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Why Do Cancer Surgeons Cure More Patients Than Medical Oncologists?
By gdpawel at 2014-04-09 19:23
Why Do Cancer Surgeons Cure More Patients Than Medical Oncologists?

 

Robert A. Nagourney, M.D.

 

Who does it really serve when a clinical trial involving 597 patients results in an increase in survival by 10 days?

 

And when the authors of the published trial results are quoted as saying, “To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine.”

 

Is this the best we can do?

 

Surgery remains the most curative form of cancer treatment. While the reasons for this are many, the most obvious being earlier stage of disease and the better performance status of the patients, there are other factors at work. Surgeons tend to be rugged individualists, prepared to make life and death decisions at a moment’s notice. The surgeon who enters the pelvis expecting an ovarian cyst only to find disseminated ovarian cancer must be prepared to conduct a total hysterectomy and bilateral ovary removal if he/she is to save the patient’s life. It is these types of aggressive interventions that have that revolutionized the treatment of advanced ovarian cancer.

 

What of the medical oncologists who, with the exception of leukemiaterm and some lymphomas, confront diseases that are difficult to eradicate and for which treatments can be toxic? Trained as incrementalists, they do not expect cures so much as palliation. Their role is not to make hard decisions, but instead to rely upon precedence. Educated in the school of small advances, these physicians are not rewarded for individual successes but they are harshly criticized for any departures from community standards.

 

Deprived of the opportunity to make bold decisions, medical oncologists follow opinion leaders who instruct them to accrue to standardized protocols. As meaningful advances are few and far between, enormous numbers of patients must be accrued to provide sample sizes with any hope of achieving statistical significance. Among the most disturbing examples of this approach was a trial reported in patients with inoperable pancreatic cancer. The study compared single agent gemcitabine to gemcitabine plus erlotinib. The trial achieved an improvement in survival that led the FDA to approve the two-drug combination. Yet, the actual improvement in median survival was a mere 10 days. The authors beamed, “To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine.” (Moore, MJ et al J Clin Oncol, 2007). To the average observer however, a clinical trial that required 569 patients to improve median survival from 5.91 months to 6.24 months (10 days) would hardly seem cause for celebration.

 

Medical oncologists have become so accustomed to these marginal advances that they are unmoved to depart from standard protocols lest they be accused of breeching guidelines. This might be acceptable if chemotherapyterm provided meaningful benefits, but the extremely modest advantages provided by even the best clinical trials scream for medical oncologists to think, well, more like surgeons.

 

While community oncologists think it heresy to step around a National Comprehensive Cancer Network (NCCN) guideline, investigators at the best institutions, the opinion leaders, have begun to question the merit of blind protocol accrual and come to recognize that many critical questions cannot be easily answered through the current trial process. Questions such as the role of liver resection for colon cancer patients with disease spread to the liver or the role of additional chemotherapy after that liver surgery, simply may not lend themselves to randomized trials. In a review of the topic by one of the leading investigators in the field, Dr. Nancy Kemeny from Memorial Sloan-Kettering in New York examined this dilemma, “The management plan for each patient should be decided by a multidisciplinary team, it may not be possible or ethically defensible to perform large randomized adjuvant trials comparing chemotherapy with surgery alone or comparing modern chemotherapy with older regimens. It may be reasonable to extrapolate from adjuvant trials and meta-analyses showing predominantly disease-free survival benefit. Each decision on postoperative chemotherapy should be viewed in context of prior treatment, surgical preference and individual patient characteristics.”

 

How refreshing. Finally a clinical investigator has recognized that patients must be managed on an “individual basis” regardless of what the clinical trial data does or does not support.

 

The concept of personalized medicine flies in the face of contemporary guideline driven treatment. Individualized care is on a collision course with the NCCN. It is time for medical oncologists to reclaim the high ground in doing what is right for patients, using resources that enable them to make smart decisions and to eschew standardized care. In cancer, the dictum “one size fits all” is more accurately “one size fits none.”



