Proton Therapy for Pancreatic Cancer R. Charles Nichols Jr., M.D. - - PowerPoint PPT Presentation

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Proton Therapy for Pancreatic Cancer R. Charles Nichols Jr., M.D. - - PowerPoint PPT Presentation

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Proton Therapy for Pancreatic Cancer R. Charles Nichols Jr., M.D. March 11, 2017 Disclosures None Confession One Disclaimers Two Photons (X-Rays) Highest Dose is near the point of beam entry. Tumor Dose is less than the entry

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Proton Therapy for Pancreatic Cancer

  • R. Charles Nichols Jr., M.D.

March 11, 2017

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Disclosures

  • None
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Confession

  • One
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Disclaimers

  • Two
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Photons (X-Rays)

Highest Dose is near the point of beam entry. Tumor Dose is less than the entry dose. Dose is also delivered beyond the tumor target.

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Protons

Entry dose is low. Highest Dose is at the depth of the tumor target. There is NO exit dose beyond the target.

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Statement:

  • Proton therapy has the potential to

improve the therapeutic index over x-rays in the treatment of many malignancies.

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Is proton therapy only...

  • A more elegant form of radiotherapy?
  • A more sophisticated form of radiotherapy
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Gray A Gentler

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Or...

  • …does the improvement in the therapeutic

index with protons offer the potential to change the management paradigm of a particular malignancy?

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Or...

  • …does the improvement in the therapeutic

index with protons offer the potential to change the management paradigm of a particular malignancy?

  • Resectable pancreatic cancer.
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Pancreatic Cancer Facts...

  • 43,140 Annual Cases

– Perhaps 50% present with localized disease

  • Perhaps 50% of these are “resectable” or “curable”

– And yet the “cure” rate is only about 20% for these “curable” patients.

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More Facts

  • Local control is a necessary condition for

cure.

  • Surgery is a necessary condition for local

control.

  • Surgery is rarely a sufficient condition for

local control.

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  • Dr. Whipple’s problem...
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The problem with the Pancreaticoduodenectomy...

…is that even with negative nodes and negative surgical margins, 50% to 80% of patients will suffer a local failure if they do not receive postoperative radiotherapy.

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…is that so surprising?

Half of the involved

  • rgan is left

behind!

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…is that so surprising?

Close retroperitoneal / vascular margins

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Are you ready for the bad news?

  • Hopkins data:

– Pawlik TM, Surgery, 2007

  • 905 Whipples from 1995 to 2005

– Node positivity was…79.3% – Margin positivity was …41.1%

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Are you ready for more bad news?

  • MSKCC Data:

– Winter JM, Annals of Surgical Oncology, 2012 – 625 resections from 2000 to 2009

  • Margin positivity…16%
  • Node positivity…70%
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So what can be done to improve local and regional control?

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Postoperative X-Rays?

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Problems with postoperative radiotherapy…

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Problems with postoperative radiotherapy…

1.) Long delay between surgery and radiotherapy.

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Problems with postoperative radiotherapy…

1.) Long delay between surgery and radiotherapy. 2.) Bowel toxicity limits x-ray dose to +/-50Gy to a hypoxic tumor bed.

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Problems with postoperative radiotherapy…

MGH data shows a 36% local/regional failure rate at 3 years after postoperative chemoradiation. RTOG 97-04 shows a 23% to 28% local failure rate.

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Summarizing…

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Summarizing…

1.) Surgery is necessary (but not sufficient) for cure.

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Summarizing…

1.) Surgery is necessary (but not sufficient) for cure. 2.) Postoperative radiotherapy may not be effective. Too Late… Too Little…

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Any suggestions?

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Preoperative radiotherapy!

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…not so fast

…50% of attendees surveyed at the 2012 international GI meeting in San Francisco would not recommend preoperative radiotherapy for a marginally resectable patient even after a non-response to first line chemotherapy.

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The bottom line...

…Many pancreas surgeons are reluctant to

  • perate on a previously irradiated patient.
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Why?

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Why?

Gastrojejunal Anastomosis Pancreaticojejunal Anastomosis Biliaryjejunal Anastomosis Postoperative Nutrition

Median duration of surgery is >400 minutes!

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Are we at an impasse?

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Maybe not...

What if we could convince you that preoperative radiotherapy could be delivered without the gastrointestinal toxicity of x-ray based therapy?

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Does dosimetry suggest that protons improve the therapeutic index for pancreatic cancer?

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Protons versus IMRT

Small Bowel V20 (15.4% vs. 47.0% p=0.03)

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Protons versus IMRT

Gastric V20 (2.3% vs. 20.0% p=0.03)

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Protons versus IMRT

Right Kidney V18 (27.3% vs. 50.5% p=0.02)

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Does dosimetry suggest that protons improve the therapeutic index for pancreatic cancer?

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Does dosimetry suggest that protons improve the therapeutic index for pancreatic cancer?

Yes.

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Does this elegant dosimetry translate into reduced radiotherapy toxicity?

