Squamous cell carcinoma of the anal canal

PURPOSE: To report the results of primary radiotherapy for treatment of anal canal carcinoma from the University of Florida series and review issues related to treatment of this disease. METHODS AND MATERIALS: Forty-nine patients were treated with primary radiation therapy (RT) for cure. Patients had a minimum 2-year follow-up (median, 9.8 years). After 1990, patients with lesions of at least 3 cm also received chemotherapy with fluorouracil (1000 mg/m(2)) plus cisplatin (100 mg/m(2)) or mitomycin (10-15 mg/m(2)) if medically fit (n = 26). RT was delivered with a 4-field box technique to deliver 45 Gy in 25 fractions. The inguinal nodes were treated daily using electrons to supplement the dose in that region to a total dose of 45 Gy if clinically negative or about 60 Gy if involved. There were no planned breaks. A 10- to 15-Gy boost was delivered using interstitial iridium 192 implant (n = 32), en face (60)Co field (n = 5), or external-beam photon fields (n = 11). RESULTS: Local control rates at 5 years were 100% for T1N0, 92% for T2N0 or N1, 75% for T3N0, 67% for T4N0, 88% for T4N(pos) or T(any)N2-3, and 85% overall. With surgical salvage, ultimate local control rates were 100%, 100%, 81%, 100%, and 88%, respectively, with 92% overall. Cause-specific survival rates at 5 years were 100% for Stage I, 88% for Stage II, 100% for Stage IIIA, and 70% for Stage IIIB. Absolute survival rates at 5 years were 62%, 68%, 100%, and 70%. Sphincter preservation rates were 83%, 79%, 75%, and 100% by stage and 81% overall. There was an improvement in local control with the addition of chemotherapy in more advanced disease, but it was not significant. There was an increase in acute toxicity with the addition of chemotherapy (12% > or = Grade 4) but not long-term toxicity. Late toxicity requiring colostomy occurred in 6% of patients and consisted of soft tissue necrosis. CONCLUSIONS: The majority of patients with anal canal carcinoma can be treated with curative intent using a sphincter-sparing approach of radiation with or without chemotherapy even with advanced disease. With the addition of chemotherapy to radiation, there is an increased risk of acute toxicity and about 1-2% incidence of toxic death. Smaller tumors (T1 and early T2) probably do not require the addition of chemotherapy.     

Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group

PURPOSE: To compare the outcome of treatment of mediastinoscopy-verified N2 non-small-cell lung cancer treated with induction chemotherapy followed by either surgery or radiotherapy (RT), with both options followed by consolidation chemotherapy. METHODS AND MATERIALS: A randomized Phase III trial for Stage IIIA (T1-T3N2M0) non-small cell lung cancer was conducted by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group between April 1990 and April 1994. After documentation of N2 disease by mediastinoscopy or anterior mediastinotomy, patients received induction chemotherapy with cisplatin, vinblastine, and mitomycin-C. Mitomycin-C was later dropped from the induction regimen. Patients were then randomized to surgery or RT (64 Gy in 7 weeks) followed by cisplatin and vinblastine. RESULTS: RTOG 89-01 accrued 75 patients, of whom 73 were eligible and analyzable. Twelve patients received induction chemotherapy but were not randomized to RT or surgery thereafter. Forty-five patients were randomized to postinduction RT or surgery. Of the analyzable patients, 90% had a Karnofsky performance score of 90-100, 18% had weight loss >5%, 37% had squamous cell histologic features, and 54% had bulky N2 disease. The distribution of bulky N2 disease was uniform among the treatment arms. The incidence of Grade 4 toxicity was 56% in patients receiving mitomycin-C and 29% in those who did not. Only 1 patient in each group had acute nonhematologic toxicity greater than Grade 3 (nausea and vomiting). No acute Grade 4 radiation toxicity developed. The incidences of long-term toxicity were equivalent across the arms. Three treatment-related deaths occurred: 2 patients in the surgical arms (one late pulmonary toxicity and one pulmonary embolus), and 1 patient in the radiation arm (radiation pneumonitis). Induction chemotherapy was completed in 78% of the patients. Complete resection was performed in 73% of 26 patients undergoing thoracotomy. Consolidation chemotherapy was completed in 75% of the patients. No statistically significant difference was found among the treatment arms. The overall progression-free survival rate was 53% at 1 year and 17% at 3 years. The median progression-free survival was 14 months. No difference in the 1-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between the surgery and RT arms. The median survival in the patients receiving induction chemotherapy only was 8.9 months. Mitomycin-C had no impact on survival (p = 0.75). No statistically significant difference was noted in the time to local failure between the surgical and RT arms. CONCLUSION: The patient accrual to this trial made its results inconclusive, but several observations are notable. In this trial, histologic confirmation of N2 disease in the surgical and nonsurgical arms eliminated the usual biases from clinical staging. In this setting, local control and survival were essentially equal between the surgical and RT arms. The 3- and 5-year survival rates of nonsurgical therapy were comparable to published surgical trials of N2 disease.     

