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Lung Cancer. Part 6

We should culture quickly and start on some appropriate form of broad spectrum antibiotics. This should be continued until the granulocyte recovery takes place. And granulocyte recovery used to be defined by achieving an absolute number. I think we can substitute for that granulocyte count is increasing on two or three successive days. I think we know that the granulocyte count is rising even if it’s only 500 you are making granulocyte counts, and remember what you see in the peripheral blood is the reserve. It’s what is left over after the granulocytes are mobilized. So I won’t feel quite comfortable for a patient who is doing well with granulocyte count that is going from 89 to 150 to 230 over three successive days, even though they are not at 500. That person is on the way up and if they don’t have a demonstrated site of infection that requires continued antibiotics appropriate for that infection, if nothing else has been cultured - and that’s usually what happens - nothing astounding in the culture, I think you can stop antibiotics safely at that point. Obviously if they have a positive culture or a demonstrated site of infection you need to give a course of therapy which is appropriate for that site of infection.

If you have cancer patients who have a fever and the granulocyte count is at a healthy level and is not falling rapidly, these patients could be managed like anybody else with a fever who comes for medical attention. Keep in mind that patients with cancer may have fevers as a result of drugs. Bleomycin, for example, they may have fevers as a result of the underlying disease, including lymphomas and renal cell cancers with liver metastases, or they may have reactions to blood products. Large differential. But you can walk not run to the nearest exit the situation if the granulocyte count is in good range.
Lung cancer

Lung Cancer. Part 5

You see also all the time it crops up in board management questions from time to time; someone who has had a malignancy that has been managed for cure - let’s say a small breast cancer or colon cancer - and has the appropriate response and in three or five years later develops a pulmonary nodule. Don’t assume ever that that’s a metastasis from a previously treated, presumed cured, malignancy. In the case of breast cancer, which is my own area of specialty and the area that I know the best, I know that over half of pulmonary nodules that present in patients with prior breast cancers are unrelated to the prior breast cancer. So again, histologic class clarification is generally the way to go in these situations.

This is some data from the Mayo Clinic that just shows what happens if you operate on coin lesions. You remember how dismal the data was when I showed you, in general, for surgery in lung cancer but these are coin lesions specifically. If you look at small coin lesions that were operated on and have no nodal involvement, the surgical survival is much better than the data I showed you in lung cancer overall. So there’s real reward in operating on these small peripheral coin lesions. So you don’t want to ignore them and you want to get a pathologic diagnosis in virtually every situation.
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Fever in the setting of malignancy. The most important thing about fever in cancer patients is; what is the granulocyte count. If the granulocyte count is 500 granulocytes per cubic millimeter, or is the white count rapidly falling. For example, in patients who have a white count of 4,000 two days ago, white count of 2,000 yesterday and a white count of 1,000 today, even if the granulocyte count may be at 600 that patient is in some sort of granulocyte free-fall and is usually the result of chemotherapy. You can expect that that patient has no granulocyte reserve for falling rapidly. So the absolute number of about 500 or expend of rapid decrease is when you really have to worry and take extra precautions for these patients. If you have a patient like this they need to be seen in an emergency room setting, they need to be cultured very quickly, fully and very quickly. You get your cultures sent off in 30 minutes or an hour - not more than that - and then the patient should receive broad-spectrum antibiotics. Even if you identify a potential source of infection - let’s say they are coughing up sputum that looks infected - they must be covered broadly because many of these patients will have more than one potential source of infection. So infected sputum or an abnormal intravenous catheter site may not be all that patient is dealing with. So the watch-word is to cover the patient broadly with antibiotics and give them monotherapy with something like ceftazidime. There’s even some literature recently about using Cipro in the outpatient setting. But you have to be careful.

