# Presentation: 541448

## Potential Use of Biomarkers or QoL Parameters in Colorectal Cancer Drug Approval

- Charles D. Blanke, M.D., F.A.C.P.
- Director, G.I. Malignancies Program
- Oregon Health & Science University Cancer Institute

## Biomarkers and QOL in CRC Drug Approval

- Biomarkers
- CEA
- CA 19-9 + others
- QoL issues
- How symptomatic are modern advanced disease patients?
- Instruments
- Problems with QoL analysis
- Recommendations + group discussion

## CEA: Background

- Serum glycoprotein member of the immunoglobulin gene superfamily
- Intercellular adhesion molecule promoting aggregation of malignant cells; involved in immunity, apoptosis, and metastasis
- Elevated in a variety of inflammatory diseases
- Malignant: Breast, lung, gastric, cervical, kidney, bladder carcinomas		      Melanoma									      NHL
- Benign:     Cirrhosis, gallstones, emphysema, PUD, diabetes
- Elevated in ~85% of metastatic CRC patients

## CEA Background (cont.)

- Most, if not all, CEA data precede modern drugs
- ASCO recommendations for use in metastatic disease:
- CEA is marker of choice for monitoring CRC
**Present data are insufficient to use CEA alone to monitor response**
- But, 2 values > baseline = progression, even without corroborating x-rays

## Changes in CEA with Cytotoxic Chemotherapy

- Analysis of sensitivity and specificity for objective response and progression available-see me later
- Positive predictive value for  CEA + true objective response:		53%
- Negative predictive value for  CEA + response:			    	100%
- PPV for   CEA + progressive disease:						85-100%
- NPV for   CEA + progressive disease:						70%

## CEA in CRC: Translation

- You can have a CEA response without a true ORR
- You can’t have a true ORR without a CEA response
- Easier to turn CEA production off than to actually kill cells
- If you kill cells, CEA falls
- You can progress without CEA progression
- You cannot have CEA progression without x-ray PD
- CEA progression may occur months before change on CT
- X-ray PD without CEA PD particularly common with growth of  anaplastic tumor clones
**CEA response correlates with survival even in absence of ORR**

## Additional Caveat: Hepatotoxicity

- Liver is major site of clearance for CEA
- Moertel adjuvant trial: 39.6% of patients on 5FU/levamisole sustained hepatotoxicity
- 19% of patients with hepatotoxicity had CEA rises, in the absence of disease recurrence
- Does not occur with 5FU alone, but ??? effect of new drugs or combinations

- Moertel JCO 11:2386, 1993

## Quality of Life: A multidimensional construct encompassing complete information on the impact of disease or its treatment on a patient’s usual or expected physical, psychological, and social well-being 

## How Symptomatic is the Average Advanced Disease CRC Patient?

- All standard texts reviewed: “Signs and symptoms are *usually* present”
- References for that statement _never_ supplied
- Seer data: No help
- Trial data: Little help-skewed to less symptomatic patient or those with minor symptoms
- Review of mito C and IFL trials: 90% asymptomatic
- Cunningham irinotecan arm 69% “with sx”, but 86% WHO PS 0 or 1
- My review of multiple series/trials: < 50% had significant sx
- With modern early diagnosis, we may have to focus more on delaying symptoms than treating them

## How Do We Measure QOL in CRC Patients?

- Generic instruments
- Cancer-specific instruments
- Symptom-focused questionnaires
- Clinical benefit response

## Generic Instruments

- Multi-item scales used across a wide-range of chronic-disease populations
- Examples: Sickness Impact Profile, Nottingham Health Profile
- Allow for comparisons of populations with different health conditions
- Insensitive for effects of specific interventions

## Cancer-Specific Instruments

- Address problems specific to a population with cancer
- Examples: EORTC Quality of Life Questionnaire (QLQ)-C30, Functional Assessment of Cancer Therapy-General version (FACT-G), Functional Living Index-Cancer (FLIC)
- May have functional, symptoms, global scales +/- single items assessing specific symptoms
- Have been used in large series which included CRC patients

## Symptom-Focused Questionnaires

- Often used with Cancer Specific Instruments, or other HRQoL questionnaires
- Some add modules for specific issues not covered by the core instrument tumor-site-specific subscales (FACT-C)
- More sensitive and specific for clinically important QoL differences
- EORTC QLQ-CR38 and FACT-Colorectal (FACT-C) designed for colorectal cancer
- Sub-sub modules being developed for CRC mets to the liver
- NB: Symptoms have many measurable dimensions, including severity, frequency, functional consequences, and distress perceived by patient

## Clinical Benefit Response

- Composite of status encompassing pain, functional impairment (PS), and weight loss
- Defined as improvement in at least one parameter, without worsening of others
- Requires sustained improvement (_>_ 4 weeks) over baseline

## Interpretation and Application of HRQoL Scores

- Mean scores for a group can be compared with “normative values” for a sample of cancer patients
- Changes in scores within a group can be assessed over time to determine effect of disease or treatment
- Differences in scores can be compared between two groups given different treatments

## Summary of HRQoL Data in CRC

- _Baseline_ QoL is itself a major prognostic factor
- Independent predictor of overall survival; stronger than PS!
- HRQoL is a good global way to balance toxicity vs. therapeutic benefit
- Review articles claim QoL improves with chemotherapy:
- Occurs in 25-33% of symptomatic patients overall
- QoL “maintained” in another 25%
- In patients without symptoms, chemotherapy not likely to affect QoL, unless adversely
- Response to chemotherapy does not influence QoL

## IFL vs. FL: Front-Line

- EORTC QLQ v2 used
- No “significant differences” between arms
- Smaller decrease in activities of daily living- IFL

