Surgery, especially minimally invasive (‘key-hole’) surgery, is an effective and safe treatment for patients with early stage lung cancer. However, between 20 to 30 percent of patients relapse in the first five years following surgical treatment alone in Stage 1 non-small cell lung cancer. In Stage 2, this percentage rises 40 to 50%. There have been many recent attempts to decrease this rate of relapse. Chemotherapy after surgery has been investigated thoroughly. Latest pooled data from the best studies have shown that chemotherapy after surgery improves survival approximately 4% more than surgery alone at five years. Because of these modest results, there has been at least one major study looking at targeted therapy using the drug erlotinib after surgery. Results of this trial are awaited. One other strategy would be to use vaccines (immunotherapy) against lung cancer.
Using the body’s own immune system to fight cancer has long been considered a possible elegant anti-cancer strategy. However vaccine therapy for cancer suffers from potential difficulties. One difficulty was that the vaccine should be targeted against the tumor alone, and not normal tissue. In other words, the genetic makeup of the tumor should contain specific targets that the vaccine would act against, leaving normal tissues unaffected.
In the early 1990s, researchers began to look more closely at the genetic makeup of cancers. It was noticed that many cancers contained a specific family of genes, named the ‘cancer-testis antigens’. These genes were most pronounced in non-small cell lung cancer. One class of these genes was called the Melanoma Associated Antigen (MAGE). In the following years many teams investigated the details of the MAGE family. Amongst the many MAGE antigens found in lung cancer, the MAGE 3 antigen was considered a good target for development of a vaccine against the lung cancer that contained this particular antigen. However, only 30% of non-small cell lung cancers contained (‘expressed’, in medical parlance) the MAGE 3 antigen.
Scientists at GlaxoSmithKline, the pharmaceutical company, then developed a specific vaccine against the MAGE 3 expressing non-small cell lung cancer. The vaccine would induce specific white blood cells to attack the tumor. In addition, the vaccine would contain a non-specific immune boosting mechanism to enhance the effect of these specific white blood cells. Early studies of this vaccine in patients with non-small cell lung cancer have shown encouraging results. This led to the establishment of a major clinical trial testing this vaccine (called the Phase III MAGRIT trial). Many centers around the world are participating in this trial. There are also smaller trials of various immunotherapy approaches going on at specific institutions in the U.S, however the MAGRIT Trial is the only vaccine trial for post-surgical patients being conducted worldwide at this time.
Patients are consented to participate in the trial following surgery. As a first step, the patient consents for the tumor that was removed at surgery to be tested for the MAGE 3 antigen. If their tumor contains the antigen it means two things – one, that the patients who are MAGE 3 positive do somewhat worse (in the long term) than people who are MAGE 3 negative and two, they are eligible for the trial. MAGE 3 positive patients are then randomized to receive the vaccine over a period of the next two years in 13 injections. The injection is given into the arm or buttock muscle, similar to a flu shot. Recent experience has shown the vaccine to be safe with very few minor side effects. The patients are randomized on a 2:1 ratio, meaning every 3rd patient receives a placebo and the other two patients receive the vaccine. This is done in a blinded fashion, meaning neither the research staff or the patient knows who is receiving the vaccine versus the placebo. I would encourage all patients who have surgery for lung cancer to discuss with their surgeon or oncologist for possible enrollment in the MAGRIT Trial.
Further lung cancer vaccines are in development, thus potentially benefiting patients that are MAGE 3 negative.
Despite much hope (and sometimes hype), personalized cancer therapy has progressed little since trastuzumab, the first genotypespecific molecular therapy, was approved for Her2-positive breast cancer in 1998. Most patients with a given cancer type and grade still receive the same treatment, regardless of genetic differences in their tumors.
After trastuzumab, genotypebased patient selection in trials was ignored as a strategy for common cancers. “Ten years go by, and then there aren’t any other examples of anybody actually doing that,” said Ross Camidge, M.D., Ph.D., a medical oncologist at the University of Colorado in Denver.
Molecular markers for targeted therapy in lung cancer: USCAP 2010I attended the Special Course at USCAP 2010, “Basic Principles and Practice of Molecular Pathology in Cancer.” One of the talks was given by Dr. Marc Ladanyi from MSKCC and one of the leaders in the field of molecular pathology of lung cancer. The title of his presentation was “Molecular Predictive Markers for Targeted Therapies in Lung Cancer.” Here’s my “take-home” points from the talk:
Term: “lung adenocarcinoma oncogenome”–(I like this) and he presented a pie chart illustrating the different (and (generally) mutually exclusive) mutations found so far in lung ACa
KRAS
EGFR
BRAF
ERBB2 (HER2)
ALK fusions (especially, ALK-EML4)
MEK1
NF1
but still about one-third of lung ACa have an unknown mutation
Although there are morphologic and clinical features associated with EGFR mutations, their predictive value are insufficient to exclude EGFR mutation testing. Thus, every adenocarcinoma should be tested for EGFR mutation (with the exception of mucinous ACa/BAC which are always KRAS mutants). Although uncommon or even rare, one does find EGFR-mutant ACa in former and current smokers and in men who could benefit from targeted therapy. This is important for testing algorithms (see below).
