Adjuvant therapy for stage II colon cancer after complete resection. Provincial Gastrointestinal Disease Site Group

GUIDELINE QUESTION: Should patients with resected stage II colon cancer receive adjuvant therapy? OBJECTIVE: To make recommendations regarding the use of adjuvant therapy in the treatment of resected stage II colon cancer. OUTCOMES: Overall survival is the primary outcome of interest. Secondary outcomes are disease-free survival and adverse effects of the treatment regimens. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 2 members of the Provincial Gastrointestinal Disease Site Group (GI DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The recommendations resulting from this review have been approved by the GI DSG, which comprise medical and radiation oncologists, surgeons and epidemiologists. Community representatives did not participate in the development of this practice guideline but will do so in future guidelines development. QUALITY OF EVIDENCE: There are 25 published randomized controlled trials (RCTs) and 1 meta-analysis. The GI DSG pooled data from 11 of the 25 RCTs that provided adequate data. BENEFITS: The 25 RCTs are grouped according to the type of therapy and whether the control patients received no treatment (observation) or other adjuvant therapy after resection. Because the trials usually included patients with stage II and III cancer, the complete trial results and those for a subset of patients with stage II disease were analysed. Although the overall trial results showed a survival benefit for adjuvant treatments, the benefit was not significant for stage II patients. A meta-analysis of 11 trials comparing adjuvant treatment with observation in patients with stage II cancer indicated no significant reduction in the odds ratio (OR) for death (OR 0.83; 95% confidence interval [CI] 0.62 to 1.10). The OR for death among patients receiving chemotherapy by portal vein infusion (PVI) was 0.62 (95% CI 0.35 to 1.11). HARMS: The toxic effects of 5-fluorouracil (5-FU) with either levamisole or leucovorin, or both, were mild to moderate and consisted mostly of stomatitis, diarrhea and myelosuppression; 5% of patients required hospital admission. 5-FU plus levamisole was associated with transient neurotoxic effects in 18% of patients. Toxic effects associated with PVI were mild, rare and mostly consisted of leukopenia and diarrhea; 1% of patients experienced bowel perforation. PRACTICE GUIDELINE: Adjuvant therapy is not recommended at this time for the routine management of patients with resected stage II colon cancer. Patients with stage II disease and high-risk factors (bowel obstruction, tumour adhesion, invasion, perforation or aneuploidy) have a poorer prognosis, similar to that of patients with stage III colon cancer. For individual management, these patients should be made aware of their prognosis; treatment can be considered after the uncertainty of the value of adjuvant therapy has been explained to the patient. The enrolment of patients with high-risk stage II disease in clinical trials is encouraged. Trials comparing adjuvant therapy with observation are needed and are ethically acceptable in stage II colon cancer.     

Vitamin therapy in cystic fibrosis--a review and rationale

An emphasis on careful surgical staging of adenocarcinoma of the colon has improved the predictive value of tumor staging systems. As a result of improved staging and carefully conducted randomized clinical trials, adjuvant therapy of locally advanced colon cancer, based on 5-fluorouracil chemotherapy, has been proven to substantially reduce recurrence rates and significantly increase overall survival for selected patients. Improved treatments and schedules are currently being studied in randomized trials and may increase the efficacy of this adjuvant therapy. Radiation therapy has not as yet been integrated into the adjuvant treatment of colon carcinoma. The application of a combined approach of surgery and chemotherapy in selected patients with liver metastases may also improve cure rates and long-term survival. The developing understanding of molecular determinants for the biological behavior of these cancers will increase the opportunities to identify, on the one hand, those patients who will benefit from specific therapies, and, on the other hand, new therapeutic strategies and treatments.     