- Saltz NEJM 343:905, 2003

## IFL vs. BSC: Second-Line

- EORTC QLQ-C30
- Rate of return 59-62%
- Later definitive deterioration QoL in “I” arm

- Cunningham Lancet 355:1041, 2000

## FOLFOX vs. LV5FU2: Front-Line

- EORTC QLQ-C30 v2.0
- 84% “participated” in analysis
- Overall QoL comparable
- Longer time to deterioration of global health-FOLFOX
- Response did not influence QoL

- de Gramont JCO 18:2938, 2000

## Problem: We Don’t Know that Palliative Chemotherapy Truly Improves QOL

- CRC Collaborative Group meta-analysis
- 13 RCT comparing palliative chemotherapy with BSC
- Chemotherapy included any single drug or combo on any schedule
- 3 trials: QOL better with chemotherapy; 2 found no differences between chemotherapy + control; 1 (ineffective chemotherapy) found QOL worse with therapy
- Conclusion: Data on the effect of chemotherapy on QOL are inadequate to draw firm conclusions about the palliative effect

- CRC Collaborative Group BMJ 321:531, 2000

## Problem: Inconsistent Methodologies  with HRQoL Assessment

- Missing data ubiquitous
- Few patients complete all serial questionnaires
-  May lead to bias, if ill/progressing patients are ones not filling out forms
- Questions may not be agent/toxicity specific/sensitive         (e.g., neuropathy not part of standard CRC questionnaires)
- Patients filling out QoL as part of studies may not be representative of general CRC population
- PS 0 patients with high initial QoL will not improve further
- Reliability depends on whether physician or patient fills out forms

## Problems with HRQoL Assessment (cont.):

- Composite scores usually generated
- Score on loss of appetite scale may not have same significance as identical score on the pain scale
- Hard to interpret magnitude of QoL changes between patients
- May not be sensitive enough to differentiate progression from chemotherapy toxicity
- Timing of QoL assessment affects results, but there are no rules when to do testing if two regimens are given on different schedules
- Changes in scores may not reflect important physical/clinical change, if tool is dominated by psychosocial domains (historically less sensitive to treatment-induced effects)

## Problem: HRQoL Reflects Efficacy and Safety (Toxicity)

- While an advantage for assessing overall impact of drug , leads to same FDA approval problem as using time-to-event
- In theory, QoL could improve in absence of effective drug (patient “doing something”), especially in an asymptomatic patient
- QoL could worsen even with major response, with a toxic drug
- Can we use clinical benefit response (CBR) instead?
- Worked for gemcitabine in pancreatic cancer
- It’s easy

## Problems with Use of CBR in CRC 

- Does not take into account all disease-related symptoms of importance
- Would be hard to develop CRC-specific CBR
- There is only fair consensus among experts which symptoms are important (fever, fatigue, pain, weight loss, diarrhea, abdominal swelling, appetite, constipation, etc.) and/or even common
- Some symptoms may require surgery to fix
- In non-pancreatic GI sites, CBR does not correlate with subjective response or QoL anywhere near as well

## Additional Problems with Using Symptom Assessment

- There has been lack of consistency in terminology used to discuss specific symptoms
- e.g., does fatigue = tiredness, sleepiness, generic decrease in PS?
- Clinical significance of improvement depends on magnitude of change, but also severity at start
- e.g., “50%” improvement in pain scale from 2 to 1 would qualify as CBR, but probably not important

## Additional Problems with Using Symptom Assessment (cont.)

- There is no good research definition for what counts as symptom “control”
- Changing definition alone has changed conclusions of clinical trials (RTOG Osseous Metastasis Trial)
- Tools not sensitive enough to evaluate all items which may be important: time of onset of relief, duration of relief, how significant relief is to patient, whether *severe* symptoms are relieved

## Colorectal Cancer Drug Approval

|  | Strong correlation with standard parameter1 | Stand-alone benefit |
| --- | --- | --- |
| CEA | +/- | - |
| QOL | +/- | +2 |

- 1Objective response rate, overall survival
- 2*If* enough patients symptomatic to start

## Biomarkers: Conclusions

- CEA (and all markers) overestimate responses and underestimate progressive disease
- Despite association of fall with improved survival, CEA change is clumsy, and I recommend against use in CRC drug approval
- ASCO recommends against using CA 19-9, DNA ploidy, flow cytometry characteristics, lipid-associated sialic acid, p53, ras, in monitoring treatment of colorectal cancer
- Certainly could not use markers to monitor new drugs, unless effect of drugs on LFT fully characterized (Moertel)

## HRQoL Assessment:Conclusions

*Baseline* HRQoL does correlate with other important endpoints (e.g., survival)
- Jury out on whether *change* in QoL reliably occurs with effective chemotherapy (my bias: probably does)
- Insensitive for discriminating between two drugs or regimens

## HRQoL Assessment:Conclusions (cont.)

- Improvements in QoL potentially multifactorial (tumor shrinkage, decrease in symptoms, joy at “fighting cancer”) and tools are unable to discriminate reason for benefit
- Worsening in QoL potentially multifactorial (progression, toxicity, concomitant divorce)
- Cannot adequately separate efficacy and safety

## Clinical Benefit Response: Conclusions

- The most promising, but needs significant tweaking before useful
- Must account for all major common symptoms in CRC patients
- Does not allow assessment of drug in asymptomatic patients (unless we use a “time-to-onset-of-tumor-related -symptoms”, which does not have good supportive data)
- Would likely be a “stand-alone” factor (i.e., of significant patient advantage by itself), rather than a correlate of other benefit (survival)
- FDA should query specific QoL experts if found worthy of future exploration (e.g., David Cella)

## DISCUSSION