The Harvard Joint Center for Radiation Therapy, 1968-1999: a unique concept and its relationship to the prevailing times in academic medicine.

PURPOSE: Institutional structure, function, and philosophy reflect the organizational needs, and tend to mirror societal values of the times. For many years, the field of radiation oncology had among its major academic centers, an organization that served as a model for collaboration among health care institutions in an effort to serve the common good of its patients, hospitals, professional colleagues, and community. For over three decades, the Joint Center for Radiation Therapy (JCRT) was a leader in developing new organizational approaches for academic and clinical radiation oncology through the philosophy of collaboration in patient care, education, and research. METHODS AND RESULTS: In tracing the development and changes in organizational philosophy and structure of the JCRT, one can see the impact on academic oncology and cancer care through the emergence of both radiation and medical oncology as independent subspecialties, the importance of the National Cancer Act of 1971 accompanied by the growth of the NIH research and training programs and, more recently, the effect of the changing attitudes and approaches of hospitals, academicians, practitioners, and policy makers to health care delivery, structures, and cooperation. CONCLUSION: Lessons learned from the 31-year history of the JCRT may help provide organizational insight useful in guiding academic oncology and academic medical centers through periods of change.

Treatment outcome after tangential radiation therapy without axillary dissection in patients with early-stage breast cancer and clinically negative axillary nodes.

PURPOSE: To determine the risk of nodal failure in patients with early-stage invasive breast cancer with clinically negative axillary lymph nodes treated with two-field tangential breast irradiation alone, without axillary lymph node dissection or use of a third nodal field. METHODS AND MATERIALS: Between 1988 and 1993, 986 evaluable women with clinical Stage I or II invasive breast cancer were treated with breast-conserving surgery and radiation therapy. Of these, 92 patients with clinically negative nodes received tangential breast irradiation (median dose, 45 Gy) followed by a boost, without axillary dissection. The median age was 69 years (range, 49-87). Eighty-three percent had T1 tumors. Fifty-three patients received tamoxifen, 1 received chemotherapy, and 2 patients received both. Median follow-up time for the 79 survivors was 50 months (range, 15-96). Three patients (3%) have been lost to follow-up after 20-32 months. RESULTS: No isolated regional nodal failures were identified. Two patients developed recurrence in the breast only (one of whom had a single positive axillary node found pathologically after mastectomy). One patient developed simultaneous local and distant failures, and six patients developed distant failures only. One patient developed a contralateral ductal carcinoma in situ, and two patients developed other cancers. CONCLUSION: Among a group of 92 patients with early-stage breast cancer (typically T1 and also typically elderly) treated with tangential breast irradiation alone without axillary dissection, with or without systemic therapy, there were no isolated axillary or supraclavicular regional failures. These results suggest that it is feasible to treat selected clinically node-negative patients with tangential fields alone. Prospective studies of this approach are warranted.

Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin's lymphoma.

PURPOSE: Low-dose total body irradiation (TBI) is used to treat non-Hodgkin's lymphoma (NHL) and several other malignancies. Large volumes of bone marrow and other tissue receive considerable exposure, but few studies have quantified late carcinogenic sequelae. PATIENTS AND METHODS: A cohort of 61 2-year survivors of NHL treated initially with low-dose TBI was monitored for second cancer occurrence. Data on primary and subsequent therapy were collected, and cumulative dose of radiation to active bone marrow (ABM) (median, 5.2 Gy) was reconstructed. RESULTS: Thirteen second primary cancers occurred. Four patients developed acute nonlymphocytic leukemia (ANLL), which represents a relative risk (RR) of 117 (95% confidence interval [CI], 31.5 to 300) compared with population rates. A fifth patient was diagnosed with myelodysplastic syndrome (MDS). All five patients with secondary hematologic malignancies subsequently received salvage treatment, with either alkylating agents alone (n = 1) or combined modality therapy (CMT) (n = 4). Overall, eight solid tumors were observed (RR = 2.0; 95% CI, 0.9 to 4.0). The 15-year cumulative risks of all second cancers and secondary ANLL were 37% and 17%, respectively. CONCLUSIONS: Despite the small number of subjects, a considerable risk of leukemia was observed among patients treated with low-dose TBI in combination with CMT including alkylating agents. Based on these results, approximately eight to nine excess ANLLs might be expected to occur among 100 NHL patients treated with low-dose TBI and salvage treatment and followed-up for 15 years.

