Cancer: A medical emergency
Introduction
Cancer may become the leading cause of death in the industrialized world within the next decade, outstripping cardiovascular disease [1]. The personal, economic, and social costs of the disease are enormous [2]. Despite significant worldwide research into the pathophysiology of cancer and the development of many effective treatments, curing clinically evident metastatic cancer remains an elusive goal.
The current paradigm for the treatment of cancer follows a fairly predictable clinical pattern and time course. Once a diagnosis of cancer is suspected, usually based upon an abnormal finding on a physical examination or an imaging study, a tissue biopsy is set up to confirm the clinical suspicion. Detailed radiologic imaging follows to assess whether the disease is resectable. The patient is then further evaluated for their ability to tolerate the proposed surgery. After surgery a period of recuperation follows. It is only after recovery from surgery that systemic chemotherapy is started.
The time from the diagnosis of many surgically resectable cancers, including breast, colon, and lung, to the initiation of systemic chemotherapy averages at least eight weeks in many industrialized nations [3], [4], [5]. Surgery can remove the primary tumor and localized disease, but any cancer remaining after surgery, whether regional spread or distant metastases, remains untreated during this time.
Metastatic disease to regional lymph nodes is detected at surgery in approximately one quarter to one third of patients with many of the more common malignancies, including breast, colon, and lung [6]. In the remaining two thirds of patients with node negative macroscopic disease, perhaps another 25% will harbor micrometastatic disease if a more detailed examination of their lymph tissue is done [7], [8]. These micrometastases have been shown to have an adverse impact on survival in many different types of cancer [9], [10], [11]. In all, approximately 40–50% of patients who undergo surgery with curative intent have spread of their disease beyond the primary tumor. These patients are at grave risk of dying from their disease.
At what point does a given cancer become incurable? The historical failure of adjuvant chemotherapies to alter the natural course of the disease suggested that cancer was incurable once it had metastasized, leading to a pervasive fatalism among oncologists towards the disease and the efficacy of their treatments. But this attitude is no longer tenable. The success of many published adjuvant trials over the last decade has made it clear that chemotherapy can cure metastatic disease at its earliest stages. For just one type of cancer, early stage non-small cell lung cancer, Vinorelbine and Cisplatin versus observation after surgical resection increased the absolute number of patients surviving five years to 69% versus 54% [12].
Similar results have been found with breast and colon cancers [13], [14], [15]. With better therapies it is reasonable to think that even more people with cancer can be cured. But conventional chemotherapeutic regimens are incapable of curing most clinically evident metastatic cancers, and the diagnosis of metastatic cancer has proven to be a death sentence with few pardons. It is intuitive that there exists a point in the disease trajectory where metastatic cancer becomes impossible to cure with our current therapeutic armamentarium. Where this point is reached is unique to each cancer and to each individual, and it is not our goal to define the variance inherent in this complex process. But it is our goal to argue that the point when a cancer becomes incurable is a function of time, and that the current waiting time now between diagnosis and the start of systemic therapy is transforming curable disease into incurable disease at high rates.
Section snippets
Eradicating metastatic disease becomes more difficult over time
There are several reasons to think that the current paradigm for treating potentially curable cancer does not parallel our understanding of the disease process. Consider the typical wait (four to eight weeks) after surgery before the initiation of systemic treatments. Surgery can activate dormant occult micrometastases, stimulate angiogenesis, and facilitate tumor growth and spread into the circulation [16], [17]. Surgery can also suppress the immune system, often dramatically, reducing the
Model
Consider early stage, IB and II, non-small cell lung cancer. We know from historical studies that after surgery approximately 50% of these patients will be cured and 50% will die. With chemotherapy after surgery an additional 20% can be cured of their disease [10]. This additional 20% represents nearly 40% of those patients who would have died of their disease if they had not received chemotherapy. Assuming that this cohort had their chemotherapy initiated on day 45 after surgery, the TCP, or
Discussion
In the mathematical model presented above the chance for curing metastatic cancer is inversely proportional to the tumor burden that must be eradicated. This tumor burden is a function of the metastatic load remaining after surgery, the intrinsic doubling time of the tumor, the time period elapsing prior to the start of effective chemotherapy, and the relative effectiveness of the immune system in eradicating residual malignant cells. The limit point alpha defines the point where cure becomes
Acknowledgments
We would like to thank the following individuals for their careful reading of this paper and their thoughtful comments: A. Sehbai, M. Auber, J. Higa, W. Petros, and E. Crowell.
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Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity
2022, Seminars in Cancer BiologyCitation Excerpt :However, so far, the modality of administering adjuvant chemotherapy for a few months has not been yet questioned. This is based on cancer cell kinetics and other presumed favourable conditions occurring soon after primary surgery [168,169] and documented by improved clinical outcomes in many trials conducted in the early 21th century [167]. Similarly, monoclonal antibody-based (trastuzumab, bevacizumab) and other molecular targeted adjuvant therapies including PD1-PDL1 inhibitors are continuously given overall for relatively short time.
Postoperative cancer treatments: In-situ delivery system designed on demand
2021, Journal of Controlled ReleaseCitation Excerpt :Tumor cells can be protected from attacks by establishing immune suppression, a long-considered critical step in both tumor formation and progression. Moreover, surgery leads to numerous factors (inflammation, blood transfusion, anesthetic agents), further consolidating a systemic immunosuppressive state [6,7,13,23]. The immunity is proved to be inhibited under surgical stress that promotes the proliferation of tumor cells, which may last for 6 months after surgery [19].
Effect of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer
2015, Clinical Colorectal CancerCitation Excerpt :Mathematical modeling has suggested that the drug sensitivity of tumors is related to their spontaneous mutation rate, which is obviously a function of time.27 Moreover, the effectiveness of a given chemotherapeutic regimen is inversely proportional to the tumor burden, suggesting that delaying AC initiation could be detrimental because of increasing tumor size.28 An important question that arises from the current study is why delayed time to 5–FU-based AC was associated with inferior survival in previous studies but not when oxaliplatin was combined with a fluoropyrimidine backbone.
Survival after community diagnosis of early-stage non-small cell lung cancer
2014, American Journal of MedicineCurrent practices and challenges of adjuvant chemotherapy in patients with colorectal cancer
2014, Surgical Oncology Clinics of North AmericaCitation Excerpt :These data suggest that the time between surgery and the start of AC is critical in preventing the development of metastatic cancer. Mathematical modeling based on empirical data has indicated the same concept: that the probability of eradicating micrometastatic cancer after surgical resection is inversely proportional to the tumor burden that remains to be destroyed, and consequently is inversely proportional to the time from surgery to AC.36 Based on this model, the window of opportunity to eradicate these metastatic sites is 100 days, after which the curative potential of AC has been surpassed.36
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