overview of advances in treatment of gastrointestinal ......9) if a patient is not candidate for...

Overview of Advances in Treatment of Gastrointestinal Malignancies

Dre Eve St-Hilaire, Hematologist-oncologist October 24th 2014

Support de recherche / Research support

Aucun / None

Employé /

Employee

Aucun / None

Consultant Aucun / None

Porteur d’action /

Major stock holder

Aucun / None

Honoraires /

Honoraria

Roche, Novartis, Bristol-Myers Squibb, Celgene, Pfizer

Comité consultatif scientifique /

Scientific advisory board

Novartis, Pfizer, Lundbeck, Celgene, Janssen, Sanofi, Alexion, Roche

Utilisation de médicaments hors indication / Off label use of medications

Aucun / None

Possible Conflicts of Interest

(

Plan

Rectal cancer, adjuvant

Colorectal cancer follow up after adjuvant treatments

Metastatic colorectal cancer

Extended RAS mutation analysis

First line treatments

Chemotherapy breaks

Metastatic pancreatic cancer

First line treatments

Second line treatments

Rectal cancer adjuvant

Staging with EUS or MRI

Stage 1 (T1-T2, N0) Stage 2 (T3-T4, N0) Stage 3 ( any T, N+)

Resection

Pathological stage

Stage 1 Stage 2-3

No adjuvant tx Adjuvant tx

Chemotx x 2 months Chemoradiation Chemotx x 2 months

Neoadjuvant chemoradiation (infusional 5FU or Capecitabine

Resection

4 months adjuvant chemotx

FOLFOX-4 or 5FU ⁄ cape ??

AIO-94

OS DFS

NEJM 351;17 october 21, 2004

AIO-94

Local recurrence Distance recurrence

NEJM 351;17 october 21, 2004

What do we know from previous trials ?

Infusional 5FU and Capecitabine are equal During radiation treatment

As adjuvant chemotherapy

There is some evidence that, compare to bolus 5FU, the infusion during radiation increases the chances of pCR. It as also been demonstrated to be superior in adjuvant chemoradiation

The addition of oxaliplatin during radiation does not lead to better rate of pCR Should not be considered as a standard

Even if there is still uncertainty about the use of adjuvant chemotherapy after neoadjuvant treatment, it is considered a standard in North America (even for patients with pCR)

Problematic for adjuvant chemotherapy ?

Use of FOLFOX-4 in rectal cancer was based on extrapolation of data from colon cancer (MOSAIC trial)

3 randomised trials presented at ASCO 2014 about oxaliplatin use in rectal cancer

ADORE trial

PETACC-6 trial

Trials AIO-04 (phase 3 N=1265)

ADORE (phase 2 N= 321)

PETACC 6 (phase 3 N= 1094)

Staging* Clinical Pathological Clinical

Investigational arm treatment

mFOLFOX-6 FOLFOX-4 CAPEOX

Control arm treatment

Bolus 5FU Bolus 5FU Capecitabine

3y DFS 75,9 vs 71,2% (HR 0,79; p=0,030)

71,6 vs 62,9% (HR 0,63; p=0,032)

74,5 vs 73,9 % (NS)

M follow up 50 months 38,2 onths 31 months

Stage 3 74% 63,8% 71%

Benefit for stage 2 (vs 3)

HR 0,56 (vs 0,91) HR 0,74 NS (vs 0,60 significant)

1,04 (vs 0,99) NS

Received all adjuvant cycles

79% 96,6% 57%

*Clinical = before neoadjuvant Pathological= after neoadjuvant

Conclusion (1)

FOLFOX as an adjuvant treatment (4 months) for rectal cancer improves 3 years DFS

CAPEOX showed no difference compare to Capecitabine

Imbalance between arms

More toxicities, fewer patients completed treatments

Before ASCO 2014

FOLFOX-4 for stage 3 only

Should we now give FOLFOX to stage 2 ?

Conclusion (2)

Majority of patients in the 3 trials were stage 3

Subgroup analysis for stage 2 (not significant in some trials)

ADORE trial is a phase 2, are these results definitive ?

What about older patients ??

Conclusion (2)

My approach

FOLFOX-4 if

clinical or pathological stage 3

young patients with stage 2 ?

Minimal downstaging after neoadjuvant treatments

Follow up of colorectal cancer after adjuvant therapy :ASCO Guidelines Update

1) Surveillance should be guided by presume risk of recurrence and functional status of patient where early detection of disease would lead to aggressive treatments including surgery

2) Medical history, physical exam and CEA q 3-6 months x 5 years

Frequency of visits should be driven by the fact that 80% of the recurrence are in the first 2,5 years

3)Abdominal and chest imaging for 3 years

For higher risk patients, q 6-12 months

JCO 2013;31(35):4465

4) For patients with rectal cancer, a pelvic CT is also recommended (annually for 3-5 years, depending on risk)

If no radiation, rectosigmoidoscopy q 6 months x 2-5 years

5) A surveillance colonoscopy should be performed approximately 1 year after initial surgery and then

q 5 years if normal

If colonoscopy incomplete before surgery, should be done as soon as adjuvant treatment completed (not wait the 1 year time point)

6) A new, persistent or worsening symptoms warrant the consideration of a recurrence

JCO 2013;31(35):4465

7) Despite the lack of high-quality evidence, it is reasonable to counsel patients on maintening a healthy body weight, being physically active and eating a healthy diet

