eCancer Consult, December 2013

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Cardiac-Sparing Radiation for Breast Cancer

One in 8 women will develop breast cancer—it is the most common solid tumor diagnosis in women. The good news is, many more patients today are “survivors” because of advanced chemotherapy and radiation therapy techniques.

But these therapies may come with some small risk of developing heart complications down the road. “We have known for years that radiation directed at the heart can cause late side effects, such as coronary artery disease and even heart attacks,” says Rahul Tendulkar, MD, a radiation oncologist at Cleveland Clinic. “We want to do everything possible to minimize these late toxicities as more patients are being cured and we have a greater number of long-term survivors of breast cancer."

The potential cardiac toll of cancer treatment has been making waves in the media, especially after a study published this spring by New England Journal of Medicine aimed to quantify the relationship between radiation for breast cancer and late cardiac events. The problem with that study, Dr. Tendulkar points out, is that the radiation techniques used were outdated. “With the latest advances in breast cancer therapy, we can take that 1-percent risk [of heart complications] down closer to zero,” he says.

Cleveland Clinic offers breast cancer patients cardiac-sparing radiation therapy options that reduce the exposure of the heart to treatment. Here are some of them:

Three-Dimensional Radiation Planning

CT scans for radiation planning ensure that radiation beams are aimed directly at the affected breast tissue. “You can see how much of the heart is being included in the [radiation beam] field,” Dr. Tendulkar says. Today, the shape and size of the radiation field is designed to minimize exposure to the heart. Through conformal treatment planning, portions of the heart are blocked out of the treatment path.

Prone Breast Radiation

Taking advantage of gravity can reduce radiation exposure to the heart when treating breast cancer patients in the prone position (lying on the belly). This position allows breast tissue to fall away from the chest wall so radiation can be aimed from underneath the breast. “There are studies that show this is an effective way of reducing the heart dose of radiation for select patients,” Dr. Tendulkar says.

ABC—Active Breathing Control

Filling the lungs with air separates the heart from the rib cage, and that physical gap minimizes the dose of radiation that reaches the heart. Active Breathing Control (ABC) involves attaching a breathing device to the patient’s mouth. Radiation therapists instruct the patient to inhale deeply and hold her breath for a few seconds while the radiation treatment is being delivered. This technique is more challenging for patients and more time consuming, but it does reduce the radiation dose that reaches the heart, Dr. Tendulkar says.

“With the advent of these technologies, from conformal treatment planning to ABC, the radiation doses the heart receives are a faction of what they were 10 to 15 years ago,” Dr. Tendulkar says, adding that every radiation treatment plan is customized for each patient. “We now have multiple cardiac-sparing breast cancer therapies to offer patients and that’s important because treatment is never one-size-fits-all.”

Teaming Up to Treat Rare Mesothelioma

The disease is rare and commonly misunderstood; yet more than 2,000 new cases are diagnosed each year. Pleural mesothelioma is a persistent cancer with a poor prognosis if not properly treated—and diagnosis is often difficult because symptoms may develop slowly and initial testing may not reveal the disease.

A team of experts at Cleveland Clinic is focused on improving the prognosis and quality of life for patients with pleural mesothelioma at a new multidisciplinary outpatient clinic at Taussig Cancer Institute. The Multidisciplinary Pleural Mesothelioma Center merges Cleveland Clinic’s expertise in medical and radiation oncology, pulmonary medicine and thoracic surgery, with experts in palliative care and pathology.

“It’s a relatively rare disease,” acknowledges David Mason, MD, Thoracic Surgeon in the Sydell and Arnold Miller Family Heart & Vascular Institute. “Determining the right treatment for each patient is difficult and all cases require input from multiple specialists.”

The center will streamline and shorten the time to diagnosis for patients, and offer treatment including surgery, radiation and chemotherapy that can prolong and improve the quality of life for patients. Individual treatment plans are designed for each patient because no two cases are the same.

“The disease is not optimally treated using a single modality,” Dr. Mason says. “That’s why we assembled this team approach.”

Diagnosing the Disease

Mesothelioma most often affects those who have been exposed to asbestos in the workplace, and the disease usually takes root in the pleura. Mesothelioma is not lung cancer—you don’t get the disease from smoking cigarettes. The “typical” patient is older than 60, though family members of those exposed to asbestos are also at risk through secondary exposure to asbestos fibers. Many patients have worked in construction/HVAC, mining, welding, auto repair or other industrial occupations where fireproofing is used. Another risk factor: chest radiation for cancer during childhood or young adulthood.

James Stevenson, MD, Solid Tumor Oncology, Taussig Cancer Institute says: “We know in most cases patients will experience occupational exposure to asbestos decades before they are diagnosed with cancer.”

Diagnosing mesothelioma can take months, or longer, because the pleural fluid may present as “negative” for the disease at first. It can be mistaken for other cancers. Diagnosis usually requires multiple physician visits, scans and procedures. Cleveland Clinic’s Multidisciplinary Pleural Mesothelioma Center aims to streamline this diagnosis process because doctors from multiple specialties perform an initial evaluation during a single patient visit. Patients reviewed at other centers can have biopsies reviewed and confirmed by a Cleveland Clinic pathologist with expertise in mesothelioma and thoracic cancers.