Intraoperative radiation therapy for biliary tract carcinoma: results of a 5-year experience.

The results of a 5-year experience with use of intraoperative radiation therapy (IORT) in the management of locally advanced bile duct carcinoma are presented. Fifteen patients received IORT doses between 5 and 20 Gy for localized disease, which was either primary and resected with microscopic residual (2 patients), primary and unresected (10 patients), or recurrent (3 patients). Thirteen patients also received postoperative radiation therapy. The median survival of the 12 patients with primary disease was 14 months, with disease controlled in the porta hepatis in 5 of 10 evaluable patients. The three patients with recurrent disease survived 2, 9, and 11 months. There were two operative deaths, for an operative mortality of 13%. Acute and chronic complications are reviewed. Cholangitis is the most frequent in both categories. This aggressive approach in the therapy for advanced disease has an acceptable level of morbidity and may warrant the use of IORT as part of the management of biliary tract cancer.

Radiation therapy of seminoma: 17-year experience at the Joint Center for Radiation Therapy.

One hundred and sixteen patients with stage I and II primary testicular seminoma were treated at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1984. Complete follow-up is available for 114 patients (98%) with a median follow-up time of 6 years. Actuarial relapse-free survival (RFS) and survival for the entire group at 10 years were 94 and 86%, respectively, with 27 patients still at risk beyond 10 years. Actuarial RFS and survival at 10 years by stage were 97 and 92% for stage I, 93 and 81% for stage IIa, 100 and 100% for stage IIb, but only 75 and 51% for stage IIc. The difference in actuarial survival between stage IIc patients and stage I, IIa and IIb patients was significant (p less than 0.01). These results indicate that radiation therapy is excellent treatment for stage I and II seminomas as long as the largest mass of disease is not greater than 5 cm (stage IIc). Patients with stage IIc seminoma are now treated with cisplatin-containing combination chemotherapy followed by radiation therapy to areas of bulk disease. Although the majority of patients with stage II disease in this series received mediastinal irradiation, this is no longer recommended at the JCRT.

Chemotherapeutic strategies in the multidisciplinary treatment of head and neck cancer.

A role for chemotherapy in the multidisciplinary treatment of patients with advanced squamous cell carcinoma of the head and neck (SCCHN) is yet to be defined. Results of uncontrolled studies indicate high response rates to induction chemotherapy and an association between a response to chemotherapy and either local-regional control or survival. Unfortunately, results of randomized, controlled trials have not confirmed an overall survival advantage with such treatment. From 1979 to the present, the Dana-Farber Cancer Institute has registered more than 224 patients on two trials of induction and adjuvant chemotherapy for patients with stage III to IV SCCHN. Protocol 80-016 (1979 to 1983) evaluated two cycles of induction cisplatin, bleomycin, and methotrexate/leucovorin (PBM) before local regional treatment in 114 patients. Eighty-nine (78%) patients responded to PBM, with 30 (28%) patients achieving a complete response (CR). After surgery and/or radiotherapy (RT), 46 responders to induction PBM entered a trial of the randomly assigned additional adjuvant PBM. Protocol 83-084 (1983 to present) randomly assigned patients to receive up to four cycles of either induction PBM or cisplatin and infusion 5-fluorouracil before local treatment. Adjuvant chemotherapy was not used in the latter study. Updated results from both trials will be presented, with their implications for future phase II and III multidisciplinary studies. Optimal approaches to the treatment of patients with advanced SCCHN can include planned reductions in the extent of surgery or RT offered to selected patients with a good response to induction chemotherapy but may require adjuvant chemotherapy for patients at high risk for recurrent disease. Until the rate of CR to induction chemotherapy is reproducibly over 50%, documentation of an improved overall survival with multidisciplinary treatment may be difficult.

Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival.

