Pathologic stages IA and IIA Hodgkin's disease: results of treatment with radiotherapy alone, 1968-1980.
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Biomedical subjects
Publications and source records attributed to S Hellman.
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This is a retrospective analysis of 120 patients with pathologically stage IIIA and IIIB Hodgkin's disease treated from April 1969 to December 1982. The median follow-up was 108 months. Treatment consisted of radiation therapy (RT) alone in 54 patients and combined radiation therapy and MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy (CMT) in 66 patients. Stage III patients treated with CMT have an improved actuarial 12-year survival as compared with patients treated with RT alone with MOPP reserved for relapse (80% v 64%; P = .026). The 12-year actuarial freedom from first relapse by treatment for stage III patients is 83% and 40%, respectively (P less than .0001). Improved survivals following combined modality therapy are seen for the following subgroups of stage III patients: stage III2, 66% (CMT) v 44% (total nodal irradiation; TNI), P = .04; stage III1, 97% (CMT) v 73% (TNI), P = .05; stage III mixed cellularity or lymphocyte depletion histology, 94% (CMT) v 65% (TNI), P = .007; and stage III extensive splenic involvement, 77% (CMT) v 58% (TNI), P = .02. These survival differences are not seen in patients with nodular sclerosis or lymphocyte predominance histology or in patients with minimal splenic involvement. These data indicate that the initial use of CMT in stage III Hodgkin's disease results in an improved survival as compared with initial treatment with RT with MOPP reserved for relapse. Patients with limited Stage IIIA disease may still be candidates for radiation therapy alone.
The murine bone marrow culture technique was used to prepare donor marrow for bone marrow transplantation across minor histocompatibility complex differences. Previous studies have shown that theta-positive cells are rapidly lost from such cultures and that transplantation of cultured marrow across major histocompatibility complex differences results in a delay in the development of lethal graft-v-host disease (GVHD). In this study, a total of 1 to 2 X 10(7) nonadherent cells (740 to 1560 CFUs [colony-forming units]) from three-day-old cultures were used as a source of donor marrow. Three strain combinations were evaluated; LP/J into C57BL/6; BIO.BR into CBA/J; and C57BL/6 into LP/J. Donor mice were immunized with recipient spleen cells prior to culture in order to increase the graft-v-host response. For LP/J marrow into C57BL/6 mice, 5 X 10(7) donor spleen cells transplanted along with the marrow were needed to induce lethal GVHD. However, lethal GVHD was seen without the addition of spleen cells for BIO.BR into CBA/J and C57BL/6 into LP/J strain combinations. Most animals receiving fresh marrow were dead of GVHD five weeks after transplantation. With the use of cultured marrow the three-month survival was 80%, 51%, and 93%, respectively, for LP/J into C57BL/6, BIO.BR into CBA/J, and C57BL/6 into LP/J strain combinations. Long-term donor engraftment in all recipient animals receiving cultured marrow was confirmed by analyzing hemoglobin polymorphisms between the strain combinations. These results demonstrate that in contrast to transplantation across major histocompatibility complex differences, the use of cultured cells for bone marrow transplantation across minor histocompatibility complex differences allows for engraftment while reducing the risk of lethal GVHD.
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Adherent stem cells (ASC) are hematopoietic stem cells of the mouse bone marrow that are equivalent to CFU-S in pluripotency (they produce CFU-S) and proliferative ability (they go through up to 25 doublings). They can be assayed in vitro by a limiting dilution overlay technique in which stromal bone marrow long-term cultures serve as underlayers. In this article we estimate the occurrence rates of ASC in fresh and adherent bone marrow cells and report the distribution of population doublings estimated for 152 ASC clones.
This article presents a new residential model that has been developed at the Massachusetts Mental Health Center. The "dormitory-inn" provides an alternative to 24-hour inpatient hospitalization for patients who traditionally would have been admitted and retained on inpatient services. Issues covered include hours and location, referrals, requirements for staff, medical and nursing coverage, and a review of the efficacy of the program.
In order to assess the cosmetic results of treatment, the results in 239 patients with early breast cancer treated by primary radiation treatment without adjuvant chemotherapy were reviewed. Four patients had bilateral cancers, making a total of 243 breasts available for analysis. Follow-up ranged from 24 to 78 months with a median of 33 months. The parameters measured were breast edema, retraction, telangiectasia, arm edema, and the overall cosmetic appearance. The cosmetic results declined over the first 3 years after treatment, but then stabilized. At 5 years, the overall cosmetic results were judged by physicians as excellent in 77%, good in 9%, fair in 9%, and poor in 5%. A fair or poor cosmetic result was highly correlated with the development of moderate or severe breast retraction. Telangiectasia was uncommonly the only cause of a fair or poor cosmetic result. Breast and arm edema were rarely noted to be significant, but were more common in patients who underwent axillary dissection. In 210 cases, a supplementary boost dose of radiation was delivered to the primary tumor area, and in 33 cases a boost was not used. This boost consisted of an interstitial iridium-192 implant in 204 cases and either high-energy photons or electrons in the remainder. At 4 years, no patient treated without a boost had a fair or poor result compared with 22% who received a boost (P = 0.13). The conclusion is that, in general, primary radiation treatment provides highly satisfactory cosmetic results for patients with early breast cancer.
