Radiation therapy for epidermoid carcinoma of the anal canal, clinical and treatment factors associated with outcome.

BACKGROUND AND PURPOSE: In recent years, treatment with combined chemotherapy and radiation has become the standard of care for epidermoid carcinoma of the anus. However, optimal radiotherapy techniques and doses are not well established. MATERIALS AND METHODS: During the period 1975-1997, 106 patients with epidermoid carcinoma of the anal canal underwent radiation therapy. Treatment policies evolved from radiation therapy alone or with surgery, to combined chemotherapy and radiation followed by surgery, to combined chemotherapy and radiation. RESULTS: Overall 74% of patients were NED (no evidence of disease) at last follow-up. The most important clinical correlate with ultimate freedom from disease (includes the contribution of salvage surgery) was extent of disease. The 5-year ultimate freedom from disease was 87+/-5% for T1/T2N0, 78+/-10% for T3N0 (15% salvaged by surgery), and 43+/-10% for either T4N0 or any N+ lesions (P<0.001, Tarone-Ware). There was no difference between planned vs. expectant surgery (5-year ultimate NED: 67+/-11% planned surgery vs. 73+/-5% expectant surgery). The most important correlate with late toxicity was a history of major pelvic surgery (surgical vs. non-surgical group: P=0.013, Fisher's exact test, two-tailed summation). Thirty-three additional malignancies have been seen in 26 patients. The most common additional malignancies were gynecologic (nine cases), head and neck (six cases), and lung cancer (five cases). CONCLUSIONS: For T1/T2N0 disease, moderate doses of radiation combined with chemotherapy provided adequate treatment. T4N0 and N+ lesions are the most appropriate candidates for investigational protocols evaluating dose intensification. T3N0 tumors may also be appropriate for investigation; however, dose intensification may ultimately prove counterproductive if the cure rate is not improved and salvage surgery is rendered more difficult. The volume of irradiated small bowel should be minimized for patients who have a past history of major pelvic surgery or who (because of locally advanced tumors) may need salvage surgery in the future. Because of the occurrence of additional malignancy, patients with anal cancer should receive general oncologic screening in long-term follow-up.

A phase I/II trial of three-dimensionally planned concurrent boost radiotherapy and protracted venous infusion of 5-FU chemotherapy for locally advanced rectal carcinoma.

BACKGROUND: Improving the response to preoperative therapy may increase the likelihood of successful resection of locally advanced rectal cancers. Historically, the pathologic complete response (pCR) rate has been < approximately 10% with preoperative radiation therapy alone and < approximately 20% with concurrent chemotherapy and radiation therapy. METHODS AND MATERIALS: Thirty-seven patients were enrolled on a prospective Phase I/II protocol conducted jointly at Washington University, St. Louis and the Catholic University of the Sacred Heart, Rome evaluating a three-dimensionally (3D) planned boost as part of the preoperative treatment of patients with unresectable or recurrent rectal cancer. Preoperative treatment consisted of 4500 cGy in 25 fractions over 5 weeks to the pelvis, with a 3D planned 90 cGy per fraction boost delivered once or twice a week concurrently (no time delay) with the pelvic radiation. Thus, on days when the boost was treated, the tumor received a dose of 270 cGy in one fraction while the remainder of the pelvis received 180 cGy. When indicated, nonaxial beams were used for the boost. The boost treatment was twice a week (total boost dose 900 cGy) if small bowel could be excluded from the boost volume, otherwise the boost was delivered once a week (total boost dose 450 cGy). Patients also received continuous infusion of 5-fluorouracil (1500 mg/m(2)-week) concurrently with the radiation as well as postoperative 5-FU/leucovorin. RESULTS: All 37 patients completed preoperative radiotherapy as planned within 32--39 elapsed days. Twenty-seven underwent proctectomy; reasons for unresectability included persistent locally advanced disease (6 cases) and progressive distant metastatic disease with stable or smaller local disease (4 cases). Actuarial 3-year survival was 82% for the group as a whole. Among resected cases the 3-year local control and freedom from disease relapse were 86% and 69%, respectively.Twenty-four of the lesions (65%) achieved an objective clinical response by size criteria, including 9 (24%) with pCR at the primary site (documented T0 at surgery). The most important factor for pCR was tumor volume: small lesions with planning target volume (PTV) < 200 cc showed a 50% pCR rate (p = 0.02). There were no treatment associated fatalities. Nine of the 37 patients (24%) experienced Grade 3 or 4 toxicities (usually proctitis) during preoperative treatment. There were an additional 7 perioperative and 2 late toxicities. The most important factors for small bowel toxicity (acute or late) were small bowel volume (> or = 150 cc at doses exceeding 4000 cGy) and large tumor (PTV > or = 800 cc). For rectal toxicity the threshold is PTV > or = 500 cc. CONCLUSION: 3D planned boost therapy is feasible. In addition to permitting the use of nonaxial beams for improved dose distributions, 3D planning provides tumor and normal tissue dose-volume information that is important in interpreting outcome. Every effort should be made to limit the treated small bowel to less than 150 cc. Tumor size is the most important predictor of response, with small lesions of PTV < 200 cc most likely to develop complete responses.