In an effort to determine the patterns of failure and survival of rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. The 5-year actuarial survival for the entire group was 67%. Survival rates decreased with increasing penetration of the bowel wall by tumor and the presence of lymph node metastasis, but only the latter reached statistical significance. Those patients who underwent an abdominoperineal resection also experienced a significant decrease in survival compared to a low anterior resection. Patterns of failure, expressed as the actuarial incidence of first failure at 5 years, were examined by stage. With the exception of stages B3 and C3, there was a trend towards increased abdominal, distant, and total failure with increasing bowel wall penetration by tumor. A similar trend was seen in local failure in those patients with positive nodes. Knowledge of these data may help identify those patients who may benefit most from adjuvant therapy.

Resectable adenocarcinoma of the rectosigmoid and rectum. II. The influence of blood vessel invasion.

Several series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, little data are available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. In patients who had tumors with extramural BVI, there was a significant decrease in five-year actuarial survival compared with patients who had tumors with intramural BVI or were BVI-negative (BVI-). When the intramural and extramural types of BVI were combined, no significant impact was noted on the patterns of failure or survival in patients with BVI+ versus those with BVI- tumors. In contrast, the presence of lymphatic vessel invasion was found to significantly decrease survival. By using a proportional hazards analysis, it was found that BVI was not an independent prognostic variable. Therefore, the use of BVI alone is not recommended for selecting patients with rectosigmoid and rectal cancer who may benefit from adjuvant therapy.

Potentially curative surgery of colon cancer: patterns of failure and survival.

In an effort to determine the patterns of failure and survival of colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. For the entire group, the 5-year crude survival rate was 68% and the actuarial rate was 80%. Survival decreased with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Although survival varied with the tumor site, none of the differences was statistically significant. Other variables, including the grade of adenocarcinoma, size, and the type of surgery had a significant impact on survival. Patterns of failure, expressed as the actuarial incidence of first diagnosed failure at 5 years, were examined by stage and site. There was a trend toward increased failure with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Abdominal failure, either as the only site or as a component of failure, was the most common type of failure. When compared by site, patients with cecal carcinoma had a significantly lower incidence of local and distant failure than patients with disease in other selected sites. No differences in patterns of failure were seen in patients with carcinomas in the mobile sections of the colon compared with those who had disease arising in the nonmobile sections of the colon. These data may be useful in identifying those patients who might benefit most from adjuvant therapy.

Potentially curative surgery of colon cancer: the influence of blood vessel invasion.

A number of series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, there are little data available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. Patients whose tumors had BVI experienced a significant decrease in the 5-year actuarial survival rate. BVI had little impact on the patterns of failure in stage B2 disease, but a significant increase in total failure and local failure (as a component of failure) occurred in stage C2. However, when examined by proportional hazards analysis, BVI was found not to be an independent prognostic variable. For patients with stage C2 tumors, which are also BVI+, radiation therapy to the tumor bed might play a contributory role in overall management.

Colloid carcinoma of the colon and rectum.

To determine the clinicopathologic significance of colloid carcinoma in carcinoma of the colon and rectosigmoid/rectum, a retrospective review of 462 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. Seventy-seven patients (17%) were identified who had tumors with some component of colloid present. Colloid carcinoma occurred in 49 (11%). The remaining 28 (6%) had adenocarcinoma with colloid features. Compared to patients with pure adenocarcinoma, the 5-year actuarial survival of patients with colloid carcinoma was lower in the colon, rectosigmoid/rectum, and colorectum. Patterns of failure, expressed as the actuarial incidence of failure at 5 years, were examined by histologic condition and stage. Patients with Dukes' Stage B colloid carcinoma had a higher incidence of total failure, and patients with Dukes' Stage C colloid carcinoma had a higher incidence of local, abdominal, and total failure. None of the differences reached statistical significance. The presence of colloid carcinoma may have a real but small impact on the patterns of failure and survival in colorectal cancer.

Nasopharyngeal carcinoma: the Dana-Farber Cancer Institute experience with 24 patients treated with induction chemotherapy and radiotherapy.