8) A treatment plan from the specialist should be sent to the patient’s other providers

9) If a patient is not candidate for systemic therapy because of comorbidities, no surveillance should be done

JCO 2013;31(35):4465

Metastatic colorectal cancer: KRAS analysis

KRAS in colorectal cancer

www.pathologyoutlines.com

RAS mutations as exclusion for anti EGFR therapy in metastatic CRC 

Presented By Sabine Tejpar at 2014 ASCO Annual Meeting

Metastatic colorectal cancer: first line treatment

CALGB/SWOG 80405: Phase III trial of FOLFIRI or FOLFOX with Bevacizumab or Cetuximab for patients w/ KRAS wild type untreated metastatic adenocarcinoma of the colon

or rectum 

Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: FINAL DESIGN

CALGB/SWOG 80405: Overall Survival

CALGB/SWOG 80405: Progression-Free Survival (Investigator Determined)

CALGB/SWOG 80405: Conclusions


Conclusion (1)

The results will have to be presented with the extended RAS analysis to confirm which combination is superior

EGFR inhibitors in Canada

Mainly used as a 3rd line option

Final recommendation of pCODR January 2014: Cetuximab not recommended for first line

Decision might change with the recent results

First line use not currently funded by provinces, under consideration by some

Metastatic colorectal cancer: Continuation of chemo vs chemo breaks ??

Background

In United States ( and some Canadian provinces), the first line treatment choice for mCRC is FOLFOX and Bevacizumab

For responders, prolong treatments = peripheral neuropathy

Different strategies studied to decrease or control this problem

OPTIMOX 1 and 2 trials were done before the use of Bevacizumab (chemo alone)

No difference in OS or PFS

Tx with FOLOFX 7 = 3 months

No difference in OS PFS 8,6 vs 6,6 months

No difference in OS or PFS

Tx with FOLOFX 7 = 3 months

No difference in OS PFS 8,6 vs 6,6 months

Based on Optimox 2, many oncologists give oxaliplatin breaks,

but tend to continue FL and bevacizumab

mCRC with response or stability after chemotherapy

Continuation Chemotherapy break

Toxicities Hospital visit Cost for patient Cost for the hospital Effect on survival ?

Better quality of life Effect on survival ?

Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal

cancer Final results and subgroup analyses of the phase 3 CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG)

Presented By Miriam Koopman at 2014 ASCO Annual Meeting

No overall survival benefit

Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line

treatment for patients with metastatic colorectal cancer (mCRC): A non-inferiority phase III trial: AIO 0207

Presented By Dirk Arnold at 2014 ASCO Annual Meeting

AIO 0207: Treatment algorithms


AIO 0207: Treatment algorithms


Hypothesis:

No treatment OR bevacizumab alone would be

NON-INFERIOR compare to FL and bevacizumab

TFS: All arms


Difference between Bev and no therapy is 12 days

Non-inferiority, vs. FP/Bev


End of maintenance: Main reasons


OS from start of maintenance


Summary


How to interpret these results ?

Compare to chemotherapy breaks, maintenance failed to show

OS benefit

Meaningful TFS for patients

Maintenance increase

Cost (for patients and institutions)

Potential of side effects

Data would have been more convincing if superiority design used

Decision as to be individualised

Pancreatic cancer

Background

Only 15-20% resectable at presentation

Close to 90% of diagnosed patients will die from their disease

NEJM 371:11 september 11 2014

Background

For metastatic pancreatic cancer, gemcitabine was the most frequently use chemo for metastatic patients until…

1) FOLFIRINOX

2) Gemcitabine+ nab-paclitaxel

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer

Inclusion criteria

18-75 yo

ECOG 0-1

Measurable disease

Bilirubin less then 1,5 x N

Primary endpoint = OS

NEJM 2011;364:1817

NEJM 2011; 364:1817

NEJM 2011; 364:1817

Median OS: FOLFIRINOX 11,1 months Gemcitabine 6,8 months

NEJM 2011; 364:1817

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine

Inclusion criteria

18 yo or more

Karnofsky 70 or more

Measurable disease

Bilirubin at or below upper range of N

Primary endpoint = OS

NEJM 2013;369:1691

NEJM 2013; 369:1691

NEJM 2013;369:1691

Conclusion (1)

FOLFIRINOX

central KT require (not with gem-nab paclitaxel)

46 hours of 5fu infusion

More nausea, more risk of febrile neutropenia BUT

Seems to be more active

QoL analysis

At 6 months, degradation in QoL in 31% with FOLFIRINOX (vs 66%)

Gemcitabine+ nab-paclitaxel

More patients able to tolerate it

Conclusion (2)

My approach

3 categories for metastatic patients

Young and fit (good performance status)= FOLFIRINOX

Unfit = gemcitabine alone or palliative care

Somewhere in the middle = gemcitabine- nab paclitaxel

Metastatic pancreatic cancer: second line therapy

PANCREOX (poster from Dr Charlene Gill, ASCO 2014)

CONKO-3 trial showed a OS benefit for OFF (oxaliplatin based regimen) after gemcitabine treatment

Trial to confirm if the same population would benefit from mFOLFOX-6

PANCREOX trial

Questions ?

overview of advances in treatment of gastrointestinal ......9) if a patient is not candidate for...

Documents