Definitive Radiation Therapy to the Primary Disease Site · Cancer surgically removed Experiment 3 Systemic endocrine instigation of indolent tumor growth requires osteopontin Perioperative

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Definitive Radiation Therapy to the Primary Disease Site

Is the horse really out of the barn?

Brendan Coutu, MD

Cancer: An Evolving History

1894 1980 1995 2019

William Halsted: “Contiguous, Orderly

Spread Theory”

Bernard Fisher “Systemic Theory”

Samuel Hellman & Ralph Weichselbaum:

“Spectrum Theory”

Curing Metastatic Disease with RT: Myth or Reality?

Improvements in Systemic Therapy

Advances in Imaging and Detection

Improvements in Radiation Therapy

Evolving Ability to Combat Metastatic Disease

Evolving Understanding of Metastatic Disease

William Halsted: Centrifugal Theory

Anesthesia (Ether)

Anatomy(Andreas Vesalius)

Sir William Halsted1852-1922

Father of the Radical Mastectomy

Contiguous, Orderly Spread Theory

Radicalism

Latin = root; meaning to dig out the buried, subterranean roots of cancer (also means aggressive, innovative, and

brazen).

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The Evolution of the Radical Mastectomy

Mastectomy (Pec Major/Minor)

Axillary LN

Supraclavicular LN

Cervical LN

Number Number Alive at 5

Years

Localizedto breast

only60 45 (75%)

Involving Lymph nodes

45 3 (7%)

Halsted’s data presented to the American Surgical Association in

Washington, D.C. in 1907

The Evolution of the Radical Mastectomy

Mastectomy (Pec Major/Minor)

Axillary LN

Supraclavicular LN

Cervical LN

Number Operated

Upon

Number Alive at 5

Years

Localizedto breast

only60 45 (75%)

Involving Lymph nodes

45 3 (7%)

Halsted’s Data presented to the American Surgical Association in

Washington, D.C. in 1907

“But even without the proof which we offer, it is, I think, incumbent upon the surgeon to perform in many cases the

supraclavicular operation” Halsted, 1907

William HalstedRadical Mastectomy

Alexander BrunschwigPelvic Exenteration

Harvey CushingGlioblastoma Resection

Hugh HamptonRadical Prostatectomy

Evarts GrahamPneumonectomy

William Halsted: The Father of Oncologic Surgery

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William HalstedRadical Mastectomy

Alexander BrunschwigPelvic Exenteration

Harvey CushingGlioblastoma Resection

Hugh HamptonRadical Prostatectomy

Evarts GrahamPneumonectomy

“Undoubtedly, if operated upon properly the condition may be cured locally, and that is the only point for which

the surgeon must hold himself responsible” –Baltimore, 1931

William Halsted: The Father of Oncologic Surgery

“If the disease was so advanced that one had to get rid of muscles in order to get rid of the tumor, then it had already spread through the system” –George Crile

Bernard Fisher: Systemic Theory

Systemic Theory NSABP B-04First Reported in 1981

Fisher et al., 2002

Bernard Fisher1927-2014

Father of Local Therapy Clinical Trials

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The Effect of Systemic Theory on Staging

AJCC 8th edition


This shows correlations between systemic and local therapies.

Until point A, the role of local therapy increases as systemic

therapy improves. However, after point A, the role of local therapy

decreases as systemic therapy improves, as all cancerous lesions can be cured by systemic therapy at point B.

Systemic Therapy Cures Metastatic Cancer

vinblastine + bleomycin

Samuels, et al., 1976

• By bringing patients to the brink of death, we have cured metastatic testicular cancer.• In the 1970’s it was logical to believe that the cure of

cancer was less than a decade away…• Unfortunately, through thousands of clinical trials we have

come to the conclusion that the balance metastatic cancer cannot be cured by systemic therapy

• Complete response with targeted therapy or immunotherapy continues to be elusive• Upon progression, patients are often switched to

second line systemic options

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The Introduction of Oligometastasis: Spectrum Theory

Samuel Hellman & Ralph WeichselbaumUniversity of Chicago, 1995

Hellman et al., 1995Tran et al., 2017

Improved Imaging: Unveiling the Metastases

Increased use of advanced imaging yields a stage migration to metastatic disease.