Adjuvant therapy of colorectal carcinoma--1998 status]

Colorectal cancer is the second leading cause of cancer death in western countries. The prognosis is strongly correlated to the TNM-staging system and patients with stage T3-4 and/or node positive disease are at high risk for locoregional or distant relapse. It is now widely accepted that patients with node positive colon cancer should be offered postoperative adjuvant chemotherapy. Evidence is accumulating that six months' adjuvant fluorouracil plus leucovorin is equivalent to twelve months' fluorouracil and levamisole, which reduces cancer related deaths by more than 30%. Other adjuvant treatment approaches are perioperative regional chemotherapy or monoclonal antibody treatment, and the results of trials comparing these different treatment options alone or in combination are eagerly awaited. In rectal cancer, the risk of locoregional recurrence can be more than 50% and this event is associated with a deterimental effect on quality of life. The technique of mesorectal excision and the use of radiotherapy, alone or in combination with chemotherapy, have evolved as the most important measures for prevention of locoregional recurrence. In addition, chemotherapy has proven to be effective in reducing metastatic relapse and prolonging survival. The timing of radiotherapy (pre- versus postoperative) and the optimal combination of chemotherapy with radiation are presently important research issues in resected rectal cancer. In both colon and rectal cancer, a common theme emerging from the experience of the last few decades is that administration of dose-intensive fluorouracil is key for the success of adjuvant treatment.     

Dissent over standards in adjuvant management of colon carcinoma

Since 5-fluorouracil (5-FU) plus levamisole substantially reduces the recurrence rate and improves survival in adjuvantly treated patients with curative resected stage III colon cancer this combination has been considered the standard therapy. Shortly thereafter folinic acid modulated 5-FU-therapy also demonstrated adjuvant efficacy compared to surgery alone. Therefore various schedules of folinic acid modulated 5-FU-therapy were compared with the standard regimen (5-FU/levamisole). Randomized multicentric studies revealed: In three of four studies 5-FU/FA is superior to 5-FU/levamisole. Treatment duration of 6 months for 5-FU/FA is similar to 12 months 5-FU/Levamisole. No benefit is obtained for 5-FU/FA by additional levamisole. The effect of regional (portal vein or intraperitoneal) treatment is controversial discussed, but combination of the treatment with systemic chemotherapy versus 5-FU/levamisole demonstrated slightly increased therapeutic efficacy. Immunotherapy with autologous tumor cell-BCG or monoclonal antibody treatment improved survival and is currently investigated in studies with conventional systemic treatment and combined chemoimmunotherapy. Beside treatment in studies patients with colon cancer stage III should be offered adjuvant chemotherapy with 5-FU/FA. Further improvements and adjuvant treatment protocols for stage II carcinoma have to be investigated in studies.     

Recent advances in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC), which represents the bulk of primary carcinomas of the lung, is an aggressive malignancy. The majority of patients with NSCLC present with advanced disease, not curable by surgery, at the time of diagnosis. Recent randomized trials have shown an improvement in survival for patients with loco-regional disease treated with combination, platinum-based, chemotherapy and curative irradiation. Similarly, randomized studies of good performance status patients with metastatic disease have documented a survival advantage, albeit a modest advantage, for those receiving chemotherapy. New chemotherapy agents with activity in NSCLC have been studied in phase II trials. These agents need to be evaluated, in loco-regional and metastatic disease, in large randomized phase III trials before conclusions can be drawn about their role in treatment. Novel treatments which among other include gene therapy, anti-angiogenic and anti-metastatic agents are currently being assessed in early phase I and II studies. Gene therapy will likely be combined with standard chemotherapy and radiation in the treatment of NSCLC, whereas anti-angiogenic and anti-metastatic agents may play a role in prevention and maintenance therapy. Finally, regardless of the approach or modality, new interventions will need to be assessed for their impact on overall survival and the quality of life of patients with NSCLC.     

Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study

We assessed Ki-ras mutations by single-strand conformation polymorphism followed by DNA sequencing, p53 expression by immunohistochemistry, ploidy status, and S-phase fraction in 66 stage II and 163 stage III colon cancer patients enrolled on a randomized trial of surgery followed by observation or adjuvant levamisole or 5-fluorouracil (5FU) plus levamisole (Intergroup Trial 0035) to see whether these factors were independently associated with survival or with differential effects of adjuvant therapy. A Cox proportional hazards survival model was used to describe marker effects and therapy by marker interactions, with adjustment for the clinical covariates affecting survival. A Bonferroni adjustment was used to account for multiple testing. Mutation of the Ki-ras gene was found in 41% of the cancers and was associated with a poor prognosis in stage II but not stage III. In stage II, 7-year survival was 86% versus 58% in those with wild type versus Ki-ras mutations. After adjustment for treatment and clinical variables, the hazard ratio (HR) for death was 4.5; 95% confidence interval (CI), 1.7-12.1 (P = 0.012). p53 overexpression was found in 63% of cancers and was associated with a favorable survival in stage III but not stage II. Seven-year survival in stage III was 56% with p53 overexpression versus 43% with no p53 expression (HR, 2.2; 95% CI, 1.3-3.6; P = 0.012). Aneuploidy was more common in stage III than in stage II (66 versus 47%; P = 0.009) but was not independently related to survival in either group. The proliferative rate was greater in aneuploid than in diploid cancers but was not related to survival. There was no benefit of adjuvant therapy in stage II nor in any of the stage II subgroups defined by mutational status. In stage III, adjuvant therapy with 5FU plus levamisole improved 7-year survival in patients with wild-type Ki-ras (76 versus 44%; HR, 0.4; 95% CI, 0.2-0.8) and in those without p53 overexpression (64 versus 26%; HR, 0.3; 95% CI, 0.1-0.7). Adjuvant therapy did not benefit those with Ki-ras mutations or p53 overexpression. The effects of adjuvant therapy did not differ according to ploidy status or proliferative rate. Ki-ras mutation is a significant risk factor for death in stage II, and the absence of p53 expression is a significant risk factor for death in stage III colon cancer after adjustment for treatment and clinical covariates. Exploratory analyses suggest that patients with stage III colon cancer with wild-type Ki-ras or no p53 expression benefit from adjuvant 5FU plus levamisole, whereas those with Ki-ras mutations or p53 overexpression do not. An independent study will be required to determine whether response to adjuvant therapy in colon cancer depends on mutational status.     

Adjuvant and neoadjuvant therapy of rectal carcinoma. The current status

BACKGROUND: The Consensus Conference of the German Cancer Society (CAO/AIO/ARO, 1.7.1998) has recently updated recommendations for patients with rectal cancer. Instead of a former reservation regarding the indication of adjuvant therapy for rectal cancer the actual version of the consensus particularly emphasizes the role of postoperative radiochemotherapy for stage-II/III tumors. This article reviews the most recent and ongoing trials of adjuvant and neoadjuvant therapy of rectal cancer. RESULTS: To avoid local recurrence is the most important aspect in the primary treatment of rectal cancer. In some series, e.g. the results of the Surgical Department of the University of Erlangen, a significant correlation between local control and survival was noted. The final results of the Swedish Rectal Cancer Trial with 1168 randomized patients not only confirmed the potential of radiotherapy to reduce local recurrence rate, but also demonstrated a significant survival advantage for patients receiving short-course preoperative radiation therapy. Postoperative combination therapy is usual in the United States and in most European countries since the publication of two randomized trials of the Gastrointestinal Tumor Study Group (GITSG) and the North Central Cancer Treatment Group (NCCTG). The survival advantage resulting from an adjuvant radiotherapy with conventional doses and concurrent fluorouracil-based chemotherapy as compared to surgery alone was recently confirmed in a Norwegian trial. Protracted venous 5-fluorouracil infusion should further improve treatment results. Numerous phase-II studies have demonstrated the efficacy of preoperative radiochemotherapy with high rates of pathological response. Thus, neoadjuvant radiochemotherapy is recommended for patients with locally advanced tumor primarily not amenable to curative surgery. Prospective randomized trials are ongoing to clarify the role of preoperative versus postoperative combined treatment for patients with resectable rectal cancer. CONCLUSION: Radiochemotherapy for rectal cancer is recommended as standard treatment outside clinical trials for stage II/III patients after curative treatment and for patients with T4-tumor prior to surgery. The optimal use of chemotherapy and the sequence of treatment modalities remains to be elucidated.     

