Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study.

Background: Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods: This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results: In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion: Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information: NCT00201396.

Post-radiation Pap smear for Chinese patients with cervical cancer: a ten-year follow-up.

BACKGROUND: To study the performance of routine follow-up Pap smears after curative radiotherapy (RT) for Chinese cervical cancer (CC) patients. METHODS: In 1996, 50 patients with non-metastatic CC received curative RT. Forty-six patients had routine follow-up Pap smears and constituted the study group. Details regarding clinical characteristics were retrospectively abstracted. Pap smear results were obtained via national Pap smear database linkage and chart review. The Pap smear results during recurrence-free survival (RFS) were analyzed and compared with clinical outcomes to study the performance characteristics. RESULTS: After 34 (2 approximately 105) months' median follow-up, the clinical outcomes were isolated central recurrence (ICR), other recurrence (OR), and no evidence of disease (NED) for six, 20, and 20 patients, respectively. During 22 months' median RFS (range 2-105), 422 Pap smears (including missing data, n = 33) were performed. Most of the Pap smear results were within normal limits (65.8%) or benign (reactive changes or atrophy with inflammation) (25.2%). Atypical cells, low-grade squamous intraepithelial lesion (LSIL), high-grade intraepithelial lesion (HSIL), and carcinoma were found in ten (2.6%), 11 (2.8%), 11 (2.8%), and three (0.8%) specimens, respectively. Follow-up of the 21 atypical cells/LSIL smears among seven patients revealed five NED with normal/benign smears, one NED with HSIL and one OR with HSIL. Follow-up of the 11 HSIL smears among four patients revealed two ICR, one OR and one NED with HSIL. Follow-up of the three carcinoma smears revealed three ICR (one followed by HSIL in a repeat Pap smear before ICR). The sensitivity for the detection of ICR by carcinoma smears was 50%, with a specificity and positive predictive value (PPV) of 100%. CONCLUSION: Few (approximately 3%) of the routine follow-up Pap smears after CC patients receiving curative RT were HSIL/carcinoma, but most (4/6) of these patients turned out to be ICR.

Quality of life in patients of nasopharyngeal carcinoma: validation of the Taiwan Chinese version of the EORTC QLQ-C30 and the EORTC QLQ-H&N35.

The authors followed the guidelines of translation and pilot testing of the EORTC QLQ-C30 and EORTC-QLQ-H&N35 questionnaires. The questionnaires were given to 50 nasopharyngeal carcinoma patients under active treatment and 50 under follow-up at our institution from November 2000 to June 2001. A retest was conducted 2 weeks after the first interview/form completion for the follow-up group. The intraclass correlation coefficients of the two questionnaires were moderate to high in the follow-up group. Cronbach's alpha coefficients of all scales of the two questionnaires were > or = 0.70 except that of cognitive functioning. Correlation of scales measuring similar dimensions of the QLQ-C30 and the SF-36 were moderate to high, while that of the QLQ-H&N35 and the QLQ-C30 and the SF-36 were moderate to low. Patients in the active treatment group had more serious acute problems due to disease and chemotherapy. Patients in the follow-up group had more serious chronic problems due to radiation therapy. We concluded that the Taiwan Chinese version of the EORTC QLQ-C30 and the EORTC QLQ-H&N35 had moderate to high test-retest reliability, high internal consistency in most scales, and could show the expected differences between patients in active treatment and follow-up group.

Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy. PATIENTS AND METHODS: Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL). RESULTS: From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis-free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis-free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival. CONCLUSION: The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

Factors affecting the overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site: experience with 60 cases.

