Libby’s H*O*P*E* Wishes All Of Our Readers A Happy St. Patrick’s Day

I know what you’re thinking.  With a last name like Cacciatore, he can’t be Irish. But alas, you would be mistaken, as I am one-half Irish and proud of it.  My old college roommate (who is a 1st generation Irish American) considers St. Patrick’s Day the holiest of holy days … along with the entire college campus of the University of Notre Dame.

In honor of the day, I provide you with an Irish toast & song as both go hand-in-hand (usually with a pint of Guinness reserved for one hand).

The Toast: “May you live to be 100 years old with an extra year to repent! Sláinte!”

The Song: “The Galway Girl“* by the Irish artist Mundy. Mundy’s live performance of this song is provided below.

*”The Galway Girl” is a song originally written by Steve Earle and recorded with the Irish fiddler Sharon Shannon on Earle’s 2000 album Transcendental Blues.  The video below features a cover version of the song made famous in 2007-2008 by the Irish artist Mundy.  Mundy’s cover version of the Irish song reached even higher profile in the U.S. after being featured by director Richard LaGravenese in the movie P.S. I Love You (click here to view a video that features the Galway Girl song and excerpts from P.S. I Love You).

The Galway Girl Performed by Mundy

Early Detection Remains Key in Updated National Comprehensive Cancer Network (NCCN) Guidelines for Ovarian Cancer

New updates to the NCCN Clinical Practice Guidelines in Oncology™ for Ovarian Cancer were presented at the NCCN 14th Annual Conference on March 14. Notable additions to the NCCN Guidelines are a section on managing allergic reactions to chemotherapy agents and new agents for recurrence therapy. Robert J. Morgan Jr., M.D., F.A.C.P. of  the City of Hope Comprehensive Cancer Center presented the updated NCCN Guidelines that continue to stress early detection of ovarian cancer and the enrollment of patients in clinical trials.

“Early Detection Remains Key in Updated NCCN Guidelines for Ovarian Cancer


New updates to the NCCN Clinical Practice Guidelines in Oncology™ for Ovarian Cancer were presented at the NCCN 14th Annual Conference on March 14. Notable additions to the NCCN Guidelines are a section on managing allergic reactions to chemotherapy agents and new agents for recurrence therapy. Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center presented the updated NCCN Guidelines that continue to stress early detection of ovarian cancer and the enrollment of patients in clinical trials.


March 16, 2009

morganrobert

Robert J. Morgan Jr., M.D., F.A.C.P., Professor of Medical Oncology, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA & Chair of the NCCN Guidelines Panel for Ovarian Cancer

HOLLYWOOD, FL — Improvements in screening and early detection remains the key for women with ovarian cancer according to Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center and chair of the NCCN Guidelines Panel for Ovarian Cancer. Dr. Morgan discussed the future of ovarian cancer and notable changes to the recently updated NCCN Ovarian Cancer Guidelines at the NCCN Annual Conference on Saturday, March 14.

Dr. Morgan began by explaining that the major challenge in treating ovarian cancer is that by the time the majority of patients (70 percent) are diagnosed with the disease, it has already progressed to stage III or IV. ‘We have not yet found a good way to screen the general population or even the high-risk population of women for ovarian cancer,’ he said.

New to the NCCN Guidelines is a section on the management of allergic reactions in patients receiving chemotherapy for ovarian cancer. Dr. Morgan explained the need for this section as ovarian cancer tends to respond to the same treatment repeatedly. Combined with the fact that recurrence rates of ovarian cancer are high, this can result in patients often being retreated with the same chemotherapeutic agent. Given that virtually all chemotherapy drugs have the potential to cause infusion reactions, including agents commonly used in ovarian cancer, the NCCN Guidelines Panel felt it was important to provide information on allergic reactions and recommendations on desensitization regimens.

‘Most patients experiencing allergic reactions are able to be desensitized allowing for continued chemotherapeutic treatment, which is vital to the management of ovarian cancer,’ said Dr. Morgan.

