A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To evaluate the therapeutic benefits by adding chemotherapy (+C) and/or accelerated-fractionation (AF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma. MATERIALS AND METHODS: From 1999 to 2004, 189 eligible patients were randomized to one of four treatment groups (CF/CF+C/AF/AF+C). The number of fractions/week was 5 for the CF groups and 6 for the AF groups. Patients in the +C groups were given concurrent cisplatin plus adjuvant cisplatin and fluorouracil. RESULTS: The AF+C group achieved significantly higher failure-free rate (88% at 5-year) than the CF group (63%; p=0.013), the AF group (56%; p=0.001) and the CF+C group (65%; p=0.027). As compared with CF alone, the increase in late toxicity was statistically insignificant (36% vs. 20%; p=0.25). Deaths due to cancer progression decreased (7% vs. 33%; p=0.011) but deaths due to incidental causes increased (9% vs. 2%; p=0.62). Improvement in overall survival reached borderline significance (85% vs. 66%; p=0.058). CONCLUSIONS: Concurrent-adjuvant chemotherapy combined with AF significantly reduced failure and cancer-specific deaths. Although the increase in major late toxicity and incidental deaths were statistically insignificant, a subtle increase in non-cancer deaths narrowed the overall survival gain.

Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma.

PURPOSE: To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All patients were irradiated with the same RT technique to > or =66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil). RESULTS: Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (p > or = 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p < 0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05). CONCLUSIONS: Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted.

Dose-response relationship of nasopharyngeal carcinoma above conventional tumoricidal level: a study by the Hong Kong nasopharyngeal carcinoma study group (HKNPCSG).

BACKGROUND AND PURPOSE: To define the dose-response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66 Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique. PATIENTS AND METHODS: Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients (n = 2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation ('boost') after 66 Gy, T-stage, N-stage, use of chemotherapy, sex and age (< or =40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed. RESULTS: On multivariate analysis, T-stage (P < 0.01; hazard ratio [HR], 1.58) and optimal boost (P = 0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease (P = 0.01; HR, 0.33); use of a boost (P < 0.01; HR, 0.60) and age (P = 0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20 Gy-boost gave a lower local failure rate than a 10 Gy-boost. There was no apparent excess mortality attributed to RT complications. CONCLUSIONS: Within the context of a multi-center retrospective study, dose-escalation above 66 Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. 'Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity.

Identification of serum amyloid a protein as a potentially useful biomarker to monitor relapse of nasopharyngeal cancer by serum proteomic profiling.

PURPOSE: Nasopharyngeal cancer (NPC) is a common cancer in Hong Kong, and relapse can occur frequently. Using protein chip profiling analysis, we aimed to identify serum biomarkers that were useful in the diagnosis of relapse in NPC. EXPERIMENTAL DESIGN: Profiling analysis was performed on 704 sera collected from 42 NPC patients, 39 lung cancer patients, 30 patients with the benign metabolic disorder thyrotoxicosis (TX), and 35 normal individuals (NM). Protein profile in each NPC patient during clinical follow up was correlated with the relapse status. RESULTS: Profiling analysis identified two biomarkers with molecular masses of 11.6 and 11.8 kDa, which were significantly elevated in 22 of 31 (71%) and 21 of 31 (68%) NPC patients, respectively, at the time of relapse (RP) as compared with 11 patients in complete remission (CR; RP versus CR, P = 0.009), 30 TX (RP versus TX, P < 0.001), or 35 NM (RP versus NM, P < 0.001). The markers were also elevated in 16 of 39 (41%) lung cancer patients at initial diagnosis. By tryptic digestion, followed by tandem mass spectrometry fragmentation, the markers were identified as two isoforms of serum amyloid A (SAA) protein. Monitoring the patients longitudinally for SAA level both by protein chip and immunoassay showed a dramatic SAA increase, which correlated with relapse and a drastic fall correlated with response to salvage chemotherapy. Serum SAA findings were compared with those of serum Epstein-Barr virus DNA in three relapsed patients showing a similar correlation with relapse and chemo-response. CONCLUSIONS: SAA could be a useful biomarker to monitor relapse of NPC.

Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine.

