Allen S. Lichter

Dose to the contralateral breast due to primary breast irradiation.

The radiation dose received by the contralateral breast during primary breast irradiation is of concern because breast tissue is subject to cancer induction from low to moderate doses of radiation. In this paper the dose to the opposite breast has been studied in detail for common breast treatment techniques. Measurements have been made on 16 patients, a water phantom, a polystyrene phantom with cork inserts to simulate lung tissue, and a body-shaped phantom with wax breasts. Thermoluminescent dosimeters (TLD), ion chambers, diodes, and film have been used in the various configurations. The patient measurements have shown that there is a wide variation in the opposite breast dose received by patients, even when all are treated with, for example, tangential fields alone. Addition of more radiation fields, such as supraclavicular/axillary and internal mammary fields, may increase the dose to the opposite breast for a particular patient. Variations in the details of the technique such as what wedges are used, the use of blocks, and the orientation of the field edges are all important to the final dose received by the patients contralateral breast. With the phantom measurements, it has been possible to determine the contributions to the opposite breast dose from each of the relevant factors. This makes it possible to explain the wide variation in patient dose measurements, and to make some relatively simple recommendations that will allow the reduction of the dose to the opposite breast from several hundred cGy to about 50 cGy for a typical treatment course dose of 5000 cGy.

Psychosocial and physical outcomes of primary breast cancer therapy: Mastectomy vs excisional biopsy and irradiation

SummaryThirty-eight patients treated for primary breast cancer as part of a prospective randomized clinical trial were questioned retrospectively as to their psychosocial adaptation to treatment. Twenty patients had received mastectomy and eighteen had received excisional biopsy plus radiation of the intact breast. Aside from body image concerns, there were no marked psychosocial differences detected between these groups. Previous studies emphasizing serious psychological problems in mastectomy patients and fewer such problems in nonmastectomy patients may be influenced by biases that are not present in a randomized study design.

Role of prophylactic cranial irradiation in prevention of central nervous system metastases in small cell lung cancer. Potential benefit restricted to patients with complete response

Abstract The records of 332 patients with small cell lung cancer treated on National Cancer Institute protocols between 1970 and 1980 were reviewed to evaluate the association of prophylactic cranial irradiation with the development of central nervous system metastases and survival. Stage of disease, involvement of liver, bone marrow, and bone, and the degree of response to systemic therapy were prognostic features significantly associated with the development of central nervous system metastases. Prophylactic cranial irradiation had no influence on leptomeningeal, spinal, or epidural metastases, but a significant reduction In intracerebral metastases was observed. There was also a statistically significant improvement in overall survival in patients who received prophylactic cranial irradiation (p

Comparison of pain, motion, and edema after modified radical mastectomy vs. local excision with axillary dissection and radiation

SummaryRecent data suggest that prognosis is similar for women with primary breast cancer whether they receive modified radical mastectomy (MRM) or local excision and axillary dissection with radiation (XRT). The effects of either of these treatments on arm mobility, pain, or edema have not been compared. To assess the impact of MRM or XRT on mobility, pain, or edema, we evaluated patients treated in a prospective randomized trial designed to assess prognosis following MRM or XRT. All were provided a standardized physical therapy program including arm mobilization, shoulder strengthening, prevention and treatment of upper extremity edema, and education about arm function.Patients were evaluated for chest wall pain, arm motion, muscle strength, and edema as determined by circumferential measurements at the wrist, forearm, and arm. Evaluations were performed preoperatively and at yearly anniversaries of their surgery. Women receiving XRT had more chest wall tenderness at 1 and 2 years after surgery than those receiving MRM (p2<0.0001 and p2=0.0007 respectively). Those receiving MRM were slower to reach their preoperative range of motion (ROM) (p2=0.043). Incidence of muscle weakness was similar in both groups. The few patients with local recurrence of tumor had more upper extremity edema than those who did not recur (p2=0.085) at 1 year and (p2=0.02) at 2 years. In patients who did not develop local recurrence, those who had received XRT had greater but nonsignificant increases in upper extremity circumferential measures compared with those receiving MRM at any anniversary evaluation.Patients receiving MRM and XRT are likely to have some differences in functional outcome. These differences may be important to individuals and be significant in helping them choose between MRM and XRT based upon individual functional needs.

Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy

Abstract The safety of prophylactic cranial irradiation (PCI) has recently been questioned, based on reports of computerized tomographic abnormalities mainly seen in children, who received PCI and chemotherapy, primarily for acute lympbocytic leukemia. In order to clarify the significance of these findings, we examined a series of adult patients who were long term survivors (18–48 months, median 26 months, after all treatment). These patients were treated with combination radiotherapy and chemotherapy for small cell lung carcinoma and received cranial irradiation in the absence of known brain involvement by tumor. Patients were divided into three groups: three patients who received PCI + intrathecal metbotrexate (MTX) (Group 1), and ten who received only PCI (Group 2). An additional three patients (Group 3) were identified as long term survivors (41–70 months after all treatments) of a similar treatment program without any central nervous system (CNS) prophylaxis. All patients received an extensive evaluation of a variety of clinical parameters, EEG, and computer tomography (CT). Although CT abnormalities were detectable (mild cerebral atrophy in eight patients, encephaiomalacia in one of the 13 patients with CNS prophylaxis, and wild atrophy in two of the three patients without CNS prophylaxis~ so significant clinical abnormalities or EEG changes were detectable. While this group of patients is small, it is a unique cohort: adults who have received cranial irradiation in the absence of known brain tumor with long term follow-up. The precise role of CNS prophylaxis in the etiology of CT abnormalities is unclear, and the lack of clinically significant changes would suggest no contraindication to PCI when indicated.

Small cell lung cancer: analysis of treatment factors contributing to prolonged survival

Seventy‐one consecutive patients with small cell lung cancer (SCLC) were treated in the Radiation Oncology Branch of the National Cancer Institute using six different radiation regimens in combination with cyclophosphamide, vincristine and doxorubicin chemotherapy. Patients treated with concurrent chemotherapy—irradiation (CT‐RT) experienced better local tumor control than patients treated with sequential CT‐RT. Maximum survival with minimum toxicity occurred in the group given a three‐week course of concurrent CT‐RT. Although concurrent therapy appeared more toxic than sequential therapy, it also appeared to result in more effective tumor control. Precise details of the timing of CT and RT represent important variables in study design of combined modality therapy for SCLC. Carefully controlled clinical trials should be undertaken to define the optimal timing and sequencing of CT‐RT, as well as the optimal dose of RT.

The impact of primary irradiation treatment of localized breast cancer on the ability to administer systemic adjuvant chemotherapy.

The impact of primary irradiation of localized breast cancer on the ability to administer Adriamycin-cytoxan adjuvant chemotherapy to patients with stage II breast cancer was examined. Patients were prospectively randomized to receive either irradiation or mastectomy as local therapy and did not differ with respect to other prognostic variables that might influence tolerance to chemotherapy. All of the patients received chemotherapy dose escalations (or reductions) until maximal tolerated drug doses were established. Patients receiving irradiation had minimally greater myelosuppression which was nearly totally explainable by lymphopenia. Irradiated patients required dose reduction nearly twice as often as mastectomy patients although commonly their dose could be reescalated. Patients managed with radiotherapy received slightly less drug than patients treated with mastectomy when treated to an identical degree of bone marrow suppression. The primary management of breast cancer by irradiation does not induce substantial changes in the ability of patients to tolerate adjuvant chemotherapy.

Haemopoietic recovery in Ewing's sarcoma after intensive combination therapy and autologous marrow infusion.

After the completion of combination therapy designed to achieve local control of Ewings sarcoma, 13 patients with either truncal primary lesions or proven metastases were given 150 rad of total body irradiation over 5 weeks followed by cyclophosphamide, doxorubicin, imidazole carboxamide, and vincristine. 11 patients received autologous cryopreserved marrow infusions. In 2 patients marrow collections were not attempted. Two patterns of haemopoietic recovery were observed: 8 patients, who had received marrow infusions, showed leucocyte, granulocyte, and platelet recovery by 27, 28, and 30 days. 5 patients, 3 of whom had also received marrow, showed more delayed recovery with leucocyt, granulocyte, and platelet recovery at 45, 53, and 77+ days. Delayed recovery in patients receiving marrow seemed to correlate with aberrations in marrow freezing-rate during phase change, and these aberrations could be shown to diminish post-freeze recovery of marrow granulocyte-monocyte precursor cells.

