Peter J. Deckers

Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer

In 1976 we began a randomized trial to evaluate breast conservation by a segmental mastectomy in the treatment of Stage I and II breast tumors less than or equal to 4 cm in size. The operation removes only sufficient tissue to ensure that margins of resected specimens are free of tumor. Women were randomly assigned to total mastectomy, segmental mastectomy alone, or segmental mastectomy followed by breast irradiation. All patients had axillary dissections, and patients with positive nodes received chemotherapy. Life-table estimates based on data from 1843 women indicated that treatment by segmental mastectomy, with or without breast irradiation, resulted in disease-free, distant-disease-free, and overall survival at five years that was no worse than that after total breast removal. In fact, disease-free survival after segmental mastectomy plus radiation was better than disease-free survival after total mastectomy (P = 0.04), and overall survival after segmental mastectomy, with or without radiation, was better than overall survival after total mastectomy (P = 0.07, and 0.06, respectively). A total of 92.3 per cent of women treated with radiation remained free of breast tumor at five years, as compared with 72.1 per cent of those receiving no radiation (P less than 0.001). Among patients with positive nodes 97.9 per cent of women treated with radiation and 63.8 per cent of those receiving no radiation remained tumor-free (P less than 0.001), although both groups received chemotherapy. We conclude that segmental mastectomy, followed by breast irradiation in all patients and adjuvant chemotherapy in women with positive nodes, is appropriate therapy for Stage I and II breast tumors less than or equal to 4 cm, provided that margins of resected specimens are free of tumor.

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.

PURPOSE The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-22) to determine if intensifying but maintaining the total dose of cyclophosphamide (Cytoxan, Bristol-Myers Squibb Oncology, Princeton, NJ) in a doxorubicin (Adriamycin, Pharmacia, Kalamazoo, MI)-cyclophosphamide combination (AC), or if intensifying and increasing the total dose of cyclophosphamide improves the outcome of women with primary breast cancer and positive axillary nodes. PATIENTS AND METHODS Patients (N = 2,305) were randomized to receive either four courses of standard AC therapy (group 1); intensified therapy, in which the same total dose of cyclophosphamide was administered in two courses (group 2); or intensified and increased therapy, in which the total dose of cyclophosphamide was doubled (group 3). The dose and intensity of doxorubicin were similar in all groups. Disease-free survival (DFS) and overall survival were determined using life-table estimates. RESULTS There was no significant difference in DFS (P = .30) or overall survival (P = .95) among the groups through 5 years. At 5 years, the DFS of women in group 1 was similar to that of women in group 2 (62% v 60%, respectively; P = .43) and to that of women in group 3 (62% v 64%, respectively; P = .59). The 5-year survival of women in group 1 was similar to that of women in group 2 (78% v 77%, respectively; P = .86) and to that of women in group 3 (78% v 77%, respectively; P = .82). Grade 4 toxicity increased in groups 2 and 3. Failure to note a difference in outcome among the groups was unrelated to either differences in amount and intensity of cyclophosphamide or to dose delays and intervals between courses of therapy. CONCLUSION Intensifying or intensifying and increasing the total dose of cyclophosphamide failed to significantly improve either DFS or overall survival in any group. It was concluded that, outside of a clinical trial, dose-intensification of cyclophosphamide in an AC combination represents inappropriate therapy for women with primary breast cancer.

Early-Stage Invasive Breast Cancers: Potential Role of Optical Tomography with US Localization in Assisting Diagnosis

PURPOSE To investigate the potential role of optical tomography in the near-infrared (NIR) spectrum with ultrasonographic (US) localization as a means of differentiating early-stage cancers from benign lesions of the breast. MATERIALS AND METHODS The protocol was approved by the institutional review boards and was HIPAA compliant; all participants signed an informed consent. One hundred seventy-eight consecutive women (mean age, 52 years; range, 21-89 years) who underwent US-guided biopsy were imaged with a hand-held probe consisting of a coregistered US transducer and an NIR imager. The lesion location provided by coregistered US was used to guide optical imaging. Light absorption was measured at two optical wavelengths. From this measurement, tumor angiogenesis was assessed on the basis of calculated total hemoglobin concentration (tHb) and was correlated with core biopsy results. For patients diagnosed with carcinomas and followed up with subsequent excision, the tHb was correlated with pathologic parameters. RESULTS There were two in situ carcinomas (Tis), 35 T1 carcinomas, 24 T2-T4 carcinomas, and 114 benign lesions. The mean maximum and mean average tHb of the Tis-T1 group were 102.0 micromol/L +/- 28.5 (standard deviation) and 71.9 micromol/L +/- 18.8, and those of the T2-T4 group were 100.3 micromol/L +/- 26.4 and 67.0 micromol/L +/- 18.3, respectively. The mean maximum and mean average tHb of the benign group were 55.1 micromol/L +/- 22.7 and 39.1 micromol/L +/- 14.9, respectively. Both mean maximum and mean average tHb levels were significantly higher in the malignant groups than they were in the benign group (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value for Tis-T1 cancers were 92%, 93%, 81%, and 97%. The corresponding values for T2-T4 tumors were 75%, 93%, 69%, and 95%. CONCLUSION The angiogenesis (tHb) contrast imaged by using the NIR technique with US holds promise as an adjunct to mammography and US for distinguishing early-stage invasive breast cancers from benign lesions.

