Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study 81-17.

One hundred twenty-four eligible patients with advanced mucosal squamous cell carcinoma of the head and neck were entered into a pilot study of concomitant cisplatin (100 mg/m2 given every 3 weeks for three doses) and standard irradiation. The initial complete response (CR) was 71% with an additional two cases salvaged by surgery for an overall 73% CR. When no keratin was identified in the histologic specimen (41 patients) the CR was 90%. The nasopharynx showed the best CR (89%) among the sites. At 4 years after treatment, the estimated locoregional tumor control rate was 43% and the survival, 34%. When no keratin was present in the specimen, the estimated locoregional control of tumor was superior (56% versus 38% with keratin identified, P = 0.02) and the estimated survival was also superior (48% versus 26%, P = 0.008). Acute treatment-related toxicities included one death due to renal damage and two patients with life-threatening renal damage. The delivery of radiotherapy was not altered. Late toxicity included necrosis -3%, fibrosis -4%, and one fistula. The results of this study justify a randomized trial for the comparison of this combination of cisplatin and radiotherapy versus radiotherapy alone in advanced mucosal carcinomas of the head and neck.

Solitary brain metastasis: results of an RTOG/SWOG protocol evaluation surgery + RT versus RT alone.

From 1983 through 1986, the Southwest Oncology Group and Radiation Therapy Oncology Group conducted an intergroup study designed to evaluate the effectiveness of surgical resection in those patients with solitary central nervous system (CNS) metastases. The study was initially designed as a prospective randomized trial. Because of difficulty accruing patients, the registration format was altered and the patients were placed on study according to physician preference. Ninety-seven patients were registered on study and 80 patients were eventually analyzed. Fifty-five patients underwent radiation therapy alone and 25 patients received surgery and radiation. Fifty-nine percent of those patients undergoing radiation therapy alone improved or stabilized while 79% of those patients undergoing surgery and radiation therapy improved or stabilized. Eventually, 22% of the surgically treated patients failed in the brain while 45% of the patients undergoing radiation therapy exhibited a CNS relapse. Survival was improved when corrected for other prognostic factors in those patients undergoing surgical resection. Although not a prospective randomized trial, this study does suggest an improvement in the survival of a select group of patients able to tolerate neurosurgical resection.

A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac tromethamine, acetaminophen plus codeine, and placebo in cancer pain.

Seventy-five patients with moderate to severe cancer pain were randomly assigned in a double-blind fashion to receive first-dose ketorolac tromethamine 10 mg orally, acetaminophen 600 mg plus codeine 60 mg orally, or placebo, followed by subsequent doses of ketorolac or acetaminophen plus codeine four times daily for 7 days. Patient characteristics were similar among the treatment groups. The first-dose observation documented that both ketorolac and acetaminophen plus codeine produced an equivalent reduction in cancer pain and were superior to placebo as measured by pain intensity differences and pain relief. Multidose comparison documented a small but statistically significant advantage in mean daily pain relief favoring acetaminophen plus codeine, although there were no differences in mean daily ratings of overall effects for either study medication. Adverse symptoms were acceptable with both ketorolac and acetaminophen plus codeine. We conclude that ketorolac has significant analgesic activity in patients with cancer pain, although its precise role in the treatment regimen of these patients remains undefined.

Radiation therapy alone or combined with misonidazole in the treatment of locally advanced non-oat cell lung cancer: report of an RTOG prospective randomized trial.

From September 1979 to February 1983, 268 patients with unresectable, locally advanced (RTOG Stage III), non-small cell lung cancer were randomized to receive radiation therapy alone (RT) (50 Gy large field and 10 Gy boost), or combined with misonidazole (400 mg/m2 2-4 hr prior to RT daily for 5-6 weeks to a maximum dose of 12 g/m2 or until tumor progression). One hundred twenty-three patients who received irradiation alone and 116 given RT + misonidazole were evaluable for toxicity, time to tumor progression, and survival as of April 1987. The distribution of patient characteristics was similar in both treatment groups; 59% of the patients had a Karnofsky score of 90 or better, 53% had adenocarcinoma or large cell tumors, and 47% had Stage T3 tumors. Complete tumor regression was reported for 33 (27%) patients treated with radiation therapy alone and 24 (21%) who received misonidazole + RT. Median survival was 8 months with RT alone and 7.4 months with misonidazole + RT. Ninety-five percent of the patients have died. Seventy percent of the patients treated with radiation alone and 77% of those treated with misonidazole + RT died of progressive disease. Three patients treated with radiation alone and two with RT + misonidazole died subsequent to radiotherapy-related pneumonitis or pulmonary fibrosis. There was no significant improvement in response rates, local control, or survival for patients who received daily misonidazole along with irradiation compared with patients treated by irradiation alone.

Radiotherapy alone and chemoradiation for nonmetastatic esophageal carcinoma. A critical review of chemoradiation.

