In practicing oncology, one of my patients’ (and even more so, the families’) greatest concerns is how long it takes between when the patient was first diagnosed with probable lung cancer and when they can begin treatment. Of course this is a completely natural reaction, and is based on a lot of very real concerns.

Often the patient perceives that the cancer came on suddenly, with chest pain or coughing up of blood, and worries that it is growing and spreading rapidly. In reality this is at the end of longer period where the cancer grew without causing symptoms until it crossed a threshold where the symptoms arose (the straw that broke the camel’s back, as it were), but the perception and worry is real. In cases where the cancer appears to be at an early, curable stage, there is also an understandable concern that if we wait too long to complete staging that the cancer will have progressed to a point where it is no longer curable.

And of course, there is the psychological distress that comes with a cancer diagnosis. I have cancer, I want it out now! Or if it is not curable, I want to begin treatment immediately so I can begin to fight back. But what time frame are we talking about here? What delay is OK without compromising outcomes? In truth, we have no idea. There have been numerous studies that have studied the growth of lung cancers over time, and most indicate that cancers (at least non-small cell lung cancers) tend to grow over a period of months rather than days or weeks.

In addition, diagnosis and staging of NSCLC is a complicated process that takes time. After an initial CT scans shows a lung tumor, there is the necessary step of getting a biopsy by bronchoscopy or needle aspiration, then a PET-CT or full body CT followed by bone scan, often pulmonary function testing prior to surgery and perhaps referral to a cardiologist for “clearance” for surgery. Surgeons often need to perform a mediastinoscopy to confirm the absence of mediastinal lymph node involvement, and if that is positive then referral to medical and radiation oncology is a necessary step. Subtle signs on scans may need to be further investigated, such as a liver MRI for a suspicious spot or a bone biopsy of a spine lesion that may or may not be cancer.

All of this takes time, but the best excuse we (as doctors) have is that knowing the right treatment is more important than starting treatment as fast as possible but possibly getting the it wrong. I think this is absolutely the right thing to do, and communicating this to the patient is important to make sure they understand why there are delays. But at the same time, I do expect these studies to happen as quickly as possible so that we can begin treatment within a couple of weeks on average.

But how would you feel if it took more than 2 months between getting that scan report and beginning treatment? That sounds to my ears like WAY too long to wait, so I can’t imagine what it would seem like to a worried patient. However, apparently this is all too common.

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   Ask and ye shall receive!  The leading requiest for a video podcast presentation was for a summary of the subject of locally advanced, unresectable stage III NSCLC.  Here you go:

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Sorry it’s a little rushed, but it’s a struggle to do a topic justice with a 10 minute limit (the most YouTube accepts).  In the future, we’ll try to divide bigger topics into two podcasts if it’s going to require cramming into a 10 minute interval.   It may help for you to have the images and transcript available, so here they are:

Locally Advanced NSCLC vodcast images

Optimal Mgmt of Loc Adv NSCLC transcript

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Malignant mesothelioma is a relatively rare but particularly deadly malignancy that arises from the lining of the pleural (chest) cavity or peritoneal (abdominal) cavity. About 70% of cases of mesothelioma are directly related to asbestos exposure, usually with about 30 or 40 years between exposure and diagnosis. While there are only about 2200 cases per year in the USA, this number is expected to increase over the next decade, as workers exposed to asbestos earlier in their lives eventually begin to manifest symptoms of the malignancy. After 2015 or so, this may begin to decline due to laws regulating exposure to asbestos in recent decades, but these laws don’t exist in the developing world, so mesothelioma is likely to be a worldwide problem for the foreseeable future.

The usual patient with mesothelioma presents with chest pain and/or shortness of breath, with x-rays showing thickening of the pleural lining with as associated pleural effusion. Many times the fluid around the lung contains no cancer cells, so a biopsy of the pleura is necessary to make the diagnosis. It usually occurs only on one side; distant spread is unusual. So if it is technically “localized”, why is it so hard to cure? The main problem with mesothelioma is that most patients present with advanced disease that has no chance of curative treatment with surgery. In fact, mesothelioma is a malignancy that classically is not thought to be really “curable” at all. Surgery is usually used for palliation, to drain the fluid and peel the malignant rind away from the lung so that the patient can breathe easier and with less pain. Of course there are case reports or case series of patients with limited disease who can be aggressively treated with surgery and have lived >5 years (most oncologists’ definition of cure), but the reality is that these patients are few and far between. To date, studies of patients treated with surgery have shown about the same average overall survival as patients treated palliatively with chemotherapy alone (about 9-12 months).