Reduction of skeletal muscle injury through stress conditioning using the heat-shock response

The heat-shock response refers to specific reversible changes in cellular metabolism that impart a protective effect on individual cells, as well as entire organisms, against subsequent noxious stimuli. Our objective was to quantify skeletal muscle injury following an ischemic event in a rat model by measuring levels of adenosine triphosphate and creatine phosphate. The animals were divided into two experimental groups. Animals in group 1 (n = 15) were subjected to limb ischemia alone, and animals in group 2 (n = 15) were treated with heat-shock conditioning prior to the onset of ischemia. Skeletal muscle specimens also were examined ultrastructurally by electron microscopy. Levels of creatine phosphate were higher in skeletal muscle obtained from animals in group 2. Mean levels of creatine phosphate ± SEM for groups 1 and 2 were 1.12 ± 0.06 μmol/gm and 1.95 ± 0.11 μmol/gm, respectively (p < 0.0001). This represents 18.4 and 31.9 percent of baseline nonischemic levels for groups 1 and 2, respectively (p < 0.0001). Adenosine triphosphate levels were measured in skeletal muscle samples from a subset of animals in each experimental group, group 1 (n = 6) and group 2 (n = 5), and were not significantly different. Electron microscopy demonstrated mitochondrial changes consistent with ischemic injury in group 1, but only nonspecific changes were noted in specimens from group 2. The presence of the primary 72-kDa heat-shock protein (HSP 72) was confirmed only in those animals treated by heat-shock conditioning. We conclude that prior stress conditioning using the heat-shock response confers significant biochemical and ultrastructural protection against ischemic injury in rat skeletal muscle. (Plast. Reconstr. Surg. 93: 1242, 1994.)

Pelvic exenteration for carcinoma of the uterine cervix. A 15-year experience.

From 1954 to 1969, 162 patients at the National Cancer Institute were treated with pelvic exenterations for carcinoma of the uterine cervix. A total cumulative 5‐year survival of 38% was obtained. Sixty‐eight of these patients presented with large, previously untreated lesions not amenable to lesser curative therapy. Their actuarial 5‐year survival was 48%. The remaining 94 patients were treated for radiation recurrent cancer with a 5‐year actuarial survival of 28%. Positive pelvic lymph nodes did not affect prognosis in patients treated for primary cancer, but survival decreased to 11% in those patients with recurrent disease and positive pelvic nodes. The 30‐day mortality was 7%, and the total intrahospital mortality was 17% (1 to 108 days). This mortality correlated with previous radiotherapy, patient age, preoperative medical status, operative time, and intraoperative transfusion requirements. Operative time and intraoperative transfusion requirements appeared to be related to the relative experience of the 17 surgeons involved in this study. Postoperative complications were similarly related to the above factors and have increased over the years in proportion to the degree that preoperative selection criteria have been liberalized. Over the 15 years encompassed in this study, there has been, however, a steady significant increase in cumulative 5‐year survival. Criteria for patient selection for pelvic exenteration are outlined, and salient suggestions are made for operative and postoperative management.

The efficacy of bone scanning in the follow-up of patients with operable breast cancer.

SummaryA considerable fraction of first metastases in breast cancer patients are found in the skeletal system. Consequently, to improve the probability of detecting bone lesions, protocols of the National Surgical Adjuvant Breast and Bowel Project (NSABP) have required radionuclide scans every six months for the first three postoperative years and yearly thereafter. The present study was conducted to evaluate the worth of 7984 bone scans performed prior to documentation of first treatment failure on 2 697 stage II (positive node) patients entered into NSABP clinical trial B-09. At the time of evaluation, there were 779 patients with a treatment failure, 163 (20.9%) of whom had their recurrence limited to bone. At most, 52 (0.6%) of the total number of screening scans were efficacious in detecting lesions in asymptomatic patients. As a result of this minimal benefit from routine scans, it was recommended that they be conducted less frequently. In presently ongoing NSABP studies, asymptomatic patients having tumors with positive axillary nodes receive scans at yearly intervals for the first three years. Future NSABP trials will require follow-up bone scans only as indicated by symptoms.