BACKGROUND: Differentiated thyroid carcinoma (DTC) in childhood has a good prognosis despite a high incidence of relapse. The use of radioactive iodine (RAI) has not been well established. PROCEDURE: This is a review of 60 patients less than 21 years of age; mean follow-up was 14 years. RESULTS: Patients had a higher relapse rate with papillary thyroid carcinoma (PTC) than with follicular thyroid carcinoma (FTC): 24.5 vs. 9.1%. Compared with 997 patients with age > or = 21, patients <21 years of age had a higher female to male ratio (7.6 vs. 3.9), higher incidence of nodal metastasis (45 vs. 28%), and lung metastasis (15 vs. 7.8%), and improved 10-year cause-specific survival (CSS) (98.3 vs. 89.5%). The 10-year rates of CSS, local-regional failure-free survival (LRFFS), and distant metastasis failure-free survival (DMFFS) for the young patients were 98.3, 79.3, and 90.7%, respectively. In patients with no distant metastasis at presentation, RAI improved 10-year LRFFS (71.9 vs. 86.5%; P = 0.04). At last follow-up, 10 of 12 patients (80%) with local-regional (LR) relapse and five of nine patients (55.6%) with distant metastasis were rendered disease-free. No patient has experienced a second malignancy. CONCLUSIONS: Prognosis of DTC in young patients was good. Patients with LR relapse and distant metastasis had a high rate of remission after treatment. RAI treatment can reduce the rate of LR relapse in patients with no distant metastasis and result in complete remission in half of those with distant metastasis. No patient experienced a second malignancy.

Papillary microcarcinoma of the thyroid-Prognostic significance of lymph node metastasis and multifocality.

BACKGROUND: It is known that patients with papillary microcarcinoma (PMC) of the thyroid gland have a very favorable prognosis. The rising incidence of PMC among papillary thyroid carcinoma (PTC) necessitates the identification of prognostic factors and the formulation of treatment protocols. METHODS: The authors conducted a retrospective analysis of 203 patients with PMC who were diagnosed on or before 1999 and were treated at the Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong. RESULTS: The cause specific survival, locoregional (LR) failure free survival, and distant metastases failure free survival rates at 10 years were 100%, 92.1%, and 97.1%, respectively. Five patients had lung metastases; 2 patients died of their metastases 12.9 years and 14.8 years after diagnosis, and 3 patients achieved clinical remission after radioiodine (RAI) treatment. Twelve patients had LR recurrences. Patients with LR recurrence were highly salvageable with a combination of surgery, RAI treatment, and external radiotherapy; all but one (who refused treatment) were alive without disease at last follow-up. Multivariate analyses did not reveal any independent prognostic factor for survival. The risk of cervical lymph node (LN) recurrence increased 6.2-fold (P = 0.01) and 5.6-fold (P = 0.02) when LN metastases and multifocal disease were present at diagnosis. RAI ablation reduced the LN recurrence rate to 0.27 (P = 0.04). The presence of LN metastasis increased the rate of distant metastasis 11.2-fold (P = 0.03). Age was not a significant factor in predicting disease recurrence or survival. Subdivision by tumor sizes 5 mm did not affect the outcome, but no patient with tumors

Reirradiation of nasopharyngeal carcinoma with intracavitary mold brachytherapy: an effective means of local salvage.

PURPOSE: To assess the role of intracavitary mold brachytherapy in salvaging local failure of nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: The outcomes of 118 consecutive NPC patients with local failure treated with mold brachytherapy between 1989 and 1996 were retrospectively reviewed. Eleven patients received additional external radiotherapy. RESULTS: All molds were tailor-made, and the whole procedure was performed under local anesthesia. Pharyngeal recess dissection was routinely performed to allow direct contact of the radioactive source with the pharyngeal recess, a common site of local failure. Initially, the molds were preloaded with 192Ir wires, but since 1992, the sources have been manually afterloaded; the mold has also been redesigned for better conformity, ease of insertion, and radiation safety. Using brachytherapy alone, 50-55 Gy was given for recurrence in 4-7 days; for persistence, 40 Gy was administered. The overall complete remission rate was 97%. The rates of 5-year local control, relapse-free survival, disease-specific survival, overall survival, and major complication were 85%, 68.3%, 74.8%, 61.3%, and 46.9%, respectively. Major complications included nasopharyngeal necrosis with headache, necrosis of cervical vertebrae with atlantoaxial instability, temporal lobe necrosis, and palsy of the cranial nerves. The afterloaded mold was as effective as the preloaded version, but with fewer complications. CONCLUSIONS: Intracavitary mold brachytherapy was effective in salvaging NPC with early-stage local persistence or first recurrence.

Follicular thyroid carcinoma: prognostic factors and the role of radioiodine.

BACKGROUND: The objective of this study was to investigate the patterns of recurrence, various prognostic factors, and the role of radioiodine in the treatment of patients with follicular thyroid carcinoma (FTC). METHODS: The clinical outcomes of 215 patients with FTC who were treated at a single institution were analyzed retrospectively. The mean follow-up was 10.8 years. RESULTS: The actuarial rates of cause specific survival (CSS), locoregional (LR) control, and freedom from distant metastasis (DM) at 10 years were 81%, 83%, and 72.3%, respectively. The independent prognostic factors for survival were metastasis at presentation (relative risk [RR], 47.7), radioiodine (RAI) treatment (RR, 0.25), extrathyroidal extension (RR, 3.8), and the postoperative absence of macroscopic disease in the neck region (RR, 0.06). In patients who were treated with RAI, both the LR failure rate (RR, 0.24) and the mortality rate (RR, 0.25) were reduced to about 25%. Subgroup analysis revealed that RAI improved the survival of patients with DM at presentation (RR, 0.17) and improved the LR control rate in patients who had no DM at presentation (RR, 0.13). For patients who underwent total thyroidectomy with negative resection margins, RAI significantly reduced the rate of LR recurrence (RR, 0.05). Patients with the minimally invasive type of FTC had a good prognosis. The 10-year rates for CSS, LR control, and freedom from DM were 97.6%, 100%, and 90.6%, respectively. The prognosis of patients with frankly invasive FTC was much poorer. The 10-year rates for CSS, LR control, and freedom from DM were 66.7%, 100%, and 45%, respectively. CONCLUSIONS: RAI is an effective treatment for patients with FTC. It was associated with improved survival rates and fewer recurrences.

Early stage nasal NK/T-cell lymphoma: clinical outcome, prognostic factors, and the effect of treatment modality.

PURPOSE: To determine the clinical outcome, prognostic factors, and effect of adding combination chemotherapy to radiation therapy on disease control and survival in early stage nasal natural killer (NK)/T-cell lymphoma. METHODS AND MATERIALS: A retrospective "intent to treat" analysis was carried out on 79 patients treated consecutively with curative intent between 1977 and June 2001. They all had early stage (Ann Arbor Stage I(E): 63, II(E):16) nasal NK/T-cell lymphoma. Sixty-one were planned for combined modality treatment (CMT); radiotherapy alone (RT) was intended for 18. Three to 6 cycles of anthracycline-containing regimens were aimed at for patients intended for CMT. Patients selected for RT were generally older or treated during the earlier part of the study period. RESULTS: The overall complete response (CR) rate was 68.4% (54/79), of whom 44.4% (24/54) relapsed after 54.9 months median follow-up of the survivors. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 35.5% and 37.9%, respectively. On multivariate analysis, good performance status (Eastern Cooperative Oncology Group [ECOG] <2) was shown to be a significant favorable factor for DFS (p = 0.011), whereas good performance status (ECOG <2) and Ann Arbor Stage I(E) disease were shown to be significant favorable factors for OS (p = 0.001 and p = 0.013, respectively). The type of intended treatment was not a significant factor for DFS (5-year DFS CMT vs. RT = 35.8% vs. 30.5%, p = 0.795) or OS (5-year OS CMT vs. RT = 40.3% vs. 29.8%, p = 0.693) though only 2 of the 16 Stage II(E) patients were intended for RT alone. Resistance to treatment, especially to chemotherapy, was common. Of 61 patients intended to be given CMT, 31 showed disease progression while receiving chemotherapy, of whom 17 progressed locoregionally. Nine of the latter group were rendered CR by salvage radiotherapy. CONCLUSIONS: The overall outcome in early stage nasal NK/T-cell lymphoma is poor. Performance status and Ann Arbor stage are significant factors influencing DFS and OS. The addition of anthracycline-containing chemotherapy to radiotherapy does not appear to confer any survival benefit in Stage I(E) patients. Therefore, radiation therapy remains the mainstay of treatment for this lymphoma type.

Differentiated thyroid carcinoma: comparison between papillary and follicular carcinoma in a single institute.

PURPOSE: To compare and contrast the clinical presentation and treatment outcome of patients with papillary and follicular thyroid carcinoma and to study the pattern of practice of treatment of differentiated thyroid carcinoma in Hong Kong. METHOD: The clinical presentation and treatment outcomes were reviewed for 1057 patients with differentiated thyroid cancers who were treated at the Queen Elizabeth Hospital, Hong Kong, from 1960 to 1997. Eight hundred forty-two patients had papillary thyroid carcinomas (PTC), and 215 had follicular thyroid carcinomas (FTC). The mean follow-up was 9.2 years. RESULTS: The differences in the clinical factors of PTC to FTC were as follows: PTC had a higher incidence (3.9:1); these patients were younger at presentation (median age, 44 vs 49), showed a higher female-male ratio (4.5 vs 2.9) and smaller primary tumor size (median 2 cm vs 3.5 cm), and a higher incidence of multifocal disease (28.3% vs 18.1%), extrathyroidal extension (39.4% vs 14%), and more lymph node metastases (33.3% vs 12.1%). The incidence of distant metastases was higher for patients with FTC (28.8% vs 8.9%), and cause-specific survival rates were lower (p =.001). The locoregional control rates were not significantly different (p =.2). The 10-year cause-specific survival, freedom from distant metastasis, and locoregional failure figures for PTC compared with FTC were 92.1% vs 81%, 90.8% vs 72.3%, and 78.5% vs 83%. CONCLUSIONS: Although patients with PTC tend to have more advanced locoregional disease compared with those with FTC, the likelihood of locoregional control is similar, and the probability of cure is better.

Cervical nodal metastases from occult primary: undifferentiated carcinoma versus squamous cell carcinoma.

PURPOSE/OBJECTIVE: Controversy exists regarding the management of cervical lymph node metastases from occult primary. Oncologists face a major challenge in adopting an optimal approach. This study attempted to compare the clinical course of two different histologic findings of this disease entity. MATERIALS AND METHODS: A retrospective analysis was performed for all patients referred to our institution between 1988 and 1998 with cervical lymph node metastases from an unknown primary. Case records of consecutive unselected patients with histologically confirmed carcinoma in cervical lymph nodes were reviewed. Those with histologic findings other than squamous cell carcinoma (SCC) or undifferentiated carcinoma (UDC) and lymphadenopathies at the supraclavicular fossa alone or below the clavicles at the time of diagnosis were excluded. There were 45 patients identified with a mean follow-up of 36 months (range, 4-110 months). Thirty-seven were men and eight were women. The mean age was 57 (range, 29-91). There were 32 patients with SCC and 13 patients with UDC. Treatment modality included surgery (S) alone in 1 patient (2%), radiotherapy (RT) alone in 24 patients (53%), and combined modality in 20 patients (45%). (Twelve patients (27%) had combined S and RT, 8 patients (18%) had combined chemotherapy and RT.) Twenty-eight patients (62%) were treated with radical intent. For those patients treated by radical RT, the RT field covered both sides of the neck and the potential mucosal primary (PMP) sites, including the entire pharyngeal axis. The median radiation doses to the lymph nodes and the PMP were 65 Gy (range, 60-70 Gy) and 60 Gy (range, 40-70 Gy), respectively. RESULTS: At the time of analysis, ultimate control of disease above the clavicles according to N stage, treatment intent, and histologic type was as follows: N1s, 7 of 7 (100%); N2s, 15 of 26 (58%); N3s, 1 of 12 (8%); radical intent, 19 of 28 (68%); palliative intent, 3 of 17 (18%); UDC, 11 of 13 (85%); SCC,11 of 32 (34%). Eleven patients remained alive and disease free, with a median follow-up of 79 months (range, 27-110 months). The 5-year disease-specific survival (DSS) for the radical treatment group and the palliative treatment group were 67% and 18%, respectively (p =.0011). Significant difference in 5-year DSS was observed among the different N groups: 100% for N1s, 55% for N2s, and 0% for N3s, respectively (p =.0001). There was also a significant difference in the 5-year DSS between UDC and SCC: 81% for UDC vs 34% for SCC (p =.01). No significant difference in the 5-year DSS was observed on the basis of treatment modality in the radically treated group: 63% for RT alone vs 75% for S + RT (p =.711). CONCLUSIONS: UDC histologic findings in our series are associated with better locoregional control and DSS than SCC. Our results in local control, emergence of primary tumor, and DSS are comparable with other published data. However, disease control of advanced nodal stage remains poor; more aggressive treatment approaches, like the use of concurrent chemoradiation or altered fractionation scheme, should be explored.

Circulating Epstein-Barr virus DNA in serum of patients with lymphoepithelioma-like carcinoma of the lung: a potential surrogate marker for monitoring disease.

