P. Wibault

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.

Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil

Undifferentiated nasopharyngeal carcinoma (UCNT) is known to be radiosensitive and chemosensitive, but the latter has never been studied prospectively with phase II methodology. After an intensive work-up, 49 patients with recurrent (REC) and/or metastatic (MTS) UCNT were treated with three monthly cycles of cisplatin (CDDP) 100 mg/m2 day 1; bleomycin 15 mg intravenously (IV) day 1, and 16 mg/m2/d continuous infusion (CI) days 1 to 5; and fluorouracil (5FU) 650 mg/m2/d CI days 1 to 5 (PBF). Of the 49 patients, 33 were North African. The sex ratio was three males:one female, and the median World Health Organization (WHO) performance status was 1.6. In the 48 patients assessable for response, we observed nine (19%) complete responses (CRs) and 29 (60%) partial responses (PRs) (60%), for a 79% overall response rate (95% confidence interval, 68% to 90%) in the assessable group and a 78% global rate. There were eight CRs (24%) observed in the group without previous chemotherapy (33 patients) compared with one CR in the chemotherapy pretreated group (16 patients). Four patients are still alive without evidence of disease after 52+, 54+, 58+, and 58+ months, respectively. All of them had less than three bone MTS sites, and received radiation therapy in these sites. The results confirm the chemosensitivity of UCNT, and the observation of unmaintained long-term responders makes curability a possible consideration.

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.

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.

Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial.

PURPOSE With the aim to increase the dose intensity of radiation therapy (RT), and subsequently the locoregional control rate, a very accelerated RT regimen was compared with conventional RT in a series of patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS Between 1994 and 1998, 268 patients with T3 or T4, N0 to N3 HNSCC (staged by 1997 International Union Against Cancer criteria) that was not eligible for surgery were randomly assigned to receive either conventional RT, delivering 70 Gy in 7 weeks to the primary tumor and 35 fractions of 2 Gy over 49 days, or to receive very accelerated RT, delivering 62 to 64 Gy in 31 to 32 fractions of 2 Gy over 22 to 23 days (2 Gy/fraction bid). RESULTS The most common tumor site was the oropharynx and most of the patients (70%) had T4 and N1 to N3 tumors in 72% of patients. The main patient and tumor characteristics were well-balanced between the two arms. The median total doses were 63 Gy (accelerated) and 70 Gy (conventional), with a median overall time of 22 days and 48 days, respectively. Acute mucositis was markedly increased in the accelerated-RT arm (P < .001). The locoregional control rate was improved by 24% at 6 years with accelerated RT. In contrast, disease-free survival and overall survival were not significantly different between the two arms. There was no difference in late effects between the two arms. CONCLUSION The very accelerated RT regimen was feasible and provided a major benefit in locoregional control but had a modest effect on survival.

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.

Changes in the oxygenation of head and neck tumors during carbogen breathing

The oxygenation of head and neck tumors and changes during carbogen breathing were assessed in 20 patients. The median oxygen tension (pO2) for each patient was lower in tumors before breathing carbogen than in normal tissues. The median pooled pO2 of all the tumors was 20 mmHg; for normal tissue it was 60 mmHg. Low values (below 10 mmHg) were found in 4 patients for the normal tissue and in 18 patients for tumors. During carbogen breathing, the median (61 mmHg) pO2 readings for all tumors was higher than that recorded before carbogen breathing. The frequency of low (< 10 mmHg) pO2 values decreased with carbogen breathing in 11 patients; only 4 patients still exhibited very low values (< 2 mmHg). Maximal effect was obtained within 1-6 min of gas exposure. The pO2 stayed high under carbogen breathing in 15 out of 16 patients. Return to pre-carbogen levels of oxygenation occurred in 1 min after the end of gas exposure. These data suggest that carbogen breathing increases tumor oxygenation as assessed by polarography. The breathing time appears to be important for therapeutical use and should to be taken into consideration.

Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study.

BACKGROUND AND PURPOSE The aim of the study was: (1) to confirm the action of pilocarpine hydrochloride (Salagen) against xerostomia: (2) to correlate the response to dose/volume radiotherapy parameters. MATERIALS AND METHODS From June 1995 to February 1996, 156 patients with severe radiation induced xerostomia received pilocarpine hydrochloride orally. IS mg per day with a 5 mg optional increase at S weeks up to a daily dose of 25 mg beyond 9 weeks. RESULTS One hundred and forty five patients are fully evaluable. Treatment compliance was 75%. Thirty eight patients (26%) stopped treatment before week 12 for acute intolerance (sweating, nausea, vomiting) or no response. No severe complication occurred. Ninety ses en patients (67%) reported a significant relief of symptoms of xerostomia at 12 weeks. Within 12 weeks, the size of the subgroup ith normal food intake almost doubled (13-24 patients) while the size of the subgroup with (nearly) impossible solid food ingestion decreased by 38% (47 vs. 29 patients). The impact on quality of life was considered important or very important by 77% of the responders. CONCLUSIONS No difference was found according to dose/volume radiotherapy parameters suggesting that oral pilocarpine hydrochloride: (1) acts primarily by stimulating minor salivary glands: (2) can be of benefit to patients suffering of severe xerostomia regardless of radiotherapy dose/volume parameters: (3) all responders are identified at 12 weeks.

