In a study published online ahead of print by the journal Science, researchers from Dana-Farber Cancer Institute in Boston, MA, reported that cancer cells on the brink of self-destruction are more likely to respond to certain chemotherapy agents than cancer cells that have yet to reach that stage.
This suggests that chemotherapy may be ineffective when faced with cancer cells that are not already close to death. At best, it may simply be that chemo-therapy can speed up the natural process of cell suicide-known as 'apoptosis'-which is what every healthy cell in the body is pro-grammed to do but, which, in cancer patients, has become disrupted.
Using a technique called 'BH3 profiling', the Dana-Farber team had previously discovered that it is possible to measure how close cells are to this apoptotic threshold. The technique employs bits of protein known as 'BH3 peptides' from a family of proteins that spur natural cell death. By adding BH3 protein bits to cell samples and measuring how much was needed to kill the cells, the scientists were able to determine how close the cells were to apoptosis. The cells that needed the least amount of BH3 peptide to be pushed onto the path of self-destruction were considered 'primed' for death.
In this latest study from the Dana-Farber Cancer Institute, the researchers first used the BH3 profiling technique in myeloma cells from patients who were about to undergo chemotherapy. Myeloma is a type of cancer that affects cells in the bone marrow called 'plasma cells'. The results showed a strong correlation between the cancer cells that were highly primed and those that were responsive to chemotherapy.
The researchers then used the profiling technique to study a variety of tumours from 85 patients, including multiple myelomas, acute myelogenous leukaemias, acute lymphoblastic leukaemias and ovarian cancers. In each case, they found the same association: chemotherapy was most likely to be effective against tumours that had the highest levels of priming (Science, 2011 Oct 27; Epub ahead of print).
Rethinking the thinking
These latest findings challenge the conventional thinking about how chemotherapy works.
The traditional view is that chemotherapy targets fast-growing cells such as cancer cells, but the new evidence suggests that the chemo homes in on cancer cells that are already on the brink of death-and may not work on the cells that aren't.
The discovery also suggests that it may be possible to predict which cancer patients are most likely to respond to chemotherapy, the researchers say. In addition, it points to a novel way to make chemotherapy drugs more effective by first pushing tumour cells closer to apoptosis.
On the other hand, it also raises some serious questions about the current status of chemotherapy itself. For example, would the cancer cells that respond to chemotherapy have died on their own without the drugs? Moreover, from the patient's point of view, if chemotherapy is merely enhancing what is already a natural ongoing process, is it worth suffering all the debilitating side-effects that come with it?
Cancer's natural course
These are questions that we can't yet answer, but they are worth-while considerations in light of the growing body of research suggesting that cancer can sometimes just go away-or, as oncologists put it, 'spontaneously regress'-on its own (see WDDTY vol 19 no 11).
Indeed, in a study of 83 non-Hodgkin's lymphoma sufferers who had not been treated for the disease, Stanford University researchers reported that 19 patients (23 per cent) experienced a spontaneous regression of their cancer (N Engl J Med, 1984; 311: 1471-5).
More recently, researchers at the Norwegian Institute of Public Health in Oslo tracked two groups of women who had similar health profiles and backgrounds, and signs of breast cancer.
One group was screened by mammography every two years from 1996 to 2001, while the other group was screened just once at the end of the study period.
After taking into account factors that could distort the results-such as cases of ductal carcinoma in situ (DCIS) that are counted as cancer, but aren't-the rate of breast cancer in the frequently screened women was 22 per cent higher than in the unscreened group at the end of the study.
The researchers concluded that, because the incidence of breast cancer among the unscreened women never came close to that of the screened group, "it appears that some breast cancers detected by repeated mammographic screening would not persist to be detectable by a single mammogram at the end of 6 years. This raises the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress" (Arch Intern Med, 2008; 168: 2311-6).
Yet another study has suggested that neuroblastoma, the child-hood cancer that attacks the adrenal glands, can also spontaneously regress. Doctors at the Saitama Children's Medical Center in Iwatsuki, Japan, adopted a 'watchful waiting' approach with 11 six-month-old infants who had neuroblastomas that were either stage I or II (early-stage disease) or had tumours that were less than 5 cm in diameter.
After six months of such 'passive observation', the tumours had reduced in size in every case, although none had completely disappeared by the end of the study. On the basis of these findings, the researchers conclud-ed that "regression of screened neuroblastoma is not a rare phenomenon" (J Clin Oncol, 1998; 16: 1265-9).
These are just a few examples of cancer regression that have been recorded in the medical literature over the years. No one knows why it happens, but the phenomenon has been associated with fever-producing infections such as those caused by viruses, fungi and bacteria (Indian J Cancer, 2011; 48: 246-51).
Although these cases suggest that the body, to some extent, is capable of fighting off cancer on its own, we don't really know how often this happens as, nowadays, very few cases of cancer-once diagnosed-go untreated. Rates of spontaneous regression are generally believed to be one out of every 60,000 cancer cases, although some scientists believe that the true figure may well be 20 to 100 times greater than that (O'Regan B, Hirshberg C. Spontaneous Remission: An Annotated Bibliography. Petaluma, CA: Institute of Noetic Sciences, 1993).
Back to basics
So, going back to the latest findings concerning chemotherapy, could it be that this popular treatment is taking too much of the credit when it supposedly beats cancer?
The finding that chemotherapy targets cancer cells that are already close to cell suicide leaves open the possibility that the cancer could have gone away on its own without the help of chemotherapy. Alternatively, it could be that the cancerous cells may not have died without the chemo cocktail to give them that final push over the edge.
These are knots that still need unravelling. But what seems clear from this and other research (see box above) is that chemotherapy is unlikely to be effective in a significant number of people. Nevertheless, the latest findings could well lead to more personalized cancer management, thereby sparing numerous patients from the array of devastating side-effects that they just don't need to suffer.
Factfile: Small gains, big risks
The latest findings using BH3 profiling suggest an explanation for why chemotherapy doesn't work in a large number of cancer cases. Indeed, when cancer specialist Dr Ulrich Abel carried out a meta-analysis of chemotherapy cure rates in cases of advanced cancer, he concluded that, apart from lung cancers and possibly ovarian cancers, there's no direct evidence that chemotherapy prolongs survival (Biomed Pharmacother, 1992; 46: 439-52).
More recently, Australian researchers assessed the benefit conferred by chemotherapy in the treatment of adults with the most common types of cancer. They concluded that, in general, chemotherapy contributes only slightly more than 2 per cent to improved survival in cancer patients. Only 13 out of the 22 malignancies they evaluated showed any improvement in the five-year rates of survival, and the improvement was greater than 10 per cent in only three of those 13 malignancies.
"Despite the early claims of chemotherapy as the panacea for curing all cancers, the impact of cytotoxic chemotherapy is limited to small subgroups of patients and mostly occurs in the less common malignancies," the researchers concluded (Clin Oncol [R Coll Radiol], 2004; 16: 549-60).
This evidence conflicts with the perception of many patients who believe that they are receiving a treatment that will significantly enhance their chances of cure and survival. Perhaps if they were more aware of these facts and figures, they would be less inclined to agree to a therapy that can severely impact their quality of life.
Indeed, aside from causing fatigue, pain, nausea and hair loss, chemotherapy can be toxic to the brain, leading to confusion, memory loss and impaired speech, according to the latest findings (JAMA, 2008; 299: 2494; Acta Oncol, 2011 Aug 18; Epub ahead of print).
WDDTY ISSUE 22 NO.9, NOV. 2011