F. Eschwege

Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.

PURPOSE To investigate the potential gain of the concomitant use of radiotherapy and chemotherapy in improving local control and reducing the need for colostomy, a randomized phase III trial was performed in patients with locally advanced anal cancer. MATERIALS AND METHODS From 1987 to 1994, 110 patients were randomized between radiotherapy alone and a combination of radiotherapy and chemotherapy. The patients had T3-4NO-3 or T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of partial or complete response, respectively. Surgical resection as part of the primary treatment was performed if possible in patients who had not responded 6 weeks after 45 Gy or with residual palpable disease after the completion of treatment. Chemotherapy was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15 mg/m2 administered on day 1. RESULTS The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for radiotherapy alone to 80% for radiotherapy and chemotherapy, and from 85% to 96%, respectively, if results are considered after surgical resections. This led to a significant improvement of locoregional control and colostomy-free interval (P = .02 and P = .002, respectively), both in favor of the combined modality treatment. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The survival rate remained similar in both treatment arms. Skin ulceration, nodal involvement, and sex were the most important prognostic factors for both local control and survival. These remained significant after multivariate analysis. The improvement seen in local control by adding chemotherapy to radiotherapy also remained significant after adjusting for prognostic factors in the multivariate analysis. Event-free survival, defined as free of locoregional progression, no colostomy, and no severe side effects or death, showed significant improvement (P = .03) in favor of the combined-treatment modality. The 5-year survival rate was 56% for the whole patient group. CONCLUSION The concomitant use of radiotherapy and chemotherapy resulted in a significantly improved locoregional control rate and a reduction of the need for colostomy in patients with locally advanced anal cancer without a significant increase in late side effects.

Phase III Randomized Trial of Amifostine as a Radioprotector in Head and Neck Cancer

PURPOSE Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients. PATIENTS AND METHODS Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point. RESULTS Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively. CONCLUSION Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.

Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients.

PURPOSE To review our experience using full-dose external reirradiation given with a curative intent for patients with unresectable head and neck carcinoma (HNC). PATIENTS AND METHODS Between January 1980 and December 1996, 169 patients who presented with unresectable nonmetastatic HNC in a previously irradiated area were included in this series. The median time between the first and the second irradiation was 33 months. Reirradiation protocols were as follows: radiotherapy alone (65 Gy over 6.5 weeks at 2 Gy/d), 27 patients; Vokes protocol, ie, five to six cycles of radiotherapy (median total dose, 60 Gy; 2 Gy/d) with simultaneous fluorouracil (5-FU) and hydroxyurea, 106 patients; and bifractionated radiotherapy (median total dose, 60 Gy; 2 x 1.5 Gy/d) with concomitant mitomycin, 5-FU, and cisplatin, 36 patients. The median cumulative dose of the two irradiations was 120 Gy. Eighty-five percent of the tumors were squamous cell carcinoma, 14% undifferentiated carcinoma of nasopharyngeal type, and 1% adenocarcinoma. Forty-four percent were local recurrences, 23% nodal recurrences, 14% both local and nodal, and 19% second primary tumors. RESULTS Mucositis grade 3 (World Health Organization [WHO]) was found in 32% and grade 4 in 14% of cases. Four patients presented with neutropenia or thrombocytopenia (grade 3 or 4 WHO). Late toxicities (> 6 months) were as follows: cervical fibrosis (grade 2 to 3 Radiation Therapy Oncology Group [RTOG]), 41%; mucosal necrosis, 21%; osteoradionecrosis, 8%; and trismus, 30%. Five patients died of carotid hemorrhage, apparently in complete remission. Six months after the onset of reirradiation, 37% of patients were in complete response. Patterns of failure were local only (53%), nodal only (20%), metastatic only (7%), and multiple (20%). Median follow-up time was 70 months. Overall survival rate (Kaplan-Meier) was 21% (95% confidence interval [CI], 15% to 29%) at 2 years and 9% (95% CI, 5% to 16%) at 5 years. Median survival time was 10 months for the entire population. Thirteen patients, of whom 12 were treated with the Vokes protocol, were long-term disease-free survivors. In a multivariate analysis, the volume of the second irradiation was the only factor significantly associated with the risk of death: relative risk=1.8 (95% CI, 1.13 to 5.7) (P=.01). CONCLUSION Full-dose reirradiation combined with chemotherapy was feasible in patients with inoperable HNC. The incidence and severity of late toxicity was markedly increased in comparison to that observed after the first irradiation. Median survival was better than that generally obtained using palliative chemotherapy alone. A small proportion of patients were long-term disease-free survivors.

