Breast cancer and delays in surgery

Every so often there are studies that I really mean to write about but, for whatever reason, don't manage to get to. Sometimes I get a chance to get back to them. Sometimes I don't. This time around I'm getting back to such a topic. This time around it's a topic I've been meaning to write about is based on a couple of studies that came out three weeks ago that illustrate why, even if a patient ultimately comes around to science-based treatment of his cancer, the delay due to seeking out unscientific treatments can have real consequences.Consider this (probably) the last unfinished bit of business from 2015.

When a patient with breast cancer comes in to see me, not infrequently I have to reassure her that she doesn't need to be wheeled off to the operating room tomorrow, that it's safe to wait a while. One reason, of course, is that it takes years for a cancer to grow from a single cell to a detectable mass. The big question, of course, is: What is "a while"? Two studies published online last month attempt to answer that question. One study (Bleicher et al) comes from Fox Chase Cancer Center and examines the effect of time to surgery on breast cancer outcomes; the other (Chavez-MacGregor et al) is from the M.D. Anderson Cancer Center and examines the effect of time to chemotherapy on outcome. Both find a detrimental effect due to delays in treatment.

Prompt surgery is better

Because I'm a surgeon I'll take a look at Bleicher et al first. This study looks at two large cancer databases, the Surveillance, Epidemiology, and End Results (SEER)-Medicare–linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort included Medicare patients older than 65 years, and the NCDB cohort included patients cared for at Commission on Cancer–accredited facilities throughout the United States. Analyses performed assessed overall survival (OS) as a function of time between diagnosis and surgery and evaluated five intervals (≤30, 31-60, 61-90, 91-120, and 121-180 days). It also looked at disease-specific survival at 60 day intervals. The patient cohort included women diagnosed with invasive breast cancer that had not metastasized beyond axillary lymph nodes who were treated with surgery first. Patients with inflammatory breast cancer were excluded, which makes sense because inflammatory cancer is generally treated first with chemotherapy. The SEER-Medicare cohort included 94,544 patients 66 years or older diagnosed between 1992 and 2009, while the NCDB cohort included 115,970 patients 18 years or older diagnosed between 2003 and 2005.

The tale is told by this graph, from the SEER-Medicare cohort and the NCDB cohort (click to embiggen):

SEER-Medicare1

As you can see, there is a decrease in survival with each increase in time from diagnosis to surgery, so that by the time you get to the 90 day interval it is quite striking, with a difference in long term survival larger than the improvement produced by most chemotherapy regimens. In the SEER-Medicare cohort, for each increasing interval, the hazard ratio (HR) was 1.09. Results from the NCDB cohort were similar. The added risk of death from all causes for each interval increase in time to surgery was 10% (HR, 1.10; 95% CI, 1.07-1.13; P < .001).

Now here's the kicker. This adverse effect from delays in surgery was most marked in the very patients most likely to delay their surgery for alternative therapy, namely patients with early stage disease. In the SEER-Medicare database, for instance, the effect of delays in treatment on breast cancer-specific mortality in stage I disease resulted in a HR of 1.84 (95% CI 1.10-3.07, P = .02), while the HR for stage II and III disease was not statistically different from 1.0. In other words, a delay of greater than 120 days was associated with a nearly two-fold increased risk of dying of breast cancer. In terms of overall survival, time to surgery was correlated with a decrease in overall survival in stage I (HR, 1.13; 95% CI, 1.08-1.18; P < .001) and stage II disease (HR, 1.06; 95% CI, 1.01-1.11; P = .01), but not in stage III (HR, 1.06; 95% CI, 0.97-1.16; P = .17). In the NCDB cohort, delay in surgery was associated with decreased overall survival for stage I (HR, 1.16; 95% CI, 1.12-1.21; P < .001) and stage II disease (HR, 1.09; 95% CI, 1.05-1.13; P < .001) but not stage III (HR, 1.01; 95% CI, 0.96-1.07; P = .64). Again, patients with stage I or II disease, which can often be associated with little or no symptoms (particularly stage I, which often does not even present with a palpable mass), are exactly the ones most likely to eschew chemotherapy.