EGFR mutation versus EGFR amplication is difficult to tease out because they frequently occur together but–
The response rate to EGFR-TKIs is high in EGFR-mutated cases regardless of the EGFR copy number.
EGFR amplified cases lacking one of the mutations have a very low response rate to EGFR-TKIs.
Why are some patients with EGFR-mutant tumors non-responders to EGFR-TKIs?
Not all EGFR mutations confer sensitivity (dependent on type of mutation detection method, i.e., direct sequencing versus targeted approach to known sensitive mutations)
There may be concurrent “downstream” mutations, e.g. BRAF, PTEN loss, PIK3CA, etc.)
Not a well-studied group.
Why do some patients with EGFR-wild type tumors respond to EGFR-TKIs?
Undetected sensitive mutations due to targeted detection method.
Poor sensitivity of direct sequencing methods
Not a well-studied group.
KRAS mutations function better as a negative predictor of response to EGFR-TKIs than EGFR mutations do as a positive predictor.
Dr. Ladanyi presented data from a MSKCC study of patients with EGFR-mutant tumors who initially responded to EGFR-TKI therapy but relapsed while on therapy and underwent re-biopsy. Two-thirds of these patients developed acquired resistance due to the development of the EGFR T790M mutation; some also were shown to have MET amplification.
BRAF mutations (most commonly exon 15 V600E) is also a negative predictor of response to EGFR-TKIs but does predict benefit from MEK-selective inhibition: PLX-4032, an experimental agent from Plexxikon which targets mutated BRAF (currently in trials for melanoma in which >50% of tumors show the V600E mutation).
Very helpful point in discerning which type of EGFR/KRAS mutation detection testing will be serve your patients: Dr. Ladanyi distinguished between “diagnostic sensitivity” and “technical sensitivity.”
Diagnostic sensitivity (the “comprehensiveness” of an assay): the percentage of all mutations that will be found with a given assay
Technical sensitivity: the percentage of tumor cells that need to be present in the specimen in order for a mutation being tested for to be identified
There is a trade-off between low technical sensitivity and the risk of false negatives and increasing comprehensiveness or high diagnostic sensitivity and the risk of false positives due to detection of rare mutations of unknown or no clinical significance.
There are mutation-specific rabbit MoAbs that are commercially available for the detection of mutant EGFR in lung ACa and these could facilitate detection in an algorithm and perhaps eliminate the need for mutation detection testing in certain situations: Antibody 3197 against EGFR exon 21 L858R mutation and Antibody 2085 against the EGFR exon 19 E746-A750del–both from Cell Signaling Technologies.
Dr. Ladanyi showed 95% sensitivity and 99% specificity for EGFR L858R Ab and 85% sensitivity and 99% specificity for EGFR exon 19 del Ab. (paper in press)
EML4-ALK detection issues: RT-PCR requires multiple assays because of multiple possible isoforms, other ALK and other kinase fusion partners have been reported, new IHC antibody clone to detect ALK fusion (rabbit mAb #3633 D5F3, Cell Signaling Technologies) may be useful in screening for EML4-ALK detection.
Dr. Ladanyi presented the testing algorithm used at MSKCC and contrasted with one published recently in J Clin Oncol 2009;27:4232-4235.
A future post will include my merged algorithm, combining these and incorporating new IHC.
Lung Cancer Patients See Amazing Results In Clinical Study
Experimental Drug Could Help One In 20 Lung Cancer Patients
POSTED: 4:40 pm MST December 2, 2009
UPDATED: 5:37 pm MST December 7, 2009
AURORA, Colo. — Lung cancer is the most fatal cancer in the U.S. However a local clinical study is providing new hope for patients.
“Once they tell you it’s stage four, and it’s lung cancer, you know you don’t have a lot of time,” said Ellen Pulhamus, a 60-year-old nonsmoker who was diagnosed with non small-cell lung cancer in April 2008.
Her left lung was removed, but after chemo and radiation therapy, the cancer spread to six other areas in her body. Feeling desperate and hopeless, she got involved with the clinical trial of a new drug called an ALK Inhibitor at the University of Colorado Cancer Center.
“I’d only been on the drug for six weeks and went in for the PET scan,” said Pulhamus.
And when compared to her PET/CT scan from the beginning of the study, doctors saw dramatic shrinkage of a tumor on her kidney.
“There were four other tumors, and some of them we couldn’t even see anymore,” said Pulhamus.
“It’s really a dramatic shrinkage of the tumor that we are seeing, and for an experimental drug it’s quite exciting to see that,” said Dr. Robert Doebele, assistant professor medical oncology at UC Denver.