Sixty-five patients with nonmetastatic (Stages I, II, and III) esophageal cancer (EC) were treated with radiotherapy (RT) alone (56.00 to 61.00 Gy in 6 to 7 weeks) or synchronous combinations of radiotherapy and chemotherapy (RT-CT). RT-CT consisted of 41.40 to 50.40 Gy in 4.5 to 8 weeks with continuous infusion 5-fluorouracil 5-FU (1000 mg/m2/d for 4 days in weeks 1, 4, and 8), mitomycin C (10 mg/m2 intravenously [IV] in weeks 1 and 8), cisplatin (75 mg/m2 IV in week 4). Maintenance CT consisted of methotrexate (200 mg/m2 IV), leucovorin (10 mg/m2 orally every 6 hours for 5 doses), and 5-FU (600 mg/m2 IV) in weeks 10, 12, and 14. Thirty-five patients treated by RT alone (Group A) were comparable in terms of age, sex, AJC staging, histologic condition, and location of primary with 30 patients treated by RT-CT (Group B). In Group A (range, 2- to 144+ months), two patients (42 and 144 months) are alive and well. In Group B (range, 2- to 59+ months), 12 patients (7 to 59 months) are alive and well. Median survival in Group A is 8 months, compared with 15 months for patients achieving a complete response (CR) in Group B. Patients in Group B achieved a 77% CR rate by endoscopy-biopsy, whereas 30% of the patients in Group A achieved a CR (P = 0.0001). The recurrence rates at the primary site/regional nodes were 77% and 27% in Groups A and B, respectively (P = 0.0001). The incidences of distant metastases were 29% and 20%, respectively (P = 0.423). In Group A, the 1-year and 2-year cumulative survival rates were 27% and 13%, respectively. In Group B, the cumulative survival rates were 53% at 1 year and 29% at 2 years (P = 0.023). Aside from reversible myelotoxicity, the incidences of pulmonary fibrosis, esophagitis, and fistulae formation were less frequent in the combined technique treatment group. A compilation of reported chemoradiation protocols for EC indicates consistently improved 1-year and 2-year survival rates, compared with surgical and RT series. The key to further improvement in the treatment of EC appears to lie in increasing the biologic response (RT fractionation and endocavitary RT) and optimal use of multiple effective CT agents with nonadditive toxicities.

Clinical potential of synchronous radiotherapy and chemotherapy for advanced squamous cell carcinoma.

The equivocal results of past treatment regimens in which concurrent radiotherapy and chemotherapy were used may have resulted from a lack of site-specific active drugs that were also true radiation sensitizers. This report demonstrates an experience with 3 chemotherapeutic agents, 5-fluorouracil, cisplatin, and mitomycin, given simultaneously with radiation for locally advanced squamous cell carcinomas of such diverse sites as the anal canal, cervix, and esophagus. Early results show that the toxicity of these combination regimens is generally acceptable and indicate that such synchronous combination treatments may be superior in local control and survival to radiotherapy alone.

Preliminary results of concomitant radiotherapy and chemotherapy in advanced cervical carcinoma.

Ten patients with advanced and previously untreated squamous cell carcinoma of the cervix were treated with a synchronous course of radiotherapy (RT) and chemotherapy (CT). RT consisted of 3600 to 4500 cGy external pelvic treatments on a 6-MeV linear accelerator followed by two intracavitary applications administering a total of 4000 mg hr of radium equivalent cesium. CT consisted of a course of mitomycin C (10 mg/m2 iv bolus) and 5-fluorouracil (5FU; 1000 mg/m2/24 hr for 96 hr) during the second week of external RT and another course of cis-platinum (CDDP; 75 mg/m2, 1-6 hr infusion) and 5FU (1000 mg/m2/24 hr for 96 hr) during the first intracavitary cesium application. Toxicity was acceptable and complete clinical response was obtained in all patients at the end of the regimen. Nine patients are alive (eight without disease) 6 to 37 months following initiation of treatment (median 20 months). One patient has developed lumbar spine bone metastases and another died of local and pulmonary disease at 28 months. This combination of 5FU/mitomycin C/CDDP and RT appears to be a practical, well-tolerated, and highly effective regimen for advanced cervical carcinoma.

Inoperable esophageal carcinoma: results of aggressive synchronous radiotherapy and chemotherapy. A pilot study.

Twenty-one consecutive patients with squamous cell carcinoma of the esophagus (EC) were referred, with advanced Stage III disease in nine patients, severe pulmonary/cardiac disease in five patients, and postsurgical recurrences or metastatic disease in seven patients. They were treated with one to four courses of 5-fluorouracil (5-FU) + mitomycin C, alternating with 5-FU + cisplatin (5-FU: 1,000 mg/m2/24 X 96-h infusion; Mitomycin C: 10 mg/m2 i.v.; cisplatin: 75 mg/m2 i.v.) simultaneously with 3,000-5,000 cGy of local radiotherapy (RT) in 3.5-5.5 weeks. These doses of chemotherapy (CT) and RT were generally well tolerated except for prolonged thrombocytopenia in two patients, pancytopenia in one, pulmonary fibrosis in one, and acute renal failure in one. Six patients were alive and free of disease 8-40 months (median, 16 months; mean, 21.5 months) after initiation of treatment. Two additional patients died of unrelated causes without evidence of viable disease at autopsy. Our experience confirms the rapid and sustained palliation of dysphagia and pain obtained within 7-14 days after initiation of treatment. Mean survival of patients receiving one to two courses of CT and less than 4,000 cGy RT was 3.4 months compared to 16 months in patients receiving more than 2 courses of CT with RT. Five of six patients who are alive and free of disease received 4,000 cGy or greater. This experience suggests that escalated and concurrent doses of RT (greater than 4,000 cGy) and CT (three to four cycles) are tolerated with acceptable morbidity and could provide good palliation and sometimes prolonged disease-free status in those patients with EC who are considered inoperable because of advanced disease or medical reasons.