Lung Cancer. Part 4

In terms of the management, we have developed increasingly better drug and radiotherapy combinations for dealing with this. Patients who have disease which is limited in presentation, clinically limited to the ipsilateral hemithorax. That is we don’t have clinical evidence of spread even though it’s thought to be there microscopically, about half of these patients will be able to go into complete remission and the overall remission duration for these patients is somewhere on the order of 15 to 20 months. If you look at a survival curve for small cell lung cancer, if you look at those with overt metastases, results are extremely poor. On the other hand, if you look at patients who have disease which is limited - as I said, clinically - to the ipsilateral hemithorax, somewhere around 20% of these patients seem to go into remission that may be durable and some of these patients may be cured of the disease. What is being looked at for these patients is; can we do anything to get the tail on the curve up a little bit. Can we do something to increase the fraction of patients with complete remission rates. Can we do something to keep these patients in remission instead of having this fall-off. Intensive therapy with stem-cell support is being looked at. There is pilot data from Elias and Ferguson that looks pretty good, but it needs to be reproduced in a larger group setting. Also it is important to understand the theory for this as considerable morbidity and even mortality, the use of intensive drugs and radiation in middle-aged or older adults who often have significant underlying pulmonary disease that has led to a lot of respiratory complications, their central nervous system, complications from prophylactic brain radiation and drug therapy. So there’s no free lunch. It’s difficult therapy and there are significant long range morbidities from the treatment but the good news is that at least a proportion of patients with limited disease are able to achieve a disease-free survival from this naturally pretty aggressive condition.
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I think you can’t leave the subject of lung cancer when talking to internists without talking about the pulmonary nodule. This is sort of a common internal medicine management problem. These are some of the things I think that should be tried in dealing with this. First of all what you want to know if there is a pulmonary nodule is; is the lesion new? And if the lesion is not new, has it changed in size? So the first thing you want to do is obtain old films. I think that today management strategies for medicine, the less people have chest x-rays on a routine basis and that may hamper making that sort of assessment. But where old films are available I think management always starts with getting the old film. If you can get some archival film from ten years ago that shows the same lesion I think you are going to have almost certainly no problem. The next step is if there is a nodule and it appears to be new, or we don’t have an old film, we need to know; is it solitary or multiple? The decision analysis will be different if you have multiple lesions. Remember, chest x-ray is a lot less sensitive than a CT in terms of showing the lung parenchyma. So what looks like a solitary lesion on a chest x-ray could turn out to be multiple lesions on a CT-scan. Once we have characterized what we have, you are going to undergo some type of pre-biopsy or pre-surgical evaluation to look at extrapulmonary sources that need to be ruled out. It doesn’t have to be exhaustive. A good history and physical and maybe a minimal amount of laboratory testing is probably useful in this setting. If the studies are negative or you don’t demonstrate conclusively that this is a metastatic presentation of some other lesion, then it is necessary to go after this thing and clarify what it is. Many of these lesions have proved to be benign lesions and even if it does prove to be an adenocarcinoma presenting as a lung lesion, the prognosis of this is relatively favorable, quite favorable indeed compared to other forms of carcinoma of the lung that are resected. No meat no treat is a good rule to follow. Don’t make assumptions based on the x-ray getting a pathologic diagnosis.

Lung Cancer. Part 3

In stage IV lung cancer, for metastatic disease, again there has been some debate. We have gone through probably 20 or 25 years of trying chemotherapy in this disease and until fairly recently the results were dismal. Colleagues at the Princess Margaret _ study in Canada where they looked at chemotherapy versus supportive therapy only for stage IV lung cancer. I think being a very conservative group their bias was that supportive care was probably going to be better than flogging patients with chemotherapy. Much to their surprise they found out that the group of patients with metastatic non small cell lung cancer received chemotherapy not only got an improvement in survival but also an improvement in quality of life as assessed by the patients, and actually a somewhat lower cost for care for patients who were given supportive care only. I think that chemotherapy has improved a lot for lung cancer. The standard regimens often involve a taxine usually, Taxol and some kind of platinum derivative such as carboplatin. I think we are getting response rates that are high enough to justify chemotherapy for patients who at least have a good performance status for advanced lung cancer. Now patients who are very terribly ill or bedridden with marked constitutional symptoms are probably not the type of patients who are going to benefit from this type of intervention but a relatively good-health patient with advanced disease is likely to benefit in all of these ways from chemotherapy.