Multidisciplinary approach to potentially curable non-small cell carcinoma of the lung

The management of patients with non-small-cell lung cancer (NSCLC) is still evolving. Newer third-generation chemotherapy (paclitaxel [Taxol]-based; vinorelbine [Navelbine]/ cisplatin [Platinol]) is more effective than second-generation cisplatin-based chemotherapy for patients with stage IIIB and IV disease. The combined use of cisplatin-based chemotherapy with sequential or concurrent radiation therapy has improved the survival of patients with unresectable stage IIIA disease. Neoadjuvant cisplatin-based chemotherapy has improved the survival of patients with resectable stage IIIA disease compared to surgery alone. Combined-modality therapy is a fertile area of innovative clinical investigations for the majority of stage III resectable and potentially curable NSCLC patients, as well as those with locally advanced unresectable stage III disease. We expect therapy to substantially improve over the next few years. Cooperative groups should move quickly to incorporate third-generation chemotherapy into large randomized trials in order to redefine the standard of therapy for patients with this disease.     

Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group

GUIDELINE QUESTIONS: 1) Does the use of postoperative, adjuvant radiotherapy or chemotherapy, alone or in combination, improve survival rates among patients with completely resected, pathologically confirmed stage II or IIIA non-small-cell lung cancer (NSCLC)? 2) Does the use of radiotherapy reduce the risk of local recurrence among patients with completely resected stage II or IIIA NSCLC? OBJECTIVE: To make recommendations about the use of postoperative adjuvant radiotherapy and chemotherapy in the treatment of patients with completely resected stage II or IIIA NSCLC. OUTCOMES: Overall survival and disease-free survival are the primary outcomes of interest. A secondary outcome of interest is local disease control. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (Lung Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence-based recommendation resulting from this review was approved by the Lung Cancer DSG, which comprises medical oncologists, radiation oncologists, pathologists, surgeons and a medical sociologist. A community representative was present at 1 meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: One meta-analysis and 22 randomized controlled trials (RCTs) were published between 1962 and 1996. The RCTs compared surgery plus radiotherapy with surgery alone; surgery plus adjuvant chemotherapy with surgery alone; surgery plus radiotherapy with surgery plus both chemotherapy and radiotherapy. Many studies included patients with stage IIIB NSCLC; some included patients with incompletely resected stage I NSCLC or with small cell lung cancer (maximum 10%). Older studies used chemotherapy or radiation that would now be considered inferior according to current standards of practice. BENEFITS: There was no survival benefit with adjuvant radiotherapy alone, although 3 RCTs reported a reduction in the rate of local recurrence among patients treated with adjuvant radiotherapy. The meta-analysis showed that postoperative, cisplatin-based chemotherapy alone reduced the relative risk of death by 13% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.74 to 1.02); in combination with radiotherapy it resulted in a 6% reduction in the relative risk of death (HR 0.94, 95% CI 0.79 to 1.11). HARMS: Postoperative adjuvant chemotherapy with alkylating agents was found in the meta-analysis to increase the relative risk of death by 15%. A study involving prolonged adjuvant chemotherapy (busulfan or cytoxan daily for 2 years) reported that 4 of 726 patients had hematologic malignancies. In 1 study, only 53% of patients received all 4 cycles of chemotherapy with cyclophosphamide-doxorubicin-cisplatin (CAP); in another, 22% of patients refused therapy with CAP because of nausea and vomiting. PRACTICE GUIDELINE: There is evidence from RCTs that postoperative radiotherapy reduces rates of local recurrence by 11% to 18% (or 1.6 to 19-fold) among patients with completely resected, pathologically confirmed stage II or IIIA NSCLC. Therefore, if the outcome of interest is a reduction in the frequency of local tumour recurrence, radiotherapy is recommended. However, there is no evidence of a survival benefit from postoperative radiotherapy alone. In a meta-analysis, postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. The survival benefit was small and achieved only with chemotherapy regimens that produced substantial toxic effects and that are no longer used. Newer chemotherapy regimens are currently being evaluated as adjuvant therapy, but there is insufficient evidence of benefit at this time to recommend them. Therefore, if the outcome of interest is survival, there is insufficient evidence to recommend current chemotherapy regimens with or without radiotherapy as postoperative, adjuvant the     

Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer

PURPOSE: This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy. PATIENTS AND METHODS: Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups. RESULTS: Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01). CONCLUSION: There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.     

