Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314.

Following documented evidence of the synergism of 5-fluorouracil (5-FU) and radiation therapy and an additive effect with mitomycin and irradiation, pilot studies have demonstrated the potential for definitive radiation therapy in the management of squamous cell and basaloid carcinomas of the anal canal, allowing sphincter preservation. Our study explored the long-term effectiveness of combined therapy at this disease site and examined the feasibility of a Radiation Therapy Oncology Group study involving concomitant radiation therapy and chemotherapy. Between 1983 and 1987, 79 assessable patients with any primary tumor stage of anal canal carcinoma were treated by external-beam irradiation combined with mitomycin given by bolus iv injection and 5-FU given by continuous infusion. Radiation was delivered to the perineum and pelvis to a total dose of 4,080 cGy in 4.5-5 weeks. The inguinal nodal areas received 4,080 cGy, calculated at a 3-cm depth in the center of the nodal area. A 96-hour infusion of 5-FU was started on days 2 and 28 of the irradiation at a dose of 1,000 mg/m2 over 24 hours, and a bolus injection of mitomycin was administered on day 2 at a dose of 10 mg/m2. The overall survival rates are 97% at 1 year and 73% at 3 years. Patients with lesions less than 3 cm in diameter and those treated strictly according to the protocol did significantly better than those with larger lesions and those whose treatment did not comply with the protocol. The interim outcome of the study demonstrates that this combined therapy is effective for patients with anal cancer and allows preservation of the sphincter and of sexual function.

Bone marrow transplantation for hematologic malignancies in patients aged 30 years or older.

During the past 10 years, 86 patients 30 to 54 years of age with hematologic malignancies were prepared with high-dose radiochemotherapy and received histocompatible bone marrow grafts. Thirty-four of these patients are surviving for 4 months to 9 years (median, 26 months) following marrow transplantation and 32 of them are in continuing complete remission (CR). Disease-free survival is 44% for 37 patients who were in first remission of acute leukemia or in the chronic phase of chronic granulocytic leukemia (CGL), 23% for 39 patients whose leukemia had relapsed at least once before transplantation or who had advanced stages of CGL, and 60% for ten patients who had hematologic malignancies other than leukemia. The median age of the surviving 34 patients is 36 years (range, 30 to 43 years). The incidence of moderate to severe acute graft-v-host disease (GVHD) was 48% and of chronic GVHD, 26%. The major causes of failure were interstitial pneumonia in 31 patients (24 of whom had antecedent acute GVHD) and recurrent leukemia in 12 patients (11 of whom had either never entered a CR or had relapsed at least once with acute leukemia or had progressive CGL before transplantation). Our data warrant further prospective studies in patients with hematologic malignancies who are older than 30 years.

Cutaneous extramedullary hematopoiesis following splenectomy for idiopathic myelofibrosis.

A 50-year-old man with idiopathic myelofibrosis had development of extensive cutaneous extramedullary hematopoiesis after undergoing splenectomy. Treatment with hydroxyurea was not effective, but electron-beam irradiation controlled the cutaneous infiltration. This rare clinical manifestation of idiopathic myelofibrosis can be confused with cellulitis, and diagnosis depends upon biopsy.

Radical radiotherapy as salvage treatment for relapse of Hodgkin's disease initially treated by chemotherapy alone: prognostic significance of the disease-free interval.

PURPOSE: A study was performed to determine the effectiveness of radical radiation therapy (RT) in the treatment of patients with Hodgkin's disease who relapsed following initial treatment with chemotherapy alone. METHODS AND MATERIALS: A retrospective review of patients treated at City of Hope National Medical Center between 1970 and 1987 revealed a total of 10 patients who received radical RT with curative intent as salvage therapy. RESULTS: Complete remission was achieved in eight of the ten patients. Patients had an overall 5-year actual survival of 60% and 10-year actuarial survival of 38%. Relapse-free survival was 30% at 5 years and at 10 years. For the five patients with a disease-free interval (DFI) of at least 12 months prior to radical RT, overall actual survival at 5 years was 100% and relapse-free survival was 60%. Three of the ten patients, all with a DFI > 12 months and in first relapse when undergoing radical RT, were long-term relapse-free survivors. CONCLUSION: Radical RT is an effective salvage regimen for select patients with advanced stage Hodgkin's disease who relapse following initial treatment with chemotherapy alone provided that relapse is limited to sites which can be encompassed by radical RT fields and the DFI is greater than 12 months. Review of other published series supports DFI > 12 months as a favorable prognostic factor. Comparison to other salvage regimens such as autologous bone marrow transplantation is limited. Reviews of other treatment modalities should perform subset analysis on patients with similar presentations to compare the relative effectiveness of various salvage approaches.

