Cancer is a complicated disease. This is an understatement. Yet there is at the gross level some simplicity. There are a few basic facts.
1. Cancer is generally clonal, one cell goes wild and keeps reproducing.
2. The reproduction rate is not quite doubling, some progeny do not survive, thus depending on the status of the tumor the growth rate is between 1 and 2 per generation. Sometimes it is less than 1 and it even regresses.
3. When there are 10E6 cells the tumor can be seen under CAT or MRI. When there are 10E9 cells it is palpable, when there are 10E12 the patient dies. Almost.
4. Cancer growth and evolution is a classic epigenetic systems process in cell growth and replication. The cell loses its ability to die, it just keeps growing and replicating itself with its functionality reduced to it replication and nothing else.
This is the simple story of cancer. We show a simple model for 4 cancers below.
Note that in this model we assume rapid growth for ovarian cancer and slow growth for prostate. This may not always be the case. For example there are certain prostate cancers which grow very aggressively, the reasons are not yet known. We show the groth below in two scales.
The above is on logarithmic scale and the one below is linear.
This shows two factors. One is that certain cancers grow so quickly that one mus have to screen on a quarterly basis to have any effect. That is very costly. Second some cancers grow so slowly that screening will result in surgeries that are not necessary since the cancer will never grow large enough to kill the person. Thus between too fast and too slow are many others, and too fast may not be too fast and too slow may not be too slow. That is the conundrum.
In a recent JAMA article the authors state:
"Early detection may not be the solution for aggressive cancers because many may not be detected early enough for cure. Some small "curable" breast cancers, categorized as low risk by National Institutes of Health criteria, have a high mortality risk when analyzed using prognostic molecular profiles such as the NKI 70 gene test. Biologically aggressive cancers present with a higher stage despite screening. Interval cancers, those that present clinically between routine screens, have a higher growth fraction and are more likely to be lethal compared with screen detected cancers. In the neoadjuvant I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) trial, in which the mean tumor size was 6 cm (accrual 2003-2006 in the United States), 91% had poor prognosis biology27 (using the NKI 70 gene test), which is much higher than the 33% poor prognosis proportion in women undergoing routine screening.21 Of women undergoing routine screening in the I-SPY TRIAL, 85% of the malignancies were interval cancers and only 15% were screen detected, suggesting that locally advanced cancers reflect the growth curve.... Similarly, the most lethal prostate cancers are those with rapidly increasing...
Screening is most successful when premalignant lesions can be detected and eliminated as in the case of adenomatous polyp removal during colonoscopy screening or cervical intraepithelial neoplasia ablation by colposcopy after detection by pap smear. Perhaps most important is that screening for cervical and colon cancer and the removal of preneoplastic lesions have been accompanied by a significant decrease in their invasive cancer counterparts; this has not been seen in breast and prostate cancer. Ductal carcinoma in situ, rare prior to widespread screening, now represents 25% to 30% of all breast cancer diagnoses (>60 000 new case-diagnoses annually are not included in the invasive cancer statistics), the majority of these lesions are low and intermediate grade. Ductal carcinoma in situ is considered to be a precancerous lesion and standard of care is excision and adjuvant treatment. However, after 2 decades of detecting and treating DCIS, there is no convincing evidence of substantial reduction in invasive breast cancer incidence. The 2002 decrease in incidence leveled off in 2005 and is attributed to a reduction in postmenopausal hormone therapy use, not DCIS removal."
The authors then suggest actions which we have detailed earlier in our BOOK on Health Care. they rephrase them as follows:
Biomarkers to Differentiate Significant- and Minimal-Risk Cancers. To help move toward a more effective solution, the first step is a change in mindset in scientific discovery efforts and clinical practice
Reduce Treatment Burden for Minimal-Risk Disease. Many diagnosed tumors will follow an indolent course for the patient's lifetime42 or are probably cured with surgical excision alone.
Develop Tools to Support Informed Decisions. Information about risks of screening and biopsy should be shared with patients before screening. At the time of cancer detection, risks and benefits of treatment for specific biological subtypes should be shared
Focus on Prevention for the Highest-Risk Patients. Ultimately, prevention is preferable to screening by reducing the risk that a patient will have a diagnosis, experience undesirable effects of treatment, and confront the specter of recurrence. For both breast and prostate cancer, available agents are proven to reduce cancer risk: finasteride and tamoxifen or raloxifene.
Demonstration Projects: Tactics for the New Strategy. To reduce morbidity and mortality from breast cancer and prostate cancer and to execute the proposed strategy, a comprehensive approach, using large demonstration projects to create a learning system, integrating both clinical care and research is needed. By spanning the spectrum from screening to treatment and survivorship, learning from diagnosis, treatment, and outcomes can be applied to developing tailored strategies for screening and prevention."
The problem is a bit more complex, however. It requires screening first, then staging. Screening is a difficult one since what is known today about the genetics of cancer growth for the most part reflects what is activated in a rapidly growing cancer. There are certain genetic predisposing genes but the problem is what turns them on and when.