Regional deep hypothermia of the spinal cord protects against ischemic injury during thoracic aortic cross-clamping

We tested in pigs the hypothesis that regional deep hypothermia of the spinal cord achieved by cerebrospinal fluid cooling will protect against ischemic injury during thoracic aortic cross-clamping. Eight control animals underwent aortic cross-clamping at the distal aortic arch and just above the diaphragm for 30 minutes. Eight experimental animals had placement of two subarachnoid perfusion catheters through laminectomies at T4 and the lower lumbar region. The subarachnoid space was perfused with normal saline solution at 6 degrees C delivered by gravity infusion, with infusion rates adjusted to maintain cord temperatures at less than 20 degrees C. After 30 minutes of aortic cross-clamping, the infusion was stopped and the cord allowed to warm to body temperature. Hind limb neurologic function was graded by Tarlovs scale. All of the animals in the control group had complete hind limb paraplegia (Tarlov grade 0) postoperatively. Seven of the 8 animals in the experimental group had preservation of hind limb motor function (Tarlov grade 2), and 1 animal had complete hind limb paraplegia (Tarlov grade 0) (p = 0.002, Fishers exact test). We conclude that regional deep hypothermia of the spinal cord in pigs does provide some protection from ischemic injury during thoracic aortic cross-clamping. Clinically this may be a useful adjunct for prevention of paraplegia during thoracic aortic operations.

PAGET'S DISEASE OF THE NIPPLE-AREOLA COMPLEX

The histogenesis of Pagets disease has been hotly debated, and only recently has epidermotropic theory become widely accepted. With the evolution of our understanding of breast cancer, it became apparent that the prognosis of Pagets disease was more a reflection of that of the underlying carcinoma, be it intraductal or infiltrating. The standard treatment of Pagets disease remains mastectomy with or without axillary dissection. In this era of breast-conserving surgery, however, there is much evidence to suggest that conservative treatment of Pagets disease of the breast is possible. A breast-conserving algorithm for the treatment of Pagets disease of the breast is proposed. Further refinements or modifications to the algorithm should be made as data from ongoing trials redefine our understanding of breast pathology and treatment.

RNA‐mediated transfer of tumor immunity —A new model for the immunotherapy of cancer

The adoptive transfer of tumor‐specific transplantation immunity was accomplished in a syngeneic rat tumor‐host system. Rats which received intravenous injections of spleen cells from Fisher 344/N rats immunized by amputation of growing isografts of a benz(a)pyrene‐induced fibrosarcoma (BP‐1R) manifested a significant decrease in the incidence of development of tumor isografts. The intravenous administration of normal spleen cells to syngeneic rats was not effective. In other experiments, Fisher 344/N rats were immunized in a similar manner, and RNA was extracted from their spleens. Normal F‐344/N spleen cells were incubated with this “immune” RNA, and injected intravenously into F‐344/N rats which were then challenged with viable BP‐1R cells. A marked decrease in tumor growth rate resulted. The intravenous administration of spleen cells incubated with RNA extracted from the spleens of unimmunized rats was ineffective. In the same tumor‐host system, RNA, extracted from the nodes and spleens of guinea pigs immunized with the BP‐1R sarcoma, was mixed with sodium dextran sulfate, a potent inhibitor of ribonuclease, and administered to normal F‐344/N rats which were then challenged with BP‐1R cells. A significant reduction in the incidence of tumor development was noted. Dextran sulfate alone had no effect on the incidence of tumor isograft development, and RNA extracted from the lymph nodes and spleens of unimmunized guinea pigs and mixed with dextran sulfate was also ineffective. The systemic administration of “immune” RNA, or the administration of autologous lymphocytes pre‐incubated in “immune” RNA to human cancer patients may be an effective method of suppressing or eliminating small foci of persistent or metastatic cancer, and could be an important immunotherapeutic adjuvant to established modalities of cancer therapy.

Pelvic exenteration as palliation of malignant disease

It has been traditional to exclude patients with radiation-recurrent carcinoma of the uterine cervix or other pelvic neoplasms, incapacitating pelvic pain, postirradiation fistulas, hemorrhage, or malodorous draining tumor necrosis from pelvic exenteration if cure of the malignant disease is not achievable. This negative attitude is a direct result of the reported high morbidity, prohibitive mortality, and low salvage rate previously associated with pelvic exenteration, the only acceptable surgical approach to these diseases. A recent experience with eighteen patients who underwent pelvic exenteration for advanced primary or recurrent carcinoma of the cervix, urinary bladder, or rectum has led us to challenge several traditional concepts regarding this operative procedure. We have observed but one operative death and our morbidity has been minimal. This may reflect our belief that an aggressive pelvic lymphadenectomy in those patients with direct visceral involvement from radiation-recurrent carcinoma of the pelvic viscera is not advantageous since no significant survival has ever been documented for patients with pathologic visceral involvement and positive lymph nodes. In addition, significant morbidity has always been associated directly with pelvic lymphadenectomy in the irradiated pelvis, and elimination of this phase of the operation in selected patients with radiation-recurrent carcinoma is indicated. Moreover, the considerable decrease in morbidity and the minimal mortality observed have led us to adopt a very liberal attitude toward preoperative selection criteria, and we regularly now use pelvic exenteration not only for cure but as intentional palliation in selected patients. We strongly believe that elimination of pain, fistulas, pelvic sepsis, hemorrhage, and malodorous areas of tumor necrosis are important for improving the quality of life for both the patient and family.