Definitive combined modality therapy of carcinoma of the anus. A report of 30 cases including results of salvage therapy in patients with residual disease.

Thirty patients with epidermoid carcinoma of the anus, ranging in age from 40 to 89 years, were treated with combined chemotherapy (CT) and radiation therapy (RT) in lieu of abdominoperineal resection. Two courses of 5-FU (1000 mg/m2/day X four days) by continuous infusion and mitomycin-C (10-15 mg/m2 IV bolus on day 1 of each course) were given 3 to 4 weeks apart simultaneously, with whole pelvis RT to 4140 to 4500 cGy. Twenty-one of 28 patients had T3-T4 primaries and ten had positive nodes (N1). Two of the 30 patients were treated for local recurrence following surgical excision and one was treated immediately after local excision. Twenty-six of the 30 patients attained biopsy-confirmed complete remission. Four of the 30 patients demonstrated residual disease at completion of therapy but all subsequently achieved complete remission with additional nonsurgical treatment. One patient, initially treated for local recurrence following excision failed locally at four years and was salvaged with chemotherapy followed by abdominoperineal resection. No patient has experienced distant failure. Twenty-seven of 30 patients were alive and disease free after 9 to 76 months of follow-up and three died, disease-free, of unrelated causes. Acute toxicities were mild and did not necessitate interruption of treatment. A brisk perineal reaction and diarrhea were noted in all patients. Late complications were unusual. All patients were treated in a community-based, private practice setting. The authors conclude that combined CT-RT, as employed herein, represents a first-line curative treatment for the majority of patients with epidermoid anal carcinoma. For patients who demonstrate residual disease following this therapy, salvage regimens such as 5-FU infusion and cisplatin, or sequential MTX-5-FU-Leucovorin with additional synchronous RT should be employed before resorting to radical surgery.

Feasibility of non-surgical definitive management of anal canal carcinoma.

The management of anal canal carcinoma has evolved over the last decade, with the combination of radiotherapy (RT) and chemotherapy (CT) offering a definitive alternative to surgery or RT alone. Twenty-two patients with basaloid/cloacogenic/squamous cell carcinoma of the anal (13 with T3-T4 lesions), were treated with synchronous RT (30.00 to 45.00 Gy in 3 1/2 to 5 weeks) and CT X 2 courses (Mitomycin C 15 mg/m2 I.V. bolus + 96 hours 5FU infusion). This regimen differed from the conventional Nigro regimen in that higher doses of RT and 2 courses of Mitomycin C were used and both CT courses were given synchronously with RT. Three patients with residual disease were salvaged with an additional course of CT and local RT, without surgery. Acute side effects including perineal dermatitis, diarrhea, leukopenia, and thrombocytopenia were reversible or transient. Twenty patients are alive and free of disease 17 to 62 months (median 45 months) following initiation of treatment. Two patients died at 7 months without evidence of disease at autopsy. These results compare favorably with other series employing RT alone, AP resection alone, and to those employing similar CT-RT regimens as well, in terms of disease-free survival rate (100%), complete response rate (19/22 or 86%), salvage rate without surgery (3/3), and acceptable morbidity. These results may be attributed to an optimal balance of RT and CT doses and refinements in RT technique which are detailed in our report.

Definitive nonsurgical therapy of epithelial malignancies of the anal canal. A report of 12 cases.

Twelve patients with epidermoid carcinoma of the anal region ranging in age from 40-89 years were treated with combined chemotherapy (CT) and radiotherapy (RT) in lieu of abdominal-perineal resection. Ten patients received no prior treatment and two patients were treated for local recurrence following limited surgical excision. Two courses of 5-FU infusion and mitomycin C were given 3-4 weeks apart simultaneously with whole pelvis RT to 3000-4140 rad. One patient received an additional tumor volume dose of 3094 rad by interstitial Iridium implant and one patient received an orthovoltage boost of 1000 rad to the anal ring. All patients completed treatment. Complete regression of the anal mass occurred in all patients. Biopsies of the anal region performed after completion of therapy revealed no evidence of residual cancer. Ten of the 12 patients are alive without evidence of disease 4-24 months (median, 14 months) after completion of treatment. Two patients have died seven months after treatment of unrelated causes and were tumor-free at autopsy. All patients developed proctitis, diarrhea, and moist perineal desquamation which resolved by four weeks posttreatment. Based on their experience and that of others recently reported, the authors conclude that the described CT-RT protocol offers a definitive alternative to surgery of epidermoid cancer of the anal region.