The ALK Inhibitor works by blocking the activity of a specific abnormal gene found in about 5 percent of lung cancer patients.
“And because this gene is so important for the growth and spread of the lung cancer, and its dependence on that gene, it actually shrinks the tumor,” said Doebele.
Technology developed at UC Denver allows doctors to genetically test a biopsy to identify those patients who are likely to benefit from the ALK Inhibitor. This leads to personalized medicine and therapies for patients.
For Pulhamus, the targeted therapy resulted in the 60 percent reduction of an egg-sized tumor, with just two pills a day.
“No chemo, no radiation. I’ve done that,” Pulhamus said with a giggle.
“If we are able to tailor our therapy to the individual patient based on what we see on molecular tests, then it will be very beneficial to the patients because we won’t spend time using very toxic drugs that may not work,” said Doebele.
With fewer and less significant side effects, the ALK Inhibitor can be administered for months, if not years longer than chemotherapy. This means that right now, Pulhamus’ wish for more time to spend with her children and grandchildren has come true.
“It changes everything, it gives me hope,” said Pulhamus. “It makes me realize that maybe there is a future for me.”
In fact, her third PET/CT scan revealed another 50 percent reduction in the size of her tumor.
Doctors at the University of Colorado Cancer Center recommend that everyone in Colorado with lung cancer be evaluated for eligibility in this clinical trial. For more information about free genetic tumor screenings and enrollment in the UCCC clinical trial, call Tiffiany Caudill, 720-848-0392.
The free lung cancer tumor testing is also taking place at:
*The Brigham and Women’s Hospital *Dana Farber Cancer Institute *Emory University/Winship Cancer Center *Moffitt Cancer Center *Johns Hopkins/Sidney Kimmel Cancer Center *MD Anderson Cancer Center *Mass General Hospital Cancer Center *Memorial-Sloan Kettering Cancer Institute *National Cancer Institute *UCLA/Jonssen Cancer Center *University of Pittsburgh Cancer Institute *University of Texas-Southwestern Cancer Center *Vanderbilt-Ingraham Cancer Center.
Biomoda`s Patent Portfolio Continues to Expand ALBUQUERQUE, N.M.–(Business Wire)– Biomoda, Inc. (OTCBB: BMOD), an Albuquerque-based cancer diagnostics company, announces that it has received notice of allowance for a U.S. Patent protecting the proprietary formula for the composition that binds to cancer cells which is utilized in Biomoda`s screening assay for the early detection of cancer. The U.S. Patent entitled “Method for Making 5, 10, 15, 20-Tetrakis (Carboxyphenyl) Porphine (TCPP) Solution and Composition Comprising TCPP,” describes the new formulation of the Biomoda assay trademarked under the name CyPath. “This patent basically gives Biomoda a lock on the `recipe` for the TCPP Labeling Solution,” said Biomoda President John Cousins. “Our formulation moves beyond the original work done on TCPP at Los Alamos National Laboratory and incorporates the cutting-edge science we are doing in our own lab.” TCPP is the foundation for several Biomoda product lines and medical diagnostics. The company`s first product, an in-vitro test for the detection of early-stage lung cancer, is currently in Phase II clinical trials. Study volunteers provide deep-lung sputum samples to be screened for cancer cells with the CyPath assay in the Biomoda lab. Results are compared to CT scans and Pap stains read by independent radiologists and cytopathologists, respectively, to confirm accuracy. Biomoda is seeking Food and Drug Administration (FDA) approval of its cytology-based screening technology as a Class III medical device. Multi-site Phase III trials, the final step before FDA approval, are scheduled to begin in early 2010. In addition to U.S. patents (6,838,248 and 7,384,764), Biomoda also holds patents for its proprietary technology in several foreign countries. Biomoda (www.biomoda.com) is a cancer diagnostics company focused on the development of accurate, inexpensive and noninvasive tests for the early detection of cancer in large populations. In addition to its first product for lung cancer, diagnostic assays for cervical, breast, colorectal, bladder, and oral cancers are targeted for development
Lung Cancer Slowed by Pfizer Drug
By Ransdell Pierson
NEW YORK — A Pfizer Inc. kidney cancer drug has also shown promise in a small mid-stage trial as a treatment for the most common form of lung cancer, researchers said on Saturday.
The new study involved 63 patients whose non-small cell lung cancer had progressed despite earlier treatments with standard chemotherapy. All patients were then given Pfizer’s once-daily pill, Sutent, as a stand-alone treatment and continued to take it until their disease progressed.
Tumors shrank by at least 50 percent in six, or 9.5 percent, of the patients. They stopped growing in another 27, or 43 percent, of the patients, researchers said at the annual meeting of the American Society of Clinical Oncology being held in Atlanta.
Sutent was generally well tolerated, researchers said, with mostly mild to moderate side effects such as fatigue, nausea and shortness of breath.
