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Dr. Jared Weiss is an Associate Professor of Clinical Research for Hematology/Oncology at the University of North Carolina School of Medicine in Chapel Hill, NC. He completed fellowship in Hematology and Oncology at the University of Pennsylvania and residency in Internal Medicine at Beth Israel Deaconess Medical Center in Boston, MA. He received his Doctor of Medicine at Yale University School of Medicine in New Haven, CT and his B.S. in neuroscience at Brown University, in Providence, RI.

World Lung Conference Day 4, 7/7/2011
Thu, 07/07/2011 - 05:38
Author
Jared Weiss, MD, Associate Professor Clinical Research Hematology/Oncology

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Good morning, GRACErs.

Plenary

The first talk was by Dr. Hisao Asamura of Tokyo, Japan who discussed a surgeon’s view on adjuvant chemotherapy.He started with a 2010 meta-analysis, which included some older regimens yet still showed a 4% increase in survival at 5 years. Another analysis restricted to more modern regimens showed 9% benefit and some oncologists claim even higher numbers with yet more modern regimens.

He also noted a philosophical problem with adjuvant chemo: most of the benefit is in a small group of patients, leaving the rest without benefit.The patient with micrometastatic disease that is cleaned up with chemo benefits a lot.However, patients with either no micrometastatic disease or micrometastatic disease that is not sterilized by chemo do not benefit.This is a fair line of thought; although I would add that some patients might not be cured, but have survival improved through effective 1st line chemotherapy.In the future, we will likely have better predictors of who will benefit from adjuvant chemotherapy, allowing us to avoid it in those will not benefit, and have confidence of large benefit in the right patients.

In the 1990s, lobectomy was accepted as superior to more limited resection.In 2011, trials are underway to reconsider this idea in smaller (2cm or less) disease.A trial was done comparing mediastinal lymph node dissection to systematic sampling; lymph node dissection did not improve survival in early stage disease.Of note, sampling must be very complete for omission of complete dissection to be safe.

Video-assisted thoracoscopic lobectomy (VATS) is feasible.It is associated with shorter hospital stay, less morbidity and fewer complications.Survival is at least as good as traditional open surgery, and possibly better.

Dr. Ruysscher next spoke about the state of the art in radiotherapy in 2011.Stereotactic body radiotherapy is now an option for medically inoperable stage I NSCLC; we talked about some new elderly-specific data from this conference yesterday.He argued that concurrent chemoradiation is better than chemotherapy followed by radiation (well accepted) and that surgery has no role after chemoradiation (controversial).Small cell lung cancer (SCLC) should be treated with accelerated chest radiotherapy together with concurrent cisplatin/etoposide chemotherapy.Prophylactic cranial irradiation (PCI) improves survival both in limited stage disease and extensive stage disease.There are evidence-based guidelines that say how radiation should be given; these should be followed.

Next, Dr. F. Hirsch spoke on the state of the art of molecular pathology in 2011.Although two patients may share the same diagnosis (stage IV lung cancer) with very similar clinical features (for example, lung nodule with lymph nodes, shortness of breath, and cough) their diseases may actually be very different on a molecular level, leading to differences in prognosis and which therapies work.Many stage I patients recur and die from lung cancer, while many stage II patients can be cured by surgery alone; therefor, are we denying adjuvant chemotherapy to some stage I patients who would benefit and over-treating some stage II patients who cannot?Many biomarkers are undergoing testing to determine who will best benefit from therapy and which therapies will work.

In advanced disease, knowledge of EGFR mutation status is crucial for treatment decisions.Yet, tarceva and iressa do not cure cancer, and about 20% of patients with mutations will have intrinsic resistance.There are different methods for detecting mutations.Sequencing is the gold standard, but without micro-dissection, its sensitivity is low.Allele-specific PCR is much more sensitive.There are now antibodies specific to both major EGFR mutations (exon 19 and L858R); this means that mutations can now be found by special staining (IHC).Detection of EGFR mutations in blood from techniques such as CTCs is promising, but not nearly ready for prime time.EGFR fish is not yet ready for use.EGFR expression may predict for benefit of cetuximab.FISH may also predict for benefit of cetuximab; this idea is being tested in an ongoing prospective trial.Crizotinib has great benefit for patients with eml4/alk rearrangement; newer techniques can find patients with fusion of other partners with alk, who may also benefit; a variety of other techniques, including IHC are being studied.T790M accounts for about half of EGFR TKI resistance, MET amplification for about 20%.Many ongoing studies seek to overcome resistance; the MetMAb study was highlighted.97% of mutations are mutually exclusive.We are only just starting to understand specific driver mutations in SqCC; this is being addressed by the cancer genome atlas project.

