50Gy N61
Median Survival 14.1m 5 yr survival 27 P
lt0.0001 8 yr 22
Locally advanced adeno or squamous esophageal
carcinoma. Cisplatin, 75 mg/m2 intravenously, on
the first day of weeks 1, 5, 8, and 11. The
patients were given a continuous infusion of
fluorouracil, 1 g/m2, for the first 4 days of
weeks 1, 5, 8, and 11. Radiation was delivered at
30 Gy in 15 fractions over 3 weeks starting on
day 1, followed by 20 Gy in 10 fractions over 2
weeks
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Chemoradiation Vs Radiation

• The trial was stopped after the results in 121
  patients demonstrated a significant advantage for
  survival in patients who received combination
  therapy.
• The patients who received combined treatment had
  fewer local (P less than 0.02) and fewer distant
  (P less than 0.01) recurrences.
• No significant relation of histology to survival
  noted

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Herscovic et al

• Side effects were greater in the combined
  modality arm
• 8 of patients in combined modality therapy
  experienced grade 4 toxic effects and 2 died.
• Versus 2 of patients in RT arm experienced had
  grade 4 toxic effects and there were no deaths.
• Of the 61 patients randomized to receive combined
  modality therapy, 37 received chemotherapy as
  planned and 56 received radiation therapy as
  planned so that 36 of the 61 received both
  therapies as planned.
• 58/62 patients in the radiation only arm received
  XRT as planned

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Chemoradiation

• Additional 69 patients were treated with the same
  combined therapy and were analyzed.
• Similar results were obtained
• Median survival 17.2 months
• 3-year survival 30
• 5 yr survival 14

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Chemoradiation Vs Radiation
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Where are we?

• Surgery remains a standard of care for
  potentially resectable disease.
• Definitive chemoradiation is a standard of care
  for locoregional disease, particularly if a
  patient is medically unfit for surgery, if a
  surgeon experienced in esophagectomies is
  unavailable, or if the patient has cervical
  disease, which would require very extensive
  surgery.
• Preoperative chemotherapy is controversial, with
  two large randomized studies resulting in two
  different conclusions regarding survival benefit.
  

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Conclusions

• Preoperative chemoradiation is controversial.
• Only one randomized trial showed a clear survival
  benefit however, the patients treated with
  surgery alone in that trial had an unusually poor
  outcome.
• Another trial was negative but statistically
  powered only to reveal a large survival
  difference and in multivariate analysis showed a
  possible trend towards improved outcome.
• However, some physicians may consider offering
  this option to patients with locally advanced
  disease, excellent performance status, and who
  understand the controversies and lack of
  consensus about this option.

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Conclusions

• Role of post op adjuvant chemotherapy currently
  undefined
• No proven benefit in node negative patients
• Node positive patients may be benefited and
  should be enrolled in clinical trials as there is
  currently no evidence of benefit.
• Patients with incompletely resected tumors or
  positive margins should receive adjuvant
  chemoradiation if they can tolerate it, otherwise
  only XRT
• No definitive trial has been or will be performed
  to determine whether chemoradiation plus surgery
  is superior to chemoradiation alone