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A thorough understanding of cardiovascular physiology is a cornerstone of patient management in the perioperative period. The primary role of the cardiovascular system is to provide sufficient blood flow to satisfy the metabolic demands of the body tissues. This chapter presents the primary determinants of tissue blood flow (arterial pressure and local vascular resistance) and the factors that alter them. Because of its critical pumping role, the physiology of the heart is given particular emphasis. The major determinants of stroke volume, i.e., preload, contractility, and afterload, are discussed. Indices of cardiac function are reviewed, including cardiac output using thermodilution, ejection fraction from image-based measurements, and myocardial contractility assessed by cardiac function curves using a pulmonary artery catheter, and by end-systolic pressure-volume relations from pressure-volume loops. The determinants of coronary blood flow and myocardial oxygen demand are described, as well as how an imbalance between these variables may produce myocardial ischemia. Other topics covered include: 1) the principles of hemodynamics, and the mechanisms regulating function of the various vessel types, including the large arteries, arterioles, capillaries, and veins; 2) the transport of oxygen by blood and its delivery to the body tissues; 3) methods to measure tissue oxygen consumption, along with their advantages and limitations; 4) the role of the capillaries in tissue oxygen delivery, and in fluid filtration and absorption; 5) the responses elicited by activation of the major circulatory reflexes (the arterial baroreceptor, Bezold-Jarisch, and Bainbridge reflexes); 6) emerging developments in noninvasive perioperative cardiovascular monitoring.

Purpose It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO2) of tumors. Our aim is to evaluate the IFP and pO2 before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of ≥ 3 cm. Patients and Methods Patients were randomly assigned, according to an institutional review board–approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m2 every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m2 (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO2 (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. Results IFP and pO2 were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO2 by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. Conclusion Paclitaxel significantly decreased the IFP and increased the pO2, whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.

The favorable prognosis associated with tubular carcinoma of the breast has led some studies to propose less aggressive treatments for patients with this disease. This study aims to address the extent of therapy needed for tubular patients.A retrospective review identified 73 cases of tubular carcinoma treated at the Massachusetts General Hospital between 1980 and 2002. Primary treatment was conservative surgery (CS) plus radiation therapy (RT) in 67%, CS without RT in 18%, and mastectomy in 15%. Median follow-up time was 90.5 months. The published literature of 529 conservatively treated tubular carcinomas was reviewed along with the 62 conservative cases from this series. : No patients developed distant metastasis or died from this disease. Local failure occurred in three (4%) of the cases, after 13, 84 and 121 months. All three had initially been treated with CS + RT. Five cases were node-positive, three of which were associated with a primary tumor smaller than 1 cm. Thirteen women, with a median age of 74, were treated by CS without RT and none recurred. A literature review showed that adjuvant RT reduces local failure following CS for tubular carcinoma.Tubular carcinoma is associated with an excellent prognosis, but long-term follow-up is essential for detecting local failures and a small primary tumor size does not preclude nodal involvement. Adjuvant RT reduces the incidence of local failure following CS for tubular carcinoma, however, elderly women treated by CS may have a very low risk of local recurrence without adjuvant RT.

Purpose: To evaluate and quantify the effect of irradiated lung volume, radiation dose, and paclitaxel chemotherapy on the development of radiation pneumonitis (RP) in breast cancer patients with positive lymph nodes. Methods and Materials: We previously reported the incidence of RP among 41 patients with breast cancer treated with radiotherapy (RT) and adjuvant paclitaxel-containing chemotherapy. We recorded the central lung distance, a measure of the extent of lung included in the RT volume, in these patients. We used this measure and the historical and observed rates of RP in our series to model the lung tolerance to RT in patients receiving chemotherapy (CHT) both with and without paclitaxel. To evaluate the risk factors for the development of RP, we performed a case-control study comparing paclitaxel-treated patients who developed RP with those who did not, and a second case-control study comparing patients receiving paclitaxel in addition to standard CHT/RT ( n = 41) and controls receiving standard CHT/RT alone ( n = 192). Results: The actuarial rate of RP in the paclitaxel-treated group was 15.4% compared with 0.9% among breast cancer patients treated with RT and non-paclitaxel-containing CHT. Our mathematical model found that the effective lung tolerance for patients treated with paclitaxel was reduced by approximately 24%. No statistically significant difference was found with regard to the dose delivered to specific radiation fields, dose per fraction, central lung distance, or percentage of lung irradiated in the case-control study of paclitaxel-treated patients who developed RP compared with those who did not. In the comparison of 41 patients receiving RT and CHT with paclitaxel and 192 matched controls receiving RT and CHT without paclitaxel, the only significant differences identified were the more frequent use of a supraclavicular radiation field and a decrease in the RT lung dose among the paclitaxel-treated patients. This finding indicates that the major factor associated with development of RP was paclitaxel treatment. Conclusions: The use of paclitaxel chemotherapy and RT in the primary treatment of node-positive breast cancer is likely to increase the incidence of RP. In patients treated with paclitaxel, reducing the percentage of lung irradiated by 24% should reduce the risk of RP to 1%, according to our calculations of lung tolerance. Future clinical trials using combination CHT that includes paclitaxel and RT should carefully evaluate the incidence and severity of RP and should also accurately monitor the extent of lung included within the RT volume to develop safe guidelines for the delivery of what is becoming standard therapy for node-positive breast cancer.