3 comments | 17811 reads

by gdpawel on Wed, 2014-04-09 19:37
The role of the surgeon is to perform the workup and then determine if cancer is present or not. Once cancer is diagnosed, the surgeon will work with the medical oncologist and radiation oncologist as a team to decide in a multidisciplinary fashion what the best treatment is, if needed.

For decades, any surgeon was considered competent to exercise all surgical skills, including cancer surgery. Indeed, while most surgeons may be acceptably competent, the specialty of surgical oncology is increasingly important. The surgical oncologist is most often the first specialist to see a patient before other oncologic specialists.

Surgical procedures for cancer are often complex and technically demanding. Studies have shown that patients have better outcomes, the lowest complications and death rates when they are treated by experienced surgical oncologists. In addition, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.

Surgical oncologists are clinical scientists with knowledge of and experience in cancer surgery that come from additional training, limitation of the scope of general surgical practice, familiarity with the biology and natural history of cancers, and the role of the other oncologic specialties in their diagnosis and management.

Surgery can be used to provide local control in advanced disease. It's not just the surgery or the surgeon, it's the process. Three factors affect outcomes. Patient factors, which you can only partially control, such as diabetes, hypertension, etc. Physician factors, skill, training experience and judgement. And process factors, which are the hardest to control and include the infrastructure of the institution. Hospitals that do higher volumes of surgeries have correspondingly lower mortality rates than those who do fewer of the procedures. This has important implications for both patients and doctors.

The tissue resected by a surgeon and analyzed by a pathologist is the source of crucial information that informs the decisions and actions of medical oncologists. It is the surgically resected tissue that possesses the information needed to define the specific characteristics of a patient's tumor, the specific therapies to which the tumor would be expected to respond and even the specific risks of adverse reactions to given therapies.

The reasons for surgery have to do with understanding the Biology of Tumor Growth and Metastasis.

In the beginnings of a tumor, most cells are in the proliferative pool

When the tumor is clinically detectable, most cells are NOT in the proliferative pool - some die and some enter a resting state (Go)

Rate: tumor growth depends on excess cell production over cell loss

Cell cycle: malignant cells use the same 5 phases as normal cells (duration of cycle differs however – G1)

Growth fraction: proportion of cells within a tumor in proliferative pool varies for different tumors - has a profound effect on chemotherapy

Mitotic figures: crude measure of growth rate; way to find out how many are in the growth fraction

Angiogenesis: important for tumor growth - brings in nutrients, pathway for metastasis - if inhibitied Þ starve the tumor; tumor cannot grow beyond 1-2 mm without a blood supply

Takes a long time for tumor to become detectable, however once detected, takes a short time to become lethal - one cell Þ 30 population doublings Þ 109 cells (1 gram, 1cm3) Þ clinically detectable - 10 more population doublings Þ 1012 cells (1000 grams) Þ lethal

What are the stages?

Cancer cells that are "out surviving" their normal counterparts often do so in a quiescent stage (GO Gx). The GO phase is a period in the cell cycle in which cells exist in a quiescent state, where the cell is neither dividing nor preparing to divide (the cells do not go through mitosis whatsoever). These cells only do what they are initially suppose to do, and do not prepare for a division. In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy.

Cell proliferation is characterized by four distinct phases: G1 phase (Gap1), S phase (DNA synthesis), G2 phase (Gap2) and M phase (mitosis). Non-proliferative or “resting cells” are referred to as being in G0 phase (GO Gx). Flow cytometry has been increasingly used to analyze cell cycle. This is achieved by performing either univariate analysis of deoxyribonucleic acid (DNA) content or multivariate analysis of DNA content and proteins associated with cell cycle.

That is why some researchers believe the reason for better survival for patients who could undergo complete resection without any tumor left behind is that these tumors are biologically less aggressive and would do better regardless of the type of treatment they receive, and that the removal of lymph nodes at the time of surgery may additionally contribute to a better outcome.