OBJECTIVE: To analyze the factors affecting overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site after a full course of radiotherapy. DESIGN: Retrospective analysis of 60 consecutive patients treated by surgical resection of the recurrent tumors, with a mean follow-up of 43.1 months (range, 19-96 months). SETTING: Academic tertiary referral center. RESULTS: The overall survival and locoregional relapse-free survival were 56% and 60% at 2 years, respectively, and 30% and 40% at 5 years. Twenty-nine (81%) of 36 patients died with uncontrolled local disease. The T stage of the recurrent tumors appeared to be an important prognostic factor. Age, sex, pathologic findings, and disease-free interval (time between previous radiotherapy and local recurrence) were not significant prognosis-affecting factors by the log-rank test. Multivariate analysis showed that patients with recurrent tumors of undifferentiated carcinoma, sarcoma, or small cell carcinoma had unfavorable prognoses. Uncontrolled local disease and the emergence of distant metastasis predicted grave results as well. Postoperative irradiation showed some benefit to patients, but the difference was not statistically significant. CONCLUSIONS: The T stage of the recurrence was the prominent prognosis-affecting factor in patients with recurrent nasopharyngeal carcinoma who received salvage surgery. Patients with local recurrence should be carefully selected for the salvage surgery. We recommend this surgery for patients with rT1, rT2, or limited rT3 lesions. The results of surgical resection in terms of local control and overall survival were slightly better than those of high-dose reirradiation, with fewer late complications.

DNA content of nasopharyngeal carcinoma: an independent prognostic indicator.

The purpose of this study was to examine whether tumor DNA content correlated with prognosis in nasopharyngeal carcinoma (NPC). DNA flow-cytometric analysis in fresh specimens of nasopharyngeal biopsy from 123 patients with clinical suspicion of NPC was collected initially. Histopathologic study and successful flow-cytometric analysis had 28 lymphoid hyperplasias and 87 NPCs. Seventeen NPC patients were treated elsewhere and were excluded. A total of 98 patients, including 28 lymphoid hyperplasias and 70 NPCs, formed the materials of this study. There were 34 (49%) diploid and 36 (51%) aneuploid in NPC patients. No lymphoid hyperplasias were aneuploid. The mean of S-phase fraction was higher in NPC than in lymphoid hyperplasia (P < .001), indicating higher cellular activity in NPC. DNA content failed to associate with age, gender, pathology, distant metastasis, and stage, indicating that DNA content was an independent prognostic indicator and possibly a clinical parameter. The log-rank test of overall survival curves was significant for stage (P = .002) and DNA ploidy (P = .042); it was almost significant for S-phase fraction (P = .057). Because the follow-up duration was not long enough, univariate and multivariate analysis were not significant for stage, ploidy, and S-phase fraction, except for distant metastasis. It is also most likely colinearity of clinical stage and distant metastasis that explained why clinical stage could not show significance in prognosis. Interestingly, the DNA content appeared to be a potential prognostic parameter in overall survival, although it was not statistically significant (P = .052). Our data suggested that NPC patients with aneuploid DNA and high S-phase fraction tend to have poor prognosis and should be treated more aggressively, even in the early stage of the disease.

Symptom profile of nasopharyngeal cancer patients during radiation therapy.

PURPOSE: This prospective, longitudinal study was aimed to describe the prevalence, severity, and pattern of symptoms over the course of radiation therapy in persons with nasopharyngeal carcinoma and to explore symptom severity by treatment modality. DESCRIPTION OF STUDY: Thirty-seven patients completed this study, and 46% received chemotherapy before radiation therapy. A self-reported radiation symptom checklist and an objective mucositis assessment tool were used weekly to document oropharyngeal, skin, nose or ear, or more general side effects, and mucositis. RESULTS: Oropharyngeal problems were the most severe complaints during radiation therapy. All patients experienced dry mouth, taste change, difficulty in swallowing, difficulty in opening their mouths, hoarseness, sore throat, and observable mucositis. Most reported moderate-to-severe dry mouth, difficulty in swallowing, and sore throat from weeks 3 through 7. Skin problems were not prominent until week 4. Patients also lost an average of 3.9 kg during the therapy. Sequential chemotherapy and radiation therapy was associated with more severe oropharyngeal problems than radiation therapy alone, but no significant differences in other problems were found. CLINICAL IMPLICATIONS: Despite recognition of the oropharyngeal side effects associated with irradiation, effective management protocols for such symptoms have not been implemented in the studied institution. The frequency and intensity of the symptoms reported indicate an urgent need for increased vigilance about radiation-related side effects and pain management. As well, patient education about expected side effects may help mitigate the anxiety that patients experience when these symptoms occur.

Induction with mitomycin C, doxorubicin, cisplatin and maintenance with weekly 5-fluorouracil, leucovorin for treatment of metastatic nasopharyngeal carcinoma: a phase II study.