This is small cell carcinoma, which as I said is a different disease. This is the pulmonary bronchial epithelium at the basement membrane. This is small cell cancer smudged in here inside mucosa. Small cell cancer is usually advanced at the time that the diagnosis is made. It is at least advanced microscopically. If you can’t find it, I think this slide shows part of the problem. One part is because it is submucosal that the early signs of cough or hemoptysis are often not present. It also has a very high growth fraction, as it has an early capacity to spread and lacks early warning signs to focus a patient or physician towards a diagnostic work-up. So we think of all patients with small cell cancers essentially as having disseminated disease at the time they are diagnoses. You remember the slide I showed you a few back - it showed the surgical cure rate for this disease is under 1%. I think that that feeds into what I’ve been saying about our thinking that we really consider this to be disseminated. The only difference is you can subdivide them into those that are overtly disseminated and those where you can’t find evidence of it but you know it’s there.

Lung Cancer. Part 2

Now the management of lung cancer, other than small cell lung cancer - which is really split off in all instances as a separate entity - the management of the other types is primarily surgical if possible. That is the treatment of choice for stage I and II disease, is to be able to resect it. There are studies that have been done and continue to be done to look at the role of adjuvant radiation therapy and systemic therapy, particularly for stage II disease; which means involvement of bronchial or hyaloid nodes. I think that although they are suggestive it remains somewhat inconclusive as to the value of adjuvant treatments. If you look at surgical management, you have to say “All right, who gets an operation and who doesn’t?” That’s something in terms that you need to understand what are the complications of surgery in lung cancer. I think one of the greatest areas of progress in small cell lung cancer is realizing the factors that are on the slide. I don’t know that we can improve the numerator greatly surgically, but we decreased the denominator by realizing which patient shouldn’t be taken for a thoracotomy and I think spared a lot of unnecessary useless morbidity. If a patient has significant co-morbid medical disease they may not be a candidate for lumpectomy or pneumonectomy. Remember, most of these are related to smoking. Most people smoking have significant underlying heart and lung disease. Anybody with small cell histology should not undergo primary surgical resection. If you know in advance that it is small cell carcinoma, it’s is not a surgical disease. Clearly if there are extrathoracic metastases there is no point in removing the primary tumor in virtually any circumstance that I can think of. If you have a paralyzed vocal cord that’s usually due to the involvement with the left vagus nerve as it goes through the aortal pulmonary window. Pleural effusion, if it has a positive cytology for malignancy is also a manifestation of inoperability. And to varying extent spread to the carotid mediastinum are manifestations of inoperability as well.
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If you look at data with surgical management of lung cancer what you see is that the results are relatively dismal overall. These are the histologic types. These are stage I cases where patients had a tumor mass under 2 cm and no nodal involvement. These are bigger. If you look at all these data for patients with complete resections you can see that less than half of all patients who are surviving five years later despite resection. If you look at the small cell, as I said, it is clearly not a surgical disease. Data couldn’t get any worse than that. So that doesn’t work for small cell carcinoma of the lung. If you look as squamous and adenocarcinoma for stage I in acute patients you can see that somewhere between 15-30% of patients with stage II disease are going to be surviving, disease free, despite apparent surgical resection. Now of all patients who come in with lung cancer, you start with four patients. Two of the four are going to be inoperable before you go into the OR, or you never get to the OR because of either obvious metastases or co-morbid diseases. So you are going to take two of the four patients to surgery. One of those two that you take to surgery will be found to be inoperable when you open the chest. So you are only doing a resection in one out of four patients. So this is data that shows that 30% or 15 % five years. But these are patients that were taken to surgery and they only represent about a quarter of the group of patients that might have initially been diagnosed with the disease. So if there was ever a need for an effective systemic therapy for disease, certainly you have that in lung cancer. And I think that with improvement in chemotherapy of the disease there are at least some trials that have been done that suggest a small advantage for adjuvant systemic therapy. I think that the next incremental improvement in survival in this disease is going to come through the use of some form of systemic treatment.

