Is there a rationale for an anesthesiologist's role against cancer recurrence?

Growth of tumors can accelerate during the peri-operative period. Accordingly, early relapse of cancer occurs in some patients during the first two postoperative years. Temporal and biologic analyses of cancer pathophysiology suggest a link between peri-operative pathophysiological changes and acceleration of tumor growth. Understanding the role of inflammation and its consequences (i.e., immune response, growth factors, dissemination of tumor cells) could lead to define a role of anesthesiologists in reducing cancer recurrence following surgery. We argue for peri-operative pharmacological interventions to reduce cancer relapse, with a focus on non-steroidal anti-inflammatory drugs.

Gene regulatory networks: a new conceptual framework to analyse breast cancer behaviour.

The study of complex systems has clearly evidenced that a few overall behavioural properties cannot be inferred from the properties of their single parts and are rather determined by their architecture. Such an approach has been recently proposed in biology to understand genome functioning and in oncology to endeavour a more consistent explanation of the variegated cancer behaviours. In the present perspective, we summarise the basic concepts of the proposed global approach and then we reconsider, in this new context, tumour dormancy and primary tumour removal effects, which recently emerged as critical points for breast cancer understanding.

Análise comparativa da coordenação motora de crianças nascidas a termo e pré-termo, aos 7 anos de idade / Comparative analysis of motor coordination in term and pre-term birth children at seven years of age

OBJETIVO: comparar o desenvolvimento motor, na idade escolar, de crianças nascidas a termo e pré-termo. MÉTODOS: participaram do estudo dois grupos de crianças, com sete anos de idade: a) grupo pré-termo com 35 crianças, de famílias de baixa renda, nascidas com idade gestacional <34 semanas e/ou peso ao nascimento <1500 g, e b) grupo controle com 35 crianças nascidas a termo, com idade, sexo e nível socioeconômico equivalente ao grupo pré-termo. Todas as crianças foram avaliadas com o teste Movement Assessment Battery for Children (M-ABC). RESULTADOS: o teste de Wilcoxon indicou diferença significativa entre os grupos no escore total (Z=-4,866, p<0,001) e nas subáreas do M-ABC, com pior desempenho no grupo pré-termo. CONCLUSÃO: 57 por cento das crianças do grupo pré-termo apresentaram sinais de transtorno da coordenação, o que ressalta a importância do acompanhamento do desenvolvimento até a idade escolar.

OBJECTIVES: to compare the motor development of school-aged term and pre-term birth children. METHODS: two groups of seven-year-old children were included in the study: a) a pre-term group of 35 children, from low-income families, born at a gestational age of <34 weeks and/or with a birth weight of <1500 g, and b) a control group of 35 term-birth children, of an equivalent age, sex and socio-economic background to the pre-term group. All the children were evaluated using the Movement Assessment Battery for Children (M-ABC) test. RESULTS: Wilcoxon's test revealed a significant difference between the two groups in terms of the overall score (Z=-4,866, p<0,001) and the score for specific sub-sections of the M-ABC, the pre-term group performing less well than the term group. CONCLUSION: 57 percent of the preterm children showed signs of coordination disorders, underlining the importance of following up the development of such children up to school age.

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.

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.

Double-peaked time distribution of mortality for breast cancer patients undergoing mastectomy.