SABR-COMET

Improved RT: Ablating the Metastases

1. Faster – allows integration with systemic therapy

2. Improved Side effects – less time off systemic therapy

3. Higher Dose – allows ablative cell kill

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Cancer: An Evolving History

1894 1980 1995 2019

William Halsted: “Contiguous, Orderly

Spread Theory”

Bernard Fisher “Systemic Theory”

Samuel Hellman & Ralph Weichselbaum:

“Spectrum Theory”

Curing Metastatic Disease with RT: Myth or Reality?


Advances in Imaging and Detection

Improvements in Radiation Therapy

Evolving Ability to Combat Metastatic Disease

Evolving Understanding of Metastatic Disease

Radiation to the Primary Site

Endocrine signaling from the primary tumor in metastatic cancer: Real Research

1. Kaplan et al. Cornell (2005): VEGFR1-positive haematopoieticbone marrow progenitors initiate the pre-metastatic niche (Nature)

2. McAllister et al. BU, Harvard, Yale, etc. (2008): Systemic endocrine instigation of indolent tumor growth requires osteopontin (Cell)

3. Weckermann et al. Klinikum Augsburg (2009): Perioperative activation of disseminated tumor cells in the bone marrow of patients with prostate cancer (JCO)

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Kaplan et al. 2005

Experiment 1

Lewis Lung carcinoma*

*Metastasizes to lung, liver

Days 12-16

Clusters of Bone Marrow Derived Cells (BMDC)- VEGFR1+- CD34- CD117- CD133

Day +1 to Day +4

Day +1: 141.3 vs 2.7 tumor cells per lung section (p<0.01)Day +4: 207 vs 14 tumor cells in lung sample (p<0.01)

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Kaplan et al. 2005

Experiment 2

Lewis Lung carcinoma*

*Metastasizes to lung, liver**Metastasizes to lung, liver, testis, spleen, kidney

B16 Melanoma**

Clusters of Bone Marrow Derived Cells (BMDC)

Systemic endocrine instigation of indolent tumor growth requires osteopontin

McAllister et al. 2008

Instigator Cells• Human

mammary epithelial BPLER cell line

• Resembles IDC

Responder Cells • Human mammary

epithelial cell line (HMLER)

• Form tumors ~25% of time @ 9 weeks

Experiment 1

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Instigator Cells• 231 cell line ±

ability to make osteopontin

Responder Cells • Human mammary

epithelial cell line (HMLER)

• Form tumors ~25% of time @ 9 weeks

Experiment 2


Osteopontin identified as signaling molecule


Instigator Cells• Human

mammary epithelial BPLER cell line

• Resembles IDC

Responder Cells • Human Colon

Cancer surgically removed

Experiment 3


Perioperative activation of disseminated tumor cells in the bone marrow of patients with prostate cancer

• 900 BMbx from 384 patients with prostate cancer undergoing RP• Stained with A45-B/B3 directed

against cytokeratins 8, 18, 19• Method to detect disseminated

tumor cells (DTC) in the bone marrow

• Patients underwent preoperative BMBx (n=244) and yearly post-op BMBx (216)

Weckermann et al. 2009

Before Surgery

After Surgery

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Endocrine signaling from the primary tumor in metastatic cancer: Real Research1. Kaplan et al. Cornell (2005): VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche (Nature)

• The microenvironment of metastases is directed by the primary tumor and precedes the arrival of metastatic tumor cells

• The location of metastases is not random, but depends on signaling from the primary tumor

2. McAllister et al. BU, Harvard, Yale, etc. (2008): Systemic endocrine instigation of indolent tumor growth requires osteopontin (Cell)

• The circulating tumor cells are dependent on a favorable microenvironment for growth

• Osteopontin may be an example of a signaling molecule that is emitted from the primary to the bone marrow

• Holds true for fresh human malignancy

3. Weckermann et al. Klinikum Augsburg (2009): Perioperative activation of disseminated tumor cells in the bone marrow of patients with prostate cancer (JCO)

• Tumor cells are circulating prior to are radiologically visible metastatic sites

• These circulating tumor cells have a poor prognostic predictive value only in the presence of the primary tumor

Study Years Site Patient Population Arms n Results

SEER (Temple et al.) MSKCC

1991-1999

CRC Stage IV (at presentation) CRCmedicare patients

±CDS 6469 of 9011 hadcolon directed surgery

Median OS: 10 vs 3 mo (SS)

SWOG 8949 (Flanigan et al.)