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

SummaryThe variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

Undifferentiated nasopharyngeal cancer (UCNT): Current diagnostic and therapeutic aspects

Undifferentiated carcinoma of the nasopharynx (UCNT) is a particular head and neck epidermoid lineage tumor related to the Epstein Barr Virus (EBV). It has geographically selective endemic epidemiologic features, without relation to external carcinogens. Its systemic agressiveness is the source of most disease-related demises, because radiotherapy achieves excellent local control and a significant percentage of cure in patients with exclusive locoregional disease. Difference in the staying systems currently in use, the recent changes in imaging and radiotherapy technology, and the lack of distinction between UCNT and squamous cell carcinoma (SCC) of the nasopharynx in Western literature reports make for some difficulty in therapeutic results evaluation when analyzing available literature. Its chemosensitivity is a relatively recent acknowledged fact, and its use in metastatic patients results in a high percentage of objective responses, many of long duration. Neoadjuvant cisplatin-based chemotherapy seems to be of benefit, but outstanding controversies in this regard will be soon answered through ongoing phase III trials. After a review of the current literature of all the above-mentioned aspects of this fascinating nosologic entity, our own experience, both in metastatic and locoregional disease patients is analyzed.

Long-Term Disease-Free Survivors in Metastatic Undifferentiated Carcinoma of Nasopharyngeal Type

PURPOSE To review incidence and analyze profile of long-term complete responders among patients with undifferentiated carcinoma of nasopharyngeal type (UCNT) treated at a single institution. PATIENTS AND METHODS We present a cohort of 20 long-term unmaintained complete responders to chemotherapy for metastatic UCNT treated at the Institut Gustave Roussy between April 1978 and November 1996. A patient was considered a long-term survivor if he or she was disease-free for more than 36 months without treatment after obtaining a complete response by chemotherapy. Patient characteristics were as follows: sex, 17 men and three women; median age, 28 years (range, 9 to 62 years); median World Health Organization performance status, 1; and initial tumor-node-metastasis stage (International Union Against Cancer-American Joint Committee on Cancer, 1987) of T3 to T4, 60%, and of N2b to N3, 75%. Epstein-Barr virus serology was characteristic in 19 patients. Of 16 pretreated patients, 11 were pretreated by radiotherapy alone and five by chemotherapy and radiotherapy. Thirteen patients had metastatic relapses of locally controlled UCNT. Tumor sites were bone in 15 patients, lung in four, and liver (biopsy-proven) in two. Chemotherapy included the following: cisplatin, bleomycin, and fluorouracil in five patients; bleomycin, epirubicin, and cisplatin in seven patients; fluorouracil, mitomycin, epirubicin, and cisplatin in four patients; and fluorouracil, bleomycin, epirubicin, and cisplatin in one patient. Three patients were treated with platinum-based regimens before 1985. Patients received a median of six cycles (range, three to 13). Thirteen patients with bone metastases received consolidating radiotherapy. RESULTS As of June 1999, 14 of 20 patients were still alive with no evidence of disease after treatment (disease-free survival time, 82+ to 190+ months), three patients died of other causes while in complete response at 61, 109, and 208 months after treatment, and three patients died of disease at 42, 89, and 115 months after treatment. Long-term complete responses were obtained in both bone and visceral disease. CONCLUSION Our data support a curative role for chemotherapy in metastatic UCNT and are a major incentive to continue research for better combinations to increase the percentage of patients with metastatic UCNT who attain complete responses and long-term survival.

Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood

BACKGROUND Radiotherapy and chemotherapy are associated with an increased risk of second malignant neoplasm (SMN). An association between SMN and familial aggregation has also been shown. The aim of this study was to investigate the role of familial factors in the risk of SMN and their potential interaction with the effect of treatment. METHODS We devised a case-control study of 25 children with SMN (cases) and 96 children with no SMN after a cancer treatment (controls), taken from a cohort of 649 children treated at our institution between 1953 and 1985. A complete family history was obtained for patients and controls and a familial index defined to evaluate the degree of familial aggregation. The radiation dose given at 151 sites in the body was estimated for each radiotherapy course for each child. FINDINGS Among family members of the 25 SMN cases, there were ten with early-onset (< or = 45 years) cancer, compared with eight among relatives of the 96 controls. Compared with patients who had no family history of early-onset cancer, those with one or more affected family members had an odds ratio for SMN of 4.7 (95% CI 1.3-17.1; p = 0.02). Adjustment for local radiation dose and exclusion of patients known to be predisposed to SMN (carriers of p53 mutation and those with Recklinghausens disease) did not affect this risk substantially. INTERPRETATION Both genetic factors and exposure to ionising radiation have independent effects on the risk of SMN. Follow-up of children treated for cancer should be especially vigilant when there is a family history of early-onset cancer.