Nasopharyngeal carcinoma traditionally has been treated with radiotherapy alone. Although the probability of cure for patients with stage I and II nasopharyngeal carcinoma is high, the probability of cure for patients with stage III and IV disease is poor because of a higher rate of local-regional and distant failure. Between February 1981 and August 1986, 24 patients with previously untreated, stage IV nasopharyngeal carcinoma were treated with two to four monthly courses of cisplatin-based combination chemotherapy prior to radiotherapy. A response to induction chemotherapy was recorded in 75% of patients (29% complete response and 46% partial) prior to radiotherapy. By actuarial estimate with a median follow-up of 42 months, the 2-year failure-free survival for all patients was 57%. In conclusion, induction chemotherapy has significant activity in nasopharyngeal carcinoma. The toxicity of this approach, as well as the influence of initial histopathology and response to chemotherapy on survival, will be discussed.

Cardiac disease after mediastinal irradiation for seminoma.

One hundred twenty-four patients with seminoma (119 primary testis, five primary extragonadal) were treated between 1968 and 1984 at the Joint Center for Radiation Therapy. Fifty-seven of the 124 patients were treated with irradiation to the mediastinum as well as to an infradiaphragmatic field. One patient received supradiaphragmatic radiotherapy only. The remaining patients had radiation treatment limited to the infradiaphragmatic field only. Median dose to the mediastinum among the 58 patients was 2400 cGy. Four patients developed heart disease (one fatal myocardial infarction, one uncomplicated myocardial infarction, one constrictive pericarditis resulting in permanent total body anasarca, and one patient requiring aortic valve replacement and coronary artery bypass grafting for atherosclerotic disease) and two died suddenly. The two sudden deaths were thought to be cardiac in origin by the patient's primary physicians. All six complications occurred in the group that received mediastinal irradiation. No cardiac disease was manifested in the group not treated with mediastinal irradiation. This difference in the incidence of cardiac disease between the two groups is statistically significant (two sided, P = 0.019). Neither group had a statistically significant difference in cardiac disease rate from a normal population (Framingham study), although the ratio of observed to expected cardiac disease was 1.97 in the group receiving mediastinal radiation. Further experience from this and other institutions is necessary to confirm this finding.

Sphincter preservation in patients with low rectal cancer treated with radiation therapy with or without local excision or fulguration.

Twenty-six patients with small cancers limited to the lower two-thirds of the rectum were treated with conservative surgery and radiation therapy (XRT). The selection factors for this approach were age, refusal of a permanent colostomy, or the high risk of local recurrence because of inadequate surgical margin or palpable residual tumor after local surgical treatment alone. In patients treated with local excision or fulguration followed by XRT, there was a 6% local failure rate (one in 17); in 16 of 17 patients receiving radiation doses above 4,500 cGy, the local control was complete for follow-up periods of 6 months to 7 years. In nine patients treated with XRT for residual tumor, local failure occurred in five (56%). The disease-free survival for those without residual tumor versus those with residual tumor was 88% and 44%, with median follow-up periods of 20 and 23 months, respectively. Serious late complications occurred only if total doses were greater than 6,300 cGy. Local excision combined with XRT proved to be a safe alternative to radical surgery in selected patients and resulted in excellent local control while allowing preservation of anal sphincter function.

Radiotherapy for prostate carcinoma: the JCRT experience (1968-1978). II. Factors related to tumor control and complications.

We have analyzed treatment failure and complications as a function of radiotherapy technique and other factors in 229 patients irradiated for prostate carcinoma from 1968-1978. Thirty-four patients (15%) developed clinical evidence of local-regional recurrence. In about one-quarter of these recurrences, there was a component of ureteral obstruction, possibly due to marginal miss in the seminal vesicles. Although different parameters of treatment technique were not significantly correlated with local failure, there was a trend toward higher failure rates for Stage B and C patients when the length and/or width of the conedown field was less than 8 cm (p = 0.27 and 0.25, respectively). As in other recent studies, patients with Stage C disease who had undergone trans-urethral resection of the prostate had a lower disease-free survival rate than patients who had only needle biopsy (39 vs. 65% at 5 years, p = 0.055). The use of larger initial fields treating the pelvic lymph nodes did not result in better local tumor control or better overall control. However, the use of larger fields did result in a higher rate of significant complications (8.7 vs. 1.6% for fields greater than or equal to 150 cm2 or less than 150 cm2, respectively, p = 0.013). In view of the higher complication rate and the absence of convincing evidence of benefit for whole pelvic treatment, irradiation of all pelvic lymph nodes can be questioned.