Why Surgery?

Surgery is an integral part of the multimodality treatment of many cancers. The line of reasoning frequently used to explain the value of surgery included five points.

First, surgery is thought to remove resistant clones of tumor cells and thus decrease the likelihood of the early onset of drug resistance.

Second, the removal of large masses likely to be associated with poorly vascularized areas of tumor improves the probability of delivering adequate drug doses to the remaining cancer cells.

Third, the higher growth fraction in better vascularized small masses enhanced the effect of chemotherapy.

Fourth, smaller masses required fewer cycles of chemotherapy and thus decreased the likelihood of drug resistance.

Fifth, removal of bulky disease enhances the immune system. Patients who present with a large mass are suffering because of that mass and they need that tumor out to relieve symptoms and to save life due to symptoms. It's important to deal with the bulk.

Sources:

Mayo Clinic
American Board of Surgeons
Society of Surgical Oncology

by gdpawel on Wed, 2014-04-09 19:48
The Surgical Specimen Is the Personalized Part of Personalized Cancer Medicine

Carolyn C. Compton, M.D., PhD.

Office of Biorepositories and Biospecimen Research, National Cancer Institute, Bethesda, MD USA

As a pathologist, I have been evaluating cancer resection specimens throughout my career and have come to have a deep appreciation of the challenges of surgical oncology. Happily for patients, surgeons cure cancer on a fairly regular basis by excising it with expert technique and detailed knowledge of human anatomy and tumor biology. The tissue resected by the surgeon and analyzed by the pathologist is the source of crucial information that, in turn, informs the decisions and actions of our medical oncology colleagues.

As cancer medicine looks forward to a new era of molecularly defined cancer subtypes and targeted therapies, however, the role of both surgeon and pathologist is evolving to require an ever greater degree of professional attention towards the surgical resection specimen. It is the surgically resected tissue that possesses the molecular information needed to define the specific molecular characteristics of the patient’s tumor, the specific therapies to which the tumor would be expected to respond, and even the specific risks of adverse reactions to given therapies predicted by the patient’s genetic make-up. This molecular information forms the basis of the “personalized” approaches envisioned for cancer patients in an age of molecular medicine. The professional responsibility to assure that the specimen’s molecular composition and integrity are safeguarded is shared by both the surgeon and the pathologist. Current momentum towards molecular medicine is rapidly elevating this professional responsibility to one of the most important aspects of cancer patient care.

Currently, however, safeguarding the molecular integrity or documenting surgical variables that impact the molecular composition of the resection specimen is not widely considered to be primary aspects of the surgeon’s professional responsibility. Manipulations of the tissue within the surgical procedure itself may have dramatic effects on the molecular make-up of that tissue. However, these manipulations are neither recorded nor controlled when and where possible. Variables such as anesthesia type and duration, drugs administered preoperatively and intraoperatively, and devascularization/ischemia time for the resected tissue may dramatically alter molecular profiles and/or molecular integrity. Once successfully resected, the specimen may spend varying amounts of time at room temperature in the surgical suite and/or holding unit before being delivered to Pathology, which may further alter the molecular composition and quality of the tissue.

Without the surgeon’s extension of professional responsibility to the resected tissue to control, when feasible, and track such variables, the advantages of personalized adjuvant approaches may be lost to the patient. In molecular medicine, the resected tissue becomes the major determinant of all downstream therapy. Therefore, the care of the specimen must be addressed co-equally with the care of the patient. This elevated bar for ensuring tissue integrity and molecular quality also must be addressed by pathologists. The fresh specimen will need to be overseen by the pathologist with the same immediacy and professional attention. More than ever, surgeons and pathologists will be required to work together closely to achieve the goal of meeting the new standards of “specimen care” required for molecular analysis.