Its effectiveness was comparable to that seen in separate earlier mid-stage trials of OSI Pharmaceuticals Inc’s Tarceva, a pill which had also been tested by itself among a similar group of lung cancer patients, said Dr. Bruce Johnson, director of thoracic oncology at the Dana Farber Cancer Institute.
“Both of these agents seem able to stablize tumors and prevent them from growing,” said Johnson, who did not conduct the Sutent trial but was chosen to help explain its findings.
Johnson said Sutent’s ability to arrest tumor growth suggests it may prove able in larger trials to actually prolong lives of lung cancer patients, as Tarceva went on to do in its own late-stage trials that helped it win approval as a lung cancer treatment in the United States.
Both drugs block specific proteins that allow tumor cells to grow, and therefore cause far milder side effects than standard cancer treatments which also harm healthy tissue as they go after tumor cells.
“Any time you have well-tolerated agents like Tarceva and Sutent that can shrink tumors by themselves, they become candidates for use with standard chemotherapy,” Johnson said, a big potential use of the two medicines.
U.S. regulators in January approved Sutent, whose chemical name is sunitinib, to treat kidney cancer as well as a rare stomach and intestinal cancer known as GIST.
Larger trials will be needed to conclusively establish Sutent’s effectiveness against lung cancer, the most common cause of death from cancer in both men and women.
Cigarette smoking is the main cause of about 90 percent of lung cancer cases in men and about 70 percent of cases in women, according to the Merck Manual
Posted June 10, 2009
Radiation for small cell lung cancer: options, techniques, latest research
As outcomes for SCLC remain poor, oncologists and radiation oncologists weigh in on radiation treatment techniques.
In the late 1970s researchers widely considered small cell lung cancer a potentially “curable” cancer. Three decades later physicians are still battling the disease, which accounts for about 20% of newly diagnosed lung cancer cases.
Radiation oncologists continue to face hurdles with treatment options. Earlier this year Zhongxing Liao, MD, presented an update on these options at the 9th Annual Oncology Update: Advances and Controversies in Park City, Utah. Liao discussed issues related to choosing the optimal radiation treatment and the accompanying toxicities, which she said is the biggest obstacle today.
The second biggest hurdle may be lack of solid comparative information on SCLC radiation treatment. This lack of data may be why many radiation oncologists are eagerly awaiting the results of a three-arm randomized study — CALGB 30610/RTOG 0538 — which is comparing the standard dose hyperfractionated accelerated radiation (45 Gy) with high–dose once daily (70 Gy) and high–dose accelerated fractionation (61.2 Gy).
HemOnc Today spoke with leading researchers to discuss the study and other hot topics in the field, such as a preferred radiation technique for treatment and the controversial use of elective nodal irradiation and prophylactic cranial irradiation.
“Outcomes for small cell lung cancer remain quite poor,” Anurag K. Singh, MD, director of clinical radiation research at Roswell Park Cancer Institute, Buffalo, N.Y., told HemOnc Today. “Therefore, we have much room for improvement in both radiation and systemic therapies.”
Anurag K. Singh, MD, said prophylactic cranial irradiation should be offered to all SCLC patients with 90% response to initial therapy.
Photo by Roswell Park Cancer Institute
All of the oncologists interviewed for this article agreed that there is a lot to do before a “cure” for SCLC will be found.
Radiation treatment options
Currently, there are no data on direct comparison of conventional, accelerated fractionation and hyperfractionated regimens.
Definitive radiation therapy with concurrent chemotherapy is the standard of care for limited-stage SCLC. Of the radiation delivery options, hyperfractionated accelerated radiation with 1.5 Gy per fraction twice a day for 30 treatments in three weeks is considered the standard of care, according to Liao.
This is supported by data from a 1999 randomized trial published in The New England Journal of Medicine that compared once-daily radiation — 1.8 Gy per fraction, 25 fractions in five weeks — vs. the hyperfractionated accelerated radiation and found a 10% improvement on five-year survival. Liao said hyperfractionated accelerated radiation “should be used at all times if possible.”
However, due to a marked increase in acute toxicity this regimen has not been embraced by all radiation oncologists, according to Suneel Nagda, MD, assistant professor, department of radiation oncology at Loyola University Chicago Stritch School of Medicine.
“The optimal radiation therapy regimen is still unknown,” Nagda said. “Theoretically altered fractionation should be better due to the biology of SCLC, ie, rapidly proliferating tumor.”
Singh agreed. “Unfortunately, we do not know which scheme is optimal. In practice, the decision regarding type of radiation is often made based on considerations such as a patient’s ability to tolerate twice-daily radiation, availability of treatment slots and physician preference,” said Singh, associate professor at the University of Buffalo School of Medicine.
Liao uses a concomitant boost fractionation. In this regimen the first three weeks of radiation is given once a day at 1.8 Gy per fraction. For the next two weeks after that the patient is given 1.5 Gy to 1.8 Gy per fraction twice a day. This fractionation schedule is based on the premise that the SCLC could have accelerated repopulation during the previous couple of weeks of the treatment, because the initial treatment kills the easy cancer cells.