1991-1998

RCC Stage IV RCC nephrectomy candidates

IFN alfa-2b±Nephrectomy

241 (120 vs 121) (17 did not have planned surgery)

Median OS: 11.1 vs 8.1 mo(SS)

EORTC 30947 (Mickisch et al.)

1995-1998

RCC Stage IV RCC nephrectomy candidates

IFN alfa±Nephrectomy

85 HR survival 0.54 (0.31-0.94)and time to progression 0.60 (0.36-0.97)

Cochrane MA (Elattar et al.)

1995-2008

Ovarian Ca

Stage III (81%) and IV (19%) Debulking vs resection

4735 Death HR 2.20-12.94

Netherlands RCT (Slotman et al.)

2009-2012

SCLC Extensive StageWHO PS 0-2Responded to CHT

PCI ±Thoracic RT (30/10)

498 OS1 28% vs 33% (p=0.066)OS2 7% -> 24% (p=0.001)

Tata Memorial RCT(Badwe et al.)

2005-2013

Breast Ca

De novo mBCa≤65 yoLife expectancy ≥1 year

LT (Sx->RT) to breast tumor and axillary LN vs no LT

350 OS2 41.9% vs 43% (NS)

Local Treatment in Non-Prostate Disease Sites

SWOG 8894

• Phase III study

• N=1286 mPCa to orchiectomy and placebo vs orchiectomy and flutamide

• In an unplanned subgroup analysis previous radical prostatectomy was associated with an improved OS5 relative to those who did not undergo earlier prostatectomy (HR 0.54, 95% CI 0.42-0.68)

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SPCG-7 (Widmark et al.)

• 1996-2002 875 (90% high risk, 78% T3, median PSA 16)

• ADT x3 mo -> ADT ± RT (70 Gy P+SV)

• OS10 61% -> 70% 10PCSM 19%->9% 15PCSM 34% -> 17%

MRC PR07 (Warde et al.)

• 1995-2005 1205 (T3-4 or T1-2+PSA>40 or PSA 20-40 + GS 8-10)

• ADT ± RT (65-69 Gy to P+SV and 45 Gy to PLN)

• OS10 49%->55%, PCSM10 22%->11%

Early benefit of localized RT in “Locally” Advanced Prostate Cancer




• OS10 61% -> 70% 10PCSM 19%->9% 15PCSM 34% -> 17%

The benefit of radiotherapy started to emerge as early as 3 years from the time of randomization with a second separation of the curves at about 6-7 years• Improbably early if the benefit of local treatment is mediated via the prevention of subsequent disease dissemination• It is more consistent with the possibility that local treatment has a beneficial impact on the rate of progression of existing micrometastatic disease

that was occult at the time of randomization due to inferior imaging techniques


• 1995-2005 1205 (T3-4 or T1-2+PSA>40 or PSA 20-40 + GS 8-10)


• OS10 49%->55%, PCSM10 22%->11%





• OS10 61% -> 70% 10PCSM 19%->9% 15PCSM 34% -> 17%

The benefit of radiotherapy started to emerge as early as 3 years from the time of randomization with a second separation of the curves at about 6-7 years• Improbably early if the benefit of local treatment is mediated via the prevention of subsequent disease dissemination• It is more consistent with the possibility that local treatment has a beneficial impact on the rate of progression of existing micrometastatic disease

that was occult at the time of randomization due to inferior imaging techniques


• 1995-2005 1205 (T3-4 or T1-2+PSA>40 or PSA 20-40 + GS 8-10)


• OS10 49%->55%, PCSM10 22%->11%


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Study Years Stage Arms Results