You might wonder why there is less of an effect of treatment delay in stage III disease. So did the authors:

We have found that OS declines when the TTS [time to surgery] increases, with OS affected in stage I and II but not stage III disease. The data for DSS [disease specific survival] are similar, with cancer-specific mortality data only available in the SEER-Medicare dataset, where patients with stage I cancer exhibited lower survival as TTS increased. This observation that preoperative delays affected only stage I DSS and stage I and stage II OS could be due to lower numbers of patients with higher-stage disease, but we believe that breast cancer survivability in its earliest stage is more influenced by the TTS than it is in later stages because baseline mortality is smaller relative to the effect imposed by a delay in treatment. In both cohorts, OS and DSS for stage III disease were not influenced by TTS, suggesting either partial biologic predestination of outcome or a mortality risk that overshadows any small effect of reducing delay by a matter of months. This effect may also be attenuated by patient age owing to competing mortality risks. Because of this and because final stage is only available postoperatively, we believe that efforts to minimize preoperative delay for all patients is advisable.

My thought is that the effect of a delay in time to surgery is relatively small on an absolute scale and therefore hard to detect in retrospective databases like SEER-Medicare and NCDB. Of course, it would be unethical to do a randomized, controlled clinical trial testing time to surgery; so these sorts of analyses are the best we're going to get when it comes to answering this question. It's also important to point out that, although the absolute value of the decrease in OS is small, it's definitely not insignificant:

The effect of TTS on survival is a ubiquitous concern of patients with cancer and a question frequently posed in consultations with surgeons. Elimination of undue delay is desirable to both reduce anxiety and lower risk, and we believe that this study provides clinicians needed data to answer patients’ questions about TTS and its effect on outcome. While the absolute magnitude of the 5-year survival difference was small (4.6% and 3.1% for ≤30 days vs 91-120 days in SEER-Medicare and NCDB patients, respectively), this benefit is comparable to the addition of some standard therapies, such as the recent extension of tamoxifen therapy from 5 to 10 years, while not having the adverse effects or costs found with most interventions.

Exactly. As the authors point out, achieving surgery in less than 30 days is difficult and therefore 30 days might be an unrealistic goal, particularly when immediate reconstruction after mastectomy is being considered and when imaging techniques and more extensive workups can cause delays that easily stretch beyond 30 days, particularly for patients seeking multiple opinions. However, 60 days should be achievable in most cases. Either way, waiting months to undergo surgery, particularly for early stage disease, can decrease chances of survival by as much as foregoing adjuvant therapy. Speaking of adjuvant therapy, delays in chemotherapy are not good, either, as we shall see.

Timing of chemotherapy matters

The next study, Chavez-MacGregor et al, asked basically the same question, except that the authors looked at time to adjuvant chemotherapy after definitive surgery. Adjuvant chemotherapy is chemotherapy given after surgery with the intent of decreasing the chance of tumor recurrence. It is standard of care for many kinds of breast cancer. For instance, in two of the kinds of breast cancer with poorer prognosis, triple negative breast cancer [PDF] and HER2(+) breast cancer, except in the case of very small node-negative tumors, nearly every patient who is healthy enough to handle it will be recommended adjuvant chemotherapy.

Their rationale:

Most patients with breast cancer start adjuvant chemotherapy within 30 to 40 days of surgery. It is thought that chemotherapy administration delayed beyond this time can decrease the benefit provided by cytotoxic systemic therapies. Possible explanations for these effects include accelerated growth of micrometastases after resection of the primary tumor, increased tumor angiogenesis, or development of primary resistance. The optimal time of chemotherapy administration for patients with breast cancer is not precisely defined. Furthermore, it is possible that the time to chemotherapy (TTC) has a different effect according to tumor subtype, tumor stage, and tumor grade. Administration of combination systemic chemotherapy within 120 days of diagnosis in women younger than 70 years with T1cN0M0 or stage II or III hormone receptor–negative breast cancer is considered a quality metric by the Centers for Medicare & Medicaid Services. This metric will now be reported by 11 cancer hospitals as part of the Prospective Payments System-Exempt Cancer Hospital Reporting Program.

The effect of delayed TTC administration has been evaluated retrospectively with contradictory results. In a recent study, we reported that a delay of 61 or more days of adjuvant chemotherapy administration was associated with adverse outcomes among patients with stage II and III breast cancer and also among patients with triple-negative and human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive tumors. Our findings suggest that among these specific patient subgroups, every effort should be made to avoid delayed adjuvant chemotherapy initiation.