Limited usefulness of observer-based cosmesis scales employed to evaluate patients treated conservatively for breast cancer.

We evaluated the relative usefulness of two observer-based scales commonly employed to assess the cosmetic outcome of patients treated by breast-preserving techniques for breast cancer. We asked 44 volunteer observers to employ one or the other scale to assess cosmetic outcome in a series of 14 projected color photographs of frontal views of treated patients. Our results demonstrate that observer concensus with either scale is rarely attained, particularly for patients with T1 or T2 tumors. Experienced observers could reach a concensus more often, although still infrequently. Moreover, the reliability of both scales is poor, since approximately one-third of observers evaluating one photograph twice during the same test session changed their answer. We conclude that while observer-based cosmesis scales demonstrate that current surgical and radiation therapy techniques can provide a "good" cosmetic result in 66-90% of patients with Stage I or II breast cancer, they lack the sensitivity and reliability to evaluate factors affecting cosmetic outcome since all forms of cosmetic change are lumped together into one assessment. Each type of cosmetic change should be evaluated separately by objective measures to determine factors related to its development.

Acute normal tissue tolerance to 7 day per week accelerated fractionation.

Fifty-six sites in 49 patients were irradiated by a 7 day/week accelerated fractionation schedule to conventional tumor doses. Daily doses were 180 to 200 rad in 85% of sites. Patients were analyzed for normal tissue tolerance. A 7 day/week accelerated fractionation appears clinically tolerable at 180 rad per fraction.

Spontaneous pneumothorax in patients irradiated for Hodgkin's disease and other malignant lymphomas.

A retrospective review of patients treated for Hodgkin's disease or other malignant lymphomas between 1953 and 1988 revealed 10 cases of spontaneous pneumothorax. Nine had Hodgkin's disease whereas one had diffuse histiocytic lymphoma. Ages of the 10 patients ranged from 11 to 54 years, although nine were less than 30-years old. Spontaneous pneumothorax was observed only in patients who had received mantle or mini-mantle radiation therapy (RT). Five patients had concurrent severe parenchymal pulmonary disease including chemotherapy-induced interstitial fibrosis, Varicella pneumonia and severe radiation pneumonitis. Pneumothorax in these patients tended to be severe, bilateral and/or recurrent. All five required chest tube placement. Three of the five also required thoracotomy. RT dose ranged from 3000-7500 cGy, exceeding 4700 cGy in three patients who required a second course of RT which included the involved lung apex. In comparison, the five who did not have concurrent severe lung disease had milder episodes of pneumothorax. Only one required chest tube placement, whereas none required thoracotomy. Pulmonary apex RT dose ranged from 3672-4257 cGy. For Hodgkin's disease patients treated by RT, the frequency of spontaneous pneumothorax in the absence of concurrent pulmonary disease was 2.2%. Limiting analysis to patients in the peak age population of 10-30 years raised the frequency to 3.0%. No RT dose-response effect could be demonstrated, although spontaneous pneumothorax was not observed in patients who received less than 3000 cGy. Spontaneous pneumothorax was not more frequent among patients who also received chemotherapy as compared to those treated only by RT. Exploratory thoracotomy in three cases with severe pulmonary disease revealed subpleural apical blebs and/or dense pleural fibrosis. Unusual aspects in the medical histories of other cases suggest the possibility that patients who develop pneumothorax may have unusually dense pulmonary and/or pleural fibrosis compared to the majority of patients who receive RT for Hodgkin's disease or other malignant lymphomas.

To boost or not to boost: decreasing radiation therapy in conservative breast cancer treatment when "inked" tumor resection margins are pathologically free of cancer.

A retrospective study was performed to compare local treatment approaches for 108 treated breasts in 105 patients with Stage I or II breast cancer. Six cases with intraductal carcinoma have shown no evidence of recurrence. The other 102 cases had invasive cancer. In 54 treated breasts in 53 patients, the treatment approach involved surgical resection of the primary tumor, pathological determination of tumor-free "inked" specimen margins and 5000 cGy to the whole breast. Local radiation therapy (RT) boosts to the primary site were not given. This approach produced a 100% local control rate (mean follow-up of 38 months). In 28 treated breasts in 27 patients, the treatment approach involved tumor excision without evaluation of specimen margins followed by RT which included a local boost by either interstitial Iridium-192 implant or electron beam. This approach yielded an actuarial local control rate of 87% at 48 months (mean follow-up of 47 months). The difference in local control rate between the two groups was statistically significant (p less than 0.03). Among patients with clear surgical margins who received a local RT boost, 1 of 9 developed a local recurrence. Among those with tumor involving specimen margins who received a local boost, 1 of 8 developed local recurrence. Local recurrence developed more frequently among patients with poorly differentiated cancers (2 of 11 cases) than among those with other invasive cancers (3 of 91 cases). Comparison of treatment approaches was limited since poorly differentiated cancer was present in 25% of cases with unknown specimen margins, as compared with only 2% of those with clear surgical margins who did not receive a local RT boost. Our preliminary findings suggest that when "inked" primary tumor resection margins are pathologically free of cancer, 5000 cGy whole breast RT appears to be highly effective for local tumor control in patients with Stage I or II disease. Our results are inconclusive as to whether patients with poorly differentiated cancers should receive a local RT boost even when surgical margins are clear.