Dr. Gandara spoke on the state of the art therapy in advanced NSCLC: 2011 looking through 2015.He said that the 20% of NSCLC still read out as, “NSCLC NOS” must be eliminated.He feels that these are mostly due to small samples and cited Italian data that special stains can distinguish probable SqCC or adenoCA in most cases.He believes that while histology has improved care, it is really just a crude test for molecular status and he gave an excellent review with future orientation on the promise of personalizing treatment based on molecular status.While EGFR has been a major success story, we are faced with a major challenge in the form of resistance.New treatments such as afatinib + cetuximab or MetMAb plus erlotinib bear real promise of overcoming resistance.He summarized: we are making real progress; we need to change our culture to get more tissue; we need to ungroup NSCLC into individual patients; we need to change how we develop new cancer drugs to account for both the complexity of the underlying biologic systems and for patient heterogeneity.

Oligometastatic Disease

Oligometastatic disease is cancer that has spread, but only to one or a small number of sites.Although diseases arise in nature, their diagnostic categories are generated by man in ways that are useful to us.Oligometastatic disease is getting more attention because of advances in radiation (SBRT).

Royce Calhoun from UC Davis spoke on the role of resection of metastases from lung to lung.He asked what the goals are for applying local therapy to a systemic disease?Cure?Palliation?Pre-palliation?Providing hope?Ego?How much are we willing to do?Pasotrino et all looked back on 5206 cases of resection of mets from other cancers to lung, showing improved survival with complete resection; fewer mets have better prognosis than more; some cancers do better than others with metatectomy (as a theme, they tend to be cancers that respond very well to chemo like testicular CA) .

Dr. Mehta spoke abut brain metastases.Lung cancer accounts for over half of brain mets.Patients with lung cancer are particularly likely to present with brain as the first site of cancer spread and are particularly likely to have brain as the only site of spread.Survival is poorer with brain mets, worse in lung cancer than in other cancers such as breast cancer, although some patients have a much better prognosis.There is no accepted definition of oligometastatic brain disease, but it is clear that you can improve survival with resection or radiosurgery compared to whole brain radiation therapy (WBRT) alone with only 1 brain met and there is evidence for survival advantage with local treatment to 2-3 mets.In contrast, for >3 mets, there is no high quality evidence to support surgery or stereotactic radiation (SRS=stereotactic radiosurgery).Therefor, one functional definition of oligometastatic disease would be up to 3 mets, because this is where we think we might be able to provide benefit with surgery or radiosurgery.We do not know whether SRS or surgery is better; some series suggest one while others suggest the other.

Local control is clearly worse when WBRT is omitted:

Study

SRS

+WBRT

P value

When

JRSOG

52%

18%

.0001

1 yr

Tufts

43%

19%

.01

1 yr

MDACC

60%

27%

.02

1 yr

EORTC22952 (S)

42%

23%

<.008

2 yr

EORTC22952 (SRS)

48%

33%

<.023

2yr

RANGE

42-60

18-33

   

Can we sometimes eliminate WBXRT?Predictors for progression in the brain when WBRT is omitted include >3 mets, extracranial disease, and melanoma.17% of patients with none of these risk factors are free from brain mets at one year without wbxrt.

Patients often fear the cognitive side effects of WBXRT.In a Japanese trial, cognitive function was better over time with WBXRT than without it.More specifically, the median time to a 3-point drop in the mini mental status examination was 16.5 months with WBRT and 7.6 months without it.Why?Progression in the brain hurts mental status worse than WBRT.

Next, Dr. David Rice of MDACC addressed adrenal mets and other sites.Solitary met in lung CA is rare—about 7% of stage IV disease.Where does lung CA go?

Site

Frequency

Lung

.11

Adrenal

.15

Liver

.22

Bone

.36

Brain

.47

Does timing matter?In a meta-analysis, single met at presentation vs. later did not seem to matter, although other data suggests that a disease free interval improve prognosis.

How big of a deal is adrenelectomy?Traditionally, adrenalectomy has a 19% complication rate, with 2.7% mortality and median 8-day hospital stay.However, results are now much better with laproscopic techniques.SBRT is an option for adrenal mets, but data is limited, particularly in limited followup.

