Nonresectable Metastatic Colorectal Carcinoma

1
Non-resectable Metastatic Colorectal Carcinoma

• Dr. Benoît Samson
• Medical Oncologist
• Hôpital Charles LeMoyne
• Greenfield Park, PQ

2
Learning Objectives

• As a result of reading the following case study,
  physicians will be able to
• Review the palliative treatment of metastatic
  colon cancer
• Describe treatment options with first-line
  chemotherapy using infusional 5-FU with
  irinotecan (FOLFIRI) and second-line treatment
  with infusional 5-FU and oxaliplatin (FOLFOX)
• Assess and discuss treatment options after
  failure from the above regimen.

3
Mr. D.B.

• 63 year old retired policeman without
  significant medical problems other than well
  controlled mild high blood pressure.
• He presented two years ago with mild hypochromic
  and microcytic anemia related to iron deficiency.

4
Mr. D.B.

• A colonoscopy revealed a hemorrhagic tumor of the
  cecum.
• The pre-operative abdominal CT scan showed no
  liver metastasis and no enlarged lymph nodes.
• Chest X ray was normal.

5
Mr. D.B.

• He underwent a right hemi-colectomy.
• No peritoneal or liver implants were noted.
• His recovery was fairly rapid.

6
Mr. D.B.

• The pathological diagnosis was consistent with
  moderately differentiated adenocarcinoma,
  intestinal type, with invasion through muscularis
  propria into the subserosa.
• Vascular and lymphatic invasion were also noted.
  
• All of the nine (9) pericolic lymph nodes were
  free of disease.
• At discharge, the diagnosis was adenocarcinoma
  of the cecum, stage II (T3N0M0). At that time,
  no adjuvant chemotherapy was offered to the
  patient.

7
Practice Point

• What is the role for chemotherapy in Stage II
  colon ca?
• Multiple trials that included this population
  failed to show conclusive benefit.
• Difficult to know who in stage II to treat, all
  comers or high risk disease.
• What is high risk disease?

8
QUASAR II

• Data from the QUASAR II trial would suggest that
  this is a case of high risk stage II colorectal
  carcinoma.
• Between June 1994 and December 2003, 3238
  patients (91 Dukes B, 71 colon cancer, median
  age 63) from 150 centers in 17 countries were
  randomized
• Randomized to observation or to treatment with
  one of two 5FU containing regimes.

9
QUASAR II

• Recurrence
• 5y recurrence rate
• 22.2 with chemo
• 26.2 on observation
• Survival
• 5y overall survival rate
• 80.3 with chemo
• 77.4 on observation

10
Stage II High Risk Disease

• T4 Lesions
• Node harvest
• Poorly differentiated
• Lymphovascular invasion

11
Mr. D.B.

• One could argue that in todays standards, Mr.
  D.B. might be considered a candidate for adjuvant
  chemotherapy.
• Vascular and lymphatic invasion were also noted.
  
• All of the nine (9) pericolic lymph nodes were
  free of disease, ie

12
Mr. D.B.

• Eight months after the surgery, Mr. D.B. was
  asymptomatic.
• A scheduled carcinoembryonic antigen (CEA) level
  of 16 ug/L.
• The liver function test showed elevated alkaline
  phosphatase.

13
Mr. D.B.

• An abdominal CT scan revealed multiple liver
  metastases measuring 24 cm in diameter

14
Practice Point

• What would be your treatment plan for a case like
  this in your own current practice?
• Palliative chemotherapy is appropriate for
  metastatic colon cancer that has spread to the
  liver. Assessment should be done for hepatic
  resection if appropriate
• Disease relapse occurred early to the liver and
  because Mr. D.B. had too many liver lesions
  (about 8 metastases of 2-4 cm in diameter in the
  left and right liver) surgical resection was not
  an option.
• In this chemotherapy-naïve patient with good
  performance status, palliative 5-FU based
  chemotherapy with three agents showed profound
  impact on the median survival. Six month median
  survival with supportive care only, was increased
  to a 16 to 20 month median survival with optimal
  front line chemotherapy.