Radiotherapy and cisplatin in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck. A phase II study.

13 male and 8 female patients with metastatic squamous cell carcinoma (SCC) of an unknown primary tumor localized to the neck were treated with radiotherapy (RT) and cisplatin (CDDP). There were 12 (58%) and 9 (42%) patients, while no patient had N1 disease. All patients underwent biopsy. RT was given to all possible sites of the primary tumor (nasopharynx, pyriform sinus, and the base of the tongue). The RT dosage planned for the whole neck or supraclavicular area was 45 Gy, increasing to 60-70 Gy on the metastatic site. CDDP was given at a dose of 30 mg/m2, once weekly during the RT course. We observed 15 (72%) complete responses (CR) and 3 (14%) partial responses, while 3 (14%) patients did not respond to therapy. 12 (58%) patients are with no evidence of disease (NED) currently. The median survival time was 34+ months (range, 18+ to 50+ months). We observed two groups of toxicities: gastrointestinal and kidney toxicity. The majority of patients experienced grade 3 (RTOG) toxicity and no patient experienced grade 4 toxicity. This treatment appears to be effective and suitable for patients with metastatic SCC of an unknown primary tumor localized to the neck.     

中晚期鼻咽癌新辅助化疗联合放疗前瞻性 临床试验的长期结果

目的：评价新辅助化疗联合放疗在中晚期鼻咽癌治疗的价值。方法：前瞻性临床试验采用化疗方案：Cisplatin20mg/m^2,1-5天,5－FU500mg/m^2,1-5 天,BLM7mg/m^2,第1、5天,化疗2－3个疗程。放射治疗鼻咽剂量：66－74Gy/33-37次,共7－9周;预部淋巴结剂量：60－70Gy/30-35次,共7－8.5周;颈部预防量：48－50Gy。结果：1992－1993年457例鼻咽癌病人进入研究,17例因各种原因退出队列,440例进入分析（化疗＋放疗组219例、单纯放疗组221例）。5年生存率及无瘤生存率实验组及对照组分别为62％vs55％（P＝0.1335)及55％vs48%(P=0.0539)。5年无局部复发生率及无远处转移生存率两组分别为82％vs74%（P＝0.0412)及79％vs75%(P=0.4177)。亚组分析显示新辅助化疗能明显提高T3－4期的局控率;对N2－3病人的远处转移率无影响。结论：新辅助化疗未能提高中晚期鼻咽癌病人的总生存率,亦未能降低远处转移率,有提高无瘤生存率的趋势。新辅助化疗的指征：T3－4期病人。     

Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study.