The combination of cisplatin and 5-fluorouracil (5-FU) (PF) is the most popular regimen for treating metastatic nasopharyngeal carcinoma (NPC) but it is limited by severe stomatitis and chronic cisplatin-related toxicity. A novel approach including induction with mitomycin C, doxorubicin and cisplatin (MAP) and subsequent maintenance with weekly 5-FU and leucovorin (FL) were designed with an aim to reduce acute and chronic toxicity of PF. Thirty-two patients of NPC with measurable metastatic lesions in the liver or lung were entered into this phase II trial. Mitomycin C 8 mg m(-2), doxorubicin 40 mg m(-2) and cisplatin 60 mg m(-2) were given on day 1 every 3 weeks as initial induction. After either four courses or remission was achieved, patients received weekly dose of 5-FU 450 mg m(-2) and leucovorin 30 mg m(-2) for maintenance until disease progression. With 105 courses of MAP given, 5% were accompanied by grade 3 and 0% were accompanied by grade 4 stomatitis. The dose-limiting toxicity of MAP was myelosuppression. Forty per cent of courses had grade 3 and 13% of courses had grade 4 leukopenia. No grade 3 or 4 cisplatin-related toxicity was observed. The overall response rate was 94% (95% confidence interval (CI) 84.9-100%) with a complete response rate (CR) of 6% (95% CI: 0-15.2%) and a good partial response (PR) rate of 28% (95% CI 11.7-44.6%), which was optionally defined as observance of only equivocal lesion identifiable under imaging study. Twenty-seven cases entered weekly FL maintenance phase. The median duration of maintenance with weekly FL was 38 weeks (8-91 weeks). There was no grade 3 or 4 toxicity noted during weekly FL. The median progression-free survival and overall survival were 11.6+/-0.4 and 18.1+/-3.6 months respectively. Six patients with a median follow-up of 19.8 months (9.6-41.0 months) were still alive and five of them had disease under control with FL. Good responders (CR and good PR) had better survival than less satisfactory responders (PR and stable disease) (P = 0.05). From Cox's multivariate regression analysis, the only significant prognostic factor for survival was good response to MAP (P = 0.042). Liver metastasis was the only significant variable in the best subset regression model that predicted good response to MAP (CR and good PR) (P = 0.027). MAP was an effective combination for metastatic NPC with minimal stomatitis and cisplatin-related toxicity but had significant myelosuppression. Weekly FL was a maintenance therapy with minimal side-effects. The response rate and overall survival of MAP-FL were better than series previously reported even when a subset of patients with poor prognosis was selected. MAP-FL's role as neoadjuvant or adjuvant therapy is worthy of further study.

Treatment, outcomes, and prognostic factors of ear cancer.

Cancer of the ear is rare and a consensus has not been reached as to the most appropriate treatment. In this retrospective study, we examined the treatment modalities, prognostic factors, and outcomes of patients treated for ear cancer at the National Taiwan University Hospital during a 15-year period. The disease-free survival rates of patients with three different disease grades were compared using the log-rank test. The effects of prognostic factors on survival were examined with Cox's proportional hazard model. Of the 61 ear cancer patients treated from January 1982 through October 1996, 47 (36 men, 11 women; mean age, 54.6 yr) had complete records and were included in this study. The tumor originated from the middle ear in 29 (62%) patients and from the external ear canal in 18 (38%). A total of 37 patients underwent radical mastoidectomy to remove the gross tumor, while six underwent wide excision of the tumor. Concomitant parotidectomy or neck dissection was performed in seven patients. Thirty-eight patients received postoperative radiation therapy and five patients received chemotherapy for palliative treatment of recurrent or inoperable tumors. All but four (9%) of 43 patients developed facial nerve palsy postoperatively. There were no deaths directly related to surgery or other major complications, including cerebrospinal fluid leakage, meningitis, or hemiparesis. The 5-year disease-free survival rate was 53% overall (n = 47), but differed significantly among patients with different grades of disease (p = 0.038): 66% for grade I (n = 27), 44% for grade II (n = 17), and 0% for grade III (n = 3). Multivariate analysis revealed that cervical lymph node metastasis was a poor prognostic factor (relative hazard, 16.4; p < 0.001). These results suggest that mastoidectomy with postoperative radiation therapy can yield satisfactory outcomes, even in some cases of advanced (grade II) disease.

