A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus

BACKGROUND: Despite well-established surgical approaches, the prognosis for patients with squamous cell carcinoma of the esophagus remains dismal. To assess the benefit of adjuvant chemotherapy and radiation therapy (CRT), a randomized trial with and without sequential preoperative CRT was undertaken; CRT combined 20 Gy and two courses of 5-FU and cisplatin. METHODS: Patients were included on the basis of the following criteria: squamous cell carcinoma of the esophagus, younger than 70 years of age, World Health Organization status below 2, estimated survival time greater than 3 months, and no previous treatment for the cancer. Patients were not included if they had experienced a loss in body weight greater than 15% or had tracheoesophageal fistula, metastases, or uncontrollable infection. RESULTS: Eighty-six patients thus fulfilled the criteria for inclusion (41 CRT, 45 non-CRT). The groups were well-matched for age, sex, tumor location, size, and grade. Operative mortality was 8.5% and 7%, respectively, for each group with a 27-day hospital stay for both groups. Long-term survival was not significantly different, with 47% of both groups alive at 1 year. CONCLUSIONS: The authors concluded that this neoadjuvant treatment did not change operative mortality or survival time for patients with squamous cell carcinoma of the esophagus.     

Combined chemotherapy and radiotherapy, followed or not by surgery, in squamous cell carcinoma of the esophagus

BACKGROUND: This study was designed to evaluate the feasibility of a neo-adjuvant combined chemo-radiotherapy in patients with localized squamous cell carcinoma of the esophagus. PATIENTS AND METHODS: Forty-two patients with squamous cell carcinoma of the esophagus, stages II and III (or stage I if considered to be poor candidates for immediate curative surgery), age less than 70 years and WHO performance status 0 to 2, were enrolled in a study of radiotherapy combined with chemotherapy, consisting of 2 (operated patients) or 3 (nonoperated patients) courses of cisplatin, vindesine, mitomycin-C or cisplatin, vinblastine. Surgery was routinely proposed to patients. RESULTS: Thirty-seven patients (88%) received full preoperative therapy. Of 30 patients responding to this preoperative therapy, 12 had a third cycle of treatment and 15 had esophagectomy. Three of the operated patients had no pathological evidence of residual tumour. Median survival of all 42 patients is 11 months and the 2-year survival rate is 29%. There is no difference in survival among responding operated or non-operated patients. Our group represents 95% of all eligible cases of squamous cell carcinoma of the esophagus occurring in Geneva during the study period. CONCLUSION: Our series gives a realistic view of the median survival of a population of patients eligible for neo-adjuvant therapy of esophagus cancer, and suggests that secondary surgery might not improve the patient survival. Furthermore, non-selected patients are at high risk for therapy-related death.     

Concomitant chemoradiotherapy of cancer of the esophagus

Many cell membrane bound receptors communicate with the inside of the cell through guanine nucleotide binding proteins (G-proteins). This holds also for olfactory receptor neurons, which respond to odorants with G-protein mediated increases in the concentration of cyclic adenosine 3', 5'-monophosphate (cAMP) and/or inositol 1,4,5-triphosphate (InsP3). These substances regulate the ionic conductivity of the wall of the cilia. We have studied a similar system, namely G-protein coupled alpha 2-adrenoceptors, present for example in the cells of certain fish scales. These receptors react on, catecholamines and the G-protein mediates a decrease in cAMP, which causes an aggregation of pigment containing granulas to the middle of the cells. The light transmission of the cell increases due to this aggregation. This simple physiological response has been used in a sensitive biosensor for noradrenaline and for pertussis toxin that is based on isolated fish scales from cuckoo wrasse (Labrus ossifagus). The results were obtained with a simple photometer. Measurements can be performed also on single isolated melanophores. The main purpose of this contribution is, however, to point out that G-protein coupled receptors together with a simple physiological response form a principle for biosensing, which could also be an interesting alternative for odour sensing.     

Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial

PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.     

Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast

BACKGROUND: Few women with locally advanced breast cancer remain disease-free, even for 2 years. Response to induction chemotherapy may be associated with longer disease-free and overall survival rates. The role of breast conservation in selected patients with response to induction chemotherapy was evaluated. METHODS: Since 1979, patients with Stages IIB and III breast cancer have undergone induction chemotherapy; patients with response continued chemotherapy until a plateau of regression was achieved. Before 1983, all patients having a response to chemotherapy underwent mastectomy; since 1983, selected patients have undergone breast conservation. Outcomes were tallied comparing these two groups of patients. RESULTS: The study group included 189 women, who were followed up for 12-159 months (median, 46 months) after diagnosis. Of the patients, 85% had a response to induction chemotherapy. Patients with no response were excluded from additional consideration in this study. One hundred three (64%) women underwent mastectomy; 55 (36%) were treated with breast conservation. The disease-free 5-year survival rate was 61% for all patients with a response to chemotherapy; 56% for those having mastectomy and 77% for those having breast conservation. The overall 5-year survival rate was 69% for all patients with a response to chemotherapy, 67% for those undergoing mastectomy and 80% for those having breast conservation. CONCLUSIONS: Induction chemotherapy achieves significant tumor regression in most women with locally advanced breast cancer, permitting subsequent breast conservation or mastectomy with a greater expectation of long-term success. Breast conservation is used more frequently with the same expectation of success as mastectomy, presuming careful selection based on response to chemotherapy.     

Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma

BACKGROUND: The results of a Phase II study of concurrent chemotherapy and accelerated fractionation radiation therapy followed by surgical resection for patients with both adenocarcinoma and squamous cell carcinoma of the esophagus are presented. Pretreatment and postinduction staging were correlated with pathologic findings at surgery to assess the role of surgical resection and the predictive value of noninvasive staging techniques. METHODS: Patients received 2 induction courses with 4-day continuous intravenous infusions of cisplatin (20 mg/m2/day) and 5-fluorouracil (1000 mg/m2/day) beginning on Day 1 and Day 21, concurrent with a split course of accelerated fractionation radiation (1.5 grays [Gy] twice daily, to a total dose of 45 Gy). All patients were subsequently referred for surgical resection. A single, identical postoperative course of chemotherapy and 24 Gy accelerated fractionation radiation was planned for patients with residual tumor at surgery. RESULTS: Seventy-four patients were entered on this study; 72 patients were considered eligible and evaluable. Induction toxicity included nausea (85%), increased dysphagia (90%), neutropenia (<1000/mm3) (43%), thrombocytopenia (<20,000/mm3) (10%), and reversible nephrotoxicity (8%). Sixty-seven patients (93%) underwent surgery, and 65 (90%) were found to have resectable tumors. Twelve of these patients (18%) died perioperatively, and 18 (27%) had no residual pathologic evidence of disease. Resolution of symptoms and normalization of radiographic studies, endoscopy, or esophageal ultrasound did not identify pathologic complete responders accurately. No patient completing induction therapy and surgery experienced a locoregional recurrence. The Kaplan-Meier 4-year projected recurrence free and overall survival rates were 49% and 44%, respectively. CONCLUSIONS: Although this regimen is feasible, there was significant preoperative toxicity and perioperative mortality. Nonetheless, the recurrence free and overall survival rates were encouraging. However, no staging tool can predict a pathologic complete response after induction therapy accurately, suggesting a continued need for surgical resection.     

Sequential transurethral surgery, multiple drug chemotherapy and radiation therapy for invasive bladder carcinoma: initial report

Forty-seven patients with muscle-invasive bladder cancer (T2-T4, Nx, M0) were treated by transurethral resection, followed by 3-4 cycles of combination chemotherapy (methotrexate 30 mg/m2 on days 1, 14; cis-platinum 100 mg/m2 on day 2; vinblastine 3 mg/m2 on days 1, 14; repeated every 21 days), and external beam irradiation (64-66 Gy to the bladder and 40 Gy to the pelvic lymphatics). Complete remission after trans urethral resection and chemotherapy was achieved in 24 out of 45 patients (53%). Cystectomy was performed in patients without complete response to transurethral resection and chemotherapy. The therapy was completed as planned in 45/47 patients. After transurethral resection, chemotherapy, and radiation therapy, biopsy proven complete response was achieved in 62% (28/45); Stage T2T3 in 67% (23/34), Stage T4 in 45% (5/11) of patients. Among 19 patients with positive biopsy findings after transurethral resection and chemotherapy, 14 underwent cystectomy. After follow-up of 4-55 months (median 23 months) 75% (34/45) are alive, 68% (31/45) have had their bladders preserved, and 53% (24/45) are free of the primary tumor. The actuarial survival of all 45 patients is 73%. Moderate nausea and vomiting during treatment were common; severe leukopenia and mucositis were observed in five patients. Late side effects such as miction disorders and diarrhea were predominantly mild. Although the observation period has been too short to allow a definitive evaluation of treatment results, we feel both from the point of bladder preservation and disease-free survival that the presented treatment approach is successful in a majority of T2T3 patients, whereas a large tumor size (T4) renders this treatment less effective.     