Also new to the updated NCCN Guidelines is the addition of new agents for recurrence therapy, most notably pemetrexed (Alimta®, Eli Lilly and Company) as well as recommendations for therapies based on the timing of recurrence.

‘Seventy-five to 80 percent of patients with stage III or IV ovarian cancer will experience recurrence and this recurrence can occur at any time – during treatment, within 6 months of completing treatment, or more than a year after completing treatment,’ Dr. Morgan noted. ‘In the updated NCCN Guidelines, we differentiated appropriate therapy for recurrence based upon the time frame on which it occurs.’

Additionally, Dr. Morgan referred to a clinical trial suggesting that pemetrexed is active in recurrent ovarian cancer, to support the new recommendation in the updated NCCN Guidelines.

Dr. Morgan described new updates to the Principles of Primary Surgery section in the updated NCCN Guidelines that included the recommendation to consider completion surgery for patients responsive to chemotherapy with initially unresectable residual disease, as well as recommendations relating to special circumstances including minimally-invasive procedures, and fertility sparing procedures.

Dr. Morgan also discussed recent clinical studies conducted abroad that studied the effect of chemotherapy as an up-front therapy in patients with ovarian cancer, and concluded that ‘in the United States, up-front debulking surgery remains the recommendation for the best overall survival.’

Another addition to the updated NCCN Guidelines is a section on the Principles of Chemotherapy. This section emphasizes the encouragement of patients participating in clinical trials during all aspects of their treatment course as well as noting that patients with newly diagnosed tumors should be informed about the different options available, particularly IV [intravenous] vs. IV/IP chemotherapy and the risks and benefits of each regimen.

‘The future of ovarian cancer lies in early detection and improvements in screening,’ Dr. Morgan noted as he discussed potential biomarkers for the detection, prediction and prognostication of ovarian cancer.

He concluded that steady progress is being made in the treatment of ovarian cancer, but further trials are necessary to investigate the role of targeted agents alone and in combination in newly diagnosed and recurrent ovarian cancer. Finally, he again stressed the need for physicians to encourage their patients to participate in clinical trials.

For questions about NCCN or for interview information, please contact Megan Martin 215.690.0576.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit www.nccn.org.

The NCCN Member Institutions are

Cited SourceEarly Detection Remains Key in Updated NCCN Guidelines for Ovarian Cancer, News, National Comprehensive Cancer Network (NCCN), March 16, 2009.

Can FDA-Approved HIV Drugs Treat Chemoresistant Ovarian Cancer?

Two recent in vitro studies conducted in the U.S. and Europe raise a provocative question:  Can FDA-approved human immunodeficiency virus (HIV) drugs be used to treat chemoresistant ovarian cancer?  Both studies were based upon the fact that HIV patients taking antiretroviral inhibitors have a lower incidence of infection-associated malignancies.  Based upon that fact, the researchers conducting both studies hypothesized that such drugs could produce anti-cancer activity.

Two recent in vitro studies conducted in the U.S. and Europe raise a provocative question:  Can FDA-approved human immunodeficiency virus (HIV) drugs be used to treat chemoresistant ovarian cancer?  Both studies were based upon the fact that HIV patients taking antiretroviral inhibitors have a lower incidence of infection-associated malignancies.  Based upon that fact, the researchers conducting both studies hypothesized that such drugs could produce anti-cancer activity.

The first in vitro study was conducted by University of Munich Hospital researchers.  The stated purpose of the German in vitro study was to determine whether nelfinavir could (i) sensitize drug resistant ovarian cancer cells to chemotherapeutic agent, or (ii) act as a monotherapy against drug resistant ovarian cancer cells.  Upon conclusion of the study, the German researchers discovered that nelfinavir induced cell death in carboplatin– sensitive and carboplatin-resistant ovarian cancer cell lines, as well as in cancer biopsies and ascites samples from patients with recurrent ovarian cancer.  The researchers noted that nelfinavir significantly changed the morphology of the ovarian cancer cells by creating the so-called “unfolded protein response” (UPR). UPR, in turn, caused ovarian cancer cell cycle arrest and death. The German researchers also observed a downregulation of cell cycle regulatory proteins after nelfinavir treatment, and hypothesized that it contributed to ovarian cancer cell death. Because nelfinavir represents a FDA-approved drug for use in humans with HIV infection, the researchers concluded that it could be tested rapidly in clinical studies as a potential treatment strategy against drug-resistant ovarian cancer.