This study didn't use the SEER database or NCDB. Instead it examined a total of 24,843 patients from the California Cancer Registry diagnosed with stage I to III breast cancer between January 1, 2005 and December 31, 2010 treated with adjuvant chemotherapy. Time to chemotherapy was defined as the number of days between the last surgery for breast cancer and the first dose of chemotherapy, and delayed time to chemotherapy was defined as 91 or more days. Overall, the authors found no evidence of adverse effects when patients started chemotherapy between 31-60 or 61-90 days after their surgery as compared to patients who started their chemotherapy in 30 days. However, for patients who started their chemotherapy 91+ days after their surgery the results weren't so good. These patients experienced worse overall survival (hazard ratio [HR], 1.34; 95% CI, 1.15-1.57) and worse breast cancer–specific survival (HR, 1.27; 95% CI, 1.05-1.53). The authors then did a subgroup analysis examining different subtypes of cancer to subtype, longer time-to-chemotherapy was associated with worse OS in the subgroups one would predict. Specifically patients with triple-negative breast cancer had worse overall survival (HR, 1.53; 95%CI, 1.17-2.00) and worse breast cancer–specific survival (HR, 1.53; 95%CI 1.17-2.07). This finding intuitively makes sense because it is patients whose tumors are estrogen receptor-negative for whom there is the greatest benefit due to adjuvant chemotherapy.

Not surprisingly, the authors found a correlation between prolonged time to chemotherapy and Hispanic ethnicity, non-Hispanic black race, lower socioeconomic status, and nonprivate insurance. This is similar to what Bleicher et al found with respect to time-to-surgery, namely that the proportion of patients with black race or Hispanic ethnicity increased with each interval delay. This is by no means a new finding; disparities in health care of this sort have been documented in many previous studies. Indeed, these sorts of disparities are likely one reason (of many) why minorities and people of lower socioeconomic status experience worse outcomes in many cancers. Indeed, there are a lot of potential confounders, many of which couldn't be accounted for in either study, as Chavez-MacGregor et al note:

Our study is limited by its retrospective nature. However, that we are aware of, this study is the largest published cohort of patients with breast cancer of known breast cancer subtype treated with contemporary regimens. We acknowledge that in clinical practice a number of factors determine the optimal TTC, and that in many cases, this time frame is determined by comorbidities or complications associated with surgery. Unfortunately, data concerning comorbidities and complications with surgery are not available in the CCR data database, and we cannot exclude that the factors associated with delays in chemotherapy administration are not also related to worse outcomes. However, the fact that we observed consistent results in our OS and BCSS [breast cancer specific survival] risk estimates makes this scenario unlikely. In addition, we acknowledge that the potential determinants of chemotherapy initiation include the recommendation of the medical oncologist and the entire multidisciplinary team. Additionally, from the patient-centered care perspective, a patient’s preferences are likely to play a role, which we were unable to take into account.

Similar comments apply to the time-to-surgery study, based on the strengths and weaknesses of each database used. But, again, it's unethical to do a randomized trial studying a question like this.

The bottom line: Timely treatment is better than delay

I realize that these two studies are about as close to "Well, duh!" studies as there are. Of course, delaying surgery for breast cancer is not a good thing. Of course, delaying chemotherapy when it's indicated is also not a good thing. These are results that are not unexpected. However, these studies are still very important because they give us estimates of how much of a delay is safe and at what point delaying care starts to have a measurable impact on patient outcomes. Putting the results of these studies together suggests that it's best to do surgery within about 60 days in patients not needing chemotherapy first, and that for patients with disease lacking the estrogen and progesterone receptor it's best to start chemotherapy within 90 days of surgery.

We can thus reassure anxious patients who want their surgery tomorrow while at the same time tell patients balking at surgery or chemotherapy how long they can safely wait before the delay starts adversely affecting their chances of survival. Unfortunately, in my practice, due to the socioeconomic status of a lot of patients, by the time some of my patient see me it's already been more than 30 days since their biopsy and diagnosis.

This sort of analysis is also yet another bit of data demonstrating that conventional treatments work. After all, if a conventional treatment didn't work, it wouldn't matter how long you waited to administer it. For instance, if you treated a woman with breast cancer with homeopathy right away, the results would be the same if you waited 120 days. I've discussed examples of patients who paid a steep price for their delaying effective treatments for their cancers, beginning with breast cancer patients over eleven years ago and a man I encountered as a resident with rectal cancer who had turned himself orange with megadoses of carrots trying to treat his disease. We also know that the use of alternative medicine as a primary treatment in breast cancer is associated with recurrence and death. Using alternative therapy for breast cancer is a good way to die when you don't have to or to die sooner than you would otherwise. Refusing surgery also results in death.