Neoadjuvant therapy for adenocarcinoma of the rectum: tumor response and acute toxicity.

PURPOSE: This study was designed to evaluate the down-staging effect and acute toxicity of preoperative radiation and chemoradiation for primary adenocarcinoma of the rectum. METHODS: The results of pretreatment staging with transrectal ultrasound and computed tomography were compared with final histologic stage in 260 consecutive patients who underwent neoadjuvant therapy and proctectomy for primary adenocarcinoma of the rectum. Patients underwent short-course radiation (2,000 cGy in five fractions), long-course radiation (4,500 cGy in 25 fractions), or chemoradiation (4,500 cGy in 25 fractions with concurrent chemotherapy). RESULTS: Down-staging of one or more T stages occurred in 116 of 260 (45 percent) patients overall (short-course radiation 34/82 (42 percent), long-course radiation 55/122 (45 percent), chemoradiation 27/56 (48 percent), P = not significant). Down-staging of one or more N stages occurred in 85 of 178 (48 percent) patients overall (short-course radiation 12/45 (27 percent), long-course radiation 49/86 (57 percent), chemoradiation 24/47 (51 percent), P = 0.003). Complete pathologic response was observed in 16 of 260 (6 percent) patients overall (short-course radiation 4/82 (5 percent), long-course radiation 5/122 (4 percent), chemoradiation 7/56 (13 percent), P = 0.08). Resection with negative margins (distal, proximal, and radial) was achieved in 211 of 227 patients (93 percent) in whom complete radial margin data were available. Permanent stomas were created in 35 percent of patients; temporary stomas were created in 15 percent. Thirty-three Grade 3 or 4 toxicities occurred in 22 of 260 (8 percent) patients overall during neoadjuvant therapy. Toxicity was more frequent in patients receiving chemoradiation (14/56; 25 percent) and long-course radiation (8/122; 7 percent) than in those receiving short-course radiation (0/82; 0 percent), P < 0.0001. Perioperative complications occurred in 93 patients overall (36 percent). The postoperative mortality rate was 0.4 percent (1/260). There was no significant difference in the complication rate between patients treated with short-course radiation (26/82; 32 percent), long-course radiation (46/122; 36 percent), and chemoradiation (21/56; 38 percent). CONCLUSION: Neoadjuvant therapy for adenocarcinoma of the rectum is well tolerated and can produce substantial down-staging and a high curative resection rate. Chemoradiation can achieve high complete pathologic response rates, although toxicity during neoadjuvant therapy is greater than for radiation alone. Short-course radiation can achieve down-staging of both T stage and N stage.

Adjuvant therapy for colon and rectal cancer.

Newly diagnosed colon or rectal cancer should be staged using the TNM (tumor, node and distant metastasis) nomenclature to determine prognostic factors. Based on this staging, it is possible to select patients in need of adjuvant therapy following surgery. In patients with stage III colon cancer, adjuvant chemotherapy with fluorouracil and levamisole has been shown to produce a 40 percent reduction in the recurrence rate at a median follow-up of 6.5 years as well as a 33 percent reduction in mortality. Adjuvant chemotherapy should be considered in all patients with stage III colon cancer and in selected patients with high-risk stage II colon cancer. A 34 percent improvement in disease-free interval and a 29 percent improvement in survival have been reported for patients receiving fluorouracil, methyl-CCNU and radiotherapy. Adjuvant chemotherapy and radiotherapy are indicated in patients with stages II and III rectal cancers.

Fatal outcome in a patient with autoimmune hemolytic anemia associated with an IgM bithermic anti-ITP.