“These two schedules are aggressive treatments needed to fight the aggressiveness of small cell lung cancer,” she said.
The better results associated with a concomitant boost fractionation also have increased treatment toxicity, such as esophagitis, Liao noted. Therefore, in community hospitals, toxicity may prevent the adoption of this more effective schedule. When oncologists make a decision on treatment schedules, they should consider the patient’s general condition, estimate their tolerance for each treatment and their daily life issues, such as whether they have transportation to come to the hospital twice a day, Liao said.
“Although there may be theoretical advantages to accelerated and hyperfractionated XRT for rapidly proliferating small cell lung cancer, the practicality makes it difficult to get patients through such a regimen two or three times daily. It is unclear what benefit would be gained with hypofractionation, except to possibly lessen the duration of treatment, particularly in a palliative setting. So, for most cases, conventional fractionation remains the treatment of choice,” said Khanh Nguyen, MD, assistant professor in the department of radiation oncology, City of Hope National Medical Center, Duarte, Calif.
Is ENI necessary?
The technique of elective nodal irradiation (ENI) has been maligned with controversy as well. ENI is the irradiation of nodal volumes potentially at risk of microscopic tumor spread but not already known to be involved with the primary tumor.
Nagda noted that unlike non–small cell lung cancer, ENI is typically omitted when treating SCLC due to the high doses of radiation therapy necessary to control the local tumor and the increased risk for radiation-related complications with large fields (ie, pneumonitis). “This practice has not necessarily translated to SCLC,” Nagda said. In SCLC, a fair volume of the mediastinum is typically included as there is usually gross disease involvement in the mediastinum. Therefore much of the mediastinum typically receives at least moderate dose of radiation therapy, probably leading to less isolated regional recurrences, even if ENI is omitted, Nagda added.
“There are no large scale studies — as there are in NSCLC — determining the risk of isolated nodal failure in those patients treated without ENI,” Nagda said. “I don’t believe that large volume ENI is necessary in the treatment of SCLC, but to what extent the volume of radiation therapy can be limited is controversial.
“The advantages of omitting ENI are that higher doses of radiation therapy can be delivered without markedly increasing risk of acute and long-term toxicity. The disadvantage of omitting ENI is that an isolated regional failure is difficult to treat with curative intention owing to the previous radiation therapy given,” Nagda said.
“The issue of ENI in SCLC relates mostly to coverage of the supraclavicular lymph nodes,” Singh said. “Isolated failures in the supraclavicular region do occur and have been reported. However, the rate of failure is fairly low and probably not worth the additional toxicity of covering that region in all patients.”
Liao agreed and said that since isolated nodal recurrence is rare after chemoradiation, ENI is not necessary.
“Most patients will have tumor return at the initial site of the primary tumor bulk, or distant spreading,” Liao said. “Adding elective nodal irradiation increases toxicity without adding too much for patient outcome. In addition, during the radiation, some nodal area gets incidental irradiation because radiation has to pass through these areas. At M.D. Anderson, we feel quite comfortable not giving elective nodal irradiation,” Liao said.
Anand Shivnani, MD, radiation oncologist at Baylor Medical Center at Irving Cancer Center Medical, in Texas, said the advantages of ENI do not outshine the problems.
Anand Shivnani
“My feeling is that we need better strategies to reduce distant and local relapses, where the majority of patients recur, before elective nodal irradiation becomes relevant,” Shivnani told HemOnc Today. “I do believe the elective nodal irradiation improves regional control. However, treating more of the mediastinum increases acute side effects, often to the point where treatment breaks may be needed, which we want to avoid. Until our systemic therapies improve, my feeling is that for most patients the benefit of elective nodal irradiation does not outweigh the risks; therefore, I do not routinely offer it.”
Conflicting data on ENI
The debate about the use of ENI is likely due to a large amount of conflicting data on the method, said Scott Herbert, MD, chief of radiation oncology at The Rosenfeld Cancer Center at Abington Memorial Hospital, Pa.
“We used to do ENI as a rule for all lung cancers, but there have been data showing that it is uncommon to fail in nodal sites that are not initially involved,” Herbert said.
The obvious downside to electively radiating the nodes is that the treatment volume is increased and more normal tissue is exposed to radiation, increasing the side effects of treatment, Herbert said.
“If there is a benefit in terms of cancer outcome, this is a risk worth taking,” he said. However, if oncologists are not changing the outcome but only increasing the morbidity of treatment, ENI is not something that should be done. With better imaging, including PET/CT scans, oncologists have a much better idea of the extent of involvement at the time of diagnosis. However, PET scans are often not the best studies for SCLC, as they are for NSCLC, according to Herbert.