It is not clear that adrenelectomy or local ablation in patients with metastatic disease generates a real survival advantage for the patient.While small series suggest it occasionally does, it is likely that they reflect patient selection and not a true advantage of local ablation.With other advances in therapy, this may change.

Next up with Dr. Kenji Suzuki who spoke about multiple pulmonary resections.He noted that differences in histology can be used to distinguish whether a second lung mass is a met vs. a different primary tumor.He described classification of multiple lung masses.He made the important point that especially in early stage disease, another nodule is very likely to be benign.

Dr. Treasure spoke about pulmonary metastectomy for oligometastases.The greatest bulk of data comes from colon cancer, where surgeons are doing resections far outside of the conditions in which the data suggest benefit.Even in appropriately selected patients, it is again not clear that good survivals are due to the surgery itself as opposed to selection for patients with good prognosis.

Supportive Care:

Our own Dr. Ramachandran chaired the session!

Analysis of Phase III studies for Palonosetron, Ondasetron, Dolasetron and Granisetron in the Prevention of Chemotherapy-induced nausea and vomiting in Patients with Lung Cancer by Dr. L Schwartzbert

Patients with lung cancer are at high risk for chemotherapy induced nausea and vomiting (CINV).Acute CINV is defined as onset within 24 hours of chemotherapy administration and delayed CINV is defined as up to 5 days later.The development of 5HT-3 antagonists (such as Zofran) was a major advance against CINV.Palinosetron is more potent and longer lasting than the older agents in this category (such as Zofran=ondansetron).This analysis seeks to answer the question of whether it actually works better.It looked at 783 lung cancer patients in 4 studies.There seemed to be a benefit, primarily in the delayed time period (numbers are all percents):

 

Acute period

Delayed period

Overall Period

Complete control

     

Palonosetron

76.9

50.7

48.4

Other agents

76.0

39.8

37.9

Use of rescue mediations

     

Palonosetron

11.6

35.7

36.6

Other agents

12

45.1

47

# of episodes of nausea

     

Palonosetron

69.3

41.0

38.9

Other agents

69.1

29.5

28.7

The most common adverse event was constipation at about 13%, regardless of use of palonosetron or older drugs in the same class.

A 3-day oral aprepitant regimen provides superior prevention of CINV over standard therapy in Chinese patients receiving high-dose cisplatin by Dr. L. Zhang

Aprepitant (emend) is a new medicine that works by a different mechanism of action than the older agents.This study looked at the value of adding aprepitant to a regimen of granisetron and dexamethasone.Complete response in cycle one was 69.6% with apreitant and 57% without it.Like the palonosetron study, the effect was driven by prevention of delayed, not acute, nausea.

Palonosetron, Aprepitant and Dexamethasone to prevent nausea and vomiting during multiple cycles of cisplatin-based chemotherapy for lung cancer patients by Dr. F Longo

If aprepitant can help and palonosetron can help, what about both?This study tried this in patients getting cisplatin.Over 90% of patients had no emesis.59-70% of patients reported no nausea at all (the range is because data was reported by cycle #).

Testing the addition of vena cava: CAT trial

VTE (venous thromboembolism=clots in arms or legs) and PE (pulmonary embolism = clot spread to lung) are big problems in lung cancer.Despite treatment with heparins, clots will grow in more than 20% of patients.One available treatment is to place a filter in the IVC.IVC=inferior vena cava and it’s the big vein that leads from the legs back to the heart, and ultimately the lungs.The basic idea is that the filter should stop DVT (clot in the legs) from spreading to become a PE (clot in lungs).Half of patients in the CAT trial were randomized to fondaparinux alone with the other half also getting an IVC filter.In this trial, one patient in each group had recurrent PE, and none had recurrent DVT.There was no survival advantage to adding a filter, and maybe a hint of harm.Of note, there was an imbalance in use of epo and darbopoitin, with 18% use in the fondaparinux only arm and 10% in the group also getting a filter.Since these agents increase clot risk, this imbalance could potentially hide harm from the filter.Overall, complete resolution rates in both groups were high; raising the hypothesis that fondaparinux may be a particularly active anticlotting agent.

GRACERs, thank you for joining me for this hectic conference.Believe it or not, what I’ve reported represents only a small portion of everything going on—at any given moment at this conference, more than a dozen talks go on at the same time.I’m off for a nap, then some time as a tourist before getting back to my patients on Monday.

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