It remains controversial as to whether the administration of chemotherapy prior to radiation following the surgical treatment for localized breast cancer compromises local control.The outcome of 290 patients who received chemotherapy prior to breast or chest wall irradiation following curative breast cancer surgery was retrospectively analyzed to determine if delaying radiation from the time of surgery adversely affects local-regional control. The patients were divided into three groups according to the time interval from definitive surgery to the start of radiation: group 1,5 months; group 2, 5 to7 months, and group 3, 7+ months. Local-regional and distant failure events were analyzed according to the time delay from surgery to radiation.The median follow-up was 6.0 years (range, 7 months to 15 years). Loco-regional failure was observed in 22 patients, 18 of which occurred within the original radiation fields. There was no significant adverse effect on local control or distant failure from delaying radiation for systemic chemotherapy. Univariate and multivariate analyses revealed that positive margins after surgery were associated with increased local recurrence.Delaying radiation therapy for greater than 7 months, in order to administer chemotherapy following curative breast cancer surgery, does not compromise local control. However, positive margins were significantly associated with higher rates of local failure and even an increase in radiation boost dose was not able to fully counteract the increased risk of local failure.

Purpose To evaluate the risk factors for lymphedema in patients receiving breast conservation therapy for early-stage breast cancer. Methods and materials Between 1982 and 1995, 727 Stage I–II breast cancer patients were treated with breast conservation therapy at Massachusetts General Hospital. A retrospective analysis of the development of persistent arm edema was performed. Lymphedema was defined as a >2-cm difference in forearm circumference compared with the untreated side. The median follow-up was 72 months. Breast and regional nodal irradiation (BRNI) was administered in 32% of the cases and breast irradiation alone in 68%. Results Persistent arm lymphedema was documented in 21 patients. The 10-year actuarial incidence was 4.1%. The median time to edema was 39 months. The only significant risk factor for lymphedema was BRNI. The 10-year risk was 1.8% for breast irradiation alone vs. 8.9% for BRNI ( p = 0.001). The extent of axillary dissection did not predict for lymphedema even within the subgroups of patients defined by the extent of irradiation. Most patients underwent Level I or II dissection. In this subgroup, the lymphedema risk at 10 years was 10.7% for BRNI vs. 1.0% for breast irradiation alone ( p = 0.0003). Conclusion Nodal irradiation was the only significant risk factor for arm lymphedema in patients receiving breast conservation therapy for early-stage breast cancer. Our data suggest that this risk is low with Level I/II dissection and breast irradiation. However, even after the addition of radiotherapy to the axilla and supraclavicular fossa, the development of lymphedema was only 1 in 10, lower than generally recognized.