The second in vitro study was conducted by University of Michigan researchers.  The stated purpose of the University of Michigan study was to (i) determine whether the protease inhibitor saquinavir could produce anticancer activity in ovarian cancer cell lines, and (ii) understand the mechanism through which such anti-cancer activity occurs.  Upon conclusion of the study, the University of Michigan researchers discovered that saquinavir induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Specifically, cellular morphology assessed by transmission electron microscopy (TEM) revealed apoptotic, autophagic, and necrotic cell death. The University of Michigan researchers concluded that saquinavir, as an FDA-approved drug for the treatment of HIV, could have clinical application in the treatment of chemoresistant ovarian cancer.

Comment:

There is no guarantee that the in vitro study results discussed above could be replicated in human beings.  The in vitro study results are nevertheless provocative because they were performed with drugs that are already FDA-approved, abeit for HIV, and therefore, such drugs were previously determined to be relatively safe. In addition, the findings of both in vitro studies are nearly identical despite the fact that two different FDA-approved HIV drugs were tested by two separate medical facilities. Given the chemoresistant nature of ovarian cancer, it seems that nelfinavir and saquinavir should be tested in future clinical trials.

Primary Sources:

Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer

… University of Minnesota researchers evaluated the use of fulvestrant [Faslodex®] in women with recurrent ovarian or primary peritoneal cancer. …Using modified-RECIST criteria 13 patients (50%) achieved SD …[T]he University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

It is well-known that the goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Previously, Fulvestrant (Faslodex®), a novel estrogen receptor (ER) antagonist, was proven clinically beneficial and well-tolerated in treating recurrent breast cancer. If a pathologist determines that a women’s ovarian cancer biopsy is estrogen receptor positive (ER+), there is a possibility that she may respond to anti-estrogen therapy.

On this basis, University of Minnesota researchers evaluated the use of fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Patients with ER+, multiply recurrent ovarian or primary peritoneal carcinoma were eligible for trial enrollment if (i) they had measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, or (ii) an abnormal and rising CA-125 blood test measurement. Treatment consisted of single agent fulvestrant, 500 mg IM (intramuscular) on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until the patient experienced intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as bimonthly CT scans. The clinical trial primary endpoint was “clinical benefit” (CB) (i.e., CB=complete response (CR) + partial response (PR) + stable disease (SD)) at 90 days).

Pursuant to the phase II fulvestrant clinical trial, the study researchers reported the following:

  • Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose;
  • Patients received a median of 5 prior chemotherapeutic regimens (range: 2-13) prior to enrollment;
  • One patient experienced CR (4%), one patient experienced PR (4%), and 9 patients experienced SD (35%) using modified-Rustin criteria (CA-125 level);
  • Using modified-RECIST criteria 13 patients (50%) achieved SD;
  • The median time to disease progression was 62 days (mean 86 days); and
  • Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients).

Based upon the foregoing results, the University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

Primary SourceA phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer; Argenta PA, Thomas SG, Judson PL et. al., Gynecol Oncol. 2009 Feb 22. [Epub ahead of print]

Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors

“The Massachusetts General Hospital Cancer Center has recently opened a new Translational Research Laboratory that will uncover the genetic codes and gene mutations from almost all of its cancer patients. … By embarking on such an ambitious approach, Cancer Center pathologists and oncologists hope to gather specific information about tumor properties that will lead to targeted therapies and better personalized treatments. Mass General will be the first and only cancer center to conduct molecular profiling of positive biopsies and tumors from all patients as part of basic patient care. …”

Genetic profiling

09/Mar/2009

massgenlab

Massachusetts General Hospital Cancer Center Opens Molecular Pathology Lab to Genetically Profile All Patient Tumors

The Massachusetts General Hospital Cancer Center has recently opened a new Translational Research Laboratory that will uncover the genetic codes and gene mutations from almost all of its cancer patients. Previously only a sampling of patients had their tumors analyzed in such a comprehensive fashion.

