When No Treatment is the Best
Treatment: Observation and
Intermittent Strategies
Brian I. Rini, M.D.
Department of Solid Tumor Oncology
Cleveland Clinic Taussig Cancer Center
2
Observation and Intermittent Strategies
• Indolent biology of RCC in a subset of patients
• Initial Observation
• Taking a break in systemic treatment
– Retrospective experience
– Prospective trial
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RCC is an Inherently Diverse Disease
Months
Initial Observation (vs. IFN) in 73 mRCC pts
• Median PFS about 2 months
• 10% of patients had not progressed by 12 months
• Overall response rate to IFN was 15%, identical to
contemporary group without initial observation
RT Oliver et al. BJU 1989
Delayed start of systemic therapy
•
Good performance status patients with ‘low-volume’, ‘slowgrowing’ and asymptomatic disease are candidates after
risk/benefit discussion with the patient.
• A prospective study has been completed at The Cleveland Clinic,
Fox Chase, USC, Vall d'Hebron and Royal Marsden
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What is the natural growth rate?
What is the clinical outcome when treatment is started?
Anxiety/depression associated with observation?
Immunomodulatory cell profile
• When to start treatment?
– Increased pace of disease, new organ sites, symptoms from disease or
MD/patient anxiety
Results (n=52)
• Pt characteristics
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median age: 67 (range, 47-88)
75% male
94% ECOG 0
96% clear cell
8% prior metastasectomy
Heng risk group favorable/intermediate 26%/74%
Baseline tumor burden (RECIST 1.0) was 3.2cm (0.8-19.6cm)
• Median time on observation until systemic therapy was started
was 14.1 months (95% C.I. 10.6-19.3), with estimated 12 month
and 24 month rates of continued surveillance of 58% and 33%,
respectively.
Rini et al. ASCO 2014
• Median change in tumor burden on study was 0.8cm (0-6.5cm);
relative change +34% (0-311%) and median growth rate 0.14
cm/month (0-1.75).
• 31 pts have come off observation; 25 pts received systemic tx
• Pts with baseline tumor burden ≤1.5 cm vs. >1.5 cm had a median
observation period of 31.6 months vs. 13.8 months (p=0.06).
• Neither location nor number of metastatic sites impacted the
length of observation.
• Anxiety/depression were not prevalent at baseline, and did not
worsen over time
• There were no significant changes in immunologic parameters
Breaks in Systemic Therapy:
Retrospective Experience
• All patients with mRCC who had a period of
drug cessation for ≥3 months for reasons
other than progressive disease were
reviewed.
• Patients could receive treatment breaks with
multiple sequences of therapy (defined
sequentially as treatment A, B, C etc.)
Mittal et al. ASCO 2014
Results: Baseline characteristics (n=112)
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75% male/ 25% female
Median age at diagnosis: 56
95% clear cell histology
19% pts. had received prior systemic therapy
By Heng criteria, 48% pts. were favorable,
48% intermediate and 4% poor risk.
Treatment
Number of pts
starting
treatment
Median duration
of therapy (months)
(95% CI)
Number of pts Median duration of
on treatment
break (months)
break
(95% CI)
A
112
13.5 (11-16.4)
112
16.8 (12.5-26.4)
B
68
16.1 ( 11.4-20)
24
9.5 (4.6-10.3)
C
43
14.8 ( 12-17.2)
10
7.1
D
15
13.8 (5.7-18.6)
3
15.9
• Treatment A primarily included sunitinib (55%), sorafenib (13%), or bevacizumab
in combination with temsirolimus (10%) / interferon (9%)
• Common reasons for breaks were toxicity/AEs (57%) & physician choice (26%)
• Achievement of CR prior to the initial treatment break (n=14) was associated with
a longer surveillance period (p=.0004)
A Phase II Study of Intermittent
Sunitinib in Previously Untreated
Patients with Metastatic Renal Cell
Carcinoma
Study Schema
NO Tumor
burden
decrease
by ≥ 10%
Metastatic clear
cell RCC; no prior
systemic therapy
Continue
therapy or
change therapy
if PD
Sunitinib 50 mg
4/2 x 4 cycles
Tumor burden
decrease ≥ 10%
Sunitinib x 2
cycles
Hold sunitinib.
Re-start with ≥ 10%
increase in tumor
burden from prebreak tumor burden
Results
 Thirty-seven pts were enrolled. Twenty pts were eligible for intermittent
therapy and all pts (100%) entered the intermittent phase.
 Pts were not eligible for intermittent sunitinib due to PD (n=13), toxicity
(n=1) or w/d of consent (n=2) prior to end of cycle #4.
 Sixteen pts (80%) had ≥ 10% TB increase off sunitinib with a median
(range) increase of 1.5 cm (0.6-2.9 cm) compared to the TB immediately
prior to stopping sunitinib.
 Four pts (20%) did not have ≥ 10% TB increase off sunitinib (3 pts after
the 1st off period; off for 12, 9 and 5 months to date and 1 pt after the 2nd
off period; off for 8 months prior to restarting sunitinib).
Results
 Most pts exhibited a stable saw tooth pattern of TB reduction on
sunitinib and TB increase off sunitinib.
To date, patients have been in the intermittent phase for a median of 7.7
months (range, 1.4-25.8). During the intermittent period patients have
received 61 cycles of sunitinib compared to156 cycles they would have
been expected to have been given.
 Four pts have discontinued intermittent tx
 One w/d consent at end of first off period.
 Three pts were taken off extended breaks due to clinical and/or
radiographic progression at the end of the first off period
 Toxicity was typical for sunitinib and completely resolved during
treatment breaks.
Representative Tumor Burden Changes
Stable saw tooth pattern
Representative Tumor Burden Changes
Declining saw tooth pattern
Representative Tumor Burden Changes
Increasing saw tooth pattern
Representative Tumor Burden Changes
Persistent TB decline off therapy
Aggregate Tumor Burden Changes for 8 Patients in
the Intermittent Phase for the Equivalent of > 3
“Stop-Start” Periods
Conclusions
• Kidney cancer has a biologically unique spectrum
of disease, including a subset of patients with
inherently indolent growth.
• Strategies to take advantage of an indolent growth
rate in some patients, including initial observation
and intermittent therapy, can better balance risk and
benefit.
• Defining the subset appropriate for these maneuvers
requires further study.