If you look at more extensive lung cancer - again, we are still staying with non small cell cancer - disease that spreads to the mediastinum is known as stage III disease and these patients don’t have just a metastasis but they have an involvement with either ipsilateral or contralateral mediastinum. For patients with involved ipsilateral mediastinum, there has been a great deal of effort to try to shrink the disease down with preoperative chemotherapy and/or radiation therapy and then take patients to surgery and then either finish up with some radiation if it wasn’t given pre-op, or some additional chemotherapy. There have been many many single institutions and some cooperative group studies done looking at this. I think it’s still not clear what the long term benefit of this approach is with 3A disease. The data we have suggests that there will be some benefit. Clearly if you can shrink the disease you can do, technically, resections in these patients. You can do it. What’s less clear is whether the long term survival is going to be improved by using two or three different modalities empirically for these 3A patients. Usually in patients with 3D disease, that is disease spread to the opposite side of the mediastinum or to the carotid, these are considered non-respectable and therapy is usually palliative with either radiation therapy or chemotherapy.

Lung Cancer

Lung cancer is the leading cause of cancer death. Prostate is now the second leading cause of cancer death in men - stomach is the one that has the big decrease. Now if you break the epidemiology data down and look at trends overall, the first thing you see - this is the overall curve, this is all ages both sexes - is that there has been a slight decrease in cancer mortality. This is seen more overall for the curve in males than in the curve for females, but there is an overall slight decrease.
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Large carcinoma of the lung. Lung cancer is divided into about four histologic types and the reason for understanding that is simply to recognize the unique syndromes that are associated with each of these tumor types. The squamous or epidermoid cancer is usually a central tumor, compatible with the last x-ray I showed you. This is a tumor that often cavitates locally and may also erode vessels producing hemoptysis or so-called Rasmussen’s aneurysm. It is certainly related to smoking, which all of these types are. And all of these types of lung cancer have fairly striking perineoplastic syndromes that are associated with the squamous or epidermal type. The main thing is hypercalcemia, which is due to production of the PTH-like growth factor, the stimulants. It’s interesting that squamous within a lung less commonly metastasis to bone, and the adenocarcinoma or small cell carcinoma, which is much more commonly associated with hypercalcemia, which is on this perineoplastic basis. These small cell carcinomas are the ones that are also generally central to higher type of presentation instead of metastasizing very early on and are associated with a large array of perineoplastic syndromes. About 70% of these will elaborate ACTH immunologically. Not all of them have Cushing’s syndrome. In fact the disease is so rapid that the physical manifestations of Cushing’s are not so common in these patients but you will see it in hypertension or electrolyte abnormalities, even if they don’t have centripetal obesity, moon-faces. Also anti-diuretic hormones are released in about half of these patients. Hyponatremia is seen. You can see carcinoid syndrome and these very unusual neurologic syndromes such as Eaton-Lambert syndrome or reverse myasthenia gravis. It’s called reverse myasthenia because as you stimulate these muscle groups they become weaker with initial stimulation, but then as you keep going the muscles actually get stronger in terms of the action so it’s known as reverse myasthenia.

The adenocarcinoma of the lung is the disease that is most often seen in the periphery of the lung or scars in the lungs that are associated with migratory thrombophlebitis with acanthosis. Also with the syndrome of pulmonary hypertrophic osteoarthropathy, which is usually associated with plumbing. This is likely to lead to the production of growth hormone. And the final type of lung cancer, the so-called large cell cancer of the lung, also is central lesion and these are most notable for the production of gynecomastia, which is related to HCG production. So each of these four types of lung cancer is associated with a unique set of peri-neoplastic syndromes that make them most notable. If you have, for example, a 55-year-old male smoker who is on no medication who develops gynecomastia you are probably dealing with this type of lung cancer.