15
Practice Point

• What chemotherapy regimen would you choose for
  first-line treatment and upon which factors would
  you base your choice?
• Efficacy data
• Toxicity
• Availability of the drugs and cost
• Convenience of administration
• There are several options for first-line
  chemotherapy and the choice should be based on a
  combination of factors.
• These include the patients performance status
• Co-morbidities
• ? Age
• The availability of the drugs and the convenience
  of the treatment.

16
Practice Point

• Treatment options for first-line chemotherapy in
  patients with metastatic colorectal cancer.
• Bolus 5FU/ LV (Mayo regimen)
• Bolus 5FU/ LV and Irinotecan (IFL, Saltz
  regimen)
• Infusional 5FU/ LV alone (de Gramont regimen)
• Infusional 5FU/ LV with Irinotecan (FOLFIRI)
• Infusional 5FU/ LV with Oxaliplatin (FOLFOX)
• Oral fluoropyrimidine (capecitabine)
• Bevacizumab and 5FU based chemotherapy

What would you offer?
17
Practice Point

• For the most part, FOLFIRI or FOLFOX6 are
  considered reasonable standard first line
  therapies

18
FOLFOX and FOLFIRIStudy V308

• Sequential administration of combination regimens

Tournigand C, et al. J Clin Oncol. 2004 Jan
1522(2)229-37
19
Overall Survival
FOLFIRI / FOLFOX
1.0
0.8
0.6
FOLFOX / FOLFIRI
Logrank p 0.9
Probability
0.4
0.2
0.0
Months
Tournigand C, et al. J Clin Oncol. 2004 Jan
1522(2)229-37
20
Treatment

• Palliative chemotherapy was offered
• He began chemotherapy with infusional
  5-fluorouracil (5FU)/ leucovorin (LV)/ Irinotecan
  (FOLFIRI regimen) given every two weeks
• Chemotherapy used in firstline treatment
• FOLFIRI
• Irinotecan  180 mg/m2 IV
• 5FU 400 mg/m2 IV
• LV 200 mg/m2 IV
• 5FU 2400-3000 mg/m2 CIV for 46 hrs

21
Treatment

• Treatment was well tolerated until the eight
  cycle when diarrhea became troublesome (grade
  II-III toxicity) despite aggressive loperamide
  prophylaxis.
• The abdominal CT scan done at that time showed an
  approximately 60 decrease in size and
  significantly less liver metastases.

January 05
April 05
22
Diarrhea with Irinotecan

• Gastrointestinal Syndrome
• Defined as a constellation of gastrointestinal
  symptoms including diarrhea, nausea, vomiting,
  anorexia and abdominal cramping
• Associated with severe dehydration, neutropenia,
  fever and electrolyte disturbance
• Radiological findings of bowel wall edema and/or
  bowel obstruction in face of no mechanical
  obstruction

Cancer. 2004 Nov 15101(10)2170-6.
23
Gastrointestinal and/or Vascular Syndromes as the
Cause of Death N9741 (Metastatic)
24
Practice Point

• Diarrhea with Irinotecan
• What recommendations would you make?
• BRAT diet
• High dose loperamide
• Quinolone antibiotic if persists 48 hours
• If grade III/IV, hospitalization
• Octreotide 100 ug sc BID to TID and increase til
  diarrhea resolves
• What is the evidence for this?
• Weak evidence for these recommendations at best
• Chemotherapy induced diarrhea working group
  proposing recommendations based on best available
  evidence.

25
Treatment

• Four more cycles with slightly reduced dose of
  Irinotecan were given
• Abdominal CT-Scan was repeated
• Unfortunately no further improvement was noticed
  and the treatment was stopped at that time.
• Follow-up was done at three months intervals.

26
Practice Point

• Practice Point Is there a role to continuing
  chemotherapy as a maintenance in a patient who
  has achieved stable disease response?
• There is really no data to support either option.
• Do you treat continuously until disease
  progression?
• Do you treat to stable disease, break and wait
  for recurrence?
• If so, do you restart the same chemotherapy
  regimen or start 2nd line therapy?

