Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer.

To explain bimodal relapse patterns observed in breast cancer data, we have proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. The half-lives of these states are 1 and 2 years respectively. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from early detection, through treatment and follow-up, and consider how dormancy and surgery-driven escape from dormancy would be observed. We examine mammography data, effectiveness of adjuvant chemotherapy, heterogeneity and aggressiveness, timing of surgery within the menstrual cycle and racial differences in outcome. Dormancy can be identified in these diverse data but most conspicuous is the sudden escape from dormancy following primary surgery. These quantitative findings provide linkage between experimental studies of tumor dormancy and clinical efforts to improve patient outcome.

The effects of surgery on tumor growth: a century of investigations.

A few clinical investigations suggest that while primary breast cancer surgical removal favorably modifies the natural history for some patients, it may also hasten the metastatic development for others. The concepts underlying this disease paradigm, i.e. tumor homeostasis, tumor dormancy and surgery-driven enhancement of metastasis development, have a long history that is reviewed. The review reveals the context in which these concepts were conceived and structured to explain experimental data and shows that they are not so new and far fetched. The idea that surgical cancer resection has both beneficial and adverse effects upon cancer spread and growth that result from the modulation of tumor dormancy by the resection should be considered a potentially fruitful working hypothesis.

Chronotherapy of ovarian cancer: effect on blood variables and serum cytokines. A case report.

A 7-year-old patient with Stage III-c ovarian cancer was subjected to 8 cycles, approximately four weeks apart, of chronobiologically-optimized treatments with combination of three anti-cancer agents: Four cycles at AM, Cytoxan and PM, cis-Platinum; four cycles at AM, Adriamycin and PM, cis-Platinum. A second look laporoscopy revealed clean intestines, no definite masses in the pelvis area although there was an apparent mass in the right upper pelvis and several slightly enlarged lymph nodes in the base of mesentery. Six cycles of Taxol were administered at about Noon. Seven months remission appeared evident as judged by no changes in monthly examinations, in blood work or in CA-125 marker levels which remained below 12 U/ml. During the eight month the CA-125 marker began to rise, 36 then to 52 U/ml. A second 6 cycle series of Taxol was initiated but the CA-125 marker continued to rise, 57, 65, 72, 86, and 87 U/ml level. The patient declined in spirit, in well-being and expired 2 weeks later, 31 months after the initial diagnosis of cancer. Blood hematology, chemistry, and cytokines variables were analyzed at about weekly intervals. Significant reductions in total WBC, neutrophiles and platelet levels were evident during the second week of all cycle treatments, while increases were noted in serum levels of IL-2, IL-6 and IL-10 following Cytoxan-cis-Platinum-Adriamycin, but not Taxol. After each infusion moderate and temporary increases in RBC levels were noted. The treatments impact on hematology, chemistry, cytokine variables and on the integrity of the patient, are presented and briefly discussed.

Circadian function in patients with advanced non-small-cell lung cancer.

This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest-activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest-activity patterns of 33 non-small-cell lung cancer patients who participated in a randomised clinical trial evaluating the benefits of melatonin. Data are reported on circadian function, health-related quality of life (QoL), subjective sleep quality, and anxiety/depression levels prior to randomisation and treatment. Actigraphy data, an objective measure of circadian function, demonstrated that patients' rest-activity circadian function differs significantly from control subjects. Our patients reported poor sleep quality and high levels of fatigue. Ferrans and Powers QoL Index instrument found a high level of dissatisfaction with health-related QoL. Data from the European Organization for Research and Treatment for Cancer reported poor capacity to fulfil the activities of daily living. Patients studied in the hospital during or near chemotherapy had significantly more abnormal circadian function than those studied in the ambulatory setting. Our data indicate that measurement of circadian sleep/activity dynamics should be accomplished in the outpatient/home setting for a minimum of 4-7 circadian cycles to assure that they are most representative of the patients' true condition. We conclude that the daily sleep/activity patterns of patients with advanced lung cancer are disturbed. These are accompanied by marked disruption of QoL and function. These data argue for investigating how much of this poor functioning and QoL are actually caused by this circadian disruption, and, whether behavioural, light-based, and or pharmacologic strategies to correct the circadian/sleep activity patterns can improve function and QoL.

Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process.

PURPOSE: The aim of this study was to better understand human breast cancer biology by studying how the timing of metastasis following primary resection is affected by adjuvant CMF (cyclophoshamide, methotrexate, 5-fluorouracil) chemotherapy. PATIENTS AND METHODS: Discrete hazards of recurrence and recurrence risk reductions for treated patients relative to controls were analyzed for all patients enrolled in two separate randomized clinical trials [study 1 (386 women): no further treatment versus 12 cycles of CMF; study 2 (459 women): six versus 12 cycles of CMF] and a historical group (396 women: surgery alone) of axillary node-positive patients undergoing mastectomy. RESULTS: (i) Nearly all CMF benefit occurs during the first 4 years following resection/chemotherapy. (ii) The CMF recurrence rate reduction is largely restricted to two specific spans. These temporally separate recurrence clusters occur during the first and third year of follow-up, while the second-year recurrences are weakly affected. (iii) Prolonging adjuvant treatment from 6 to 12 months partially alters this recurrence timing, without appreciably affecting the overall recurrence rate. (iv) These effects upon the dynamics of post-resection occurrence are menopausal status-independent. CONCLUSIONS: At least two different therapeutically vulnerable proliferative events, resulting in clinical appearance of two metastasis temporally distinct clusters of post-resection cancer recurrence, apparently occur during the administration of adjuvant chemotherapy. Metastases that transpire outside of these temporal windows are refractory to adjuvant therapy. The dynamics of both post-treatment recurrence risk and CMF effectiveness are similar for both pre- and postmenopausal women, suggesting that post-resection mechanisms by which chemotherapy prevents metastases are similar, but of different magnitude in pre- and postmenopausal women. These findings are consistent with a metastasis model that includes tumor dormancy in specific micrometastatic phases (single cells and avascular foci) and with the acceleration of the metastatic process by the surgical resection of the primary breast cancer.