“I tend to treat non–small cell lung cancer without elective nodal radiation as I feel PET imaging is an excellent tool for localizing disease. However, since we don’t have the benefit of PET imaging for small cell lung cancer and disease tends to be central, I tend to treat patients with small cell lung cancer with elective nodal radiation to the mediastinum and hilum,” Herbert said.
“For histology such as small cell lung cancer, where regional and systemic spread may be quite high, omitting ‘elective’ nodal radiation may be a mistake,” Nguyen said.
“Even for non–small cell history, the data supporting omission of elective nodal irradiation are sparse,” Nguyen said. “Salvaging a mediastinal or hilar nodal recurrence can be quite challenging, given the dose limits of surrounding critical organs. Thus, it may be more prudent to address regional irradiation for high-risk patients upfront,” Nguyen said.
Prophylactic cranial irradiation
Brain metastases are a frequent problem in patients with SCLC. Increasing data support the use of prophylactic cranial irradiation to prevent intracranial relapse and to improve survival both for patients who achieve a complete response after initial therapy and for those who have a more limited response.
Ben Slotman, MD, PhD, chairman of radiation oncology department at VU University Medical Center, Amsterdam, Netherlands, was an investigator on a randomized study published in The New England Journal of Medicine in 2007 that examined prophylactic cranial irradiation in patients with extensive SCLC who had a response to chemotherapy.
One hundred forty-three patients in two groups aged 18 to 75 had been diagnosed with extensive SCLC. Patients in the irradiation group had a lower risk of symptomatic brain metastases (HR=0.27; 95% CI, 0.16-0.44). The cumulative risk of brain metastases within one year was 14.6% in the irradiation group (95% CI, 8.3-20.9) vs. 40.4% in the control group (95% CI, 32.1-48.6). Irradiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization (all times measured from randomization, which was after completion of chemotherapy).
The one-year survival rate was 27.1% (95% CI, 19.4-35.5) in the irradiation group, and 13.3% (95% CI, 8.1-19.9) in the control group. Irradiation had adverse effects but did not have a clinically significant effect on global health status.
“Prophylactic cranial irradiation should be given to all — limited or extensive — SCLC patients who have responded to chemotherapy, because it reduces the risk of intracranial relapse, improves survival and is generally well tolerated,” Slotman told HemOnc Today.
Craig W. Stevens, MD, PhD, professor and chair in the department of radiation oncology at H. Lee Moffitt Cancer Center, Tampa, Fla., said that for unclear reasons, patients with SCLC start treatment with lower neurocognitive scores than age-matched controls. However, prophylactic cranial irradiation does not appear to exacerbate this problem, according to Stevens.
“We routinely offer prophylactic cranial irradiation to all patients with limited-stage disease who have an excellent response,” he said.
“In contrast, we do not routinely offer prophylactic cranial irradiation to extensive-stage patients who have a complete or near complete response. The controversial European study [Slotman, et al], published in The New England Journal of Medicine last year, demonstrated an improvement in overall survival for those patients who underwent prophylactic cranial irradiation. However, the brain was not routinely imaged prior to prophylactic cranial irradiation treatment, as is the standard in the United States. This fact potentially confounds their results,” Stevens said.
Optimal radiation for PCI
Herbert said the data are very strong for prophylactic cranial irradiation. Recent reports showing a benefit in survival with prophylactic cranial irradiation in patients with extensive disease has expanded its usage to most patients with SCLC.
“Previously, we were only offering prophylactic cranial irradiation to patients with limited-stage disease who achieved an excellent response to chemotherapy and thoracic radiation,” Herbert said.
“Studies have shown that prophylactic cranial irradiation decreases the risk of brain metastases and increases overall survival in this group of patients. Now there is a role for prophylactic cranial irradiation in almost all patients who respond to initial treatment,” he said.
Herbert noted the recent publication of an RTOG trial (06023) looking at the optimal radiation schedule for prophylactic cranial irradiation. It compared three different schedules: two weeks of daily treatment, 3.5 weeks of daily treatment, and twice daily treatment. There was no difference among the three schedules. Most experts think that that the shortest, lowest-dose schedule — once daily, 250 cGy per day for 10 fractions over two weeks for a total of 2,500 cGy — should represent the standard of care as it was equally effective with the least chance for causing cognitive injury, he said.
“Typically, I will treat patients with limited stage disease with thoracic radiation starting with the second cycle of chemotherapy,” Herbert said. “Patients will receive the third of four cycles of chemotherapy during the thoracic radiation. After radiation is completed, patients receive their final cycle of chemotherapy. They are then restaged (including an MRI of the brain) and prophylactic cranial irradiation is offered.
“For patients with extensive stage disease at presentation, I will restage them after six cycles of chemotherapy and offer prophylactic cranial irradiation if there is a favorable response to treatment,” Herbert said.
Nguyen, however, warns oncologists not to get ahead of themselves.
“Although randomized trials and meta-analyses may support prophylactic cranial irradiation, clinical judgment should be the prevailing factor in determining whether to offer patients such treatment,” Nguyen said. “Patients with good performance status and reasonable life expectancy may benefit from such an approach, but it remains difficult to know who those patients are.”