A Multidisciplinary Approach

Customized treatment for patients may include a combination of surgery, radiation and chemotherapy—and prolonged remissions are possible. The key is an individualized, innovative approach. Aggressive therapies that save lives are available at Cleveland Clinic’s Multidisciplinary Pleural Mesothelioma Center. One is pleurectomy, a lung-sparing surgery where diseased pleura is removed without lung resection. Concurrently, intraoperative hyperthermic lavage is performed to treat residual microscopic cancer.

In addition to complex surgeries, specific radiation therapy plans must be executed to successfully treat mesothelioma. “Treatment is complicated and demanding,” says Gregory Videtic, MD, a staff member in the Department of Radiation Oncology with expertise in thoracic diseases.

As for the future of treating mesothelioma, Cleveland Clinic is on the leading edge of exploring multi-model approaches for surgical candidates, and is also involved in tissue banking, genomic research and analysis.

ASTRO Oral Presentations

At Taussig Cancer Institute, we strive to continually undertake activities that encompass a unique combination of high-volume and challenging clinical cases, extensive basic and translational scientific activities and credible laboratory research in an environment that nurtures the future leaders of our specialties. Below are the abstracts from our oral presentations given at ASTRO.

Redefining Stage IV Prostate Cancer: Is There a Subset Who May Be Cured?

M.E. Shukla, C. Reddy, C. Yu, M. Abdel-Wahab, K. Stephans, and R. Tendulkar

Purpose/Objective(s): Stage IV prostate cancer (CAP) is defined by AJCC as T4N0M0, TanyN1M0 or TanyNanyM1 disease. The purpose of this study is to compare prostate cancer specific mortality (PCSM) among patients in the three subgroups of Stage IV CAP with stage III CAP with the hypothesis that T4 and N1 M0 patients merit curative intent therapy and whose prognoses are better than M1 disease.

Materials/Methods: All patients diagnosed with CAP from 1988-2005 were queried from the Surveillance, Epidemiology, and End Results (SEER) database. Those with in-situ disease, incomplete staging information and diagnosis of CAP only at autopsy were excluded. Within this overall set of 508,595 patients we identified 155,409 patients receiving prostatectomy with pathologic staging available. For the overall group and the surgery subset we examined PCSM for the following groups: T3aN0M0, T3bN0M0, T4N0M0, TanyN1M0, TanyNanyM1. We further stratified these groups by grade as coded in the SEER database.

Conclusions: Stage IV prostate cancer is a diverse group with PCSM in various subgroups ranging from 17% to 69% at 10 years. Considering the favorable outcomes of those with T4 or N1 M0 CAP relative to M1 disease, we propose a new stage IIIB in which T4 or N1 M0 CAP should be reclassified, and patients offered curative intent therapy whenever possible.

Radiation Therapy Oncology Group (RTOG) Protocol 0915: A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy (SBRT) Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer

G.M. Videtic, C. Hu, A. Singh, J.Y. Chang, W. Parker, K. Olivier, S. Schild, R. Komaki, J. Urbanic, and H. Choy

Purpose/Objective(s): To select the most favorable treatment regimen based on the rate of grade 3 or higher protocol-specified adverse events (psAEs) at 1 year.

Materials/Methods: Patients with documented baseline medical conditions precluding lobectomy and biopsy-proven peripheral (greater than 2cm from the central bronchial tree) T1/T2, N0 (clinically node negative by PET), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in one fraction (arm 1) or 48 Gy in 4 consecutive once-daily fractions (arm 2). Rigorous central accreditation and quality assurance assessments were used to assure patients were treated according to protocol guidelines. The study was designed to detect whether psAEs rate > 17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included primary tumor control (PC) rate, 1-year overall survival (OS), progression-free survival (PFS). The regimen selection criteria were based on pre-specified rules of psAEs and PC for each arm. Formal comparisons were not performed.

Conclusions: At one year, 34 Gy in one fraction met pre-specified criteria with respect to adverse events and primary control, and therefore is selected as the experimental arm for a planned phase III trial.

Effect of Patient Breathing on Y90 PET Dosimetry for Y90 Radioembolization of Liver Cancer

N. Yu, H. Qu, S. Srinivas, K. Stephans, M. Abdel-Wahab, and P. Xia

Purpose/Objective(s): The recent progress in the use of Y90 PET imaging for dosimetry of Y90 radioembolization of liver cancer has enabled us to quantitatively analyze the delivered tumor dose distribution for this treatment modality. Because the gated acquisition of Y90 PET is not practical, the breathing effect on the quantitative dose distributions from free breathing post treatment Y90 PET (post-PET) is unknown. The purpose of this study is to develop a method to remove the breathing effect from the post-PET and quantitatively evaluate the dose discrepancy from the post-PET with and without the breathing effect removed.