Eight patients with relapsed B-cell non-Hodgkin's lymphoma were treated with intensive chemoradiotherapy and reconstituted with autologous bone marrow rendered free of tumour cells by the B-cell-specific monoclonal antibody anti-B1 and complement. Before the autologous marrow transplantation patients were induced with chemotherapy, radiotherapy, or both, into a minimum disease state with less than 5% bone-marrow involvement with tumour. All patients treated achieved a complete clinical response and had stable haematological engraftment by 8 weeks. No significant acute or chronic toxic effects have occurred. B cells could be detected by 2 months after transplantation and normal immunoglobulin levels were achieved by 6 months. Six of eight patients are disease free in unmaintained remission more than 20, 19, 10, 8, 5, and 3 months after transplantation.
Thirty-four gross and histologic features of the primary tumor in 231 cases of clinical Stage I and II invasive breast cancer were reviewed in an attempt to identify features which might correlate with an increased risk of local recurrence within the breast following biopsy and primary radiation therapy. Local recurrence risk at 5 years was calculated for each feature studied. While results are reported in terms of 5-year actuarial local recurrence risk, not all patients were followed for 5 years (median follow-up period, 44 months). Patients with cases in which the biopsy was less than excisional had a considerably greater actuarial risk of local recurrence at 5 years than those in which the biopsy was excisional (36% versus 8%; P = 0.0005). Among 154 infiltrating ductal carcinomas treated by excisional biopsy prior to radiotherapy, histologic features associated with a significantly increased local recurrence risk at 5 years were the combination of extensive intraductal involvement by carcinoma and high nuclear grade and/or high mitotic index. Twenty-seven tumors demonstrated this constellation of features, and there was a 5-year actuarial local recurrence risk of 39% among this group. The local recurrence risk for the remainder of the population was only 4% (P less than 0.0001). Thus, through pathologic examination of the primary, the authors identified a subgroup of patients with a considerably increased risk of local recurrence following biopsy and primary radiotherapy.
The treatment of operable breast cancer by primary radiation therapy instead of mastectomy is undergoing evaluation in the United States and Europe. Retrospective studies of patients treated by primary radiation therapy show that local control and survival rates are comparable to those obtained by mastectomy. Detailed analysis of local failure following primary radiation therapy indicates the importance of excisional biopsy of the primary tumor, moderate doses of radiation to the breast and draining lymph node areas, and the use of a boost to the primary tumor area in maximizing local control. Further, the judicious use of local excision combined with meticulous radiotherapy technique yields highly satisfactory results for the majority of treated patients. Preliminary results from prospective trials also indicate that primary radiation therapy provides both local control and survival rates equivalent to mastectomy. Primary radiation therapy is becoming an increasingly important alternative to mastectomy where surgical and radiotherapeutic expertise are available to optimize both local tumor control and the final cosmetic outcome.
Current management of patients with locally advanced breast cancer is not satisfactory. Establishing local tumor control is a problem with either surgery or radiation therapy alone. There is some suggestion that the two modalities should be combined when possible. Regardless of local control, distant metastasis is quite common. An example of the results of primary radiation therapy for locally advanced breast cancer is described in the study from the Joint Center for Radiation Therapy where the actuarial rate of local control was 54% and the 5-year survival was 30%. Recently, adjuvant chemotherapy has been introduced in the management of these patients. The authors' studies indicate that adjuvant chemotherapy not only increases the 5-year survival, but also improves local tumor control. At this time it is unclear whether adjuvant chemotherapy has improved the cure rate or simply increased the time to treatment failure. Current studies are directed toward the optimum interfacing of local treatment and adjuvant chemotherapy. It is only through an aggressive approach to both the local disease as well as the subclinical distant metastases that an increased cure for patients with locally advanced breast cancer will be achieved.
Hematopoietic stem cells with high proliferative capacity can be assayed when stromal bone marrow cultures are overlaid with limiting dilutions of marrow samples. This leads to hematopoietic growth after 4 weeks in a fraction of cultures, consistent with expectations based on Poisson statistics. It will be shown that monoclonal cultures are obtained that last from 2 to 15 weeks and that can generate up to several million mature granulocytes. The originating clone-forming cell is named adherent stem cell (ASC) because of its adherence to plastic or stromal surfaces. The ASC is comparable to the CFU-S in frequency, proliferative capacity and in its ability to give rise to CFU-S. As an unexpected additional finding we report that a mode of "clonal succession" was apparent in cultures which expressed more than one clone.