SEER (Culp et al.) U

of Virginia

2004-2010 mPCa 7811 NLT

245 RP

129 BT

OS5 NSR/RP/BT 22.5%/67.4%/52.6%

DSS5 NSR/RP/BT 48.7%/75.8%/61.3%

Local Therapy improved OS5 and DSS5 (p<0.001)

SEER (Satkunasivam

et al.) U of S. Cal

2004-2009 mPCa 3827 NLT

47 RP

88 IMRT

107 3D

PCSM6mo:

RP: 52% decrease (HR 0.48, 95% CI 0.27-0.85)

IMRT: 62% decrease (HR 0.38, 95% CI 0.24-0.61)

3D conformal: No improvement

NCDB (Loppenberg

et al.) Henry Ford

2004-2012 mPCa 14031 NLT

1470 LT

OS3: 54% -> 69% (p<0.001)

SEER (Pompe et al.)

Germany

2004-2014 mPCa 13357 NLT

375 RP

175 BT

CSM by bPSA within different M1 substages:

Survival benefit for M1a and ≤60 ng/ml PSA

No survival benefit for M1b above 60 ng/ml PSA and for M1c patients regardless of bPSA

NCDB (Parikh et al.)

Rutgers

2004-2013 mPCa 5224 NLT

622 RP

52 IMRT

153 3D/2D

OS5

LT: 17.1% -> 45.7% (P<0.01)

RP: (HR =0.51; 95% CI 0.45-0.59, p<0.01)

IMRT (HR=0.47; 95% CI 0.31-0.72, p<0.01)

Munich Ca Reg

(Bryan et al.) UK

1998-2010 mPCa 1464 NLT

74 RP

OS5: 21% -> 55% (p<0.01)

PS (Steuber et al.)

Germany

2008-2015 Oligomet PCa 40 BST

43 CRP

OS, Castrate resistant Survival NS

Reduction in locoregional complications: 7% vs 35% (p<0.01)

PS (Jang et al.)

Korea

2005-2015 Oligomet PCa 38 RARP

41 ADT

Median FU: 40 mo

Median PFS: 75 vs 28 mo (p=0.008)

Median CSS: not reached vs 40 mo (p=0.001)

Case Control (Cho et

al.) Korea

2003-2011 Oligomet PCa 63 NT

39 Palliative RT

38 Prostate RT

Prostate RT vs Palliative RT

OS3: 69% vs. 43%, p = 0.004

BCFFS3: 52% vs. 16%, p= 0.002

RR and Small PS Assessing LT (RP or RT) in mPCa

Study Years Stage Arms Results

SEER (Culp et al.) U

of Virginia

2004-2010 mPCa 7811 NLT

245 RP

129 BT

OS5 NSR/RP/BT 22.5%/67.4%/52.6%

DSS5 NSR/RP/BT 48.7%/75.8%/61.3%

Local Therapy improved OS5 and DSS5 (p<0.001)

SEER (Satkunasivam

et al.) U of S. Cal

2004-2009 mPCa 3827 NLT

47 RP

88 IMRT

107 3D

PCSM6mo:

RP: 52% decrease (HR 0.48, 95% CI 0.27-0.85)

IMRT: 62% decrease (HR 0.38, 95% CI 0.24-0.61)

3D conformal: No improvement

NCDB (Loppenberg

et al.) Henry Ford

2004-2012 mPCa 14031 NLT

1470 LT

OS3: 54% -> 69% (p<0.001)

SEER (Pompe et al.)

Germany

2004-2014 mPCa 13357 NLT

375 RP

175 BT

CSM by bPSA within different M1 substages:

Survival benefit for M1a and ≤60 ng/ml PSA

No survival benefit for M1b above 60 ng/ml PSA and for M1c patients regardless of bPSA

NCDB (Parikh et al.)

Rutgers

2004-2013 mPCa 5224 NLT

622 RP

52 IMRT

153 3D/2D

OS5

LT: 17.1% -> 45.7% (P<0.01)

RP: (HR =0.51; 95% CI 0.45-0.59, p<0.01)

IMRT (HR=0.47; 95% CI 0.31-0.72, p<0.01)

Munich Ca Reg

(Bryan et al.) UK

1998-2010 mPCa 1464 NLT

74 RP

OS5: 21% -> 55% (p<0.01)

PS (Steuber et al.)