PURPOSE: This phase II trial was designed to evaluate the feasibility, toxicity, response rates, and survival for neoadjuvant chemotherapy and radiotherapy (RT) followed by surgical resection in newly diagnosed patients with surgically staged IIIA non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: Previously untreated patients with NSCLC underwent bronchoscopy, chest and abdominal computed tomography (CT), bone scan, and surgical staging of the mediastinum. Neoadjuvant treatment consisted of concurrent chemotherapy and RT. Patients then underwent surgical resection, which was followed in turn by additional chemotherapy and RT. Chemotherapy included cisplatin 100 mg/m2 on days 1 and 29, vinblastine 3 mg/m2 on days 1 and 3 and 29 and 31, and fluorouracil (5-FU) 30 mg/kg/d by infusion on days 1 to 3 and 29 to 31 (FVP). RT began on day 1 and included 3,000 cGy in 15 fractions. Surgery took place on day 55, and one more cycle of chemotherapy and an additional 3,000 cGy of RT began on day 85. RESULTS: Forty-one eligible patients (median follow-up, 53 months) were studied. N2 disease was present in 80%, whereas 20% had T3N0 or T3N1 lesions. Response to neoadjuvant chemotherapy and RT included no complete responses (CR), 21 (51%) partial responses (PR) or regressions, 19 (46%) stable disease (SD), and one (2%) progressive disease (PD). Thirty-one patients underwent surgery, and 25 were resected. In four of the 25 resection specimens, no viable tumor was present, whereas in three of the six unresectable patients, extensive biopsy results demonstrated only necrotic tumor. The maximum response achieved using all protocol treatment was 27 (66%) CRs, seven (17%) PRs or regression, six (15%) SDs, and one (2%) PD. Toxicity was substantial and primarily hematologic. There were six (15%) treatment-related deaths, which included three perioperative deaths and three chemotherapy-related toxicity deaths. The Kaplan-Meier curve indicated a 1-year survival of 58% and a median survival of 15.5 months. Nine patients (22%) remain disease-free. CONCLUSIONS: There was a reasonably high rate of PR associated with concurrent neoadjuvant chemotherapy and RT, and a high percentage of patients who ultimately were rendered completely disease-free. However, treatment-related morbidity and mortality was common. Median survival seemed to be only modestly improved beyond that achieved with less intensive means of treatment. However, a group has emerged of patients who enjoy prolonged disease-free survival and possible cure.     

Paclitaxel and carboplatin in neo-adjuvant and concomitant chemoradiotherapy in locally advanced head and neck squamous cell carcinoma

AIM AND BACKGROUND: To evaluate feasibility of neoadjuvant chemotherapy (NA-CT) followed by CT + radiotherapy (RT) in locally advanced or unresectable head and neck squamous cell carcinoma (HNSCC). METHODS: 22 HNSCC patients were enrolled (18 males, 4 females; median age, 59.5 years; median ECOG PS, 1). Sites of disease: oral cavity, 18.2%; oropharynx, 40.9%; hypopharynx, 18.2%; larynx, 4.6%, multiple sites, 18.2%. T (tumor) category: T2, 13.6%; T3, 31.8%; T4, 54.5%. N (nodes) category: NO, 9.1%; N1, 18.1%; N2, 40.9%; N3, 31.8%. Stage: III, 4.6%; IVA, 63.6%; IVB, 31.8%. Induction carboplatin (AUC = 6) and paclitaxel (200 mg/m2) x 3 cycles (q21 days) were given. Responders received definitive radiotherapy with concurrent carboplatin (35 mg/m2/day from days 1 to 5 in weeks 1, 3, 5 and 7) and paclitaxel (50 mg/m2 on days 10, 24 and 38). Patients with node involvement were suggested to undergo postradiotherapy neck dissection. RESULTS: NA-CT. 97% of planned chemotherapy cycles were administered. Prevalent toxicity was hematologic: 50% G4 neutropenia and 31.8% G3, one neutropenic fever. All patients had alopecia. Complete responses in T and N were 4 (18.2%) and 3 (15%), respectively. Partial responses were 13(59%) and 9 (45%). There was 1 progressive disease. CT + RT. 79.9% of planned cycles of CT were administered. In 19 patients (86.4%) more than 50% of planned cycles of CT were completed. Median dose of RT was 70.2 Gy on T/N+ and 54 Gy on NO. Limiting toxicity was mucositis in 77.3%, followed by neutropenia (59.1% G3-G4). Median weight loss was 4.9%.18.2% of patients required hospitalization. Complete responses in T and N were 15 (68.1%) and 8 (40%), respectively. Partial responses were 5 (22.7%) and 7 (35%). CONCLUSIONS: The preliminary results of this study are encouraging, despite the toxicity. Adequate follow-up is required to evaluate efficacy in terms of local-regional control and overall survival.     

Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: Subgroup analysis of two Phase III trials

PURPOSE: Induction chemotherapy has not been shown to improve survival in nasopharyngeal carcinoma (NPC) in Phase III trials. To evaluate the effect of induction chemotherapy in NPC further, we performed subgroup analysis of two Phase III trials according to the T and N stage. METHODS AND MATERIALS: Data from two phase III trials comparing cisplatin/epirubicin or cisplatin/bleomycin/5-fluorouracil followed by radiotherapy (RT) vs. RT alone in NPC were pooled together for analysis. Patients were stratified into four subgroups according to the 1997 American Joint Committee on Cancer T and N stage: T1-T2N0-N1, Group 1 (early-stage disease); T1-T2N2-N3, Group 2 (advanced N disease); T3-T4N0-N1, Group 3 (advanced T stage); and T3-T4N2-N3, Group 4 (advanced T and N disease). Group 1 consisted entirely of patients with Stage IIB disease. A total of 784 patients were included for analysis on an intent-to-treat basis. The median follow-up for the surviving patients was 67 months. RESULTS: No significant differences in overall survival, locoregional failure-free, or distant metastasis-free rates were observed between the combined and RT arms in Groups 2 to 4. Significant differences in the overall survival and distant metastasis-free rates were observed only in Group 1, favoring the combined chemotherapy and RT arm. The 5-year overall survival rate was 79% in the combined arm and 67% in the RT-alone arm (p = 0.048). The corresponding 5-year distant metastasis-free rates were 86% and 74% (p = 0.0053). CONCLUSIONS: Our results have shown that patients in Group 1, with early-stage NPC treated by RT alone, had relatively poor survival because of distant metastases. The observation of improved outcomes in this subgroup after the addition of induction chemotherapy has not been previously reported and warrants additional investigation.     

TPF方案诱导化疗加同期顺铂化放疗治疗晚期鼻咽癌的临床研究

 目的　探讨多西紫杉醇（TAX）、顺铂（DDP）、5-氟尿嘧啶（5-Fu）三药联合方案诱导化疗加DDP同期放化疗治疗晚期鼻咽癌的近期疗效及可行性。方法　40例初诊局部晚期（UICC分期Ⅲ、Ⅳ期）鼻咽癌患者入组,随机分为诱导化疗加DDP 3周方案组（A组）,诱导化疗加DDP单周方案组（B组）。两组均先行2个疗程诱导化疗,方案为TAX 60 mg／m2第1天;DDP 60 mg／m2第1天;5-Fu 600 mg／m2 第1天至第5天,每3周重复,共2个周期。第7周开始放疗,放疗第1天同时行化疗。A组：DDP 80 mg／m2第1天,每3周1次,共2次;B组： DDP 30 mg／m2第1天,每周1次,共6次。放疗采用二维适形照射,鼻咽原发病灶68～72 Gy,34～36次,7周,颈部淋巴结阳性区60～66 Gy,30～33次,6～6.5周。结果　40例共完成78个疗程诱导化疗,A、B组各1例出组。38例可评价疗效和不良反应。A组17例完成2个疗程同期DDP化疗;B组10例按计划完成6个周同期化疗,4例完成5周化疗,4例完成4周化疗,1例只完成2周化疗。诱导化疗后CR 4例（10.5 %）,PR 27例（71.1 %）,SD 7例（18.4 %）,总有效（CR+PR）率81.6 %。治疗结束后CR 32例（84.2 %）,PR 5例（13.2 %）,SD 1例（2.6 %）,总有效率 97.4 %。结论　TPF诱导化疗加DDP同期放化疗是治疗晚期鼻咽癌的可行方案,推荐使用同期DDP 3周化疗方案。剂量强度可否提高,有待进一步研究。     

RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck

Purpose: Patients with recurrent squamous cell cancer of the head and neck (SCH&N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil.

Methods and Materials: The eligibility requirements included SCH&N presenting as a second primary or recurrence ≥6 months after definitive RT to ≥45 Gy, with ≥75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by ≥6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m² of a 5-fluorouracil IV bolus given 30 min before each second daily fraction.

Results: Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p = 0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p = 0.083).

Conclusion: Repeated RT with concurrent chemotherapy as given in this study is a feasible approach for selected, previously irradiated patients with SCH&N and may produce increased median and 1-year survival rates compared with systemic chemotherapy trials reported in the literature. A randomized study should be conducted to compare these two different approaches.     

Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: comparison with radiotherapy treatment alone.

PURPOSE: To assess the results of treatment in 33 patients with stage IIA/B seminoma who were treated with carboplatin and radiotherapy (RT) between January 1989 and December 1996. PATIENTS AND METHODS: Thirty patients received single course single agent carboplatin (400 mg/m2 or area under curve (AUC 7), two patients received two courses carboplatin, and one patient received single course carboplatin and etoposide, all 4-6 weeks prior to infra-diaphragmatic RT. Results were retrospectively compared with those obtained for 80 patients treated from 1970 to 1998 with radiotherapy alone. RESULTS: There was minimal toxicity associated with the use of carboplatin prior to RT. With a median follow-up of 4 years (range 2-70 months) 2/33 patients treated with chemotherapy and RT have relapsed, 5-year relapse free survival (RFS) = 96.9% (95% confidence interval (CI) 72.9-99.4%), and one patient has died of progressive disease, 5-year overall survival (OS) = 96.7%. With a median follow-up of 11.2 years (range 6 months to 25.8 years) 15/80 patients treated with RT alone have relapsed, 5-year RFS = 80.7% (95% CI 70.1-87.9%), including 13/61 patients treated with infra-diaphragmatic RT, 5-year RFS = 77.9%, and 2/19 treated with additional supra-diaphragmatic RT, 5-year RFS = 89.5% (P = 0.277). Eleven out of 80 patients have died, 5-year OS = 94.7%. For stage IIA, 1/14 patients treated with chemotherapy and RT have relapsed, 5-year RFS = 92.3%, compared with 5/34 treated with infra-diaphragmatic RT alone 5-year, RFS = 84.9% (P = 0.527). For stage IIB, 1/19 patients relapsed (at 69 months) following chemotherapy and RT (5-year RFS = 100%), whereas 8/27 relapsed following infra-diaphragmatic RT alone, 5-year RFS = 69.4% (P = 0.0595). CONCLUSION: Infradiaphragmatic RT alone cures the majority of patients with stage II seminoma, but the relapse rate remains high particularly for patients with stage IIB disease. As compared with historical controls, carboplatin with RT appears to reduce the relapse rate in stage II seminoma with minimal additional toxicity and the results approach statistical significance for stage IIB patients. Confirmation would require a phase III randomized comparison.     

Metastatic squamous cell carcinoma of an unknown primary localized to the neck. Advantages of an aggressive treatment

Treatment of patients with squamous cell carcinoma (SCC) of an unknown primary localized to the neck is still controversial, particularly regarding advanced disease. We reviewed 41 such patients treated with surgery and/or radiotherapy (RT) (n = 25) or with combined modality treatment including chemotherapy (CH) (n = 16). The male to female ratio was 28 to 13, and the median age was 58 years (range, 32 to 94 years). There were 27 (66%) patients with poorly differentiated SCC and 8 with moderately differentiated or well-differentiated cancer. Twenty-three (56%) patients had N3 disease, 16 (39%) had N2, and 2 had N1. The majority of N3 patients have been treated with CH and RT (n = 12) or with RT alone (n = 9). The combined CH-RT was well tolerated, with no life-threatening toxicity. The complete response (CR) to CH-RT was 81% (11 patients have no evidence of disease [NED] currently). The median survival time of this group was 37+ months. Of the 25 patients who had surgery and/or RT as their first planned treatment, 7 (28%) have NED currently. The median survival time of this group was 24 months. Patients with N3 disease who received CH had a higher CR rate and a longer survival time as compared with those treated with surgery and/or RT, despite a higher (N3) stage of disease. These findings warrant further investigation in randomized cooperative studies.     