Breast cancer patients treated by primary radiation therapy who have positive axillary lymph nodes now typically receive adjuvant chemotherapy. In order to evaluate the effect of adjuvant chemotherapy on the response of the breast to radiation treatment, we compared the cosmetic results of 49 patients treated with adjuvant chemotherapy and 206 patients not treated with adjuvant chemotherapy. A variety of chemotherapy regimens were employed, most commonly a combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The median follow-up time for all patients was 33 months. Cosmetic results were scored by the physician at each follow-up evaluation as excellent, good, and fair or poor, depending on the presence and extent of radiation-related changes in the treated breast. Patients who received adjuvant chemotherapy were less likely to have an excellent overall cosmetic result than patients who did not receive adjuvant chemotherapy. At 24 months 24% of these patients had an excellent cosmetic result compared with 64% of patients who did not receive adjuvant chemotherapy (p = 0.0002). This difference was due primarily to a shift in chemotherapy-treated patients from an excellent to a good overall cosmetic result. Breast retraction was noted to be the most frequent determinant of a fair or poor cosmetic result and was more common in patients treated with adjuvant chemotherapy. At 24 months, 62% of these patients had evidence of breast retraction compared with 44% of patients who did not receive adjuvant chemotherapy (p = 0.06). We conclude from this preliminary analysis that adjuvant chemotherapy modifies the response of the breast to radiation, most notably by increasing the development of retraction.
A 300 kvp orthovoltage machine has been permanently installed in an operating room for delivering intraoperative radiation therapy (IORT). A historical review of orthovoltage IORT and our present approach are described. The preliminary experience with 38 patients treated with orthovoltage IORT indicates that this technique is feasible, has low acute morbidity, and can be useful for palliation. "Radical" radiation therapy consisting of IORT "boost" treatment combined with external beam was used in 24 patients with primary or recurrent cancer. Local failure in 27 patients treated with IORT +/- external beam radiation therapy was 56%, but varied from 11% (1/9) for patients with resected disease to 78% (14/18) for patients with unresected disease. Complications occurred in nine patients (24%) and have been acceptable. There are 17 patients alive and six are NED, with follow-up of 4-18 months. There appears to be a role for orthovoltage IORT especially when combined with surgical resection for local control of advanced cancer arising in the abdomen where the use of high doses of external radiation therapy are hazardous.
We have investigated X-ray survival parameters and repair of potentially lethal damage ( PLDR ) in ten early passage squamous cell carcinoma cell lines derived from patients who were biopsied before initiation of radiotherapy or after radiation therapy failure. Radiosensitivity (D0) ranged from 1.07 to 1.93 (Gy), extrapolation numbers (-n) from 1.17 to 2.14 and PLD recovery at 24 h from 1.4 to 20.3. Despite significant differences in these parameters amongst the cell lines, a firm correlation between radiocurability and any individual radiobiological parameter could not be established. Our data suggest that the mechanisms associated with radioresistance are complex and that any single radiobiological parameter may not predict clinical success or failure.
The frequency, time course, and prognosis of local recurrence following primary radiation therapy in 152 patients with early breast cancer treated before 1967 were examined. Local recurrence occurred at a constant rate over the first 14 years after treatment. The crude 15-year local recurrence rate was 22%. Of the 30 patients who developed an isolated local recurrence and underwent definitive secondary surgery, the 10-year freedom from distant relapse rate was 50%. These results indicate that breast cancer patients treated by primary radiation therapy require long-term follow-up to detect curable local recurrences.
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The use of the bone marrow culture technique was studied as a means to prepare donor marrow for bone marrow transplantation to avoid lethal graft-versus-host disease (GVHD). Preliminary experiments demonstrated the rapid loss of theta-positive cells in such cultures, so that theta-positive cells were not detected after 6 days. Initial experiments in C3H/HeJ (H-2k, Hbbd) recipients prepared with 900 rad demonstrated improved survival when 3-day cultured C57BL/6 (H-2b, Hbbs) donor cells were used in place of hind limb marrow for transplantation. However, hemoglobin typing of recipient animals revealed only short-term donor engraftment, with competitive repopulation of recipient marrow occurring. Subsequent experiments were done in 1,200-rad prepared recipients, with long-term donor engraftment demonstrated. The majority of 1,200-rad prepared animals receiving cultured allogeneic cells died of GVHD, but animals receiving 28-day cultured cells had an improved 90-day survival and a delay in GVHD development over animals receiving hind limb marrow or marrow from shorter times in culture. In addition, animals receiving anti-theta-treated, 3-day nonadherent cells had an improved survival (44%) over animals receiving anti-theta-treated hind limb marrow (20%). These experiments demonstrate modest benefit for the use of cultured cells in bone marrow transplantation across major H-2 histocompatibility complex differences.