Germany

2008-2015 Oligomet PCa 40 BST

43 CRP

OS, Castrate resistant Survival NS

Reduction in locoregional complications: 7% vs 35% (p<0.01)

PS (Jang et al.)

Korea

2005-2015 Oligomet PCa 38 RARP

41 ADT

Median FU: 40 mo

Median PFS: 75 vs 28 mo (p=0.008)

Median CSS: not reached vs 40 mo (p=0.001)

Case Control (Cho et

al.) Korea

2003-2011 Oligomet PCa 63 NT

39 Palliative RT

38 Prostate RT

Prostate RT vs Palliative RT

OS3: 69% vs. 43%, p = 0.004

BCFFS3: 52% vs. 16%, p= 0.002

RR and Small PS Assessing LT (RP or RT) in mPCa

Caveats• Pervasive selection bias towards healthier patients with lower tumor burden is likely a

meaningful source of confounding

• Patients treated locally are a very small percentage of the entire cohort in these reports

• Database studies unable to identify if EBRT was to primary site or sites of metastasis

Randomized Data

• HORRAD (Prostate)

• STAMPEDE Arm H (Prostate)

• Gomez Phase 2 Study (Lung)

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Liselotte et al, 2018

HORRAD

• Phase 3• 28 Centers across the Netherlands

• Eligibility: Newly diagnosed metastatic prostate cancer (treatment naïve)

• PSA >20 ng/ml• Exclusions:

• Age >80• PSA <20• Previous treatment• Concurrent malignancies

• Randomization: ADT ± EBRT

• ADT• Bicalutamide (50 mg) -> LHRH agonist

• EBRT• 70 Gy/ 35 fx (7 wks)• 57/76 Gy/ 19 fx (3.04 Gy) QOD (6 wks)• IMRT or 3D Conformal• Pelvic nodes not included

• Primary endpoint: OS• Secondary endpoints: time to PSA progression


HORRAD

• Patients accrued between 11/2004-9/2014• n=432

• Initial accrual goal was 500 to detect prolonged median survival of 10 months

• With higher events noted at interim analysis accrual goals were adjusted to 425 patients

• Randomized 216 EBRT vs 216 control

• Metastatic Burden• 160 (37%) patients had low metastatic burden

(<5 lesions)

• 272 (63%) patients had high metastatic burden (5+ lesions)


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HORRAD

• Median follow-up: 47 months

• Entire Cohort• Median OS: 45 mo (EBRT) vs 43 mo

(ADT) (NS)

• Median time to PSA progression: 15 mo vs 12 mo (p=0.02)

• Low Metastatic Burden (<5 lesions)• Median OS: HR 0.68 (95% CI 0.42-

1.10)


HORRAD• Median follow-up: 47

months

• Entire Cohort• Median OS: 45 mo (EBRT) vs

43 mo (ADT) (NS)• Median time to PSA

progression: 15 mo vs 12 mo (p=0.02)

• Low Metastatic Burden (<5 lesions)• Median OS: HR 0.68 (95% CI

0.42-1.10)


HORRAD• Caveats

• “70 Gy is lower than is currently applied for localized prostate cancer”• Did not collect data on nodal involvement• Did not stratify based on extent of metastatic disease• Did not receive Abiraterone or Docetaxel• Did not treat oligomets

• Conclusion• “Local treatment of the prostate in patients with primary bone mPCa

should not be performed outside of clinical trials”


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Parker et al, 2018

STAMPEDE

Parker et al, 2018

STAMPEDE: Arm H

• Phase 3: 117 hospitals in Switzerland and the UK• Eligibility: Newly diagnosed metastatic prostate cancer

• No contraindications to RT• No clinically significant cardiovascular history

• Randomization: ADT ± EBRT• ADT

• Lifelong ADT with up-front docetaxel permitted from 12/2015• LHRH agonists or antagonists or orchiectomy

• EBRT• 55 Gy/20 fx over 4 weeks or weekly 36 Gy in 6 fractions over 6 weeks to the prostate (no pelvic nodal radiation therapy)