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    Several years ago, I participated in a clinical trial with a combination of carboplatin and irinotecan for treatment of extensive SCLC, just now being published (abstract here).   As a bit of background about the potential utility of irinotecan, the well established cornerstone of treatment of extensive SCLC for about two decades has been a platinum agent (cisplatin or carboplatin) with etoposide, but an important trial in Japan suggested that a cisplatin/irinotecan regimen may be superior to cisplatin/etoposide (abstract here).  Subsequent work done in the US did not support that conclusion, and one leading consideration is that there are meaningful differences in the activity and side effect profiles of different chemotherapy drugs in different racial populations, due to factors like the enzymes that alter metabolism of these agents.  Nevertheless, irinotecan and its cousin topotecan are still high on the list of drugs most active in SCLC.

    The clinical trial in which I participated combined irinotecan with carboplatin, the alternative to cisplatin that is often substituted because of generally comparable activity and a more favorable side effect profile.  In this trial, both agents were given IV on a single day every three weeks.  There were two different groups of patients enrolled, with 40 patients in each: one had received no prior treatment for extensive SCLC, and the other had previously received first line chemotherapy (with cisplatin or carboplatin and etoposide) and had now relapsed.  For the group that had received prior chemo, a lower dose of irinotecan was given (150 mg/square meter vs. 200 mg/square meter every three weeks).  Patients received up to six cycles of this combination.

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   Although there has always been lattitude for individualizing treatment, I think developments in the last few years have added so many options that pretty much any standards we had from a few years ago have eroded. Particularly in a world in which the eligibility for avastin (bevacizumab) has is debatable (with growing experience of little risk when treating patients with brain mets, on coumadin, etc.), some less impressive results on the AVAiL trial with cis/gem +/- avastin, marginally positive results with erbitux (cetuximab), and a complete free-for-all in the transition from first line to second line (timing? maintenance?).

   I thought it would be interesting to take the pulse on where the experts were, since my sense is that there’s a lot of variability in how people are interpreting the data now. I sent an e-mail to about 30 expert colleagues from around the country and different institutions, with a simple thumbnail sketch of a fairly typical patient and asked specific questions of what treatment they would recommend as first line therapy, when they would stop it, and whether they would continue a maintenance therapy or switch to a new treatment, and if a new treatment, when. I also asked whether they would send any molecular markers. Here’s the thumbnail sketch of the patient:

   A never-smoking Caucasian 62 year-old woman has a cough, sees her MD, found after full workup to have a lung adenocarcinoma metastatic to lungs, liver, adrenals on PET/CT. Brain MRI shows multiple sub-centimeter asymptomatic brain mets without edema. She is referred to you for systemic therapy after seeing a rad onc, getting whole brain irradiation. Her PS remains good, kidney function fine, insurance would cover anything (this is something that can limit our treatment decisions).  Summary: A healthy, motivated Caucasian woman with advanced adenocarcinoma of the lung, recently treated asymptomatic brain mets.  And though I asked whether people would want to send for molecular markers, I limited responses to clinical variables, for the sake of argument I asked them to presume that there adequate tissue for this, and/or the patient refused another biopsy.

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  With the recent publication of the Eli Lilly-sponsored phase III trial of immediate versus delayed Taxotere (docetaxel) after the completion of first-line chemotherapy in patients with advanced NSCLC (abstract of paper by Fidias and colleagues here), I think the time has come to critically evaluate this as a potentially practice-changing concept. Call it whatever you want: maintenance therapy, sequential treatment, or early/immediate second-line therapy, but whatever you do, don’t call it a fluke. The idea behind maintenance is simple: after finishing your initial 4-6 cycles of platinum-doublet chemotherapy, you move immediately on to more treatment rather than stopping and waiting for the cancer to progress. In the last year and half, we have seen four major phase III trials test some version of maintenance treatment with chemo or Tarceva, and all have generally supported a benefit. The Fidias paper is the first of these to be published, so let’s take a closer look at the design:

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In this trial, 566 previously untreated patients with metastatic NSCLC were all initially treated with carboplatin and gemcitabine. Those that finished four cycles without progression were randomly assigned to either receive Taxotere immediately and continue it for a maximum of 6 cycles, or to be followed and receive Taxotere once their cancer started to progress. The trial was designed to be large enough to see a 4 month improvement in overall survival (OS), which in retrospect seems ridiculously ambitious. To give you a comparison, the ECOG 4599 trial, which led to the approval of Avastin in lung cancer, only showed a 2 month improvement in OS.