By embarking on such an ambitious approach, Cancer Center pathologists and oncologists hope to gather specific information about tumor properties that will lead to targeted therapies and better personalized treatments. Mass General will be the first and only cancer center to conduct molecular profiling of positive biopsies and tumors from all patients as part of basic patient care.

Scientists and researchers have already identified over 110 genetic mutations responsible for causing tumor growth, many of which are involved in several different types of cancers. Codirectors of the Transplational Research Laboratory, Leif Ellisen, MD, PhD, and A. John Iafrate, MD, PhD, have equipped the lab with state-of-the-art robotic technology, which will make it possible to quickly genotype tumor specimens within a short period of time.

‘This new and improved classification of cancers that we are doing is intended to give our oncologists more information about a individual patient’s cancer, so they can treat it in a very specific way, thereby significantly increasing the odds of success,’ says Iafrate.

Several new cancer drugs that are currently available or in development are able to block some of the mutations and pathways that cause tumor cells to proliferate. By targeting tumor gene mutations with these smart drugs, doctors may be able to eradicate malignant cells without using traditional treatments like chemotherapy and radiation, which have significant side effects.

The lab’s new tumor genotyping initiative should also expedite the time it takes to find the right drug for the right patient. According to Ellisen, ‘If we are able to identify a mutation in, say, a case of lung cancer, and we know that a particular drug has been successful in treating colon cancer patients with the same mutation, then we have good reason to believe that drug will work turning off the cancer-causing mutation in the lung cancer patient as well.’

The lab will start with the genotyping of Mass General’s lung cancer patients and phase in different disease groups over the next few weeks. It is anticipated that the profiling of all possible patient tumors will occur gradually over the coming months.

Learn more about research at the Cancer Center

Cited SourceMassachusetts General Hospital Cancer Center opens molecular pathology lab to genetically profile all patient tumors, News, Massachusetts General Hospital, Mar. 9, 2009.

Update:

  • Making Personalized Cancer Care Routine, In Depth, NCI Cancer Bulletin, Volume 6 / Number 11, National Cancer Institute, June 2, 2009 (noting that Massachusetts General Hospital & Memorial Sloan-Kettering Cancer Center are performing genetic profiling of all lung cancer tumors).

Preliminary Findings of a Large British Study Indicate That CA-125 Blood Test & Transvaginal Ultrasound Test Can Detect Early Ovarian Cancer

“Ovarian cancer has a high case—fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. …”

“Background

Ovarian cancer has a high case—fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS.

earlydetecttrialdesign1

The United Kingdom Collaborative Trial of Ovarian Cancer Screening - Overall Trial Design

Methods

Between 2001 and 2005, a total of 202,638 post-menopausal women aged 50—74 years were randomly assigned to [1] no treatment (control; n=101,359); [2] annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50,640); or [3] annual screening with transvaginal ultrasound (USS; n=50,639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032.

Findings

In the prevalence screen, 50,078 (98.9%) women underwent MMS, and 48,230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1,490 USS). Overall, 4,355 of 50,078 (8.7%) women in the MMS group and 5,779 of 48,230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1,894 (3.9%) women in the USS group required clinical evaluation. 97 of 50,078 (0.2%) women from the MMS group and 845 of 48,230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0—61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers.

Interpretation

The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

Funding

Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart’s and the London, and Special Trustees of University College London Hospital.”

Primary Source

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS); Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS); Usha Menon MD, Aleksandra Gentry-Maharaj Ph.D., Rachel Hallett Ph.D. et. al, The Lancet Oncology, Early Online Publication, 11 March 2009 doi:10.1016/S1470-2045(09)70026-9.