Singh said he believes prophylactic cranial irradiation should be offered to all patients with SCLC who have a 90% or greater response to initial therapy. Given the survival advantage, it should be considered in patients who have a more partial response as well, he said.
High-dose TRT
Another issue in treating SCLC has been with the typical radiation therapy dose increasing from approximately 45 Gy to more than 70 Gy during the last two decades.
According to Nagda, the rise in dosage is due in part to increasing notice of a relatively high risk of intrathoracic failure after lower-dose radiation therapy and improvement in radiation therapy techniques — such as the ability to deliver more conformal and safer radiation therapy.
Liao agreed that even though doses of 60 Gy to 70 Gy are often used, little data are available that compare efficacy, toxicity or influence on survival.
“After 45 Gy, we know that about 40% to 50% of patients will have their tumor come back at the original site of the tumor,” Liao said.
“We also know that high radiation dose will decrease this treatment failure. Therefore, it is logical to escalate the total dose of radiation. The concomitant boost schedule is one way to achieve this goal.”
“Depending on the results of the trial, we may still be left with the question of whether a slightly lower dose of conventionally fractionated radiation therapy can be just as effective in the setting of SCLC,” Nagda said.
“It’s unclear whether high radiation therapy doses at standard fractionation will be of any benefit for small cell lung cancer,” Nguyen said. “Because it has a high propensity for systemic spread, increasing the duration of a local treatment may delay the resumption of higher doses of chemotherapy, thus potentially hindering the effectiveness of combined modality treatment.”
For patients with SCLC, local-regional recurrence is still a big problem, according to Stevens.
“More dosage may well be important, but intensity of treatment matters too,” said Stevens, adding that accelerated regimens may be just as important as dose in SCLC because of its rapid doubling time.
“We eagerly await the results of the RTOG comparison,” Stevens said. –by Angelo Milone
The use of computed tomography (CT) to screen people for lung cancer leads to high rates of false positives, often triggering follow-up tests and invasive procedures, researchers said at the ASCO annual meeting. Concerns about the risks and benefits of lung cancer screening with CT have been raised previously, but this is the first report to quantify the risk of obtaining false-positive results.
Dr. Jennifer M. Croswell of the NIH Office of Medical Applications of Research and her colleagues analyzed data from the Lung Screening Study (LSS), a randomized trial that compared two screening methods—CT and chest x-ray—in more than 3,000 current or former smokers between the ages of 55 and 74. The LSS, which was the feasibility study for the ongoing NCI-sponsored National Lung Screening Trial (NLST), found significantly more false positives in the CT group.
For participants in the CT group, the risk of a false positive was 21 percent after one scan and 33 percent after a second. By comparison, those in the x-ray group had a false-positive risk of 9 percent after one test and 15 percent after two. Because the LSS only included two rounds of screening, Dr. Croswell said, its findings could provide only a conservative estimate of the impact of regular lung cancer screening with CT.
Of those with false-positive results, approximately 60 percent underwent at least one follow-up imaging exam, and slightly less than 2 percent had surgery. Complication rates from these surgeries were low, but a few patients had to be hospitalized for a collapsed lung or blood in the lung (less than 1 percent), and another 1 percent were treated for infections, the researchers said. Additional imaging exams and invasive procedures were also associated with false-positive chest X-rays.
All medical interventions, including screenings, have potential risks as well as potential benefits, the researchers stressed. False positives can create psychological stress and burden the health care system, Dr. Croswell noted.
JOHN BOGERT: Get your nails done today, help new charity
By John Bogert, Staff Writer, The Daily Breeze, serving the south bay in Los Angeles county
Posted: 05/02/2009 07:05:42 AM PDT
I was maybe a little surprised to find myself with Kim Norris the other afternoon.
Not that the Palos Verdes Estates resident isn’t a delightful person to talk to. It’s just that we were discussing the miraculously fast take-off of her fledgling Lung Cancer Foundation of America.
What’s unusual about that, unusual to the point of being almost unheard of, is that this nonprofit charity exists at all five years after she conceived of it.
Hang around the news business long enough and the one thing that you’ll run into is foundations, new ones, all of them worthy and nearly all of them quickly vanishing without a trace in an ocean of red tape and endless work.
Mind you, when I met the articulate, organized, 50ish and attractive Norris two years ago I had the feeling that if anyone could make a go of such a monumental feat it would be her.
For starters, she is a businesswoman, one with connections. In addition, her father is a retired circuit court judge and it doesn’t hurt that she has no problem taking her sense of urgency and mission to a public far more threatened by this disease then they may realize.
Tragically, Norris’ husband, Roy Spiegel, died of lung cancer in 1999 at the age of 47. They had been together 20 years and you might think that such a loss after a horrific 24-month struggle might stop people from asking her the standard lung cancer question, “Was he a smoker?”