27
Mr. D.B.

• Six months later, Mr. D.B. returned to the
  cancer clinic complaining of abdominal pain.
• The liver was slightly enlarged and the CEA
  increased to 123 µg/L.
• Abdominal CT scan revealed progressive disease.
• Patients performance status was ECOG 1.

April 05
October 05
28
Mr. D.B.

• Second-line treatment was initiated with
  infusional 5FU/ LV/ oxaliplatin (FOLFOX
  regimen).
• At the beginning, treatment was well tolerated
  with no more than brief digital cold dysesthesia,
  
• Persistent discomfort became obvious as the
  treatment continued.

29
Practice Point

• Practice Point What, if anything, can be done
  for prophylaxis against Oxaliplatin associated
  cold induced dysesthesias?
• Stop-and-go technique of alternating Oxaliplatin
  with no Oxaliplatin
• Venlafaxine (Effexor) has previously shown
  therapeutic effects for the management of chronic
  and neuropathic pains. A dose of 50 mg of
  venlafaxine was given orally at the beginning of
  the oxaliplatin infusion. Patients did not
  experience any or very low paresthesias, even in
  the cold. (Durand, J., Anticancer Drugs. 2003
  Jul14(6)423-5.)

30
Practice Point

• Practice Point What, if anything, can be done
  for prophylaxis against Oxaliplatin associated
  cold induced dysesthesias?
• Calcium and Magnesium Infusion
• A retrospective cohort of 161 patients treated
  with oxaliplatin 5-fluorouracil and leucovorin
  for advanced colorectal cancer, with three
  regimens of oxaliplatin (FOLFOX4, 6, 7)
• Ninety-six patients received infusions of Ca
  gluconate and Mg sulfate (1 g) before and after
  oxaliplatin (Ca/Mg group) and 65 did not.
• Only 4 of patients withdrew for neurotoxicity in
  the Ca/Mg group versus 31 in the control group
  (P 0.000003).
• The tumor response rate was similar in both
  groups.
• The percentage of patients with grade 3 distal
  paresthesia was lower in Ca/Mg group (7 versus
  26, P 0.001). Acute symptoms such as distal
  and lingual paresthesia were much less frequent
  and severe (P 10-7), and pseudolaryngospasm was
  never reported in Ca/Mg group.
• At the end of the treatment, 20 of patients in
  Ca/Mg group had neuropathy versus 45 (P
  0.003). Patients with grade 2 and 3 at the end
  of the treatment in the 85 mg/m(2) oxaliplatin
  group recovered significantly more rapidly from
  neuropathy than patients without Ca/Mg.
• Gamelin, L., Clin Cancer Res. 2004 Jun 1510(12
  Pt 1)4055-61

31
Treatment

• After twelve cycles of chemotherapy
• Disease assessment by CT scan showed a 70
  decrease in the size of liver metastases.
• CEA levels decreased to 31 µg/L.
• Mr. D.B. felt well and decided to take a four
  month vacation that had been planned prior to his
  diagnosis of cancer.
• Chemotherapy was stopped.
• He did well except for persistent symptom of
  neuropathy.

32
Treatment

• Upon his return, his CEA level had increase to
  340 µg/L
• CT scan results showed evidence of disease
  progression.
• He had mild discomfort in his upper abdomen
• He was eating well, maintaining his weight
• Displayed a good performance status (ECOG 1).
• He met his oncologist and they discussed further
  medical options.
• He understood very well the medical facts about
  his prognosis and was willing to undergo other
  treatments if they could extend his life while
  maintaining the quality.

33
Treatment

• Physical Examination
• Good general appearance although underweight
• Mucosa and skin is normal, not jaundiced
• Weight 66 kg
• No palpable lymph nodes
• Liver palpable 2 cm under the right costal margin
• No clinical evidence of ascites

34
Treatment
Laboratory Data
35
Practice Point

• Does one continue the same FOLFOX6 regimen or
  assume disease resistance and consider 3rd line
  therapies?
• What do you do in your practice?
• Treatment options to be discussed with Mr. D.B.
  