Comment

During an interview with the New York Times, Dr. Ian Jacobs, director of the Institute for Women’s Health at University College London, and director of the trial, discussed the optimism and the caveats associated with the preliminary clinical study results as follows:

We have now demonstrated we can pick up the vast majority of women with ovarian cancer earlier than they would have otherwise been detected and before they have symptoms, .. and that a good proportion of those women have earlier stage disease than we would normally expect them to have. … [W]omen thinking of having this must understand and realize that there’s a possibility it will do more harm than good. We have reason to think it will save lives, … and then the question is, will it save enough lives to balance out the harm it does? [Emphasis added].

Robert Smith, director of cancer screening for the American Cancer Society informed the New York Times that “[w]e’re not even remotely close to knowing how to screen women of average risk with these tests, or even if we should.” Mr Smith added that it is important to run large clinical trials, but that the preliminary results of this study must be interpreted with caution.

Secondary Sources

High-Dose Stereotactic Body Radiation Therapy Effective Treatment For Patients With Low Volume Lung or Liver Metastases

Libby’s H*O*P*E*™ previously reported on potential treatments for “oligometastasis,” which is defined as cancer that spreads to a few distant body sites, on June 23, 2008 and August 17, 2008.  Two related U.S. multi-institutional, phase I/II clinical studies and one Canadian Phase I clinical study reported recently results from an evaluation of the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with liver or lung metastases.  A description of each study and its findings is provided below.  In addition, we have provided an excerpt from an editorial published in the Journal of Clinical Oncologythat comments upon the lessons learned from the three SBRT clinical studies described below, as well as other related studies.

Libby’s H*O*P*E*™ previously reported on potential treatments for “oligometastasis,” which is defined as cancer that spreads to a few distant body sites, on June 23, 2008 and August 17, 2008.  Two related U.S. multi-institutional, phase I/II clinical studies and one Canadian Phase I clinical study reported recently results from an evaluation of the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with liver or lung metastases.  A description of each study and its findings are provided below.  In addition, we have provided an excerpt from an editorial published in the Journal of Clinical Oncology that comments upon the lessons learned from the three SBRT clinical studies described below, as well as other related studies.

sbrtU.S. SBRT Liver Metastases Study

In the first U.S. clinical study, patients with one to three hepatic lesions (with maximum individual tumor diameters less than 6 cm) were enrolled and treated on a multi-institutional, phase I/II clinical trial in which they received SBRT delivered in three fractions. During the phase I clinical study, the total radiation dose was safely escalated from 36 Gy to 60 Gy. During the phase II portion of the clinical study, the dose was 60 Gy. The study primary end point was local control of the hepatic metastases. Hepatic metastatic lesions with at least 6 months of radiographic follow-up were considered assessable for local control. The study secondary end points were toxicity and survival.

As part of this clinical study, 47 patients with 63 lesions were treated with SBRT. Among those patients, 69% had received at least one prior systemic therapy regimen for metastatic disease (range, 0 to 5 regimens), and 45% had extra-hepatic disease at study entry. Forty-nine discrete lesions were assessable for local control. Median follow-up for assessable lesions was 16 months (range, 6 to 54 months). The median maximal tumor diameter was 2.7 cm (range, 0.4 to 5.8 cm). Based upon this criteria, the researchers reported the following findings:

  • Only one patient experienced grade 3 or higher toxicity (2%);
  • Local progression occurred in only three lesions at a median of 7.5 months (range, 7 to 13 months) after SBRT;
  • Actuarial in-field local control rates at one and two years after SBRT were 95% and 92%, respectively;
  • Among lesions with maximal diameter of 3 cm or less, 2-year local control was 100%; and
  • Median survival was 20.5 months.

Based upon the foregoing, the U.S. researchers concluded that the multi-institutional, phase I/II clinical study demonstrates that high-dose liver SBRT is safe and effective for the treatment of patients with one to three liver metastases.