1. Cancer is generally clonal, one cell goes wild and keeps reproducing.
2. The reproduction rate is not quite doubling, some progeny do not survive, thus depending on the status of the tumor the growth rate is between 1 and 2 per generation. Sometimes it is less than 1 and it even regresses.
3. When there are 10E6 cells the tumor can be seen under CAT or MRI. When there are 10E9 cells it is palpable, when there are 10E12 the patient dies. Almost.
4. Cancer growth and evolution is a classic epigenetic systems process in cell growth and replication. The cell loses its ability to die, it just keeps growing and replicating itself with its functionality reduced to it replication and nothing else.
This is the simple story of cancer. We show a simple model for 4 cancers below.
Note that in this model we assume rapid growth for ovarian cancer and slow growth for prostate. This may not always be the case. For example there are certain prostate cancers which grow very aggressively, the reasons are not yet known. We show the groth below in two scales.
The above is on logarithmic scale and the one below is linear.
This shows two factors. One is that certain cancers grow so quickly that one mus have to screen on a quarterly basis to have any effect. That is very costly. Second some cancers grow so slowly that screening will result in surgeries that are not necessary since the cancer will never grow large enough to kill the person. Thus between too fast and too slow are many others, and too fast may not be too fast and too slow may not be too slow. That is the conundrum.
In a recent JAMA article the authors state:
"Early detection may not be the solution for aggressive cancers because many may not be detected early enough for cure. Some small "curable" breast cancers, categorized as low risk by National Institutes of Health criteria, have a high mortality risk when analyzed using prognostic molecular profiles such as the NKI 70 gene test. Biologically aggressive cancers present with a higher stage despite screening. Interval cancers, those that present clinically between routine screens, have a higher growth fraction and are more likely to be lethal compared with screen detected cancers. In the neoadjuvant I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) trial, in which the mean tumor size was 6 cm (accrual 2003-2006 in the United States), 91% had poor prognosis biology27 (using the NKI 70 gene test), which is much higher than the 33% poor prognosis proportion in women undergoing routine screening.21 Of women undergoing routine screening in the I-SPY TRIAL, 85% of the malignancies were interval cancers and only 15% were screen detected, suggesting that locally advanced cancers reflect the growth curve.... Similarly, the most lethal prostate cancers are those with rapidly increasing...
Screening is most successful when premalignant lesions can be detected and eliminated as in the case of adenomatous polyp removal during colonoscopy screening or cervical intraepithelial neoplasia ablation by colposcopy after detection by pap smear. Perhaps most important is that screening for cervical and colon cancer and the removal of preneoplastic lesions have been accompanied by a significant decrease in their invasive cancer counterparts; this has not been seen in breast and prostate cancer. Ductal carcinoma in situ, rare prior to widespread screening, now represents 25% to 30% of all breast cancer diagnoses (>60 000 new case-diagnoses annually are not included in the invasive cancer statistics), the majority of these lesions are low and intermediate grade. Ductal carcinoma in situ is considered to be a precancerous lesion and standard of care is excision and adjuvant treatment. However, after 2 decades of detecting and treating DCIS, there is no convincing evidence of substantial reduction in invasive breast cancer incidence. The 2002 decrease in incidence leveled off in 2005 and is attributed to a reduction in postmenopausal hormone therapy use, not DCIS removal."
The authors then suggest actions which we have detailed earlier in our BOOK on Health Care. they rephrase them as follows:
Biomarkers to Differentiate Significant- and Minimal-Risk Cancers. To help move toward a more effective solution, the first step is a change in mindset in scientific discovery efforts and clinical practice
Reduce Treatment Burden for Minimal-Risk Disease. Many diagnosed tumors will follow an indolent course for the patient's lifetime42 or are probably cured with surgical excision alone.
Develop Tools to Support Informed Decisions. Information about risks of screening and biopsy should be shared with patients before screening. At the time of cancer detection, risks and benefits of treatment for specific biological subtypes should be shared
Focus on Prevention for the Highest-Risk Patients. Ultimately, prevention is preferable to screening by reducing the risk that a patient will have a diagnosis, experience undesirable effects of treatment, and confront the specter of recurrence. For both breast and prostate cancer, available agents are proven to reduce cancer risk: finasteride and tamoxifen or raloxifene.
Demonstration Projects: Tactics for the New Strategy. To reduce morbidity and mortality from breast cancer and prostate cancer and to execute the proposed strategy, a comprehensive approach, using large demonstration projects to create a learning system, integrating both clinical care and research is needed. By spanning the spectrum from screening to treatment and survivorship, learning from diagnosis, treatment, and outcomes can be applied to developing tailored strategies for screening and prevention."
The problem is a bit more complex, however. It requires screening first, then staging. Screening is a difficult one since what is known today about the genetics of cancer growth for the most part reflects what is activated in a rapidly growing cancer. There are certain genetic predisposing genes but the problem is what turns them on and when.
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