• Nominated prior to randomization• Primary outcome: OS

• Secondary outcome were FFS, PFS, metastatic PFS, PCSS, and symptomatic local event-free survival• Planned subgroup analyses

• Baseline metastatic burden assessed by bone scan, CT, or MRI(as per CHAARTERD Trial)• High: 4+ bone metastases w/ 1+ outside of vertebral bodies or pelvis, or visceral metastases or both• Low: Not High

Parker et al, 2018

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STAMPEDE Arm: H• Patients accrued between 1/22/13-9/2/16

• n=2061

• planned 1250 in 4 years but opened accrual as both treatment regimens were being accrued to equally)

• Randomized 1029 control vs 1032 RT

• Adjusted protocol to allow for docetaxel after STAMPEDE Arm C resulted• 367 (18%) received docetaxel

• 3 week cycles of 75 mg/m2 ± prednisolone 10 mg daily

• Metastatic Burden• 819 (40%) patients had low metastatic burden (per CHAARTED criteria)

• 1120 (54%) patients had high metastatic burden

Parker et al, 2018

STAMPEDE Arm: H• Grade 3-4 toxicity n=48 (5%)

during and 37 (4%) after RT

• In entire cohort:• OS3 62% vs 65% (HR 0.92 p=0.266)

• FFS3 23% -> 32% (HR 0.76, p<0.0001) but not

• In patients with low metastatic burden:• OS3 improved 73%->81% (SS)

• FFS3 improved 33% -> 50% (SS)

Parker et al, 2018

STAMPEDE Arm: H• Grade 3-4 toxicity n=48 (5%)

during and 37 (4%) after RT

• In entire cohort:• OS3 62% vs 65% (HR 0.92 p=0.266)

• FFS3 23% -> 32% (HR 0.76, p<0.0001) but not

• In patients with low metastatic burden:• OS3 improved 73%->81% (SS)

• FFS3 improved 33% -> 50% (SS)

Parker et al, 2018

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SAMPEDE: Arm H

• Conclusions:• “Prostate radiotherapy improves survival of men with a low metastatic burden and

that it should now be a standard treatment”• “Radiotherapy would also improve survival for men with pelvic node-positive

prostate cancer”• 60% of patients were N1 in both the high and low metastatic burden subgroups

• “The optimum dose schedule and technique are uncertain”• Standard fractionation felt to be too burdensome for patients with metastatic disease• Did not treat lymph nodes• Did not treat oligometastases

• Caveats• Baseline scans to assess for metastatic burden only available in 94% of patients• Compliance with allocation to prostate radiotherapy was 94%• Mean follow-up was 37 months however median survival was 46 months

Parker et al, 2018

Gomez et al., 2019

Stage IV NSCLC≤3 metastasesNo progression after first line systemic therapy (3+ months)

Gomez et al., 2019


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Gomez et al., 2019


Overall survival (OS) after disease progression among patients originally assigned to local consolidative therapy (LCT) or maintenance therapy or observation (MT/O).

Management of Primary in Oligometastases

• HORRAD• Whole Cohort (CHAARTED Criteria)

• Median OS: 45 mo (EBRT) vs 43 mo (ADT) (NS)• Low Metastatic Burden (<5 lesions)

• Median OS: HR 0.68 (95% CI 0.42-1.10)

• STAMPEDE Arm H• Whole Cohort

• OS: HR 0.92, 95% CI 0.80-1.06; p=0.266• Low Metastatic Burden (CHAARTED Criteria)

• OS: HR 0.68, 95% CI 0.52-0.90; p=0.007

• Future Studies• Is the role of RP similar to that of EBRT?

• G-RAMMP trial• TROMBONE Trial

• What is the value of prostate radiotherapy in men receiving Abiraterone?• PEACE1 Trial• STOPCAP M1 meta-analysis (of PEACE1 and STAMPEDE H)

“New ideas pass through three periods: 1) It can’t be done;

2) It probably can be done, but it’s not worth doing;

3) I knew it was a good ideal all along!”

–Arthur C. Clarke

Documents

Definitive Radiation Therapy to the Primary Disease Site · Cancer surgically removed Experiment 3 Systemic endocrine instigation of indolent tumor growth requires osteopontin Perioperative