Experience of radiotherapy in lethal midline granuloma with special emphasis on centrofacial T-cell lymphoma: a retrospective analysis covering a 34-year period.

Lethal midline granuloma (LMG) is characterized by progressive ulceration and destruction of the midfacial tissue. It occurs more frequently in Oriental than in Western populations. Because of the progress in clinical pathology and immunohistochemistry, most cases have been proven to be malignant lymphomas, especially of T-cell lineage. We describe 92 cases of lethal midline granuloma or centrofacial malignant lymphoma in the period 1959-1993. All received complete courses of radiotherapy. Twenty of them also received combination chemotherapy. Thirty-six cases had specimens available for immunohistochemical study; 25 (69%) of these had a T-cell phenotype, and 6 (17%) were of B-cell lineage. The dose to the nasal region was in the range of 3000-7500 cGy in 11-58 days, and to the neck 3000-6400 cGy in 11-48 days. The overall survival rate for the LMGs was 59.5% at 5 years and 56.2% at 10 years (Kaplan-Meier). Combined chemotherapy seemed not to improve the overall survival in this study (p = 0.63), but the patient number was too small to make a firm conclusion. Based on the results of this study, we recommend a dose of 4500-5000 cGy to the midfacial region, since a higher dosage did not improve the treatment results (p = 0.88). Irradiation has a definite role in good locoregional control of this disease. The recent clarification of the disease nature and the recognition of the background clinicopathological features should provide valuable information for future patient management and prospective studies.

Chromosome aberrations induced in human lymphocytes after partial-body irradiation.

Chromosomal aberrations in peripheral blood lymphocytes obtained from two patients before and after they received one fraction of partial-body irradiation for palliative treatment were analyzed. Blood samples were taken 30 min and 24 h after radiation treatment. The yield of dicentrics obtained from case A 30 min after a partial-body (about 21%) treatment with 8 Gy was 0.066/cell, while the yield obtained 24 h after radiation treatment was 0.071/cell. The fraction of irradiated lymphocytes that reached metaphase at 52 h was 0.08 as evaluated by mixing cultures of in vitro irradiated and unirradiated blood. The yield of dicentrics for blood from case B 30 min after 6 Gy partial-body (about 24%) irradiation was 0.655/cell, while the yield 24 h after irradiation was 0.605/cell. The fraction of irradiated cells was 0.29. Estimation of doses and irradiated fractions for the two cases using the method proposed by Dolphin and the Qdr method is discussed. Although there was no significant difference between the mean yields of dicentrics per cell obtained 30 min and 24 h after radiation treatment, the data obtained at 24 h seemed more useful for the purpose of dose estimation. When a higher dose (8 Gy) was delivered to a smaller percentage of the body, underestimation of the dose was encountered.

Determination of changes in tumor blood perfusion after hydralazine treatment by dynamic paramagnetic-enhanced magnetic resonance imaging.

Magnetic resonance imaging, using the paramagnetic chelate gadopentetate dimeglumine as a perfusing agent, was used to investigate the effect of the vasoactive drug hydralazine on tumor blood perfusion. The method requires measurements of the magnetic resonance image intensity changes with time on a pre-selected region of interest in the tumor image, immediately following intravenous injection of gadopentetate dimeglumine. The present study showed that the initial slope of the intensity-time curve can be used, to a first approximation, to infer tumor blood perfusion. With the dynamic imaging technique, it was demonstrated that, in the KHT sarcoma implanted intramuscularly in the hind leg of C3H/HeN mice, intraperitoneal administration of hydralazine reduced the volume-averaged tumor blood perfusion in a dose-dependent manner. The intrinsically high spatial resolution of magnetic resonance imaging allows a detailed study of the heterogeneous nature of tumor blood perfusion. The potential applications of this imaging technique to study the differential effects of hydralazine on perfusion between tumor and normal tissues will be discussed. The clinical utility of the technique should be promising because of its non-invasive nature.