But it doesn’t.
“The fact is, most people who have cancer of any kind have it because of something that they did or something that they were exposed to,” she said, as her big beige cat strolled across her living room. “But what does it matter how you get a disease?” What the printing company owner needed when he was diagnosed back in 1997 was help in dealing with the only form of cancer that comes with an “I told you so” attached. This even though 60 percent of lung cancers turn up in people who have never smoked or have long given up the habit.
“We were two reasonable people turned instantly into blubbering idiots,” she recalls of the months spent ferreting out scarce treatment options.
Then came the realization that lung cancer is the most neglected and under-funded form of the disease even though it is the leading cause of cancer death for men and women, accounting for 30 percent of all cancer fatalities. Which is more than deaths from breast, prostate, colon, liver, skin and kidney cancer combined.
Most frightening is its 15 percent survival rate. In 2006 there were 174,470 cases of the disease reported and 162,460 deaths. What’s more, the cancer is usually discovered only when symptoms appear, which is often too late.
While other forms of cancer draw hundreds of millions in urgently needed donations, lung cancer research limps along on $10 million a year from the American Cancer Society and another $1.3 million from eight private foundations. In 2005, federal funding for lung cancer research worked out to $1,829 per cancer death compared with $23,474 for certain other forms of the disease.
Which are numbers that Norris didn’t begrudge at all, not when she realized how badly money was needed by the nation’s neglected network of lung cancer doctors and researchers.
“Traditionally, the biggest problem for fundraising was in the fact that there are few lung cancer patients well enough to speak out or rally around,” she said, not needing to mention that there are few lung cancer survivors, period.
Finally it came to a point where she had to choose between grieving and assuming the mantle.
Thus was born the Lung Cancer Foundation of America, which not long ago won 501(c)(3) nonprofit status after the laborious, all-volunteer assembly of Web site, logo and everything else that must first be put in place before she and partners (and lung cancer survivors) David Sturges and Lori Monroe could start appealing for tax-deductible donations.
“It was like starting a business from scratch,” she said of an unpaid, full-time project that began with legalities and progressed through a fundraiser thrown by her parents in February of last year. There she met Dr. Howie Mandel and his wife, Susan, whose brother, ER doctor Michael Weitz, is now fighting this same terrible disease.
The Mandels then held a fundraiser that attracted Suzi Fischmann, founder of O-P-I, an L.A.-based maker of nail polish known for its unique colors and clever names.
It turned out that Fischmann’s son is best friends with Dr. Weitz’s son and her first words to Norris were, “We’re making a polish for you.”
Called Breathe Life, it is a lovely, sheer opalescent silvery blue (see www.LCFAmerica.org) polish now advertised in a host of national magazines and sold for the exclusive benefit of the foundation.
Today volunteers will polish nails for donations near the Manhattan Beach Pier from 1 to 4 p.m.
The fact is, anyone can obtain the polish free of charge and host a fundraising booth almost anywhere. All the details (including cancer facts and other ways to help) are on the Web site, which went from zero to hundreds of hits in a single month because nearly everyone, as Norris discovered, has lost someone to this killing disease.
“The door,” she said, “is at long last open.”
Open for us all.
I want to hear your comments. Connect with me at john.bogert@dailybreeze.com
In a small percentage of patients with lung cancer, multiple tumors that look similar under the microscope can arise in several parts of the lung, either synchronously (at the same time) or metachronously (in succession). Whether these multifocal tumors arise from a single malignant cell or form separately due to widespread carcinogenic effects on the lung tissue—from exposure to tobacco smoke, for example—has not been clear.
A new study led by researchers from Indiana University and published online April 7 in the Journal of the National Cancer Institute provides genetic evidence indicating that the majority of these cancers may arise from a single cell and should therefore be classified as advanced-stage cancers.
The researchers collected formalin-fixed, paraffin-embedded tissue samples from 30 patients (23 women and 7 men) with multifocal lung cancer, for a total of 70 separate tumor samples. Three different types of genetic changes were analyzed in the tumor samples: loss of genetic material on several chromosomes; mutations in a gene called TP53; and epigenetic changes on the X chromosomes in samples taken from women.
Complete concordance, or an identical loss of genetic material among multifocal tumors, was seen in 26 out of 30 patients. Out of 18 patients whose samples could be screened for TP53 mutations, 10 had identifiable mutations, and in 8 patients these mutations were identical among multifocal tumors. Out of 19 women whose tumor samples could be used for epigenetic analysis, 15 had a concordant pattern of changes between multifocal tumors.
When results of the three analyses were combined, “23 (77 percent) of 30 patients had identical genetic changes, consistent with a monoclonal origin of these separate tumors rather than separate independent primary lung tumors. Our findings support the current classification of multifocal lung cancers as advanced-stage cancers…rather than separate primary cancers and the use of therapeutic strategies tailored for patients with advanced-stage cancers,” concluded the authors.