Some chemotherapy (CT) drugs, including taxanes, may enhance the effectiveness of radiation therapy (RT). However, combining these therapies may increase the incidence of radiation pneumonitis, a lung inflammation. In a retrospective cohort study, we evaluated the incidence of radiation pneumonitis in breast cancer patients treated with RT and standard adjuvant CT by use of doxorubicin (Adriamycin) and cyclophosphamide, with and without paclitaxel.Forty-one patients with breast cancer were treated with RT and adjuvant CT, including paclitaxel. Paclitaxel and RT (to breast-chest wall in all and lymph nodes in some) were delivered sequentially in 20 patients and concurrently in 21 patients. Paclitaxel was given weekly in some patients and every 3 weeks in other patients. The incidence of radiation pneumonitis was compared with that among patients in our database whose treatments did not include paclitaxel (n = 1286). The percentage of the lung volume irradiated was estimated. The Cox proportional hazards model was used to find covariates that may be associated with the observed outcomes. All P values were two-sided.Radiation pneumonitis developed in six of the 41 patients. Three patients received paclitaxel concurrently with RT, and three received it sequentially (P =.95). The mean percentage of lung volume irradiated was 20% in patients who developed radiation pneumonitis and 22% in those who did not (P =.6). For patients treated with CT including paclitaxel, the crude rate of developing radiation pneumonitis was 14.6% (95% confidence interval [CI] = 5.6% to 29.2%). For patients treated with CT without paclitaxel, the crude rate of pneumonitis was 1.1% (95% CI = 0.2% to 2.3%). The difference between the crude rates with or without paclitaxel is highly statistically significant (P.0001). The mean time to develop radiation pneumonitis in patients treated concurrently with RT and paclitaxel was statistically significantly shorter in patients receiving paclitaxel weekly than in those receiving it every 3 weeks (P =.002).The use of paclitaxel and RT in the primary treatment of breast cancer should be undertaken with caution. Clinical trials with the use of combination CT, including paclitaxel plus RT, whether concurrent or sequential, must evaluate carefully the incidence of radiation pneumonitis.

Purpose/Objective: Two randomized trials of patients treated by breast conserving therapy have demonstrated a significant increase in local control, for patients with negative margins, when a tumor bed boost was used in addition to whole breast irradiation. However, in patients with positive or close margins, the adequacy of tumor bed boost for local control and the optimal boost dose remain controversial. Published reports have suggested that tumor bed boost, even at higher doses, is not sufficient to overcome the negative effect of close or focally positive margins. The purpose of this study is to assess the impact of boost dose on local recurrence rate according to margin status. Materials/Methods: Six hundred thirty-five patients with clinical Stage I or II breast cancer were treated by breast-conserving surgery and radiation between 1992 and 1998 at the Massachusetts General Hospital. The median follow up was 54 months (range 6 ‐120). As an institutional policy, all pathologic specimens were re-reviewed upon referral and prior to de finitive treatment. Final margin status was determined based on the distance of invasive or in situ carcinoma from inked surgical margin: negative (no residual tumor or at least 2 mm from margin), close (less than 2 mm from margin), focally positive, or grossly positive. Patients received 50 Gy to the whole breast using 2 Gy per fraction, followed by a 10 Gy en face electron boost in 5 fractions for patients with negative margins and a 15‐18 Gy (15Gy/5 fractions in 28, 18 Gy/9 fractions in 80) high dose boost for focally-close, focally-positive or grossly-positive margins. Results: Sixty-five percent of the patients were T1, 35% T2, 72% N0, and 28% N1-2. Margin status was as follows: negative 71% (n450), close 18.4% (n117), and focally positive 11% (n68). There were no patients with grossly positive margin. The 5-year Kaplan-Meier local recurrence rates (LR) in the different margin groups were: 1.4% for negative margin, 3.2% for close margin, and 5.6% for focally close margin (p0.1169). When close (2mm) or focally positive margins were grouped together, the 5-year local failure rate was 4.1% (compared to LR of 1.4% in negative margin, p0.0115). Overall, the local recurrence rate was not statistically different in the standard versus high boost dose (p0.1745). Furthermore, in each of the margin groups, there was no statistically signi ficant difference between standard tumor bed boost and high tumor bed boost dose. The 8-year LR was identical to the 5-year LR. 5-year overall survival rates were 92.1% for negative margin, 89.9% for close margin and 79.4% for focally positive margin (p0.0087). Eight-year overall survival rates were 82.4%, 87.8%, and 64% (p0.0019), respectively. On univariate and multivariate analysis, only margin status was signi ficant in predicting local recurrence. Lymph node status, tumor size, age, and boost dose were not predictive of local recurrence (p0.12, p0.67, p0.98, and p0.34). Conclusions: This study shows increased local recurrence rate with close or focally positive final surgical margin in breast conserving therapy, which was not significantly altered by increasing the boost dose. Patients with negative surgical margin prior to radiation had low local recurrence rate of 1.4%, which was durable at 8 years. Patients with close or positive margin, however, had nearly 3x higher local recurrence rate, observed in the first 5 years of follow-up and persistent at 8 years. A risk of recurrence around 5% may still be regarded as acceptable in breast conserving therapy, but improving the margins surgically can further improve local control. Patients with close or focally positive margins should therefore undergo re-excision to render them margin-negative prior to radiation.