Squamous cell carcinoma of the anal canal: treatment by external beam irradiation.

External beam radiation therapy alone or in combination with curietherapy is the recommended treatment for anal canal carcinoma in some countries. In others, surgery is the sole accepted treatment. The results for 64 patients treated by external radiotherapy alone show excellent survival for stage T1T2 tumors but results are poor for large tumors (stage T4). The overall 5 year crude survival rate is 46%. The 5-year results are better for stage T1T2 (72%) than for stage T3T4 (35%). The presence of inguinal node involvement at first examination is a very poor prognostic sign. Local recurrences and metastases are infrequent for stage T1T2, but are more common for stage T3 and T4. Complications follow radiotherapy more frequently in those with stage T3 and T4 tumors. The analysis of local recurrences, complications and survival shows that radiation therapy may be sufficient treatment for stage T1 and T2 and for some stage T3 tumors. The importance of anal sphincter involvement and the poor quality of life for patients who are cured but develop complications, shows the need for combined treatment with surgery and perhaps with chemotherapy. For small tumors the results obtained by external radiotherapy alone are comparable with those obtained by external radiotherapy and curietherapy in terms of survival and complications.

Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers.

High-risk human papillomaviruses (HPVs) have been associated to the development of cervical and some other human cancers. Most of them express E6 and E7 oncoproteins, able to bind to p53 and retinoblastoma (pRb) tumor suppressor proteins respectively and neutralize their function. Restoration of these pathways by blocking E6 and E7 expression would provide a selective therapeutic effect. Here, we show that a clinically approved antiviral agent Cidofovir reduced E6 and E7 expression in cervical carcinoma Me180 and head and neck squamous cell carcinoma HEP2 cells at the transcriptional level. Cidofovir induced the accumulation of active p53 and pRb associated to induction of cyclin dependent kinase inhibitor p21WAF1/CIP1 in Me180 and HEP2 cells. p53 induction was also shown in Hela HPV-positive cervical carcinoma cell line. In addition, S phase cell cycle accumulation with concomitant decrease of cyclin A expression were associated to the antiproliferative activity of Cidofovir in HPV-treated cells. Combining Cidofovir to irradiation both in vivo and in nude mice xenografts resulted in a marked radiosensitization in HPV-positive cells, which was not observed in virus negative cells. This study provides the basis for a new anticancer strategy to enhance the antitumor effect of ionizing radiation in HPV-related cancers, without increase deleterious effects.

Cervico-facial adenoid cystic carcinoma: Study of 102 cases. Influence of radiation therapy

One hundred two patients with cervico-facial adenoid cystic carcinoma were treated with surgery alone, radiotherapy alone or both from 1951 to 1980. All the cases have a 5-year minimum follow-up. The local control rate is 55.5% at 5 years and 37.7% at 10 years. The 5-year local control rate is 44% with surgery alone, 65.8% with radiotherapy alone and 77.8% with post-operative radiotherapy. The difference between surgery alone and radiosurgical association is significant (p less than 0.01). The bone involvement diminished local control rate (32.2%/k 68.8%). The 5-year survival rate of the patients who recurred and have been retreated is 70.5%. The 5-year survival rate of the patients after the appearance of a metastasis is 38.1% and 2 patients have survived more than 10 years. The NED 5-year survival rate is 48.8%. There is no significant difference in the NED 5-year survival rate according to sites or treatments. The crude 5-year survival rate is 70%, 51.4% at 10 years and 32.2% at 15 years. Our study shows that adenoid cystic carcinoma have a peculiar and slow evolution. Surgery with post-operative radiotherapy obtains the best local control. These results and the radiosensibility of these lesions allow us to propose an aggressive treatment for the recurrence and the primary tumor of the directly metastatic patients.