PURPOSE: To gather information on the natural history of breast cancer from the time-distribution of deaths of patients undergoing mastectomy alone. PATIENTS AND METHODS: A total of 1173 patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy without any adjuvant therapy for operable breast cancer, were examined. The risk of death at a given time after surgery was studied utilizing the death-specific hazard rate. The risk distribution was assessed relative to tumor size, axillary lymph node involvement, and menopausal status. RESULTS: The hazard rate for death presented an early peak at about the 3rd-4th year after surgery and a second late peak near the 8th year. The double-peaked pattern was almost completely generated by N+ patients, while N- patients did not show relevant structures. Pre-menopausal patients showed an initial mortality wave covering about 6 years, with maximum height at the 4th year, followed by a peak 8 years after surgery, while post-menopausal patients showed an early high mortality surge peaking at the 3rd year, followed by a modest increase at the 8th year. Detailed analysis revealed that post-menopausal patients with early mortality had significantly larger tumors and higher nodal involvement, while no special trait characterized the corresponding pre-menopausal patients. Moreover, patients of the late mortality peak were more likely to have suffered early local-regional or contra-lateral recurrence or to be pre-menopausal patients recurring anywhere at the second recurrence peak. CONCLUSION: The double-peaked hazard curve confirmed the occurrence of discontinuous features in the natural history of breast cancer for patients undergoing mastectomy. Indeed, the mortality pattern maintained definite signs of the previous double-peaked structure of recurrences. However, death events did not parallel the corresponding recurrence events and, moreover, pre and post-menopausal patients revealed dissimilar survival after recurrence, at least for early deaths. These findings, showing disconnection of mortality pattern from recurrence pattern for subsets of patients, suggest that parameters other than those influencing the recurrence risk may determine the survival of recurred patients.

Tumour dormancy: findings and hypotheses from clinical research on breast cancer.

Breast cancer metastatic development is commonly considered as resulting from continuous tumour growth from tumour seeding until clinical recurrence is documented. Continuous growth model inferences, however, fail to explain clinical findings concerning local recurrences, as well as the time-distribution of first treatment failure and mortality for patients undergoing mastectomy. The tumour dormancy hypothesis is considered to provide a more reasonable description of the natural history of breast cancer, while primary tumour removal is believed to be a potential perturbing factor for metastasis development. A new model of the natural history of operable breast cancer, incorporating tumour dormancy and starting signals from surgery for micrometastatic growth is proposed.

Does surgery modify growth kinetics of breast cancer micrometastases?

Surgery should be considered as a major perturbing factor for metastasis development in laboratory animals. The different time distribution of mortality for 1173 patients undergoing mastectomy in comparison with 250 untreated patients suggests that primary tumour removal could result in changes of the metastatic process even for breast cancer.

Premenopausal status accelerates relapse in node positive breast cancer: hypothesis links angiogenesis, screening controversy.

Much attention has been given to determining the benefit of mammographic screening to reduce breast cancer mortality. Eight randomized clinical trials have been conducted in four countries: the US, Canada, Scotland and Sweden. Trials report an early and stable 30% reduction in breast cancer mortality for women aged 50-59. For women under 50, unexpectedly, the early years of screening produce a disadvantage to the screened population. Only in later years does an advantage appear. To help understand this, we studied relapse patterns using a breast cancer database of 1,173 pre- and postmenopausal, node negative and positive patients treated with surgery only and having 16-20 years of follow-up. This approach is relevant since at least five of the eight screening trials began before the widespread use of adjuvant chemotherapy in the 1980s. Surgical cure rates were independent of menopausal status. However, a major difference in early relapse rate was found. In premenopausal and node positive patients, 27% of all distant relapses occurred within the first 10 months following resection. This is twice the early relapse frequency of any other clinical group. Using computer simulation, we interpret that these early relapses probably result from a disadvantage induced at surgery. A disinhibition or surgery/wounding induced angiogenic surge might be responsible. Disinhibition is known to occur in animal models such as Lewis lung where lung metastases are avascular and dormant until the primary is removed. Sudden outgrowth of tumor after wounding has been observed for a century. According to the simulation, in breast cancer this induction apparently accelerates inevitable relapses by a median of two years. This is offset in later years with a balancing reduction in relapses. These data suggest that the angiogenic switch may be upregulated more frequently among premenopausal women, perhaps depending upon the sex hormones. The acceleration would cause 0.11 deaths per 1,000 screened aged 40-49 subjects in years 2-3, a value comparable to the early year excess mortality in trials of a significant 0.15 deaths per 1,000 subjects. Equal screening advantage is predicted for node negative (but not node positive) pre- and postmenopausal patients. The acceleration of relapse after surgery may explain the paradoxical effect of mammographic screening for women under 50.

Phase I/II study of gemcitabine in association with vinorelbine for metastatic breast cancer.