Fortunately, however, relatively few patients rely only on alternative medicine. I mention them mainly because the delays in treatment leading to unnecessary death from such treatments has been a major theme of my blogging over the years. However, where this study is most helpful is in providing patients with evidence-based recommendations regarding how urgently they need to proceed with treatment, calming those who think they're going to die if they don't get their surgery or chemotherapy tomorrow, and trying to persuade those who are indecisive or too slow to act. They will also help those of us in quality improvement determine whether time to treatment should be a metric we measure and, if so, what standards we should set. Prompt treatment is better, but it's tricky to define what exactly constitutes "prompt." These studies help.

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I appreciate these results and wonder if this could be extrapolated to other cancers?

Thank you for this. I have a sister newly diagnosed with breast cancer. Her first panicked thought was double mastectomy the very next day. (Really, she was all for it.) Her surgeon calmed her down, they did a lumpectomy and a sentinel node within 2 weeks, and now she's deciding chemo yes/no. This answered a lot of questions that I didn't know the answer to.

After mammography screening, "the lack of change in the incidence of metastatic disease is consistent with the hypothesis that breast cancer is a systemic disease by the time it's detectable" (Welch et al., NEJM, 2015). Then one may wonder how prompt surgery could prevent death from breast cancer.
One of the statements must be wrong.

By Daniel Corcos (not verified) on 12 Jan 2016 #permalink

@Orac

To play quack's advocate...

After all, if a conventional treatment didn’t work, it wouldn’t matter how long you waited to administer it.

The quack would argue that conventional treatment kills the patient one way or the other, but it does so faster the more progressed the disease. Of course, that's what controls are for, but for woo sake, we'll just ignore those.

I don't understand the numbers with Stage lll. At that point, the train is really rolling. My wife had a double (IDC, ER+, Stage 3A) within 45 days of biopsy and diagnosis, followed by eight rounds of chemo, then radiotherapy over the next six months. I would think that any delay at Stage lll would result in higher mortality rates than Stage l or ll.

Interesting.

One of the issues I encounter when talking with those with BC who are advocating alternative treatment is that - one of the reasons that they want to pursue alternative treatment (other than the usual BIG PHARMA conspiracies) - they want to "save" conventional treatment for "later", when they might need it. They don't understand that there may not be later and, if there is, it may be too late. And if advancing disease "forces" them to pursue conventional treatment, and their disease continues to progress, somehow it's never the delay, but the conventional treatment that's "not working" or is "poisoning" their bodies.

It's enough to make me want to bang my head against a wall.

By Selena Wolf (not verified) on 12 Jan 2016 #permalink

@ Todd W:

One of the loons I survey proposes that receiving SB treatment first sabotages the altie nonsense - which works *perfectly* always- so I suppose delay would be good.
People die because of SB treatment not the illness itself.

By Denice Walter (not verified) on 12 Jan 2016 #permalink

People die because of SB treatment not the illness itself.

That sounds much like the advice to avoid hospitals, because people die there all of the time. Except that the latter was intended to be a joke (I forget which comedian's line it is), and alt-med people use the former seriously.

By Eric Lund (not verified) on 12 Jan 2016 #permalink

That sounds much like the advice to avoid hospitals, because people die there all of the time.

I heard that most accidental deaths happen at home, so I moved.

By Mephistopheles… (not verified) on 12 Jan 2016 #permalink

Given the facts noted by Daniel Corcos and the fact that the vast majority of the Medicare database (not surprisingly) died of something during the lengthy follow-up, it is worth asking if this is partially false causation. Are women who delay treatment by 120 days not likely to be in some ways different from those who are treated within weeks?

I know, it would be comforting to assume they were all Quacks and Woomeisters who delayed from stupidity. More common, I suspect, is that they have economic and family circumstances that make it a challenge to drop everything to enter expensive and disabling treatment. Lower economic status, in America, means lower life expectancy, higher all-cause mortality, and for most a reduced ability to, e.g., eat the sort of diet that is correlated with lower breast cancer recurrence and mortality.

Others, especially in the Medicare group, may have delayed voluntarily because their age or comorbidities caused them to wonder whether they might die of something else before the cancer got them, or whether they could endure the treatments. These people will have worse odds of survival.

Some might have hesitated for such reasons and then decided to treat after all because they saw evidence of progression (e.g., the lump getting quickly larger). Women with cancers that do that have worse prognoses than women with cancers that don't, even when the latter aren't outright overdiagnosis victims. This could stack the <1% of the data set who had very long delays to treatment with women who had more aggressive cancers. (Did another handful go away and never get treated? We don't see the stats on them.)

In short, while the advice is probably qualitatively correct and there is never going to be a randomized trial, the numbers in these studies cannot be quoted to patients without the caveat that there is no randomization, control, or correction for differences among groups.