High rate of clinical complete response to weekly outpatient neoadjuvant chemotherapy in oral carcinoma patients using a new regimen of cisplatin, 5-fluorouracil, and bleomycin alternating with methotrexate and epirubicin

BACKGROUND: A Phase II trial was initiated to evaluate the response to and toxicity of a new regimen of weekly outpatient neoadjuvant chemotherapy in patients with oral carcinoma. METHODS: Patients with previously untreated squamous cell carcinoma of the oral cavity were eligible for this trial. The neoadjuvant chemotherapy was comprised of cisplatin, 25 mg/m2, 5-fluorouracil, 1000 mg/m2, and bleomycin, 10 mg/m2, mixed in normal saline as a 24-hour intravenous (i.v.) infusion, alternating with methotrexate, 30 mg/m2, and epirubicin, 30 mg/m2, as an i.v. bolus (PFB/ME) on a weekly schedule for 8-12 weeks. In patients with American Joint Committee on Cancer Stage IV disease who completed neoadjuvant chemotherapy, surgery was preferred to radiotherapy, unless patients refused surgery. RESULTS: A total of 40 patients (82.5% with Stage IV disease) with previously untreated oral carcinoma were enrolled. The median size of the primary tumor was 7 cm (range, 3-13 cm). Fifty percent of patients had tumor penetrating through the oral mucosa to the cheek skin and 62.5% had bony destruction. Detectable cervical lymph nodes were noted in 77.5% of patients. After neoadjuvant weekly chemotherapy, 22 patients (55%) showed complete response (CR) and 15 patients (37.5%) showed partial response, for an overall response rate of 92.5%. World Health Organization Grade 3/4 toxicity included mucositis (7.5%), leukopenia (25%), anemia (10%), and thrombocytopenia (2.5%). Eleven of 33 patients with Stage IV disease underwent surgery, and pathologic CR (2 patients) or microscopic residual tumor (4 patients) was noted (54.5%). CONCLUSIONS: The results of the current study indicate that a weekly PFB/ME neoadjuvant chemotherapy regimen is highly effective for the treatment of patients with oral carcinoma. In addition, this regimen has low toxicity. The authors believe that implementation of this regimen into a multimodality therapy protocol deserves further study.     

Induction chemotherapy with cisplatin, vinorelbine, and mitomycin-C followed by surgery for patients with pathologic N2 non-small-cell lung cancer

PURPOSE: The treatment strategy for patients with non-small-cell lung cancer (NSCLC) involving ipsilateral mediastinal lymph nodes is still controversial. We performed a phase II feasibility study of induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC. PATIENTS AND METHODS: Patients with mediastinoscopy- positive stage IIIA N2 NSCLC received 2 cycles of cisplatin 80 mg/m2, vinorelbine 25 mg/m2, and mitomycin-C 8 mg/m2. Patients without progressive disease underwent thoracotomy and lobectomy with lymph node dissections 2-4 weeks later. RESULTS: From January 2000 to July 2004, 24 eligible patients (15 men, 9 women) were enrolled. Induction chemotherapy was completed as planned in 23 patients (95.8%). Hematological toxicity was the primary grade 3/4 toxicity. Twelve (50%) patients achieved a partial response. Twenty-three patients underwent surgical resection, and complete resection was achieved in 22 patients (95.7%). There were no surgery-related deaths. Pathologic complete response in metastatic lymph nodes was achieved in 5 patients. With a median follow-up of 5.4 years (range, 2.88-7.7 years), the estimated 5-year survival was 51.8% (95% CI, 41.3-62.3) and progression-free survival was 46.6% (95% CI, 36-57.2). CONCLUSION: Induction chemotherapy followed by surgery for patients with pathologic N2 NSCLC was feasible and associated with high response to lymph node metastasis and good survival.     

Intraarterial cisplatin with intravenous paclitaxel and ifosfamide as an organ-preservation approach in patients with paranasal sinus carcinoma

