Review of Joseph Herman’s 07Jun2017 Let’s Win Article

Dr Herman, in his recent article below, makes two pro-SBRT claims based upon two research studies in which he participated. Those two research abstracts are also below.

1.  His “Let’s Win” article asserts that there was an “eight point reduction in pain from a baseline measure of 25.” The claim is based on his study reported in Cancer.

The claim is true. However, the actual report notes that the “median overall survival was 13.9 months”, which is not great, and may be partly (or greatly) due to Gemcitabine. The report also states: “Four [of the 49] patients (8%) underwent . . . surgical resections.” That is not a large percentage, not enough to claim that consistently the “tumor actually changes to a form that can be more easily pried away from the vessel.”

2.  Referring to a trial reported in the Journal of Surgical Oncology, Herman claims: “19 patients with tumors previously considered inoperable (unresectable or locally advanced) were able to have surgery after SBRT.” That’s 21.6% of 88 patients.

Unfortunately, 21.6% is not a large percentage, and the authors acknowledge that there was a “limited radiographic response to therapy.”

The Oncology report also states: “Median OS from date of diagnosis was 18.4 months . . . and median PFS was 9.8 months.” These values are not huge for locally-advanced patients, who might have benefitted from another intervention, like Irreversible Electroporation.

Stereotactic Body Radiation Therapy (SBRT) for Select Pancreatic Cancer Patients

7 June, 2017 | http://letswinpc.org/promising-science/2017/06/07/stereotactic-body-radiation-therapy-emerging-standard-treatment-option-pancreas-cancer/?utm_source=Let%27s+Win!&utm_campaign=a47591fadc-EMAIL_CAMPAIGN_2017_06_07&utm_medium=email&utm_term=0_02715713fc-a47591fadc-121532657

As researchers search for ways to combat pancreatic cancer, one treatment gaining significant attention from the science community—and patients—is stereotactic body radiation therapy, or SBRT.

An SBRT Primer

With traditional treatment, patients with early stage pancreatic tumors generally undergo surgery followed by chemotherapy, and sometimes radiotherapy as well. This conventional or standard radiation is delivered in relatively low doses, usually daily over the course of five to six weeks concurrently with chemotherapy.

But with SBRT higher doses of carefully targeted radiation is used to treat tumors, delivered in a few “fractionated” doses. “High doses of radiation are delivered over the course of only five days with limited toxicity,” explains radiation oncologist Joseph Herman, M.D., M.Sc., a leading researcher in the use of SBRT in pancreatic cancer.

Much of the credit for SBRT’s potential in treating pancreatic cancer has been due to technologic advances. “Basically what’s happened is that radiation technology has improved and now we have very sophisticated image guidance that pinpoints the exact three-dimensional location of a tumor,” he says. “That’s allowed us to more precisely deliver radiation to tumors at much higher doses. These higher doses can lead to improved local control and possibly survival.”

Other improvements to the treatment include the control of a patient’s breathing motion since pancreatic tumors, like liver tumors, actually move during breathing. Doctors have developed ways to control for this phenomenon by tracking a patient’s breathing motion or directly managing it. “Essentially what we do is have a patient inhale deeply, hold that breath, and then we freeze the tumor in space and treat it,” says Herman, who serves as professor and director of clinical research at MD Anderson Cancer Center, Houston, Texas. SBRT has also been aided through the use of fiducials—tiny gold markers—placed into the tumor that act as a kind of radiologic landmark, defining the target lesion’s position with millimeter precision, he adds.

Early Trials Answer Important Questions

In a multi-institution study published in the journal Cancer, Dr. Herman and colleagues treated 49 patients with locally advanced pancreatic cancer with SBRT. The patients received SBRT in five fractionated doses and chemotherapy with gemcitabine before and after the radiotherapy treatment. Four weeks after SBRT, all 22 patients who completed a quality of life questionnaire reported an eight point reduction in pain from a baseline measure of 25, and their quality of life stayed the same, which Herman says is encouraging.

In a second study, published in the Annals of Surgical Oncology, Herman and his colleagues analyzed information on patients with pancreatic cancer who received SBRT and chemotherapeutic drugs at between 2010 and 2014. (Patients were treated at Johns Hopkins.) The study looked at acute and late toxicity of SBRT in locally advanced and borderline resectable pancreatic cancer.

Of 88 patients, eight experienced severe gastrointestinal side effects. Most of the patients who had side effects also had tumors that were invading into the intestines or stomach. For this reason, these patients should only get SBRT if the plan is to go to surgery following completion of SBRT. In this study, 19 patients with tumors previously considered inoperable (unresectable or locally advanced) were able to have surgery after SBRT. Several patients had a complete response at the time of surgery, meaning there was no tumor left behind.

To give people a surgical option is especially important since pancreatic tumors can often attach to and grow around blood vessels, making them difficult to remove, Herman says. “But after SBRT, the tumor actually changes to a form that can be more easily pried away from the vessel,” he adds, citing the current published data with SBRT over five days provides at least equivalent or better outcomes in terms of survival, with less toxicity, and better pathologic response rates than what is generally seen with standard treatment over five to six weeks.
“In general, we don’t usually see this kind of response with standard radiation or chemotherapy alone,” he says.