The reverse hockey stick technique: postmastectomy radiation therapy for breast cancer patients with locally advanced tumor presentation or extensive loco-regional recurrence.

A combination of photon and electron radiation therapy (RT) fields was devised to treat patients with initial or recurrent breast cancer presentations which extensively involved the chest wall (CW) and/or the axilla. The ipsilateral supraclavicular, infraclavicular, axillary, and lateral CW regions are treated in continuity by anterior and posterior opposed photon beam "reverse hockey stick" fields. The internal mammary and medial chest wall regions are treated by an anterior electron beam field which is tightly junctioned to the photon beam fields. Electron beam energy and thickness of applied bolus are selected so that the electron beam 80% depth isodose curve matches the anterior pleural surface and/or deepest extent of tumor. The goal of treatment is to deliver 4400-5000 cGy to regions at risk of microscopic tumor with local boosts to 6000-7500 cGy to sites of gross disease. Between January 1977, and June 1985, this technique was selectively used in 46 patients, 31 patients with loco-regional tumor recurrence and 15 post-mastectomy patients who initially presented with locally advanced disease. A minimum tumor dose of 4400 cGy was delivered in all except five patients. A diffuse moist skin reaction developed in 31 of the 44 (70%) patients who received at least 3800 cGy. This healed in less than 1 month in all except seven. Frequency of CW diffuse moist skin reaction within the electron beam field was related to the daily applied RT dose. Diffuse moist skin reactions were also noted to be more frequent among patients who had received prior or concurrent Adriamycin. Significant complications included symptomatic arm lymphedema in seven; CW ulcer in two; and acute radiation pneumonitis; steroid-withdrawal radiation pneumonitis, pleuritis, and marked thrombocytopenia in one patient each. With a follow-up of 36-100 months, there was no evidence of loco-regional tumor relapse in 55% of patients treated for recurrent disease and in 73% treated following mastectomy for locally advanced presentations. In summary, we find the reverse hockey stick technique to be a simple, highly reproducible and effective RT approach for postmastectomy breast cancer patients with extensive initial presentation or recurrent disease.

Breast edema in patients treated conservatively for stage I and II breast cancer.

Breast edema was evaluated in 45 patients with Stage I or II breast cancer (including two with simultaneous, bilateral disease), who were treated by breast-preserving treatment approaches. Multiple variable statistical analysis revealed that bra cup size was the only factor significantly related to the appearance of breast edema. Breast edema occurred in 3 of 20 breasts (15%) with bra cup size A or B, as compared to 13 of 27 breasts (48%) with bra cup size C, D or DD(p less than 0.03). Breast edema was more likely to occur in patients who underwent full axillary dissection as compared to those who underwent axillary sampling or no axillary surgery. This observation, however, was not statistically significant. Neither the radiation therapy parameters nor the use of adjuvant chemotherapy were found to be related to the development of breast edema. Breast edema appears to be a transient phenomenon observed most frequently in the first year after the end of irradiation. It was observed much less frequently in those patients evaluated over 1 year following the end of radiation therapy.

Patient self-evaluation of cosmetic outcome of breast-preserving cancer treatment.