BACKGROUND: The objectives of this study were to determine the efficacy, organ-preservation rate, and safety of intraarterial (IA) cisplatin in combination with intravenous paclitaxel and ifosfamide in patients with locally advanced carcinoma of the paranasal sinuses who required orbital exenteration or major craniofacial resection for complete tumor resection. METHODS: Patients were treated with intravenous paclitaxel (135 mg/m(2)) on Day 1, ifosfamide (1000 mg/m(2)) on Days 1-3, sodium mercaptoethanesulfonate (600 mg/m(2)) on Days 1-3, and IA cisplatin (100 mg/m(2)) on Day 1 every 21 days. RESULTS: Of 24 study participants, 20 patients received at least 1 course of IA cisplatin, 1 patient had an early death, and 19 patients were evaluable for response. Five of those 19 patients (26%) achieved a complete response (CR), 6 patients (32%) achieved a partial response, and 8 patients (42%) had stable disease or developed progressive disease. Eye-sparing surgery followed by radiotherapy (RT) was feasible in 7 of 24 patients, RT was offered to only 7 patients, whereas 3 patients received chemotherapy and RT, 2 patients refused further therapy, 3 patients underwent craniofacial resection with orbitectomy, and 1 patient was treated systemically for metastatic disease. At the completion of treatment, 14 of 23 patients (61%) with locally advanced disease were disease free, and the orbit was preserved in 21 of 24 patients (88%). The overall survival, progression-free survival, and disease-free survival rates at 2 years were 60%, 50%, and 84%, respectively. Toxicity was substantial, with two patients experiencing cerebrovascular ischemia (one transient and one cerebrovascular accident) and three patients experiencing cranial neuropathy, which was reversible in two patients. CONCLUSIONS: Despite the encouraging organ-preservation rate, the approach studied resulted in substantial toxicity, and more effective adjunctive therapy is needed. Alternative approaches, including the integration of targeted therapy agents in induction chemotherapy regimens followed by concomitant chemotherapy and RT or eye-sparing surgery, need further exploration.     

Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019.

PURPOSE: There are no published survival data after chemoradiotherapy (chemoRT) in pathologically documented stage IIIB non-small-cell lung cancer. Studies of radiotherapy (RT) alone or chemotherapy followed by RT yield 5-year survivals less than 10%. The Southwest Oncology Group (SWOG) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy, safety, and long-term outcome of replacing postinduction surgery with additional chemoRT. PATIENTS AND METHODS: Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1, T4N2, or N3 stage IIIB non-small-cell lung cancer. They had pulmonary function adequate to withstand combined-modality therapy, identical to the requirements of the previous trial with postchemoRT surgery. Induction therapy was two cycles of cisplatin plus etoposide (PE) concurrent with once-daily thoracic RT (45 Gy). In the absence of progressive disease, RT was completed to 61 Gy, with two additional cycles of cisplatin plus etoposide. RESULTS: Fifty eligible patients were accrued with tumor-node (TN) substage confirmed on central review: 18, T4N0/1; 12, T4N2; and 20, N3. Grade 4 neutropenia was the most common toxicity (32%). Grade 3/4 esophagitis occurred in 12% and 8%. Median follow-up was 52 months, and overall median survival was 15 months (10 to 22, 95% confidence interval). Three- and 5-year survivals were 17% and 15% (5-year T4N0/1, 17%; T4N2, 13%; and N3, 15%). CONCLUSION: Feasibility and long-term survival support the application of these results as a standard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared. These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials.     

Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial.

PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.     

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.     

Analysis of in-field control and late toxicity for adults with early-stage Hodgkin's disease treated with chemotherapy followed by radiotherapy