• Continue FOLFOX6
• Participation in a clinical study using new drugs
  or new combination if available
• Treatment with Cetuximab or and Bevacizumab
• Best supportive care

36
Practice Point

• At any step along the way here, the patient could
  have been considered for therapy with Bevacizumab
  and Cetuximab
• For this patient, no clinical trials were
  available at the time
• Data and consideration of the biologic therapies
  will be considered in subsequent cases.

37
First Line TherapyBevacizumab

• The only randomized phase III trial of first line
  Bevacizumab was presented at ASCO 2003.
• It added 5 months survival with a duration of
  response of 3 months over IFL alone.
• First line therapies using FOLFOX4/6, FOLFIRI and
  Xeloda combinations currently underway

Hurwitz H, et al. N Engl J Med. 2004 Jun
350(23)2335-42
38
First Line TherapyCetuximab

• First line studies being completed, small numbers
  (ie 80 patients)
• Cetuximab FOLFOX4
• RR 81, Disease control 98
• Cetuximab FOLFIRI
• PR 43 Disease control 88

Abstract 3512, Proc ASCO 2004 Abstract 3513, Proc
ASCO 2004
39
Summary

• Many treatment options are now available for
  patients with metastatic colorectal cancer.
• In the mid 1980s the overall survival was 6
  months in patients treated with supportive care
  alone.
• The survival is now increased to almost 2 years.
  The superior efficacy and toxicity profile of
  three-drug regimens (e.g. 5-FU/ LV and irinotecan
  or oxaliplatin) have been clearly shown.
• Addition of biologics will only improve on these
  numbers

40
References

• Grothey A, Sargent D, Goldberg RM, et al.
  Survival of patients with advanced colorectal
  cancer improves with the availability of
  fluorouracil-leucovorin, irinotecan, and
  oxaliplatin in the course of treatment. J Clin
  Oncol. 2004 Apr 122(7)1209-14.
• Efficacy of intravenous continuous infusion of
  fluorouracil compared with bolus administration
  in advanced colorectal cancer. Meta-analysis
  Group In Cancer.J Clin Oncol. 1998
  Jan16(1)301-8.
• Goldberg RM, Sargent DJ, et al. A randomized
  controlled trial of fluorouracil plus leucovorin,
  irinotecan, and oxaliplatin combinations in
  patients with previously untreated metastatic
  colorectal cancer. J Clin Oncol. 2004 Jan
  122(1)23-30. Epub 2003 Dec 09.
• Douillard JY, Cunningham D, et al. Irinotecan
  combined with fluorouracil compared with
  fluorouracil alone as first-line treatment for
  metastatic colorectal cancer a multicentre
  randomised trial. Lancet. 2000 Mar
  25355(9209)1041-7. Erratum in Lancet 2000 Apr
  15355(9212)1372.
• Tournigand C, Andre T, et al. FOLFIRI followed by
  FOLFOX6 or the reverse sequence in advanced
  colorectal cancer a randomized GERCOR study. J
  Clin Oncol. 2004 Jan 1522(2)229-37. Epub 2003
  Dec 02.
• Van Cutsem E, Twelves C, et al. Oral capecitabine
  compared with intravenous fluorouracil plus
  leucovorin in patients with metastatic colorectal
  cancer results of a large phase III study. J
  Clin Oncol. 2001 Nov 119(21)4097-106.
• Hurwitz H, Fehrenbacher L, et al. Bevacizumab
  plus irinotecan, fluorouracil, and leucovorin for
  metastatic colorectal cancer. N Engl J Med. 2004
  Jun 350(23)2335-42.
• Cunningham D, Humblet Y, Siena S, et al
  .Cetuximab monotherapy and cetuximab plus
  irinotecan in irinotecan-refractory metastatic
  colorectal cancer. N Engl J Med. 2004 Jul
  22351(4)337-45.
• Bruce J Giantonio, Paul J Catalano, Neal J
  Meropol et al. High-dose bevacizumabin
  combination with FOLFOX4 in patients with
  previously treated advanced colorectal cancer
  results from the Eastern Cooperative Oncology
  Group (ECOG) study E3200 J Clin Oncol
  200523(June 1 Suppl.)1s (Abstract 2)