BACKGROUND: Several cold autoantibodies (usually IgG) with IT specificity have been reported previously, as have autoantibodies with joint I and P blood group specificities (IP1, ITP1, iP1, IP). A fatal outcome associated with an IgM cold autoantibody of ITP specificity is reported. CASE REPORT: A 54-year-old man suffered from progressively severe cold autoimmune hemolytic anemia for 9 months. Hemoglobin concentration ranged from 6 to 7 g per dL (60-70 g/L) and reticulocytes from 3 to 5 percent (0.030-0.050). The direct antiglobulin test was weakly positive for IgM and strongly positive for C3d. The serum contained a cold agglutinin that reacted strongest with cord i red cells (RBCs) > adult I RBCs > adult i RBCs, which is consistent with IT specificity. The Donath-Landsteiner test was positive; the reaction was neutralized by globoside. The serum reacted weakly or was negative with RBCs from five group p blood donors, which suggests anti-ITP specificity. Dithiothreitol treatment of the serum abolished the cold agglutinin reactivity, which suggests that the anti-IT was IgM. The patient received > 40 RBC transfusions and failed to respond to oral steroids, oral cytoxan, high-dose pulse intravenous steroids, and plasma exchange at room temperature and at 35 degrees C. He died of sepsis following an unsuccessful trial of chlorambucil. Autopsy revealed unsuspected disseminated non-Hodgkin's lymphoma. CONCLUSION: Serologic studies are consistent with our patient's having a single IgM cold autoantibody with IT and P specificities (anti-ITP) and requiring both specificities on the same RBC to permit maximal antibody expression.

Respiratory muscle weakness and ventilatory failure in AL amyloidosis with muscular pseudohypertrophy.

Generalized muscle weakness culminating in ventilatory failure developed in a 59-year-old man with kappa light chain multiple myeloma. Physical examination demonstrated skeletal muscle enlargement, severe proximal muscle weakness, and macroglossia, consistent with amyloid-associated muscle pseudohypertrophy. Pulmonary function studies revealed a severe restrictive abnormality with a low maximal inspiratory pressure and maximal voluntary ventilation. Arterial blood gas values and chest radiographic results were normal. There was no clinical evidence of cardiac or central nervous system disease. At autopsy, skeletal muscles and diaphragm were diffusely infiltrated by amyloid. There was also multifocal deposition of amyloid in alveolar septae, esophagus, and subendocardium. This report suggests that ventilatory failure may occur as a complication of myeloma-associated (AL) amyloidosis involving the respiratory muscles.

Adjuvant chemotherapy with adriamycin, cytoxan, and cis-platinum in high-grade carcinoma of the prostate treated with definitive radiotherapy (RTOG pilot 81-12).

In a phase I-II trial, a regimen of Adriamycin, Cytoxan, and cis-Platinum has been tested as an adjuvant to definitive radiotherapy in patients with high-grade (Gleason score 8-10) locally advanced carcinoma of the prostate limited to the pelvis. The patients had no evidence of distant disease, were in good general condition, and had satisfactory cardiac, hepatic, and renal function. Radiation therapy consisted of 4,320-4,500 rad in 23-25 fractions to the pelvis followed by a boost to the prostate to a total of 6,480-7,020 rad in 36-39 treatments. Chemotherapy was scheduled to start 4 weeks after completion of radiotherapy and consisted of 300 mg/m2 of Cyclophosphamide, 30 mg/m2 of Adriamycin, and 50 mg/m2 of cis-Platinum cycles given at 4-week intervals. The primary aim of the study was evaluation of toxicity of the combined regimen. Nine patients were evaluable. No adverse effects of chemotherapy on the incidence and severity of radiation-related toxicity in the pelvis have been observed. Myelosuppression has been significant and has prevented delivery of full doses of chemotherapy. Although planned, no dose escalation was possible. Further reduction of dosage was necessitated in 67% of the patients. Delays in the delivery of chemotherapy were necessary in four patients; the delays ranged from 1 to 14 weeks. Although the regimen had been reported to produce a high rate of response in disseminated disease and has not been associated with an increased incidence of radiation-chemotherapy toxicity in the irradiated pelvis, it does not appear suitable for further testing in an adjuvant setup in patients treated with definitive radiotherapy.

Chemotherapy for head and neck cancer. Comparison of cisplatin + vinblastine + bleomycin versus methotrexate.

One hundred ninety-one patients with recurrent or metastatic squamous cell carcinoma of head and neck origin were allocated at random to chemotherapy with conventional-dose weekly intravenous methotrexate or the combination of cisplatin, vinblastine, and bleomycin. Methotrexate induced responses in 16 of 98 patients (16%), whereas 22 of 92 (24%) responded to the combination regimen (P = not significant). Remission duration (20.2 weeks methotrexate; 15.1 weeks combination) was similar on both arms, as was survival (31.4 weeks methotrexate; 29.0 weeks combination). Therapy was relatively well-tolerated on both treatment arms, although methotrexate produced more mucositis and the combination more gastrointestinal and renal toxicity. Response to chemotherapy and disease confined to the locoregional area were associated with somewhat longer survival. Combination chemotherapy as given in this study did not improve any observed parameter, and the results of treatment were poor in both arms.