After mammography screening, “the lack of change in the incidence of metastatic disease is consistent with the hypothesis that breast cancer is a systemic disease by the time it’s detectable” (Welch et al., NEJM, 2015). Then one may wonder how prompt surgery could prevent death from breast cancer.
One of the statements must be wrong.

Not necessarily, because the two statements are about two different forms of breast cancer: metastatic and non-metastatic. Welch et al are saying that early detection doesn't decrease the incidence of metastatic cancer, and (if I'm understanding them correctly) hypothesizing that the reason is that cancer has a metastatic or non-metastatic phenotype right from the beginning, as opposed to the idea that cancers are non-metastatic early on and then become metastatic later, and thus can be prevented from becoming metastatic if caught early.

Whereas Bleicher et al were looking at the effect of delaying surgery specifically for the subset of breast cancers that weren't inflammatory and hadn't metastasized beyond the metastatic lymph nodes - the kind where surgery would be the first line of treatment.

@ jane - Actually, the authors did control for the factors you mention, and many more. A partial list from the Bleicher paper includes:

Adjustments were made for age, sex, race, marital status, income, education, size of metropolitan area, geographical region, year of diagnosis, sequence of breast cancer (within a history of other cancers), Charlson and Elixhauser comorbidity scores, histologic findings, grade, tumor size, number of lymph nodes examined, number of positive lymph nodes, AJCC stage, surgery type, chemotherapy use, and radiotherapy use, via propensity score–based weighting.

Orac also discusses some of these factors, particularly those connected with socioeconomic staus, within the post.

@ Sarah A
Are you saying that mammography screening is inefficient because it detects metastatic or inflammatory cancers?
@ Jane
You are perfectly right, but I am inclined to think that the first statement (early detection does not prevent metastasis) is wrong.

By Daniel Corcos (not verified) on 12 Jan 2016 #permalink

In short, while the advice is probably qualitatively correct....

This is again USian, but for some reason, this instantiation of "jane's dropping by" immediately brought to mind my aesthetic condemnation of the elimination of the scratchy-OMG-voice intros to "Emergency Alert System"* radio tests.

* I sent out a shortwave rig with vintage CONELRAD markings for repair two-and-a-half years ago. I have a bad feeling about the outcome.

@ Daniel Corcos - I'm not knowledgeable enough about breast cancer to venture a hypothesis as to why increased screening doesn't appear to decrease metastatic disease. What I'm saying is that the hypothesis that breast cancer is intrinsically metastatic or non-metastatic before it is detectable by mammography is not, in fact, incompatible with the finding that delaying surgical treatment of non-metastatic leads to worse patient outcomes.

OT but it's late and we're all in need of a laugh I venture..

Mikey has resurrected his old pre-naturalnews site for political/ economic "news"
and there is a new site called

Pharma Death Clock.com

which instantly counts deaths 'caused' by SBM in detailed sub-categories - in just the manner you might imagine-

adding up to MILLIONS..

By Denice Walter (not verified) on 12 Jan 2016 #permalink

DW @16

Pharma Death Clock

Didn't they open for Slayer at one time?

By Militant Agnostic (not verified) on 13 Jan 2016 #permalink

"Mikey has resurrected his old pre-naturalnews site for political/ economic “news”
and there is a new site called

Pharma Death Clock.com"

Kind of reminds me of that song from the fictitious band "Dethklok - Dethsupport"

I wonder... What is it about the current system that drives the wait time beyond 30 days? It sounds like there could be better synchronization across specialists and test services. Would we do better with parallel, co-ordinated work instead of sequential ping-ponging between offices? Even a 1-2% decrease in mortality would be significant in terms of absolute numbers.

So, I have a friend who has had what everyone thought was a skin infection that has developed over the last couple of months. Since it did not respond to antibiotics, they are now considering the possibility of inflammatory breast cancer. I know a radiologist suggested a biopsy at some point prior to the 21st, that was originally supposed to happen on the 27th but instead she had a consult with a surgeon who suggested an MRI, which won't happen for much of another week. The surgeon thinks it has some characteristics of IBC but not all, so nothing is happening yet.

I know there's no MUST OPERATE TOMORROW a lot of the time, but given the aggressiveness of IBC I keep thinking WHAT ARE THEY WAITING FOR?

From what I can find about IBC if that is in fact what she has things look really bleak from a long-term perspective. Do you know if there's any recent research that is a bit more hopeful?

By Emma Crew (not verified) on 28 Jan 2016 #permalink