Canadian SBRT Liver Metastases Study

In the phase I Canadian clinical study, patients with liver metastases who were inoperable or medically unsuitable for resection, and were not candidates for standard therapies, were eligible for this individualized SBRT study. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%).  Additional patients were treated at the maximal study dose (MSD) in an expanded cohort.  Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks.  Based upon this criteria, the Canadian researchers reported the following findings:

  • Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated;
  • Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL);
  • The highest RILD risk level investigated was safe, with no dose-limiting toxicity;
  • Two patients experienced grade 3 liver enzyme changes, but no RILD or other grade 3 to 5 liver toxicity was seen, resulting in a low estimated risk of serious liver toxicity;
  • Six patients (9%) experienced acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) patient experienced grade 4 toxicity (thrombocytopenia);
  • The 1-year local control rate was 71%; and
  • The median overall survival was 17.6 months.

Based upon the foregoing, the Canadian researchers concluded that individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.

U.S. SBRT Lung Metastases Study

In the third study, patients with one to three lung metastases (with cumulative maximum tumor diameter smaller than 7 cm) were enrolled and treated as part of a U.S. multi-institutional phase I/II clinical study in which they received SBRT delivered in 3 fractions.  During the phase I clinical study, the total dose was safely escalated from 48 to 60 Gy. During the phase II portion of the clinical study, the phase II dose was 60 Gy.  The study primary end point was local control.  Metastatic lung lesions with at least 6 months of radiographic follow-up were considered assessable for local control.  The study secondary end points included toxicity and survival.

As part of this study, 38 patients with 63 lesions were enrolled and treated at three U.S. participating institutions. Among those patients, 71% received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, 0 to 5 regimens). Two patients had local recurrence after prior surgical resection. Fifty lesions were assessable for local control.  Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Based upon this criteria, the researchers reported the following findings:

  • There was no grade 4 toxicity;
  • The incidence of any grade 3 toxicity was 8% (3 of 38 patients);
  • Symptomatic pneumonitis occurred in one patient (2.6%);
  • Actuarial local control at one and two years after SBRT was 100% and 96%, respectively;
  • Local progression occurred in one patient, 13 months after SBRT; and
  • Median survival was 19 months.

Based upon the foregoing, the U.S. researchers concluded that the multi-institutional phase I/II clinical study demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Using a Bigger Hammer: The Role of Stereotactic Body Radiotherapy in the Management of Oligometastases Journal of Clinical Oncology Editorial

“… What can we learn from these three trials [described above]?

First, we have learned once again that it is possible to conduct prospective trials of new technological approaches. This is an important lesson. This is how future technologies, such as proton therapy, should be tested.

Second, although the poor overall survival of patients in these trials competes with the risk of local relapse, possibly leading to overestimation of the probability of local control at 2 years, it seems likely that SBRT is a good treatment for such patients. It would seem that a standardized dose/fractionation scheme, such as 60Gyin three fractions, works well for tumors smaller than 3 cm; larger ones may benefit from an individualized approach, such as described by Lee et al. [Canadian study decribed above, ftnote omitted]. However, we must continue to remember past experiences with hypofractionation of large volumes, which can produce severe late normal-tissue effects, especially fibrosis. Even if small volumes are irradiated, catastrophic complications can occur.  In the case of lung cancer, severe unacceptable complications (bronchial fibrosis or hemorrhage) have been associated with treatment of lesions within 2 cm of major airways.  A more protracted (five-fraction) regimen is about to be tested in a Radiation Therapy Oncology Group (RTOG) trial that will open in the coming months that will determine if these toxicities can be avoided.  Lesions close to the chest wall may also benefit from a more protracted fractionation to avoid rib fractures.  In the case of medial or central liver lesions, hypofractionation can cause intestinal obstruction or biliary fibrosis.

Finally, we should recognize that the methodology used in these trials applies to patients with relatively normal liver and lung functions.  At this time, it is not clear how to account for organ dysfunction in patients with lung cancer or primary liver tumors.  Certainly, differences in tolerance to radiation between patients with liver metastases and those with primary liver tumors have been observed before [ftnote omitted].  Therefore, although SBRT seems to have given us a bigger hammer, we still have much to learn about how and when to strike the nails.”

Primary Sources: