Kwan-Yee Chan

Long-term survival of nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy

PURPOSE The purpose of this study is to demonstrate long-term survival of nasopharyngeal carcinoma treated with concomitant chemotherapy and radiotherapy (CCRT) followed by adjuvant chemotherapy. METHODS AND PATIENTS One hundred and seven patients with Stage III and IV (American Joint Committee on Cancer, AJCC, 1988) nasopharyngeal carcinoma (NPC) were treated with concomitant chemotherapy and radiotherapy (CCRT) followed by adjuvant chemotherapy between April 1990 and December 1997 in Koo Foundation Sun Yat-Sen Cancer Center, Taipei. The dose of radiation was 70 Gray (Gy) given in 35 fractions, 5 fractions per week. Two courses of chemotherapy, consisting of cisplatin and 5-fluorouracil, were delivered simultaneously with radiotherapy in Weeks 1 and 6 and two additional monthly courses were given after radiotherapy. According to the AJCC 1997 staging system, 32 patients had Stage II disease, 44 had Stage III, and 31 had Stage IV disease. RESULTS With median follow-up of 44 months, the 5-year overall survival rate in all 107 patients was 84.1%, disease-free survival rate was 74.4%, and locoregional control rate was 89.8%. The 3-year overall survival for Stage II was 100%, for Stage III it was 92.8%, and for Stage IV, 69. 4% (p = 0.0002). The 3-year disease-free survival for Stage II was 96.9%, for Stage III it was 87.7%, and for Stage IV it was 51.9% (p = 0.0001). CONCLUSION CCRT and adjuvant chemotherapy is effective in Taiwanese patients with advanced NPC. The prognosis of AJCC 1997 Stage II and III disease is excellent, but, for Stage IV (M0), it is relatively poor. Future strategies of therapy should focus on high-risk AJCC 1997 Stage IV (M0) cohort.

Examining prognostic factors and patterns of failure in nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy: impact on future clinical trials

PURPOSE Concomitant chemotherapy and radiotherapy (CCRT), followed by adjuvant chemotherapy, has improved the outcome of nasopharyngeal carcinoma (NPC). However, the prognosis and patterns of failure after this combined-modality treatment are not yet clear. In this report, the prognostic factors and failure patterns we observed with CCRT may shed new light in the design of future trials. METHODS AND PATIENTS One hundred forty-nine (149) patients with newly diagnosed and histologically proven NPC were prospectively treated with CCRT followed by adjuvant chemotherapy between April 1990 and December 1997. One hundred and thirty-three (89.3%) patients had MRI of head and neck for primary evaluation before treatment. Radiotherapy was delivered either at 2 Gy per fraction per day up to 70 Gy or 1.2 Gy per fraction, 2 fractions per day, up to 74.4 Gy. Chemotherapy consisted of cisplatin and 5-fluorouracil. According to the AJCC 1997 staging system, 32 patients were in Stage II, 53 in Stage III, and 64 in Stage IV (M0). RESULTS Univariate analysis revealed that WHO (World Health Organization) Type II histology, T4 classification, and parapharyngeal extension were poor prognostic factors for locoregional control. Multivariate analysis revealed that T4 disease was the most important adverse factor that affects locoregional control, the risk ratio being 5.965 (p = 0.02). Univariate analysis for distant metastasis revealed that T4 and N3 classifications, serum LDH level > 410 U/L (normal range, 180-460), parapharyngeal extension, and infiltration of the clivus were significantly associated with poor prognosis. Multivariate analysis, however, revealed that T4 classification and N3 category were the only two factors that predicted distant metastasis; the risk ratios were 3.994 (p = 0.02) and 3.390 (p = 0.01), respectively. Therefore, based on the risk factor analysis, we were able to identify low-, intermediate-, and high-risk patients. Low-risk patients were those without the risk factors mentioned above. They consisted of Stage II patients with T2aN0, T1N1, and T2aN1 categories and of Stage III patients with T1N2 and T2aN2 categories. Their risk of recurrence is low (4%). Intermediate-risk patients were those with at least one univariate risk factor. They are Stage II patients with T2bN0 and T2bN1 categories and Stage III patients with T2bN2 and T3N0-2 categories. The risk of recurrence is modest (18%). High-risk patients have risk factors by multivariate analysis. They are stage T4 or N3 patients. Their risk of recurrence is high (36%). CONCLUSION Low-risk patients have an excellent outcome. Future trials should focus on reducing treatment-associated toxicities and complications and reevaluate the benefit of sequential adjuvant chemotherapy. The recurrence in treatment of intermediate-risk patients is modest; CCRT and adjuvant chemotherapy may be the best standard for them. Patients with T4 and N3 disease have poorer prognosis. Hyperfractionated radiotherapy may be considered for the T4 patients. Future study in these high-risk patients should also address the problem of distant spread of the disease.

Concomitant Radiotherapy and Chemotherapy for Early-Stage Nasopharyngeal Carcinoma

PURPOSE Early-stage nasopharyngeal carcinoma (NPC) continues to carry a failure rate of 15% to 30% when treated with radiotherapy alone; the benefit of concomitant radiotherapy and chemotherapy (CCRT) in early-stage NPC is unclear. The purpose of this report is to describe our efforts to improve treatment outcome in early-stage NPC after CCRT. PATIENTS AND METHODS Of 189 newly diagnosed NPC patients without evidence of distant metastases who were treated in our institution between 1990 and 1997, 44 presented with early-stage (stage I and II) disease according to the American Joint Committee on Cancer (AJCC) 1997 NPC staging system. Twelve of these patients were treated with radiotherapy alone and 32 with CCRT. Each patients head and neck area was evaluated by magnetic resonance imaging or computed tomography. Radiotherapy was administered at 2 Gy per fraction per day, Monday through Friday, for 35 fractions for a total dose of 70 Gy. Chemotherapy consisting of cis-diamine-dichloroplatinum and fluorouracil was delivered simultaneously with radiotherapy in weeks 1 and 6 and sequentially for two monthly cycles after radiotherapy. RESULTS Patients who were treated with radiotherapy alone primarily had stage I disease, whereas none of those who were treated with CCRT had stage I disease (11 of 12 patients v none of 32 patients; P =.001). The locoregional control rate at 3 years for the radiotherapy group was 91.7% (median follow-up period, 34 months) and was 100% for the CCRT group (median follow-up period, 44 months) (P =.10). The 3-year disease-free survival rate in the radiotherapy group was 91.7% and was 96.9% in the CCRT group (P =.66). CONCLUSION Our results reveal excellent prognosis of AJCC 1997 stage II NPC treated with CCRT. Stage II patients with a greater tumor burden treated with CCRT showed an equal disease-free survival, compared with stage I patients treated with radiotherapy alone. A prospective randomized trial is underway to confirm the role of CCRT in stage II NPC.

Prognostic features and treatment outcome in locoregionally advanced nasopharyngeal carcinoma following concurrent chemotherapy and radiotherapy

PURPOSE Concurrent chemotherapy and radiotherapy (CCRT) are effective in treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). However, the prognostic factors after CCRT have not been evaluated. We therefore attempt to evaluate factors that influence treatment outcomes following CCRT. METHODS AND MATERIALS Seventy-four (5 in stage III and 69 in stage IV) patients with locoregionally advanced NPC were treated with CCRT. Radiotherapy was delivered either at 2 Gray (Gy) per fraction per day up to 70 Gy or 1.2 Gy, 2 fractions per day, up to 74.4 Gy. Concurrent chemotherapy consisted of cisplatin and 5-fluorouracil. Cox proportional-hazards model was used to analyze the prognostic factors which included age, gender, pathologic type, T, N, lactate dehydrogenase (LDH), and infiltration of the clivus. RESULTS The primary tumor control rate at 3 years was 96.7% (95% confidence interval [CI]: 92.5-100), distant metastasis-free survival 81.1% (95% CI: 70.6-91.6), disease-free survival 77.0% (95% CI: 65.3-88.7), and overall survival 79.8% (95% CI: 69.2-90.4) with a median follow-up interval of 29 months (range 15-74 months). Cox proportional-hazards model revealed that infiltration of the clivus and serum level of LDH before treatment were the most two important factors that predict distant metastases. Infiltration of the clivus and the serum LDH level greater than 410 U/L were strongly associated with distant metastasis-free survival (p = 0.0004 and p = 0.0002, respectively). When these two risk factors were considered together, no distant metastasis was observed in 40 patients with both intact clivus and LDH < or = 410 U/L. On the contrary, 13 of the remaining 34 patients with at least one risk factor developed distant metastasis (p = 0.0001). CONCLUSION Our study demonstrates that CCRT can improve the primary tumor control of 96.7% and disease-free survival of 77.0% at 3-year follow-up. Distant metastasis, however, is the major cause of failure. Infiltration of the clivus by the tumor and LDH greater than 410 U/L are the two independent and useful prognostic factors in patients with locoregionally advanced NPC who were treated with CCRT. Good- and poor-risk patients can be distinguished by virtue of their having both conditions.

Improvement of local control of T3 and T4 nasopharyngeal carcinoma by hyperfractionated radiotherapy and concomitant chemotherapy

PURPOSE When the primary tumor of nasopharyngeal carcinoma (NPC) is treated at the base of skull and intracranium with conventional radiotherapy, the result is generally poor. In this report, we investigated whether hyperfractionated radiotherapy (HFRT) and concomitant chemotherapy (CCT) could achieve better local control and survival in NPC patients with T3 and T4 lesions. PATIENTS AND METHODS Forty-eight patients (11 T3 and 37 T4 NPC) were treated with HFRT and CCT. HFRT was administered at 1.2 Gy per fraction, two fractions per day, Monday-Friday for 62 fractions for a total dose of 74.4 Gy. Concomitant chemotherapy consisting of cis-diamino-dichloroplatinum (CDDP) alone or CDDP and 5-fluorouracil was delivered simultaneously with radiotherapy during Weeks 1 and 6. Adjuvant chemotherapy consisted of CDDP and 5-fluorouracil for 2 to 3 cycles and was given monthly beginning 1 month after completion of radiation. RESULTS With a median follow-up of 57 months (range: 28-94 months), the 3-year locoregional control rate was 93%, the disease-free survival rate was 71%, and the overall survival rate was 72%. For T4 patients, the 3-year locoregional control rate was 91%, disease-free survival was 62%, and overall survival was 63%. The major acute toxicity was Grade 3 mucositis in 73% and Grade 2 weight loss in 31% of patients. Fifty percent of patients were tube fed. Most patients tolerated the combined modality treatments relatively well; 88% of patients completed their radiation treatment within 8 weeks. CONCLUSION HFRT and CCT for T3 and T4 NPC were associated with excellent local control and improved survival. The treatment-related toxicity was acceptable and reversible. We would recommend using HFRT with CCT for advanced T-stage NPC if the three-dimensional conformal radiation planning shows a significant portion of the brainstem to be inside the treatment field.

The Benefit and Risk of Postmastectomy Radiation Therapy in Patients with High-risk Breast Cancer

To evaluate the efficacy of postmastectomy radiation therapy (PMRT) for prophylaxis against locoregional recurrence in high-risk breast cancer patients, and the rate of complication associated with such treatment, we retrospectively reviewed 79 breast cancers in 78 patients, who were given therapy (PMRT) between April 1990 and March 1995. Radiation doses were 46-50 Gy in 2-Gy fractions. High-risk factors included primary tumor (> or = 5 cm) in 19 (24.1%) patients, positive axillary lymph nodes (> or = 4) in 56 (70.9%) patients, positive or close (< or = 2 mm) surgical margins in 14 (17.7%) patients, and central or inner quadrant tumor with positive axillary nodes and lymphovascular invasion in seven (8.9%) patients. Adjuvant chemotherapy was also given to 69 of 78 (88.5%), patients and hormonal therapy to 41 of 78 (53.7%) patients. The median follow-up time was 25 months (range, 7-66 months) after mastectomy. Our study revealed that locoregional failure as the first site of failure occurred in only one of 78 (1.3%) patients. Relapse-free survival at 3 years was 67.7% [95% confidence interval (CI), 52.0-81.3], and overall survival was 76.9% (95% CI, 63.3-90.6). The incidence of radiological evidence of lung fibrosis increased significantly in patients whose internal mammary chain was included in the radiation field. The occurrence of lung fibrosis can be reduced by changing radiation treatment technique and keeping central lung distance (CLD) of tangential field to < or = 2.8 cm in tangential field technique or < or = 1.4 cm in tangential with a separate internal mammary field technique. We concluded that the risk of locoregional recurrence in high-risk breast cancer patients can be much reduced by PMRT. With careful selection of radiation treatment fields, radiotherapy technique, and limitation of CLD to < or = 2.8 cm in tangential technique or < or = 1.4 cm in separate technique, the risk of symptomatic radiation pneumonitis is minimal. PMRT should be recommended for breast cancer patients who are at high risk for locoregional recurrence.

DIAGNOSTIC THORACIC-COMPUTED TOMOGRAPHY IN RADIOTHERAPY FOR LOCO-REGIONAL RECURRENT BREAST CARCINOMA

PURPOSE This study was initiated to evaluate whether pretreatment diagnostic thoracic CT scan was useful for patients with loco-regional recurrent breast carcinoma, and to assess its impact on the design of radiotherapeutic treatment. METHODS AND MATERIALS Between March 1991 and January 1997, 44 patients underwent thoracic CT examination with contrast material before the consideration of radiotherapy for their isolated loco-regional recurrent breast carcinoma. The CT radiographs were prospectively reviewed for additional findings clinically undetected by prior physical examination and plain-chest radiograph. The changes made in treatment design and dosage of radiation as a result of CT findings were recorded for analysis. The correlation between prognostic indicators and the CT findings was also studied. RESULTS Twenty-two of 44 (50%) patients were found to have additional abnormalities detected only after thoracic CT examinations were performed. The strategy of radiation therapy was altered in 17 of 22 (77%) patients as a result. Patients with shorter disease-free interval (p = 0.08) and multiple sites of recurrence (p = 0.05) tended to have greater numbers of findings on CT scan previously unsuspected. Thus, CT scan is a valuable guide to treating loco-regional recurrent disease. CONCLUSION Pretreatment diagnostic thoracic CT scan offers essential information that can alter treatment planning and thus optimize treatment strategy for a large proportion of patients with clinically isolated loco-regional recurrent breast carcinoma. In this population of patients we recommend that thoracic CT examination be considered before the initiation of radiation therapy.

The Significance of Tc-99m SPECT and MRI Findings in the Diagnosis of Skull Base Invasion in Nasopharyngeal Carcinoma

Purpose: To evaluate the role of Tc-99m SPECT in the diagnosis of skull base invasion in nasopharyngeal carcinoma (NPC) and to compare its findings to magnetic resonance imaging (MRI). Materials and Methods: We retrospectively analyzed 179 newly diagnosed NPC patients treated between August 1, 1997 and December 31, 2000 in our institute. All patients were examined with both MRI and Tc-99m SPECT of the skull base prior to treatment. Bone involvement was suspected on MRI when there was a defect in cortical intactness or an abnormality or asymmetry in the signal intensity of the marrow. Malignancy in the skull base was suspected on SPECT when there was an abnormal focal area of increased uptake or left-to-right asymmetry in the skull bone radioactivity. Patients were staged according to the 1997 AJCC classification of NPC based on physical exam and MRI findings. Primary tumor control rates for patients stratified by T stage and MRI or SPECT results were analyzed using the Kaplan-Meier method and the log rank test. Results: Out of 179 patients, a total of 92 (51.4%) had an abnormal SPECT (positive or questionable for malignancy) in the skull base (T1: 10, T2: 14, T3: 24, and T4: 44), while 78 (43.6%) demonstrated skull base malignancy on MRI (T3: 30 and T4: 48). The 3-year primary tumor control rate of the 92 patients with an abnormal SPECT was 87.1%, versus 98.2% for the patients with a normal SPECT in the skull base (p=0.11). Twenty-three patients in stages T1-T2 had an abnormal SPECT but a normal MRI in the skull base, and their 3-year primary tumor control rate was 100%. Conclusions: An abnormal SPECT in the skull base without corresponding MRI findings is not a poor prognostic factor by itself and patients are not at an increased risk for primary tumor recurrence. However, SPECT appears to be more sensitive than MRI, although specificity is low, and it can be a helpful adjunct to MRI in the pretreatment evaluation of NPC.

Brain Stem Doses for Patients of T3/T4 Nasopharyngeal Carcinoma Treated by Bid Irradiation and Concomitant Chemotherapy

Purpose: Our prior study revealed that at least 1 cm safe margin at clivus direction is necessary to obtain good local control of nasopharyngeal carcinoma (NPC). We retrospectively studied whether hyperfractionation irradiation to treat T3/T4 NPC patients could decrease the long-term side effect to the brain stem. Patients and Methods: Sixty-nine patients with T3/T4 (American Joint Committee on Cancer, 1997 staging system) NPC were treated with concomitant chemotherapy and twice a day radiation followed by adjuvant chemotherapy between September 1991 and December 1998 in Koo Foundation Sun Yat-Sen Cancer Center, Taipei. The planning dose of radiation was 74.4 Gy in 62 fractions, twice a day, 5 days per week. Every patient had 15 mm safe margin at clivus direction in the initial field to 40.8-43.2 Gy, 7mm to 10 mm to 60Gy at the 2nd boost field, and 3-7 mm at the final boost field to a total dose of 74.4 Gy. Twenty-five patients were treated between 1996 and 1998; their previous treatment plan data could be retrieved for analysis in our current CMS (Computerized Medical Systems, INC) three dimension treatment planning system for dose volume histogram calculation of brain stem. Five patients died from disease within 3 years after completion of treatment were excluded from the analysis. Results: With a minimal and median follow-up of 49 and 97 months, respectively, 5-year local control rate of the 20 patients was 93.8%. Brain stem toxicity was observed in one of 20 patients with the manifestation of grade Ⅱ sensory loss at ipsilateral upper limb. There was no treatment related death. The average maximal dose to brain stem was 75.12 Gy and mean dose was 35.56 Gy. The average volumes of brain stem dose more than 50 Gy, 55 Gy, 60 Gy, 65 Gy, and 70 Gy were 10.32 ml, 7.72 ml, 5.67 ml, 3.58 ml, and 1.72 ml, respectively. Conclusion: Our data indicated that adequate irradiation dose could be given safely with hyperfractionation for T3/T4 NPC patients to achieve good local tumor control without significant long-term side effect to brain stem.

Definitive Radiotherapy with or Without Chemotherapy for Resectable Head and Neck Cancer

Purpose: To retrospectively analyze the feasibility, toxicity and outcome of definitive radiotherapy with or without chemotherapy for patients with resectable head and neck cancers. Materials and Methods: Thirty patients with resectable head and neck cancers were treated with definitive split-course radiotherapy with or without concurrent chemotherapy. One patient had stage I, 4 stage II, 3 stage Ⅲ and 22 stage IV diseases. Radiotherapy was given once daily or twice daily with total dose of 68-74 Gy. Chemotherapy included 2 cycles with CDDP+/-SFIJ during radiotherapy, and 2 cycles with CDDP+5FU after radiation treatment. Survival outcome was calculated by the Kaplan-Meier method. Prognostic factors were determined by log-rank test. Results: The median follow-up time was 50.8 months. The 4-year overall survival, disease-free survival and locoregional control rates were 55.7%, 64.9% and 75.8%, respectively. Treatment-related toxicities were tolerable. T1/T2 diseases were associated with heifer locoregional control (p=0.03). The presence of residual disease on post-treatment MRI or CT was the prognostic factor for overall survival (p=0.05), disease-free survival (p=0.009) and locoregional recurrence-free survival (p=0.0001). Conclusion: Definitive radiotherapy with or without chemotherapy can be an alternative to radical surgery for patients with resectable head and neck cancers, with acceptable toxicity and outcome. The presence of residual disease on post-treatment imaging studies demands further investigation and possibly salvage treatment.