Thirty-two patients with Stage I or II breast cancer who had completed conservative breast-preserving treatment were asked to rate their cosmetic outcomes. Within this group, extent of the surgical excision of the breast tumor varied, with biopsy scars ranging from 2 to 19.5 cm. All patients had received external beam radiotherapy, with local boost doses in 17 cases. The average interval between self-evaluation and the completion of radiotherapy was 19 months. Patients completed a questionnaire rating the appearance of the treated breast, the degree of difference between breasts and overall satisfaction with cosmesis. They were asked to describe differences between breasts and to make any additional comments. Appearance of the treated breast was rated good to excellent by 94%, although 88% noted a difference of slight to moderate degree between treated and untreated breasts. Overall, 78% of patients were very to extremely satisfied, while moderate satisfaction was reported by 19%. Reports of breast differences included reduced size of the treated breast (44%), increased firmness (31%), elevation (25%), and skin color changes (22%). Reasons for dissatisfaction included chronic breast pain in 3 patients, breast edema in one and arm edema in one. Two patients wanted the untreated breast reduced in size. Statistically significant inverse relationships were found between the length of the biopsy scar and patient ratings of both appearance of the treated breast and overall satisfaction. These results indicated that although most patients were satisfied with cosmetic results of breast-preserving treatments, they are quite discriminating in their evaluations of differences between breasts. Functional factors such as pain and edema had a negative impact on satisfaction with cosmesis.

Breast retraction assessment: an objective evaluation of cosmetic results of patients treated conservatively for breast cancer.

Breast Retraction Assessment (BRA) is an objective evaluation of the amount of cosmetic retraction of the treated breast in comparison to the untreated breast in patients who receive conservative treatment for breast cancer. A clear acrylic sheet supported vertically and marked as a grid at 1 cm intervals is employed to perform the measurements. Average BRA value (+/- standard deviation) in 29 control patients without breast cancer was 1.2 cm (+/- 0.7 cm). Average BRA value in 27 patients treated conservatively for clinical Stage I or II unilateral breast cancer was 3.7 cm (+/- 2.1 cm). BRA values in breast cancer patients ranged from 0.0 to 8.5 cm. Statistical analysis revealed that tumor size, employment of adjuvant chemotherapy and use of separate radiation lymph node fields were not factors in breast retraction. Patients who received a local radiation boost to the primary tumor bed site had statistically significantly less retraction than those who did not receive a boost. Patients who had an extensive primary tumor resection had statistically significantly more retraction than those who underwent a more limited resection. In comparison to qualitative forms of cosmetic analysis, BRA is an objective test that can quantitatively evaluate factors which may be related to cosmetic retraction in patients treated conservatively for breast cancer.

Tube feeding enteral nutritional support in patients receiving radiation therapy for advanced head and neck cancer.

A retrospective study evaluated the role of tube feeding enteral nutritional support in patients receiving radiation therapy (RT) for Stage III and IV squamous cell carcinoma of the head and neck. Tube feeding (TF) by either nasogastric, cervical esophagostomy, or gastrostomy route was based on individual physician preference and patient acceptance. TF feeding starting before and continuing through RT (planned TF) was completed in 17 patients, whereas 9 patients did not receive TF until they lost weight during RT (interventional TF). No tube feeding was performed in 63 patients. By the end of RT, the planned TF group lost an average of 4.8% of initial body weight, compared to 7.1% in the no TF group and 9.4% in the interventional TF group. At the end of RT, only 6% of the planned TF group had lost over 10% of initial body weight, compared to 24% of the no TF group and 44% of the interventional group. Excluding patients who continued to lose weight after the end of RT due to rapidly recurrent tumor, 49% of the no TF group had a post-RT nadir weight loss over 10% of initial body weight, compared to 0% of the planned RT group. However, failure to receive the full RT dose and/or lengthy rest periods during RT were just as likely to occur in the planned TF group as in the no TF group. This retrospective review also could not demonstrate improved survival in the planned TF group. Complications, including peptic ulcer disease, aspiration pneumonia, cervical stoma abscess, and hepatic encephalopathy, occurred in 7 of the 26 patients (27%) receiving either planned or interventional TF. We conclude that TF will help minimize weight loss due to side effects of RT for head and neck cancer, particularly when TF is instituted before the onset of significant weight loss due to RT side effects. Survival differences, however, were not apparent.

Arm lymphedema in patients treated conservatively for breast cancer: relationship to patient age and axillary node dissection technique.

Arm lymphedema (ALE) was evaluated in 74 patients treated conservatively for breast cancer. ALE was defined based upon measurements performed upon 35 volunteer subjects who did not have and were never treated for breast cancer. Multiple variable statistical analysis of 74 breast cancer patients revealed that age at diagnosis was the most important factor related to the subsequent development of ALE. ALE appeared in 7 of 28 patients (25%) 60 years of age or older but in only 3 of 46 (7%) younger patients (p less than 0.02). Axillary node dissection (AND) was the only other statistically significant factor. For the younger patients, obesity and post-operative wound complications appeared to be contributing factors. For the older patients, AND technique was the only significant factor. ALE developed in only 1 of 10 (10%) of the older patients who underwent AND without splitting the pectoralis minor muscle (PMM), but in 6 of 11 (55%) who underwent AND with PMM split (p less than 0.03). Splitting the PMM during AND did not yield more lymph nodes for pathological analysis nor did it yield a higher incidence of patients with nodal metastases. Neither the use of lymph node radiation therapy fields, radiation to the full axilla, nor systemic chemotherapy was associated with ALE. We conclude that older patients are at higher risk of ALE and that this complication can possibly be reduced by not splitting the PMM during axillary node dissection.