Accelerated hyperfractionated radiation therapy and concurrent 5-fluorouracil/cisplatin chemotherapy for locoregional squamous cell carcinoma of the thoracic esophagus: a phase II study

PURPOSE: To improve the poor prognosis of patients with locoregional esophageal squamous cell cancer, we used concurrent accelerated hyperfractionated radiation therapy (ACC HFX RT) and chemotherapy (CHT). MATERIAL AND METHODS: Between January 1988 and June 1993, 28 patients were treated with ACC HFX RT with 1.5 Gy twice daily, to a total dose of 54 Gy concurrently with 5-fluorouracil (5-FU) (300 mg/m2, days 1-5) and cisplatin (CDDP) (10 mg/m2, days 1-5), both given during weeks 1 and 4 of the ACC HFX RT course. Following the ACC HFX RT/CHT, two additional courses of 5-FU (500 mg/m2, days 1-5) and CDDP (20 mg/m2, days 1-5) were both given during weeks 7 and 10. The median age and Eastern Cooperative Oncology Group performance status were 62 and 1, respectively. The American Joint Committee on Cancer (AJCC) stage was I in 12 patients, II in 10, and III in 6. RESULTS: The median survival time was 26 months, and the 5-year survival rate was 29%. The rates at 5 years for freedom from relapse, locoregional recurrence, and distant metastasis were 29%, 61%, and 45%, respectively. Univariate analysis revealed that performance status, stage, weight loss, tumor length, and tumor location influenced survival, while age and sex did not. The most frequent acute high-grade (3 or 4) toxicities were esophagitis and leukopenia, seen in 50% and 39% of patients, respectively. Late high-grade toxicity was infrequent. There were no treatment-related deaths. CONCLUSION: The results of this study compare favorably with those of previous studies, albeit of relatively high incidence of acute high-grade toxicity. Further studies are warranted to compare its efficacy with other approaches.     

Neoadjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy or surgery for operable thoracic esophageal carcinoma

PURPOSE: A prospective clinical trial was undertaken to investigate the feasibility of concurrent chemoradiotherapy for esophageal carcinomas. MATERIALS AND METHODS: Between June 1989 and May 1996, forty patients with operable squamous cell carcinoma of the thoracic esophagus (Stage 0 to III: UICC 1987), ages 45 to 78 years (mean: 64), were enrolled in a study of neoadjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy (CRT group) or surgery (CRT-S group). Neoadjuvant chemoradiotherapy consisted of 44 Gy in 40 fractions for 4 weeks (2.2 Gy/2 Fr/day) through 10-MVX rays, with 2 courses of cisplatin (80-100 mg/body, mean: 60 mg/m2, Day 1, bolus injection) and 5-fluorouracil (500-1000 mg/body/day, mean: 400 mg/m2, Days 1-4, continuous infusion). After completion of neoadjuvant chemoradiotherapy, an intermediate clinical response was assessed by barium swallow, esophagoscopy with/without biopsy, EUS in most cases, thoracic and upper abdominal CT scan, and cervical US. Definitive chemoradiotherapy was performed in patients when regression of more than 75% was evident (CRT Group), and esophageal resection was indicated in those who remained at less than 75% (CRT-S Group). In CRT Group, a cumulative dose of 60-70 Gy for Tis, T1 and 65-75 Gy for T2-T4 tumor with high-dose-rate intraluminal brachytherapy and a total of 3 courses of chemotherapy were planned. In CRT-S Group, intraoperative radiotherapy for abdominal lymphatic system and postoperative supraclavicular irradiation were added. RESULTS: At the time of intermediate assessment, complete response (CR) was observed in 16 patients, a partial response (PR) in 22, and no change (NC) in 2. Thirty responding patients (CR, 16; PR, 14) entered the CRT Group, and 10 nonresponding patients (PR, 8; NC, 2) were followed by surgery (CRT-S Group). Radiotherapy was completed satisfactorily, but chemotherapy was suspended in 26 patients (65%) because of acute toxicity. Clinical CR rate at the completion of treatment showed 90% in CRT Group, and pathologic CR rate 10% in CRT-S Group. The overall median survival was 45 months, survival at 1, 2, and 3 years being 100%, 72%, and 56%, respectively. Local-regional failure was observed in 7 patients (all in CRT Group), distant failure in 6 (3 in CRT Group, 3 in CRT-S Group) and local-regional with distant failure in 1 (CRT Group). Four patients with local-regional recurrence in the CRT Group were salvaged by surgery. Overall survival at 2 and 3 years for CRT vs. CRT-S Group was 72%, 64% vs. 75%, 38%, respectively. No treatment-related mortality was observed. The rate of the 'esophagus conservation' was 65% (Stage 0: 1 of 1, 100%; Stage I: 11 of 12, 92%; Stage II: 8 of 17, 47%; Stage III: 6 of 10, 60%). CONCLUSION: Our results demonstrated that almost all early disease (Stage 0-I) and about half of advanced disease (Stage II-III) could be conserved, their esophagus treated by the multidisciplinary approach centering on high-dose radiotherapy and concurrent chemotherapy.     

Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study

PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.     

A proper sequence for the treatment of B16 melanoma: chemotherapy, surgery, and immunotherapy

The therapeutic effectiveness of surgery, chemotherapy, and immunotherapy alone and in combination were studied in the B16 melanoma model. The sequence of chemotherapy and immunotherapy as adjuvants to surgery proved important: Chemotherapy was significantly better when given before surgery; immunotherapy was more effective when delivered after surgery. The most effective therapeutic regimen was a combination of all three modalities: a single course of chemotherapy preceding surgery followed by immunotherapy.     

Radiotherapy for carcinoma of the esophagus in aged patients

One hundred fifty-four patients with esophageal carcinoma were treated with either irradiation alone or irradiation combined with surgery at the University of Occupational and Environmental Health Hospital between January 1980 and February 1992. The number of patients 75 years old and older was 25. In patients 74 years old and younger, the overall five-year survival rate by Kaplan-Meier method was 24.5%. The survival rate was best in the patients who were treated by a combination of irradiation and surgery. In patients 75 years old and older, the one-year survival rate was 59%, and the three-year rate was 20%. Aged patients had a tendency to be worse in performance status, and there was no correlation between treatment modality and survival time. We conclude that radiotherapy is useful for treating esophageal cancer in aged patients particularly when maintenance of the quality of life is considered.     

Postoperative prognostic factors for carcinoma of the thoracic esophagus

To evaluate significant postoperative prognostic factors for esophageal carcinoma, clinicopathological findings and several markers for biological malignant potential were studied, including cell nuclear DNA contents, EGF receptor, p53 protein, MMP-2, Ki-67 positive cell rate, and tumors infiltrating Leu 7 cells. The subjects of this study were 96 patients with thoracic esophageal carcinoma, who underwent radical surgery with extended lymphadenectomy. In the pathological findings, the postoperative survival rate significantly correlated with depth of invasion (pT1(-2) vs. pT3, p = 0.003), lymph node involvement (pNo vs. pN1, p = 0.0002), vascular invasion (-vs. +, p = 0.0003), stage (pSt. 1-2A vs. 3, p = 0.0018), and the number of node involvements (1-3 vs. more than 4, p = 0.025). Analyzing the markers for the malignancy, a significant difference in postoperative mortality due to the relapse was recognized with p value of 0.0009 between Ki-67 positive (under 1%) and Ki-67 negative (over 1%) tumor. Ki-67 positive tumor significantly correlated with the mortality in both cases with pNo (p = 0.024) and pN1 (p = 0.020). Low-grade tumor infiltrating Leu 7 cells significantly correlated with the mortality (Grade 1+ vs. 2+, p = 0.013; Grade 1+ vs. 3+, p = 0.008). These results suggest that Ki-67 study is a useful prognostic factor after radical surgery for thoracic esophageal carcinoma.     