Our knowledge about the affects of iatrogenic variables such as surgical manipulation, intraoperative drug delivery, and pathological handling on the molecular profiles that reflect the biology in resected tissues is growing rapidly.1–5 Postoperative tissue ischemia time, for example, has been shown to alter gene and protein expression profiles within minutes following surgical excision in colectomy specimens and prostatectomy specimens.1–3 Not surprisingly, even before resection has been completed, intraoperative manipulations have been shown to markedly alter gene transcription levels during radical prostatectomies.4 The effects of different peri- and intraoperative variables on molecular profiles in different types of tissues are just beginning to be understood, but it is clear that surgeons and pathologists alike contribute significantly to the final molecular composition and integrity of the resected tissue.5

Procedures that maximize specimen quality respect the fact that resected tissues are vital and biologically reactive. Until they are fixed or frozen, biospecimens are viable and capable of reacting to physiological stress. They are a living part of the patient from which they come and are responsive to changes in temperature, perfusion, oxygenation, and other physiological and biochemical variables, both pre- and intraoperatively as well as postoperatively. Typically, once a tumor is successfully resected, the surgeon’s attention turns to patient and relatively little is directed towards the specimen. Unless an intraoperative consultation such as a frozen section is requested and the specimen is immediately addressed for this purpose, it may sit unattended for varying periods of time before being prepared for delivery to the pathology laboratory. The conditions of delivery itself may vary, as may the immediacy of the specimen handling once it has arrived in the pathology laboratory. Furthermore, some of the newer surgical techniques, such as robotically assisted prostate resections, may further compromise the quality of the resection specimen if it is allowed to remain in the operative site at body temperature for significant amounts of time after devascularization.

In this emerging age of molecular medicine, a new level of awareness of and attention to “the state of the specimen” will be required by surgeons, operating room staff, pathologists, and pathology staff. All play essential roles in the series of events leading up to stabilization of the tissue that impact its molecular make-up and molecular integrity. Surgeons are the initiators and controllers of many of these events and therefore represent the “gatekeepers.” The powerful molecular analysis technologies now at our disposal and the increasingly sensitive and specific analysis platforms under development provide us with unprecedented abilities to define the molecular features of cells and tissues. However, they also pose new risks by providing us with the ability to derive the wrong answer with even greater speed and accuracy unless the analytes are of high quality and are derived from high-quality specimens. It is our joint professional responsibility to follow procedures that will ensure the quality of the biospecimen and to document the specimen handling history for the patient’s record.

In this dawning era of molecular medicine, where a hard-won understanding of the molecular details of cancer is leading to more powerful and accurate diagnostics and therapeutics, I foresee surgeons and pathologists playing a new and more pivotal role in cancer medicine. They are the custodians of the specimens and therefore the molecules that represent the personalized part of personalized medicine. Surgeons will continue to cure cancer with greater success rates through earlier detection and excision; but as the custodians of the tissue, they will also be central to improving cancer management through molecularly targeted interventions.

References

1. Spruessel A, Steimenn G, Jung M, Lee SA, Carr T, Fentz A-K, et al. Tissue ischemia time affects gene and protein expression patterns within minutes following surgical excision. BioTechniques. 2004;30:1030–7.

2. Dash A, Maine IP, Varambally S, Shen R, Chinnaiyan AM, Rubin MA. Changes in differential gene expression because of warm ischemia time of radical prostatectomy specimens. Am J Pathol. 2002;161:1743–8.

3. Lin DW, Coleman IM, Hawley S, Huang CY, Dumpit R, Gifford D, et al. Influence of surgical manipulation on prostate gene expression: implications for molecular correlates of treatment effects and disease prognosis. J Clin Oncol. 2006;23:3763–70.

4. Schlomm T, Näkel E, Lübke A, Buness A, Chun FK-H, Steuber T, et al. Marked gene transcript level alterations occur early during radical protatectomy. Eur Urol. 2008;53:333–46.

5. Signoretti S, Bratslavsky G, Waldman FM, Reuter VE, Haaga J, Merino M, et al. Tissue-based research in kidney cancer: current challenges and future directions. Clin Cancer Res. 2008;14:3699–705.

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