Total skin electron irradiation for mycosis fungoides: relationship between acute toxicities and measured dose at different anatomic sites.

From June 1978 to June 1986, 50 patients with primary and recurrent mycosis fungoides were treated with total skin electron irradiation (TSEI), using the Stanford technique, to a total dose of 3600 cGy. TSEI was used alone, or in combination with low dose total body photon irradiation, or MOPP. Thermoluminescent dosimeter (TLD) measurements of the prescribed skin dose were obtained on twenty patients. The dorsum of the foot was 24% higher. The axillae, the bottom, and the arch of the foot were significantly underdosed. Frequencies of acute toxicities noted at 2000 cGy were: Skin, Grade I-II (RTOG) 80%. Partial epilation: scalp, 100%; eyebrows and at eyelashes, 20%. Nail dystrophy, 48%. Edema: hands and feet, 44%. Bullae: dorsum of feet, 8%; hands, 4%; and 3600 cGy: Skin, grade III 22%. Total epilation: scalp, 66%; eyebrows and eyelashes, 56%. Nail loss, 38%. Edema: hands and feet, 76%. Bullae: dorsum of feet, 34%; hands, 12%. Conjunctivitis, 4%. Large bullae, were more significant on the dorsum of the feet. Severe moist desquamation occurred in eight patients who had ulcerated lesions on initial presentation. Three patients were hospitalized due to ulceration and skin infection. All patients completed treatment after a short to moderate break. No patient developed skin necrosis, or corneal ulceration. No correlation exists between dose level, degree and onset of toxicity with previous chemotherapy or TBI. We conclude that the overall toxicity of TSEI is well tolerated.

Bone marrow transplantation for acute nonlymphoblastic leukemia during first complete remission. An analysis of prognostic factors.

Sixty-nine patients with acute nonlymphocytic leukemia in first remission received total-body irradiation and chemotherapy followed by allogeneic bone marrow transplantation from histocompatible sibling donors. Patient age was between 1 and 41 years: 20 patients 1-19 years (group 1); 27 patients 20-29 years (group 2); and 22 patients 30-41 years (group 3). Two pretransplant radiochemotherapy regimens were employed: The first 45 patients received total-body irradiation (in a single dose) with cytosine arabinoside and cyclophosphamide; the next 24 patients received total-body irradiation (in a fractionated schedule) with cyclophosphamide alone. For all patients, actuarial disease-free survival is 51% (37 of 69 patients are alive and in continuous remission between 5 months and 9.3 years, median 3.7 years). For group 1 actuarial survival is 56%, group 2 48%, and group 3 48%. When analyzed for pretransplant factors that might predict disease-free survival after bone marrow transplantation neither patient age, white cell count at the time of diagnosis, FAB leukemic subtype, length of time before achieving remission, nor length of time between remission and bone marrow transplantation were established as prognostic.

Preoperative chemotherapy and radiotherapy for cancer of the esophagus.

BACKGROUND: We wished to determine the role and significance of preoperative chemotherapy and radiotherapy in management of operable cancer of the esophagus. METHODS: Twenty-two patients with clinical stage I-II cancer of the esophagus were entered in a prospective study of preoperative chemotherapy (5-fluorouracil/cisplatin) and radiotherapy (3405 cGy) administered concomitantly during 21 days followed by restaging and total esophagectomy. RESULTS: Five patients did not complete the protocol (three had toxicity, one refused surgery, and one had interim distant metastasis). Seventeen patients underwent total esophagectomy with cervical anastomosis. Two postoperative deaths resulted from sepsis. Thirteen (76%) of 17 patients were considered to have complete clinical response (esophagoscopy and computed axial tomographic scanning) before surgery, but only 5 (29%) of 17 were free of cancer. The median survival was 18 months (median follow-up 57 months). No difference in survival was seen between complete and partial pathologic response. CONCLUSIONS: (1) Preoperative chemotherapy and radiotherapy did not result in increased survival compared with historic controls (surgery alone). (2) Preoperative chemotherapy and radiotherapy clinical staging overestimates the incidence of complete tumor response. (3) Combination chemotherapy is well tolerated, but until newly developed drugs show their efficacy for treatment, surgery should continue to be the major modality for local control and an integral part of clinical investigational trials.