In any case, the trial did not quite make the 4 month improvement, missing it by a little over a month (OS 12.3 months for immediate Taxotere versus 9.7 months for delayed; p=0.085), but it did have an impressive improvement in progression-free survival (PFS; 5.7 versus 2.7 months; p=0.0001), which is a measure of patients still alive without progressive cancer. Essentially what this means is that patients who started immediately on Taxotere delayed the progression of their cancer by 3 months compared to those who waited, and lived an average of almost 3 months longer. This is a pretty clinically significant improvement, although there are some important things to point out about this trial. First, only 309 patients (out of the original 566) made it to the randomization, so these were already the patients who were doing very well after first-line chemo. Second, 37% of the patients (58 of 156) who were designated to receive the delayed Taxotere never got it (as opposed to only 8 patients in the immediate arm), about half of them because their cancer progressed so much that they were unable to get more treatment. So it is unclear if the benefit of immediate Taxotere was truly better effect, or just the results of most of the patients in the immediate Taxotere group actually getting the chemo.

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   We have long noted that there is a clear association of smoking history with effectiveness of oral EGFR tyrosine kinase inhibitors (TKIs).   Part of this is because never-smokers have a high incidence of carrying activating EGFR mutations, but also potentially because current smokers actually metabolize EGFR TKIs faster (see prior post).   We’ve seen a consistent association of rash development with better outcome (see prior post), and current smokers have been disproportionately likely to develop little or no rash.  A recent study just coming out in the Journal of Clinical Oncology from a group in the UK has studied blood levels with dose escalation of  tarceva (erlotinib) among current smokers (abstract here) and suggests a possible value in giving higher than standard tarceva dosing among current smokers, so that they can achieve the same blood levels as never-smokers or former smokers.  Will this lead to better results for these patients?

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    A press release today informs us that the ATLAS trial of maintenance avastin (bevacizumab)  combined with tarceva (erlotinib) vs. avastin with placebo was positive for a significant improvement in progression-free survival (PFS).  We had already learned that the very similar SATURN, of maintenance tarceva vs. placebo in patients who weren’t on avastin was also positive for an improvement in PFS (see prior post), though we don’t have details yet.  Here’s the design of these two trials:

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    What we’ve learned so far about the ATLAS trial is that an interim planned analysis of safety and efficacy showed that there was a significant improvement in progression-free survival that led to the stopping of the trial and disclosure of these early results of more favorable PFS in the recipients of tarceva combined with avastin.  It had already enrolled 1157 patients, which was its goal, and these patients received avastin with any of several different platinum-based chemotherapy doublets (carboplatin/gemcitabine, carboplatin/paclitaxel, carboplatin/docetaxel, cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine).  If patients hadn’t progressed after four cycles of this combination, they would be randomized to avastin maintenance with either tarceva or a placebo pill.  The results apparently showed no evidence of any unexpected safety problems, which is important both for broadening our experience of different chemo agents with avastin and because patients with therapeutic doses of blood thinners were able to be enrolled, as were patients with more peripheral squamous cancers that were far from the center of the chest (a minority of squamous cancers).

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   Video presentation describing the concept behind angiogenesis and the evidence on the anti-angiogenic agent avastin (bevacizumab) in NSCLC.  

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Or access via web link here. 

Slide/figure images from the video presentation are available as a pdf here: Angiogenesis FL Adv NSCLC Vodcast images

Transcript is here: Angiogenesis FL Adv NSCLC Vodcast Transcript

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   We’ve seen clear evidence that patients who have tumors with certain mutations in the EGFR gene are highly likely to respond to oral EGFR inhibitors like tarceva (erlotinib) or iressa (gefitinib) – with response rates that are in the 70% range and often last for many months or even a few years (see prior post).   On the other hand, K-Ras mutations are associated with a very low probability of responding to EGFR mutations (see prior post).

   But the overall favorable or unfavorable results of these mutations may not be limited to their associations with how patients respond to EGFR inhibitors and/or other systemic therapies.  I’ve noted how patients with advanced NSCLC and EGFR mutations have a superior survival even if they don’t receive an EGFR inhibitor.  Another approach to assessing the prognostic value of mutations is to look at survival of patients with resected earlier stage NSCLC tumors.

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