BACKGROUND: Gemcitabine (G) and vinorelbine (V) have favorable safety profile and antitumor activity in metastatic breast cancer. To exploit their different mechanism of action and lack of overlapping toxicity, we performed a phase I and II study of G and V in combination. PATIENTS AND METHODS: Fifty-three patients with metastatic breast cancer were treated. In the dose-finding phase, seven cohorts of patients (22 women) received increasing doses to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination. Patients recruited in the phase II portion of the study (31 women) received the dose level immediately below the one defined as MTD (i.e., G 1200 mg/m2, V 30 mg/m2, on day 1 and day 8, every 3 weeks). RESULTS: Dose escalation was discontinued at G 1400mg/m2 and V 30 mg/m2 because of toxic death due to thrombocytopenia and CNS hemorrage. No other limiting toxicities were observed, and tolerability was similar at all dose levels studied in the escalation portion of the study. The main toxicity was granulocytopenia of grade 3/4 in 36 and 48% of the patients on phase I and II respectively, without episodes of neutropenic fever. Thrombocytopenia was uncommon. Other side effects were usually mild to moderate. In 46 evaluable patients, the response rate was 24% (complete response 7%, partial response 17%). Disease stabilization was observed in further 17%. The median duration of response was 12 months (range 5-14) and the median survival was 20 months (range 1 to 45+). CONCLUSIONS: G and V, on day 1 and 8 of 3-weekly cycles, can safely be administered to patients with metastatic breast cancer at the dose of 1200 and 30 mg/m2, respectively. The antitumor activity of G and V in combination was similar to that reported when using either drug as single agent.

Five-day infusion fluorouracil plus vinorelbine in women with breast cancer previously treated with anthracyclines and paclitaxel.

UNLABELLED: The continuous infusion of fluorouracil presents a superior pharmacological profile than its bolus administration, while vinorelbine is a new drug associated with good clinical activity in pretreated metastatic breast cancer. We investigated the combination of this two antitumor drugs with the aim to determine a tolerant and active second-line therapy in metastatic pretreated patients. PATIENTS AND METHODS: Fifty six patients pretreated with chemotherapy received a median of six cycles [2-11] of fluorouracil, 700 mg/m2 for 5 day-continuous i.v. infusion and vinorelbine, 20 mg/m2 on days 1 and 6, every three weeks. The inclusion and evaluation criteria required measurable disease by conventional clinical and/or instrumental means. FINDINGS: Iatrogenic toxicity in 340 administered cycles was mild: stomatitis = 11% (Grade 3 = 5%), constipation and abdominal pain = 12%, G2 neutropenia = 4%, G1 thrombocytopenia = 0.5%. In nine cases moderate infections occurred and six women experienced catheter related complications. Complete and partial remissions were observed in 12% and 36% of evaluable patients, respectively. In particular major tumor regression was documented in 28% of anthracyclines or taxol unresponsive cases. CONCLUSIONS: This drug combination is active in metastatic pretreated breast cancer patients and devoid of serious iatrogenic toxicity. Although it deserves future optimization, for instance with the inclusion of oral fluoropirimidines, it represents a good choice for second-line or non cross-resistant regimens.

Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of 'cures'.

PURPOSE: To comparatively analyse the risk of recurrence at given times after surgery for breast cancer patients receiving or not receiving adjuvant CMF. PATIENTS AND METHODS: A total of 1452 node positive patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy for operable breast cancer, were examined. In 575 cases no further treatment was performed, whereas 877 pts were given 6 or 12 courses of adjuvant Cyclophosphamide, Methotrexate, Fluorouracil (CMF). The recurrence risk was estimated by the event-specific hazard rate for first failure and distant metastases, and, following Efron, hazard rates were fitted by logistic regression models. RESULTS: The hazard rate for first failure and distant metastases showed a double peaked pattern for both treated patients and controls, with a first major peak at about 18-24 months from surgery (early metastases), a second minor peak at the 5th-6th year, and a tapered plateau-like tail extending over 10 years from surgery (late metastases). As expected, the recurrence risk of CMF treated patients was lower than the corresponding risk of patients undergoing surgery only. However, the difference was highly evident for early recurrences, while it declined and disappeared afterwards. CONCLUSION: Our findings confirm previous reports on patients not receiving adjuvant chemotherapy, suggesting that the recurrence risk for operable breast cancer has a multipeak pattern. As far as CMF treated patients are concerned, the unchanged peak timing together with the early recurrence risk reduction in comparison to controls are much more consistent with the real nonappearance of some early recurrences (putatively 'cured' patients) than with the delay in their manifestation. As late relapsing patients seem to have at most marginal benefits from adjuvant CMF, ways to recognize patients doomed to have late recurrence and new ways for treating micrometastases resulting in late recurrences are required.