PURPOSE: The purpose of this work was to study the sera of patients with lymphoepithelioma-like carcinoma (LELC) of the lung for circulating EBV DNA. EXPERIMENTAL DESIGN: Prospectively collected serum samples from five female patients with advanced, inoperable LELC of the lung were measured for free circulating EBV DNA using a quantitative PCR technique. EBV-encoded small RNA (EBER)-1 was assayed in serial serum samples of three of the five patients, either from the start or during the initial phase of chemotherapy/radiotherapy until their terminal event or last follow-up. There was only a single-point sample for analysis in the fourth and fifth patients. Six other patients with LELC of the lung were also retrospectively identified, and their sera were tested for EBER-1 at either the first visit plus the last follow-up visit (n = 2), the first visit only (n = 2), or the last follow-up visit only (n = 2). RESULTS: Prospectively collected serum samples from five patients and retrospectively collected serum samples from two patients who had clinical disease at initial serum measurement showed detectable levels of EBER-1. Retrospectively collected serum samples from four patients with no clinical disease had negative sera. There is consistent correlation between the clinical response to treatment and subsequent clinical course of LELC and serum EBER-1 levels in the three prospective patients with longitudinal serum monitoring. CONCLUSIONS: This study shows for the first time that free EBV DNA can be detected in the serum of patients with LELC of the lung and further suggests the feasibility of its use for monitoring response to therapy in advanced cases.

Central nervous system metastasis from nasopharyngeal carcinoma: a report of two patients and a review of the literature.

BACKGROUND: Central nervous system (CNS) metastasis from nasopharyngeal carcinoma (NPC) is an extremely rare occurrence, although direct intracranial invasion is not infrequent in patients with NPC at a locally advanced stage. Only five other patients have been reported in detail in the English literature. METHODS: The clinical records of two such patients with NPC who were diagnosed with metastasis to the spinal cord (intradural) and to the occipital lobe, respectively, were reviewed. The literature was searched for a review of similar incidents. RESULTS: Both patients had locally advanced disease at the time of presentation and were treated with neoadjuvant chemotherapy and radical radiotherapy. The CNS metastases in both patients were accompanied by disease recurrences in multiple sites after a prolonged period of clinical remission. Spread through cerebral spinal fluid was postulated for the patient with spinal cord metastasis, and hematogenous spread was postulated for the patient with brain metastasis. Aggressive surgical resection with or without postoperative radiotherapy conferred reasonable survival and symptom control. The patient with brain metastasis died 6 months later of lung metastasis, whereas the other patient is still alive 40 months from the diagnosis of spinal metastasis. CONCLUSIONS: Good symptom control and disease control can be achieved for patients with CNS metastasis after surgery with or without radiotherapy. After aggressive therapy, the ultimate survival depends on control of extracranial disease.

Papillary thyroid carcinoma: prognostic factors and the role of radioiodine and external radiotherapy.

PURPOSE: To evaluate the role of radioiodine and external radiotherapy treatment in papillary thyroid carcinoma (PTC). METHODS AND MATERIALS: This is a retrospective study of 842 patients with the diagnosis of PTC registered from 1960 to 1997 at the Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong. The mean follow-up was 9.2 years. The stage distribution according to UICC/AJCC TNM staging was as follows: 58.6%, Stage I; 9.6%, Stage II; 26.1%, Stage III; 2.3%, Stage IV; and 3.4%, not stated. RESULTS: The 10-year cause-specific survival (CSS) rates were as follows: Stage I, 99.8%; Stage II, 91.8%; Stage III, 77.4%; and Stage IV, 37.1%. Multivariate analysis showed that the statistically significant poor prognostic factors for CSS were as follows: age older than 45, postoperative gross locoregional (LR) residual disease, distant metastasis (DM) at presentation, and lack of radioactive iodine (RAI) treatment. In patients with no DM and no postoperative LR disease, adjuvant RAI ablation reduced both LR failure (RR [relative risk] = 0.29) and DM (RR = 0.2), although the CSS was not affected. In the subgroup of T1N0 M0 disease, no patient with RAI treatment had a relapse. External radiotherapy reduced the risk of LR failure to 0.35. Subgroup analysis revealed that external radiotherapy was particularly effective in increasing the probability of LR control of disease in patients with gross postoperative LR disease (RR = 0.36). CONCLUSIONS: Both RAI and external radiotherapy were effective treatment in PTC. Total or near-total thyroidectomy followed by RAI treatment appears to result in the best outcome. External radiotherapy to improve LR control is indicated in patients with gross postoperative residual disease. Treatment should be individualized for patients with T1N0 M0 disease.