Another factor to consider is that shorter treatment times with SBRT may provide other benefits such as allowing patients access to full-dose chemotherapy much more quickly than those undergoing standard radiation which, because of its longer schedule, potentially gives cancer more time to spread, he says.

Quality of life is also an important factor. “Most patients we treat with SBRT have tumors that can’t be removed by surgery and that means average survival is only about one year,” Herman says. “These patients generally have to go through about six weeks of standard chemotherapy and radiation. That can be difficult for patients and their families. But with SBRT it’s only about five days. That means patients spend a lot less time getting treatment and get to spend more time with family. I believe that’s incredibly important for everyone.”

Ongoing studies are testing combinations of SBRT with immunotherapy and researchers are also continuing to study the effectiveness of various radiation doses used in SBRT.

Looking to the Future

Based on current data, Herman is hopeful that more studies will lead to SBRT becoming a standard-of-care option for patients with locally advanced or unresectable and borderline resectable pancreatic cancer with blood vessel involvement. Patients with involvement of the stomach or duodenum are not good candidates for SBRT, unless they are surgical candidates.

“There’s a lot of work to be done, and I want to stress this is not a cure,” Herman says. “We absolutely need randomized trials and we need to figure out the optimal dose and fractionation that will sterilize tumors for patients,” For example, researchers must still determine how best to combine SBRT with targeted or immunotherapeutic agents. Personalizing treatment based on factors like genetics and the tumor microenvironment are also goals.

“Pancreatic cancer patients need more options, and we need the trials to determine what their best options may be,” Herman states. “SBRT provides another weapon in the battle against pancreas cancer.”

The Cancer article:

Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma.

Herman JM1, Chang DT, Goodman KA, Dholakia AS, Raman SP, Hacker-Prietz A, Iacobuzio-Donahue CA, Griffith ME, Pawlik TM, Pai JS, O'Reilly E, Fisher GA, Wild AT, Rosati LM, Zheng L, Wolfgang CL, Laheru DA, Columbo LA, Sugar EA, Koong AC.

Cancer. 2015 Apr 1;121(7):1128-37. doi: 10.1002/cncr.29161. Epub 2014 Dec 23. https://www.ncbi.nlm.nih.gov/pubmed/25538019

Abstract

BACKGROUND:

This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).

METHODS:

A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT.

RESULTS:

The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥ 2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.

CONCLUSIONS:

Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy.

KEYWORDS: chemoradiation; locally advanced; pancreatic cancer; positron emission tomography; stereotactic body radiotherapy; unresectable

PMID: 25538019

PMCID: PMC4368473

DOI: 10.1002/cncr.29161

The Journal of Surgical Oncology article:

The Role of Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Single-Institution Experience

Shalini Moningi BA, Avani S. Dholakia BS, Siva P. Raman MD, Amanda Blackford Sc.M, John L. Cameron MD, Dung T. Le MD, Ana M. C. De Jesus-Acosta MD, Amy Hacker-Prietz MS, Lauren M. Rosati BS, Ryan K. Assadi BS, Shirl Dipasquale RN, Timothy M. Pawlik MD, Lei Zheng MD, Matthew J. Weiss MD, Daniel A. Laheru MD, Christopher L. Wolfgang MD, Joseph M. Herman MD
Gastrointestinal Oncology

Volume 22, Issue 7 / July , 2015 http://www.annsurgoncol.org/journals/abstract.html?v=22&j=10434&i=7&a=4274_10.1245_s10434-014-4274-5&doi=

Abstract
Background

Stereotactic body radiation therapy (SBRT) is a promising option for patients with pancreatic cancer (PCA); however, limited data support its efficacy. This study reviews our institutional experience of SBRT in the treatment of locally advanced (LAPC) and borderline resectable (BRPC) PCA.

Methods

Charts of all PCA patients receiving SBRT at our institution from 2010 to 2014 were reviewed. Most patients received pre-SBRT chemotherapy.Primary endpoints included overall survival (OS) and local progression-free survival (LPFS). Patients received a total dose of 25–33Gy in five fractions.

Results

A total of 88 patients were included in the analysis, 74 with LAPC and 14 with BRPC. The median age at diagnosis was 67.2years, and median follow-up from date of diagnosis for LAPC and BRPC patients was 14.5 and 10.3months, respectively. Median OS from date of diagnosis was 18.4months (LAPC, 18.4 mo; BRPC, 14.4 mo) and median PFS was 9.8months (95% CI 8.0–12.3). Acute toxicity was minimal with only three patients (3.4%) experiencing acute grade ≥3 toxicity. Late grade ≥2 gastrointestinal toxicity was seen in five patients (5.7%). Of the 19 patients (21.6%) who underwent surgery, 79% were LAPC patients and 84% had margin-negative resections.

Conclusions

Chemotherapy followed by SBRT in patients with LAPC and BRPC resulted in minimal acute and late toxicity. A large proportion of patients underwent surgical resection [21.6% is large?] despite limited radiographic response to therapy. Further refinements in the integration of chemotherapy, SBRT, and surgery might offer additional advancements toward optimizing patient outcomes.

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Authors and Affiliations

·  ShaliniMoningi1