PURPOSE: We analyzed in-field (IF) control in adults with early-stage Hodgkin's disease who received chemotherapy followed by radiotherapy (RT) in terms of the (1) chemotherapeutic regimen used and number of cycles delivered, (2) response to chemotherapy, and (3) initial tumor size. Cardiac toxicity and second malignancies, particularly the incidence of solid tumors in terms of the RT field size treated, were also examined. METHODS AND MATERIALS: From 1980 to 1995, 286 patients ranging in age from 16 to 88 years (median: 28 years) with Ann Arbor clinical Stage I or II Hodgkin's disease underwent chemotherapy followed 3 to 4 weeks later by RT. There were 516 nodal sites measuring 0.5 to 19.0 cm at the start of chemotherapy, including 134 cases of bulky mediastinal disease. NOVP, MOPP, ABVD, CVPP/ABDIC, and other chemotherapeutic regimens were given to 161, 67, 19, 18, and 21 patients, respectively. Patients received 1-8 (median: 3) cycles of induction chemotherapy. All 533 gross nodal and extranodal sites of disease were included in the RT fields. The median prescribed RT dose for gross disease was 40.0 Gy given in 20 daily 2.0-Gy fractions. There was little variation in the RT dose. Eighty-five patients were treated with involved-field or regional RT (to one side of the diaphragm), and 201 patients were treated with extended-field RT (to both sides of the diaphragm), based on the protocol on which they were enrolled. RESULTS: Follow-up of surviving patients ranged from 1.3 to 19.9 years (median: 7.4 years). Based on a review of simulation films, there were 16 IF, 8 marginal, and 15 out-of-field recurrences. The chemotherapeutic regimen used and the number of cycles of chemotherapy delivered did not significantly affect IF control. IF control also did not significantly depend on the response to induction chemotherapy. In cases where there was a confirmed or unconfirmed complete response as opposed to a partial response or stable disease in response to induction chemotherapy for bulky nodal disease, the 5-year IF control rates were 99% and 92%, respectively (p = 0.0006). The 15-year actuarial risks of coronary artery disease requiring surgical intervention and of solid tumors were 4.1% and 16.8%, respectively. There was a trend toward a greater risk of solid tumors in patients who received extended-field RT rather than involved-field or regional RT (p = 0.08). CONCLUSIONS: In patients with nonbulky disease, induction chemotherapy followed by RT to a median dose of 40.0 Gy resulted in excellent IF control, regardless of the chemotherapeutic regimen used, the fact that only 1-2 cycles of chemotherapy were delivered, and the response to chemotherapy. There was a trend toward a higher incidence of solid tumors in patients who received consolidation RT to both sides rather than only one side of the diaphragm. Ongoing Phase III trials will help clarify whether lower RT doses and smaller RT fields after chemotherapy can maintain the IF control seen in our study, but with a lower incidence of late complications in patients with Stage I or II Hodgkin's disease.     

Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck

BACKGROUND: The objective of this study was to determine prognostic factors for response and survival on three consecutive institutional trials utilizing concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck (SCCHN). METHODS: Since 1985, patients with locally advanced SCCHN at the University of Maryland have been managed with concurrent chemotherapy and radiation therapy (RT). Three consecutive pilot studies have been performed evaluating the utility of weekly chemotherapy with standard fractionated RT. Chemotherapy consisted of carboplatin either alone (28 patients) or in combination with bleomycin (23 patients) or paclitaxel (60 patients). In all three studies, RT was given to 70.2 gray (Gy) at 1.8 Gy/fraction/day to the primary site. All patients had locally advanced SCCHN and were believed to be poor surgical candidates. Sixty-seven percent of patients had T4 disease, and 21% had T3 disease. Seventy-five percent of patients had N2-N3 disease. One hundred eleven patients were examinable for toxicity, response, and survival analysis. Factors including age, race, gender, primary site location, histologic grade, T classification, N classification, and treatment regimen were evaluated to identify predictors of these endpoints. RESULTS: The median follow-up for patients treated on study 1 (carboplatin and RT) and study 2 (carboplatin and bleomycin [C + B]/RT) was 98 months, and it was 30 months for study 3 (carboplatin and paclitaxel [C + P]/RT). The complete response rates were 54%, 52%, and 70% respectively (P = 0.01). Multivariate analysis identified length of treatment break (< 1 week vs. > 1 week) as the only predictor of complete response to therapy. The local control for the entire group was 50%. The local control for C + P/RT was 63%, versus 32% and 36% for C/RT and C + B/RT respectively (P = 0.004). The 2-, 3-, and 5-year disease free and overall survivals for the entire population were 41%, 41%, and 35% and 42%, 36%, and 33%, respectively. The 3-year overall survival rates by treatment regimen were 18% (C/RT), 35% (C + B/RT), and 47% (C + P/RT; P = 0.01). On univariate analysis, age younger than 50 years (P = 0.01), treatment with C + P/RT (P = 0.005), and treatment break of 5 days or fewer (P < 0.05) were also predictive of improved overall survival. On multivariate analysis, only complete response (P < 0.0001) and treatment with C + P/RT (P = 0.02) remained statistically significant. CONCLUSIONS: Chemoradiation provides patients with locally advanced SCCHN the opportunity for long term survival. Among the three chemoradiation regimens studied, C + P/RT was associated with the best complete response and survival rates. Complete response to therapy was the single most important predictor of overall survival. These three consecutive concurrent chemotherapy and radiation trials achieved a 5-year survival of greater than 30% for the entire population. These results support the use of this nonoperative approach for this group of patients with a historically poor prognosis.