Adriamycin, BCNU plus cyclophosphamide (ABC) in advanced carcinoma of the head and neck.

Forty-four patients with advanced carcinoma of the head and neck were treated with cyclophosphamide, 400 mg/m2 plus BCNU, 100 mg/m2 day 1 followed by adriamycin 40 mg/m2 day 2, with therapy repeated every 4 weeks. Of 31 evaluable patients, there were 1 complete response, and 10 partial responses (35%). Four of 8 patients without prior chemotherapy had complete or partial responses, as did 7 of 23 patients who had received prior chemotherapy. The mean survival for patients with partial responses was 8.8 months, and for patients with stable disease was 7.8 months. The mean time to progression for patients with partial responses was 5.4 months, and for patients with stable disease was 3.2 months. Granulocytopenia was the dose limiting toxicity, and patients with increasing degrees of myelosuppression appeared to have higher quality responses and longer survival. The ABC treatment program is useful in the palliative management of patients with advanced carcinoma of the head and neck.

Phase I study of thymidine plus 5-fluorouracil infusions in advanced colorectal carcinoma.

In order to determine the minimal toxic dose of a 5-day infusion of 5-fluorouracil (5--FU) in combination with an infusion of thymidine (TdR), 12 patients, received TdR at a dose of 8 g/m2/day for 5 1/2 days, beginning at the same time as a 5-day infusion of 5-FU at doses of 5--20 mg/kg/day. Myelosuppression was the dose-limiting toxicity, and the minimal toxic dose of 5--FU was found to be 7.5 mg/kg/day. Gastrointestinal toxicity was minimal to absent. In eight patients with carcinoma of the colon who had received no prior chemotherapy, there were two patients with partial responses (at doses of 5.0 and 7.5 mg/kg/day of 5--FU), two patients with stable disease, one patient with progressive disease, and three patients with early death (two drug-related deaths and one disease-related death). In four patients who had received prior 5--FU, one had stable disease, one had progressive disease, and two had early death (one drug-related death). We conclude that the addition of TdR to 5--FU infusions changes the dose-limiting toxicity from gastrointestinal toxicity to myelosuppression. The minimal toxic dose is decreased to approximately one third of that when 5--FU is administered alone.

Hydroxyethyl starch and prednisone as adjuncts to granulocyte collection.

A total of 232 leukaphereses were performed with a continuous flow (CFC) of 89 donors related to recipients to obtain granulocytes for infected granulocytopenic recipients. One hundred fifteen runs were done without pretreatment of the donors and were used as controls. Pharmacological pretreatment of the remaining one hundred seventeen donors included Prednisone, given in an oral dose (50 mg) the evening prior to the run, and/or 250ml of 6 per cent hydroxyethyl starch added to the input line of the CFC throughout the run. A median of 9.2 liters of donor blood was processed with each run. The pretreatment of the donors with Prednisone plus the addition of HES to the input line significantly increased the number of granulocytes collected. Donors tolerated the leukapheresis procedure well, and no significant side effects were associated with Prednisone or HES administration. Early and frequent use of such granulocytes was effective in the short-term control of fever in the granulocytopenic recipients who failed to respond to 48 hours of broad spectrum antibiotic coverage.

Pancytopenia and "caillary leak syndrome" with infectious mononucleosis.

A 19-year-old man with documented infectious mononucleosis presented with pancytopenia and a megaloblastic bone marrow. He developed a "capillary leak syndrome" with an expanded plasma volume of 9,290 ml and normal right heart and pulmonary artery pressures. The patient had a dramatic recovery after corticosteroid therapy.

Correlation of anemia with infradiaphragmatic involvement in Hodgkin's disease and other malignant lymphomas.

A staging laparotomy and splenectomy were performed in 41 patients with Hodgkin's disease and 11 with other malignant lymphomas. There was a significant correlation (P = 0.025) between the presence of unexplained anemia and involvement of the spleen or abdominal lymph nodes by tumour. The anemias were of mild degree; hemolysis was documented in three and iron deficiency in four, while 21 cases were unexplained. Bone marrow was not involved by lymphoma in this series. The complication rate in exploratory laparotomy was higher than previously reported. Severe complications were observed in 17% of these patients while another 15% had minor complications. The association we have discovered may be helpful in the staging of patients who cannot tolerate an operative procedure. The absence of infradiaphragmatic involvement is suggested in the presence of normal hemoglobin concentrations.