Materials/Methods: Nineteen patients were chosen for this retrospective study. Following the tip of the delivery catheter, we obtained the patient specific tumor motion trajectories in the superior/inferior direction from the fluoroscopic images acquired during the treatment. The probability density functions (PDF) that characterized the breathing patterns in this direction were developed and used to deconvolute the post-PET to remove the breathing effect from the PET images (dec-PET). The Van- Cittert algorithm was used for the deconvolution. The delivered Y90 dose distributions were calculated with the post-PET and dec-PET images using a previously published dose kernel obtained with Monte-Carlo calculations. The volumes encompassed by the selected isodose lines such as 200 Gy, 120 Gy, and 80 Gy lines from two paired PET images were compared. For each volume generated from the post-PET isodose line, a dose volume histogram was generated for the dec-PET dose. Quantitatively, the dec-PET dose received by 95% of the volume of a selected post-PET dose line, d, denoted as D95,d were used to assess the discrepancy between the dose distributions from the post-PET and dec-PET.

Conclusions: A method is developed to remove the breathing effect on the dose distributions calculated from a free breathing PET, using a deconvolution method based on patient specific breathing patterns. The dose distributions calculated from the deconvoluted PET and the free breathing PET are similar. For each calculated free breathing PET isodose line at a specific dose level d, D95 from the deconvoluted PET is within 20% of the corresponding post-PET dose level.

Automatic CBCT-Based Online Adaptive Prostate Therapy

A.R. Godley, A. Zhao, and K. Stephans

Purpose/Objective(s): To automatically adapt prostate treatment plans to the daily anatomy as imaged in the pre-treatment cone beam (CBCT) to improve on the current standard of daily patient repositioning.

Materials/Methods: Five IMRT prostate patients with kV CBCT image guidance were chosen. The patients were replanned with Direct Aperture Optimization IMRT, 5 mm margin, prescribed PTV D95 of 76 Gy, prostate D100 of 78 Gy. Our previously reported method of deforming prior days contours and then combining them with STAPLE provided accurate contours for organs and targets on nine CBCTs per patient. The plan CT is deformably registered to each CBCT during the contour generation. A two stage replan is investigated, firstly morphing the segments according to the change of target shape in the beam’s eye view (SAM), and then optimizing the weights of each segment (SWO). SAM requires only the contours, SWO requires the electron density from the deformed plan CT. The adapted plans were compared to the current standard of repositioning. All plans were calculated with heterogeneity corrections.

Conclusions: Our adaptive approach is significantly better than the current standard of repositioning. Other studies have demonstrated SAM/SWO but relied on CT-on-Rails images. While CToR provides superior image quality, it is not common clinically. Our study overcomes the lower image quality of the more common CBCT and so can lead to a high clinical impact. SAM alone shows sufficient improvement over repositioning such that deforming the plan CT for electron density is not necessary, (a potential source of error). Contours can be manually drawn requiring a clinic to obtain only a tested (in the manner described here) aperture morphing scheme for CBCT-based adaptive therapy.

Taussig Cancer Institute Clinical Trials

CCF IRB 12-1084
Phase II study of TKI258 (Dovitinib) in patients with recurrent or progressive Glioblastoma who have progressed with or without anti-angiogenic therapy (including anti-VEGF therapy)

CCF IRB 12-344
A Phase 2 Evaluation of TRC105 in Combination with Bevacizumab for the Treatment of Recurrent or Progressive Glioblastoma that has progressed on Bevacizumab

CCF IRB 13-445
Title: A Prospective Phase II Trial of NovoTTF-100A with Bevacizumab (Avastin) in Patients with Recurrent GBM

CCF IRB 13- 1081
Phase II study of Radioimmunotherapy with Zevalin® (Ibritumomab Tiuxetan) Therapy for Patients with Refractory or Relapsed Primary Central Nervous System Lymphoma (PCNSL)

VERA 1513 | 13-885
A Phase II Randomized Double-Blind, Placebo-Controlled, Multicenter Study of VS-6063 in subjects with malignant pleural mesothelioma (Verastem, Inc.)

THRS 1711
A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination with Doxorubicin vs. Doxorubicin Alone in Subjects with Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

CASE1A09 / CC-902
Azacitidine with lenalidomide and dexamethasone for relapsed/refractory myeloma

CASE2A10 / CC-00079
Placebo controlled trial to assess efficacy of glutamine in prevention of bortezomib induced neuropathy

CASE1A13 / 13-870
“Mini” allogeneic stem cell transplant with bortezomib as graft versus host disease prophylaxis and delayed low dose lenalidomide maintenance with the goal to maximize graft versus myeloma effects

SWOG1211 / 13-063
The antiCS-1 antibody elotuzumab together with bortezomib, lenalidomide, and dexamethasone for high risk multiple myeloma

GENE 1813
A Phase II, randomized study of MPDL3280A administered as monotherapy or in combination with Bevacizumab versus Sunitinib in patients with untreated advanced renal cell carcinoma

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