This essay discusses how curative treatment of aggressive adult cancers, as discussed in our strategic plan to substantially reduce cancer deaths, will likely require combinations of combinations of therapy.

In our discussion essay #3, we noted that childhood leukemia is curable by using combinations of therapies that primarily target only one aspect of the malignant process - cancer cell growth (Pomeroy 2022). Combinations of therapies are necessary because biologic functions such as cell division are based on a multidimensional web of interacting networks so that even if one path is completely blocked by a therapy, there are alternative pathways for cells to achieve a similar function. For this reason, curative therapy must damage multiple pathways to sufficiently interfere with this cell function.

Treating aggressive adult cancer should build on this success by using combinations of therapy for not just the main cancer (usually a solid tumor) but for as many biologic networks as possible that support or promote the malignant process. These networks include the tumor microenvironment (i.e., neighboring cells, vasculature, stroma, extracellular matrix and other local factors) (Pernick: Strategic plan for curing cancer, initial version 2021), metastases and their microenvironment, systemic inflammation that drives the malignant process; the damaged immune system that tolerates or promotes the cancer cells, hormones that push cells towards malignancy and DNA variations present at birth that advance the malignant process. Curative treatment plans may also require moving cancer cells that survive treatment into less aggressive networks (Pernick: Curing cancer - Curative cancer treatment based on complexity theory 2022, Pernick: How Lung Cancer Arises, Based on Complexity Theory 2021).

We speculate that for each cancer type, even the most aggressive, there exists a combination of 8 - 10 therapies that individually may be only partially effective but together can be substantially effective in reducing cancer deaths (Pernick: Combinations of therapy to substantially reduce cancer deaths 2021). As a single therapy is inadequate to cure most childhood cancers, it seems highly unlikely that any single therapy could both eradicate most adult cancer cells and restore order to the large number of networks that have been altered during the long malignant process. Thus, focusing solely on one therapy as being curative, whether related to driver mutations, immune system alterations, vasculature or otherwise, does not seem sensible (Pernick: Combinations of therapy to substantially reduce cancer deaths 2021). To determine the optimal combinations, we may need to develop 30 or more partially effective therapies to choose from (Pernick: Pancreatic cancer update 2021) and then use deep learning, cell lines, animal models and ultimately clinical trials to test the huge number of potential combinations (Pernick: Curing cancer - Curative cancer treatment based on complexity theory 2022).

For long term success, we must also reduce the chronic cellular stressors or risk factors that promoted the original cancer (Pernick: How Cancer Arises Based on Complexity Theory 2017) and will continue to promote premalignant and malignant conditions unless stopped. This will require behavioral changes and perhaps drug therapy.

The next essay will discuss why we are initially focusing on aggressive cancers that cause the most cancer deaths.