A pilot study of protracted venous infusion of 5-fluorouracil and concomitant radiation therapy.

A method to potentially increase the effectiveness of combination 5-fluorouracil (5-FU) and radiation therapy (XRT) using protracted (more than 30 days) venous infusion (PVI) of 5-FU with conventionally fractionated XRT (180 to 200 cGy per day) (100 cGy = 100 rad) is described. Forty-one patients were treated with this combination with acceptable acute toxicity. In 95% of patients, the toxicity was mild or moderate and symptom control was achieved with medications or a short treatment interruption. In two patients (5%), severe gastrointestinal side effects resulted in cessation of all therapy. This method of administration of 5-FU is feasible, and we have demonstrated that it can be safely used with a course of conventionally fractionated, high-dose (approximately to 6,500 cGy) radiation therapy.

Radiotherapy for localized prostate carcinoma.

We reviewed the radiation therapy treatment experience for localized prostate carcinoma at the Joint Center for Radiation Therapy from 1968-1978 (N = 229 patients, median follow-up of 5 years). Actuarial 5 (and 8) year survival rates for clinical Stage A (N = 25), B (N = 85), and C (N = 88) disease were 96% (82), 77% (63), and 61% (38). The corresponding 5 (and 8) year relapse-free survivals were 84% (67), 68% (61), and 53% (36). Actuarial rates of clinical local failure at 5 (and 8) years were 0%, (0), 12% (20), and 15% (30) for Stage A, B, and C respectively. There was a suggestion of a decrease in the force of local and overall recurrence after 8 years, although further follow-up will be necessary for confirmation. Among 42 patients who underwent pelvic lymphadenectomy followed by irradiation, lymph node status appeared to be a strong predictor of distant failure (9% (3/32) failures for node (-) patients compared to 70% (7/10) for node (+) patients). Twenty-nine patients received radiotherapy after radical prostatectomy for clinically palpable (Stage B and C) tumor. Only one of 16 patients treated post-operatively because of microscopic or gross residual disease has developed recurrence. By contrast, only 2 of 13 patients irradiated because of clinical local tumor recurrence remain alive and free of disease. We conclude that radiation therapy can provide effective long-term local control of prostate carcinoma, but that the ultimate radiocurability of the disease is not yet known.

Orthovoltage intraoperative radiotherapy: a new look at an old idea.

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.

Quality assurance in radiation therapy: clinical considerations.

Efforts to develop a Quality Assurance Program at the Joint Center for Radiation Therapy will be described. This will include defining the clinically relevant considerations, describing acceptable goals and allowable variation, developing mechanisms for determining compliance with these goals, and educational approaches toward common understanding. Consideration toward the development of regional and national Quality Assessment Programs will also be discussed concerning auditing techniques, developing a satisfactory reporting format, and creating a worthwhile learning experience for all involved.

Radiation therapy in the management of patients with mesothelioma.

The results of radiation therapy in the management of 27 patients with malignant mesothelioma were reviewed. Eight patients were treated with a curative intent combining attempted surgical excision of tumor (thoracic in 6 and peritoneal in 2), aggressive radiation therapy, and combination chemotherapy using an adriamycin-containing regimen. One patient achieved a 2-year disease-free interval followed by recurrence of tumor above the thoracic irradiation field. This patient was retreated with localized irradiation and is disease-free after 5 years of initial diagnosis. One patient has persistent abdominal disease at 18 months; the other 6 patients suffered local recurrence within 8-13 months of initiation of treatment. Radiation therapy was used in 19 other patients who received 29 courses for palliation of dyspnea, superior vena cava syndrome, dysphagia, or neurological symptoms of brain metastasis. A palliation index was used to determine the effectiveness of irradiation and revealed that relief of symptoms was complete or substantial in 5 treatment courses, moderately effective in 6 courses and inadequate in 18 treatment courses. Adequate palliation strongly correlated with a dose at or above 4,000 rad in 4 weeks. The management of patients with mesothelioma requires new and innovative approaches to increase the effectiveness of radiation therapy and minimize the significant potential combined toxicity of pulmonary irradiation and adriamycin.