Guide lines for the clinical and pathologic studies for carcinoma of the esophagus

The neuro-radiological findings in 38 cases of precocious puberty of central origin and 9 cases of hypopituitarism (craniopharyngiomas excepted), are reported. The radiological examination consisted of plain films of the skull and pneumo-encephalography. In the 9 cases with hypopituitarism radiological examination was normal in 4 and localised but quite diverse anomalies were discovered in 5. Out of 38 patients presenting with isosexual precocious puberty, 29 were female and 9 male. Out of the 29 girls, neuro-radiological examination was normal in 20 and showed a hypothalamic anomaly in 9. Out of the 9 boys, 8 had a hypothalamic anomaly, and only one examination was normal. In precocious puberty we found 1 ectopic pinealoma and 2 gliomas of the chiasma. In these three cases the clinical context and radiological examination made the diagnosis obvious. Masses were discovered in 7 (3 spongioblastomas and 4 heterotopias). In 2 cases (spongioblastomas) neurological symptoms were present and made an operation mandatory. In 5 cases (1 spongioblastoma, 4 heterotopias) precocious puberty was an isolated finding. It was not possible to make, on a clinical or radiological bases, a distinction between spongioblastoma and heterotopia. As time has passed the role of surgery has changed. Formerly, surgery aimed at excision of the lesion, but with advances in medical treatment surgical intervention is now directed towards biopsy and the histological study of lesions which may be treated by radiotherapy.     

Basaloid squamous cell carcinoma of the esophagus: diagnosis and prognosis

BACKGROUND: Basaloid squamous cell carcinoma (BSCC) is a recently recognized, poorly differentiated variant of squamous cell carcinoma (SCC), which is located predominantly in the upper aerodigestive tract. METHODS: In this study, clinical and pathologic parameters of 17 BSCCs and 133 typical SCCs of the esophagus that underwent potentially curative resection (no distant metastases, no residual tumor) were compared. In addition, light microscopic, electron microscopic, and immunohistochemical features of BSCC were investigated, to determine whether this type of carcinoma could be differentiated from other poorly differentiated carcinomas of the esophagus. RESULTS: Light microscopic study showed that BSCC was composed of relatively small tumor cells, arranged in solid lobules with abundant comedo-type necrosis. BSCC was almost invariably accompanied by areas of concomitant typical SCC, foci of squamous cell differentiation, and/or severe squamous cell dysplasia or carcinoma in situ of the adjacent mucosa. Ultrastructurally, BSCC inconsistently showed features of squamous cell differentiation. Immunohistochemically, BSCC displayed poor reactivity for antibodies against wide-range cytokeratins and cytokeratin subtypes that are typical of squamous cell epithelia (cytokeratin 13 and cytokeratin 14). Infrequently, expression of Leu7, smooth muscle actin, and S-100 protein was found. In comparison with typical SCC, the characteristic features of BSCC were older patient age, higher proliferative activity (MIB-1 labelling index), and higher apoptotic indices. No differences were found with regard to pT classification, pN classification, tumor size, blood vessel invasion, lymphatic vessel invasion, neural invasion, or patient gender. Moreover, no differences in overall survival rates were found. CONCLUSIONS: BSCC is a distinct histopathologic variant of SCC, characterized by a poor degree of differentiation and high proliferative activity. However, after potentially curative resection, the prognosis of patients with BSCC of the esophagus does not differ from that of patients with typical SCC.     

TNM classification of carcinoma of the esophagus

TNM classification of esophageal carcinoma was first described in the supplement to the first edition of the TNM classification in 1973. In the second edition, the classification was changed based on the data of 1,000 cases from the Task Force on Esophagus of American Joint Committee. In this edition, only the clinical classification was described, but the third edition included both clinical and post-surgical histopathological classification. But the criteria for T and pT classification differed. Before the fourth edition, specialists from Japan and the United States met in Hawaii in 1984. Data of the Japanese Nationwide Registration, including 7,742 patients from 1969 to 1978, were presented. After discussion based on these data, T was classified according to the depth of invasion, and perigastric lymph nodes were included in Regional Nodes in the fourth edition. Then, the TNM Research Committee of ISDE collected patient data of esophageal carcinoma from seven countries, and they were studied according to many factors. Based on these data, two proposals were made to the UICC TNM Committee. First, T1 should be divided into two categories: T1a, Tumor invasion of lamina propria; and T1b, Tumor invasion of submucosa. Second, metastases to distant lymph nodes should be grouped into the N classification instead of M classification. The first was accepted in the TNM Supplement of 1993, and the second will be accepted in the Fifth Edition, which will appear in 1997. It is important to accumulate data on many patients using the uniform registration form and to follow these patients very closely in the discussion of revisions to the TNM classification.     

Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis

BACKGROUND: In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. PURPOSE: This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. METHODS: We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. RESULTS: The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. CONCLUSIONS: Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. IMPLICATIONS: Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.