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UF Experience: 3/09 to 4/12

  • 20 evaluable patients
  • Unresectable / Inoperable disease … 10
  • Marginally resectable disease … 5
  • Resected (postop RT) … 5
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Proton Dose

  • 20 patients

– Unresectable / Inoperable …59.40CGE – Marginally resectable … 50.40CGE – Resected (postop) … 54.00CGE

  • All patients received Capecitabine at 1000mg PO

BID during RT.

  • 90% to 100% of prescribed doses taken

– Median 99%

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Grade 3 acute toxicity

  • None
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Grade 3 late toxicity

  • None
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Grade 2 GI toxicity

  • 3 (out of 20) patients

– Vomiting … 3 – Diarrhea … 2

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Field design (early)

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Field design (current)

PAO:Rt.Lateral weighted 3:1

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Grade 2 GI toxicity (current field arrangement)

  • None
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Weight loss (17 patients -current field design)

  • Median 1.1lbs
  • Range +10.4 to -14.1lbs
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Does this elegant dosimetry translate into reduced radiotherapy toxicity?

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Does this elegant dosimetry translate into reduced radiotherapy toxicity?

Yes.

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What about efficacy?

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UFPTI PC01 Protocol

  • 11 Patients analyzed.
  • Celiac axis or SMA encasement,
  • cclusion of the SMV, portal vein or

both confluences.

  • 59.40Gy(RBE) in 33 fractions with

capecitabine (1000mg PO BID).

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PC01 Protocol (continued)

  • Median age 68 years (range 51 to 86)
  • Median follow up for all patients … 14

months (range 5 to 25)

  • 4 patients underwent attempted

resection after PT. 3 resections performed.

  • No grade 2 or greater GI toxicity.
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PC01 Protocol (continued)

Median Survival 18.4 months 2 Year Local Control 69% 2 Year Overall Survival 31%

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What about surgery after proton therapy?*

  • 5 resections performed after

59.40Gy(RBE) for patients with unresectable disease.

– One patient also received 50.40Gy(RBE) electively to the high risk nodal targets

*Nichols PTCOG-NA, 2014

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Operations Performed ...

  • 3 … laparoscopic standard

pancreaticoduodenectomy.

  • 1 … open pyloris sparing

pancreaticoduodenectomy.

  • 1 … open distal pancreatectomy with

IRE of the pancreatic head mass.

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Outcomes (1)...

  • 2 … R0 resections with minimal

residual tumor in specimen.

  • 1 … after negative pancreatic head

biopsy, IRE followed by distal pancreatectomy with NTS in specimen

  • 2 … R2 resections
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Outcomes (2)...

  • Median OR Time …419 minutes
  • Median EBL …850cc
  • Median ICU stay…1 day(range 0 to 2)
  • Median hosp. stay…10 days(5 to 14)
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Outcomes (3)...

  • No late complications or morbidity

attributable to proton therapy.

  • Operative Time, EBL and LOS

comparable to published surgical series on unirradiated patients.

  • Median survival 24 months (range 10

to 30)

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Outcomes (4)...

  • And, most importantly…

– No complaints from the 5 surgeons who did the operations.

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Summary #1

  • Surgical outcome data demonstrates

a high rate of local failure which is

  • nly marginally improved with

postoperative radiotherapy.

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Summary #2

  • Many surgeons are reluctant to

recommend preoperative radiotherapy for fear that it may complicate the surgery or the recovery period.

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Summary #3

  • Our experience suggests that these

fears are unjustified with proton therapy:

– Dosimetry – Lack of acute or late radiotherapy toxicity – Surgical experience showing no increase in complications for unresectable patients receiving high dose radiotherapy before surgery.

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Summary #4

  • The lack of toxicity associated with proton

radiotherapy may improve the willingness of surgeons to accept neoadjuvant (proton) radiotherapy for patients with operable disease.

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Summary #5

  • If this happens, proton therapy will change

the management paradigm for patients with resectable pancreatic cancer.

  • Improve local/regional control rates
  • …and perhaps improve the cure rate for

this lethal malignancy.

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UFPTI protocols:

– PC01 … Unresectable disease … 59.40CGE with concomitant Capecitabine (closed) – PC02 ... Resectable and marginally resectable disease … 50.40CGE with concomitant Capecitabine. – PC03 … Postoperative adjuvant with weekly Gemcitabine

  • 50.40CGE for R0 resections
  • 54.00CGE for R1 resections
  • 59.40CGE for R2 resections
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UFPTI protocols:

– PC04 … “initally unresectable” disease… 63CGE in 28 fractions (mimics NRG 1201) with concomitant capecitabine.

  • +/- equivalent of 70CGE at 2CGE per fraction
  • Intensification for marginally resectable

patients based on MDACC data showing that

  • nly 50% of marginally resectable patients

receiving preop chemoradiotherapy are converted to resectability.

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Thanks...

  • Soon Huh
  • Meng Wei Ho
  • Zuofeng Li
  • Brad Hoppe
  • Mike Rutenberg