Estimate of tumor growth time for breast cancer local recurrences: rapid growth after wake-up?

To obtain an estimate of the subclinical tumor growth time (TGT) for breast cancer, a series of 31 patients with local recurrence as first event after mastectomy was evaluated. The recurrence diameter was measured, and the minimum growth rate (mGR) consistent with the sequence 'no detection at the preceding physical examination-->recurrence of diameter Dr' was obtained. The growth rate for uninterrupted exponential growth from surgery (GRu) was also calculated. mGR was significantly higher than GRu (p < 0.0001), and unrelated to the recurrence-free survival (RFS). Therefore, starting points of local recurrence growth curves had to be set at times variously delayed after mastectomy. The estimate of the delay lower limit (mD), which was obtained from mGR and GRu, showed a strong linear correlation with RFS (R = 0.984; p < 0.0001). From the regression equation, TGT for local recurrences could be estimated at 30+/-8 weeks or less. These findings support the concept that the lag time between surgical treatment of breast cancer and clinical evidence of local recurrence may be explained by a period of tumor dormancy followed by a tumor growing phase. The TGT estimate is remarkably shorter than previously believed and could considerably change the current picture of breast cancer history.

Computer simulation of a breast cancer metastasis model.

Recent analysis of relapse data from 1173 untreated early stage breast cancer patients with 16-20 year follow-up shows that frequency of relapse has a double peaked distribution. There is a sharp peak at 18 months, a nadir at 50 months and a broad peak at 60 months. Patients with larger tumors more frequently relapse in the first peak while those with smaller tumors relapse equally in both peaks. No existing theory of tumor growth predicts this effect. To help understand this phenomenon, a model of metastatic growth has been proposed consisting of three distinct phases: a single cell, an avascular growth, and a vascularized lesion. Computer simulation of this model shows that the second relapse peak can be explained by a steady stochastic progression from one phase to the next phase. However, to account for the first relapse peak, a sudden perturbation of the development at the time of surgery is necessary. Model simulations predict that patients who relapse in the second peak would have micrometastases in states of relatively low chemosensitivity when adjuvant therapy is normally administered. The simulation predicts that 15% of T1, 39% of T2, and 51% of T3 staged patients benefit from adjuvant chemotherapy, partially offsetting the advantage of early detection. This suggests that early detection and adjuvant chemotherapy may not be symbiotic strategies. New therapies are needed to benefit patients who would relapse in the second peak.

Five-day infusion fluorouracil plus vinorelbine i.v. in metastatic pretreated breast cancer patients.

The aim of the present study was to evaluate the clinical activity and side effects of a combination chemotherapy consisting of a five-day continuous infusion of fluorouracil and i.v. vinorelbine in metastatic previously treated breast cancer patients. The patient population was represented by 28 women with evaluable disease, previously subjected to chemotherapy, including anthracycline-containing regimens in 89% of patients. Treatment consisted of five-day infusion of 700 mg/m2/day of fluorouracil and vinorelbine, 20 mg/m2 i.v. bolus on day 1 and 6. In the absence of Grade > 3 leukopenia and stomatitis, cycles were repeated every three weeks, for a total of six cycles. Four complete and thirteen partial responses were documented, accounting for a response rate of 61% (95% CI: 40.5-78.5); the clinical efficacy was high even in patients unresponsive to prior anthracycline treatment. The median response duration calculated from the first drug injection was 8 months (range 4-11). Treatment was well tolerated, with 4% Grade 4 stomatitis and 20% Grade 3 leukopenia as the main toxic reactions. This drug combination is active in metastatic previously treated breast cancer patients, is devoid of severe side effects, and warrants further testing.