LONG-TERM RESULTS OF BRACHYTHERAPY FOR CARCINOMA OF THE PENIS CONFINED TO THE GLANS (N- OR NX)

PURPOSE To analyze the results of exclusive interstitial low-dose-rate brachytherapy (BT) for squamous cell carcinoma (SCC) of the penis, strictly confined to the glans. METHODS AND MATERIALS A total of 144 patients with SSC of the glans penis were treated with BT. Inguinal nodal dissection was performed in 19% of patients (all N-). After circumcision, BT was performed using the hypodermic needle technique. Median iridium length per patients was 24 cm (range, 4-108) and median dose was 65 Gy (range, 37-75). Median treated volume was 22 cm(3) (range, 5-110) and median reference isodose rate was 0.4 Gy/h (range, 0.2-1.2). RESULTS Median follow-up was 5.7 years (range, 0.5-29). The 10-year penile recurrence, inguinal lymph node recurrence, and inguinal nodal metastasis rates were: 20% (CI 95%, 11-29), 11% (CI 95%, 5-17), and 6% (CI 95%, 2-10), respectively. After salvage treatment, 86% patients with local failure were in a complete remission at last follow-up. The 10-year probability of avoiding penile surgery (for complication or local recurrence) was 72% (CI 95%, 62-82). The 10-year cancer-specific survival rate was 92% (CI 95%, 87-97). Diameter of tumor significantly increased the risk of recurrence (p = 0.02). The 10-year painful ulceration and stenosis risk rates were: 26% (CI 95%, 17-35) and 29% (CI 95%, 18-40), respectively. Seven patients required excision for necrosis. Treated volume and reference isodose rate significantly increased the risk of complications. CONCLUSION BT is an effective conservative treatment for SCC confined to the glans. Salvage local treatment is effective. Dose rate should be limited to decrease toxicity.

Analysis of p53 Serum Antibodies in Patients With Head and Neck Squamous Cell Carcinoma

BACKGROUND Mutation of the p53 tumor suppressor gene (also known as TP53) often leads to the synthesis of p53 protein that has a longer than normal half-life. Mutant p53 protein that accumulates in tumor cell nuclei can be detected by means of immunohistochemical staining techniques. Serum antibodies directed against p53 protein (p53-Abs) have been detected in some cancer patients. PURPOSE We assayed serum samples from 80 patients with head and neck squamous cell carcinoma (HNSCC) for the presence of p53-Abs, and we evaluated potential associations between the presence of these antibodies and other histopathologic and clinical features. METHODS Serum was collected from each patient at the time of diagnosis. In addition, tumor biopsy specimens were obtained before the initiation of treatment. An enzyme-linked immunosorbent assay was used to detect p53-Abs. The accumulation of p53 protein in tumor cell nuclei was assessed immunohistochemically by use of the anti-p53 monoclonal antibody DO7. Patient treatment consisted of radiotherapy alone, primary chemotherapy followed by radiotherapy, or surgery and postoperative radiotherapy. Relapse-free and overall survival from the beginning of treatment were estimated by use of the Kaplan-Meier method; survival comparisons were made by use of the logrank statistic. Univariate and multivariate analyses were conducted to identify factors associated with survival. Reported P values are two-sided. RESULTS Fifteen (18.8%) of the 80 patients had p53-Abs. Tumor cell nuclei in 43 (58.9%) of 73 assessable biopsy specimens exhibited strong p53 immunostaining. Patient treatment method and the accumulation of p53 protein in tumor cell nuclei were not associated with increased risks of relapse or death. In univariate analyses, advanced tumor stage (> T1 [TNM classification]) and the presence of p53-Abs were significantly associated with an increased risk of death (P for trend = .007 and P = .002, respectively), whereas advanced tumor stage, substantial regional lymph node involvement (> N1), and the presence of p53-Abs were associated with an increased risk of relapse (P for trend = .002, P = .02, and P < .0001, respectively). In multivariate analyses, advanced tumor stage and the presence of p53-Abs were significantly associated with increased risks of relapse (p for trend = .04 and P = .003, respectively) and death (P for trend = .04 and P = .03, respectively). At 2 years of follow-up, the overall survival proportion was 63% (95% confidence interval [CI] = 47%-80%) when no p53-Abs were detected compared with 29% (95% CI = 4%-54%) when p53-Abs were detected. Relapse-free survival at 2 years was 62% (95% CI = 49%-76%) if no p53-Abs were detected compared with 13% (95% CI = 0%-31%) if p53-Abs were detected. CONCLUSIONS AND IMPLICATIONS The proportion of patients with HNSCC who have serum p53-Abs is smaller than that of patients exhibiting tumor cell accumulation of p53 protein. The presence of p53-Abs is significantly associated with increased risks of relapse and death.