The hematopoietic toxicity of regional radiation therapy. Correlations for combined modality therapy with systemic chemotherapy

Using circulating granulocyte‐monocyte precursor colony‐forming units in culture (CFUc) numbers as a probe along with standard blood count (CBC), the authors have quantitatively examined the hematopoietic toxicity of conventionally fractionated radiation therapy (RT) when combined with concurrent systemic chemotherapy or when used alone. Among 20 patients with limited stage small cell lung cancer receiving systemic chemotherapy with cyclophosphamide, CCNU, and methotrexate, the addition of involved field chest RT resulted in increased hematopoietic toxicity as judged by increased need for platelet transfusion (P < 0.05) and decreased frequency of measurable CFUc (P < 0.04). Among 22 patients receiving regional radiotherapy alone consistent hematopoietic toxicity was also observed. This toxicity, although generally of only mild to moderate clinical significance, was detected earlier and to a greater degree in patients who required radiation to larger treatment volumes, who had significant amounts of bone marrow in the port, and who had a high percentage of cardiac output flowing through the port. These data suggest that the hematopoietic toxicity of regional radiotherapy may be additive to that of concurrent systemic chemotherapy and may occur more promptly and to a greater degree when treatment volumes are larger or incorporate increased amounts of marrow volume or cardiac output.

A Randomized Trial of Adjuvant Chemotherapy and Tamoxifen Timing in Postmenopausal, Endocrine-Responsive, Node- Positive Breast Cancer

BACKGROUND Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. METHODS We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. FINDINGS Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. INTERPRETATION Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. FUNDING National Cancer Institute (US National Institutes of Health).The most common presentation of breast cancer is an estrogen receptor-positive (ER+) tumor in postmenopausal women, for whom tamoxifen is the gold standard against which other systemic adjuvant treatments are compared.(1–4) Whether to add chemotherapy to endocrine therapy is attractive in theory(5), but there is no consensus regarding such treatment in postmenopausal women with tamoxifen-responsive disease.(3,4) Individual phase III trials that compared chemotherapy plus tamoxifen versus tamoxifen alone did not show a significant survival benefit in older women.(6–9) A recent meta-analysis of all existing trials based on individual patient data found that the addition of chemotherapy to tamoxifen is only marginally beneficial in older women, in contrast to major survival improvements in premenopausal populations (see Figure 4, reference 10 for the EBCTCG metaanalysis) Figure 4 Southwest Oncology Group trial SWOG-8814 (North American Breast Intergroup 0100) forest plots of hazard ratios and 95% confidence intervals for major subsets for disease-free survival. Panel A describes the disease-free survival advantage for chemotherapy ... Most individual trials in postmenopausal women tested the addition of regimens based on cyclophosphamide, methotrexate and 5-fluorouracil (CMF) to tamoxifen(3,4, 6–8, 10), but in certain breast cancer study populations, CMF may be inferior to anthracycline-based regimens(11–16). No clinical trials have shown, however, that anthracycline-based therapy adds to the benefit of tamoxifen specifically in postmenopausal patients with ER+ disease. Moreover, interference with drug-induced cytotoxicity has been found in vitro when tamoxifen is added to cancer cell lines concurrently with chemotherapy(17–20), yet concurrent tamoxifen and CMF has been a common practice in clinical trials. Our two objectives were to determine if chemotherapy, consisting of 6 months of cyclophosphamide, doxorubicin (AdriamycinR), and 5-fluorouracil (CAF) plus 5 years of tamoxifen, was superior to tamoxifen alone; and to assess if CAF followed by tamoxifen was better than CAF plus concurrent tamoxifen. The CAF program we used was the most dose-intense combination among the commonly used regimens when this trial was designed.(11) This report presents 10-year outcomes for both objectives.