Studies with high-dose chemotherapy and subsequent autologous stem cell transplantation in breast carcinoma

Survival rates for several subgroups of patients with breast cancer treated with conventional therapy remain poor. Only about 30% of patients with primary breast cancer involving more than 9 axillary lymph nodes remain disease-free at 5 years from diagnosis despite surgery, conventional-dose chemotherapy and radiotherapy. Metastatic breast cancer with 5 year survival rates of about 3% generally represents incurable disease. Chemotherapeutic agents are conventionally limited by side effects. The easy procurement of haematopoietic stem cell support through mobilization of peripheral blood progenitors has spurred the development of new strategies employing high-dose treatment for treatment of high risk breast cancer. Autologous stem cell support antagonizes chemotherapy-induced myelotoxicity and thereby allows dose escalation by a factor of 1.5 to about 20. Pilot studies evaluating significant dose escalation in adjuvant treatment of patients with advanced disease have resulted in an apparent improvement in event-free survival rates to over 70%. Repetitive applications of chemotherapy at myeloablative doses are now increasingly being used. Data from prospectively randomized phase III trials will not be available before the end of 1998. For metastatic breast cancer one prospective, randomized clinical trial has been published. Results are significantly better for patients who have been treated by high-dose chemotherapy compared to patients who received conventional polychemotherapy (median survival 90 vs. 45 weeks). For methodological reasons (small patient numbers, patient selection, weak standard therapy etc.) results from the trials cited above are under discussion. Until publication of further results from ongoing phase III trials HDC for breast cancer remains experimental and should not be given outside of clinical trials.     

Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: impact on disease-free survival and overall survival

PURPOSE: The rationale for using adjuvant chemotherapy in colorectal cancer is to achieve better disease control and thus reduce the high rates of tumor recurrence and mortality in patients who undergo curative surgery. The current literature, including relevant abstracts, on clinical trials of fluorouracil (5-FU) in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer is reviewed. The intent is not to present new data, but to present the reader with a broad perspective and larger patient experience on which to base well-reasoned treatment decisions. DESIGN: Published clinical trials and abstracts presented at the 1996 American Society of Clinical Oncology (ASCO) meeting that assessed 5-FU in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer were surveyed. End points of interest were disease-free survival (DFS), overall survival, and toxicity. RESULTS: In randomized trials that used high-dose leucovorin at doses that ranged from daily-times-five 200 mg/m2 to weekly 500 mg/m2 in combination with 5-FU, significant improvements in both DFS and overall survival were observed over surgery alone (control). In patients treated with high-dose leucovorin/5-FU, DFS rates ranged from 71% to 77% compared with control (58% to 64%). A similar trend was seen in overall survival, with a range of 75% to 84% compared with control (63% to 77%). Toxicities observed for high-dose leucovorin administered on a weekly or daily-times-five schedule were diarrhea, stomatitis, myelosuppression, and nausea. CONCLUSION: Overall, the results of these randomized trials support the use of high-dose leucovorin/5-FU as adjuvant therapy for colorectal cancer. Longer follow-up studies are needed to compare the benefits of these different regimens in terms of survival and to characterize adverse effects, especially those that may not be immediately evident. Adjuvant therapy with high-dose leucovorin/5-FU is an effective regimen that is well tolerated by many patients with colorectal cancer.     

Adjuvant systemic chemotherapy in colon cancer

The prognosis for patients with cancer of the colon is dubious. An intendedly curative colon resection is performed in two-thirds of these patients, but half of them will subsequently die from metastatic disease. Randomized trials of adjuvant therapy with fluorouracil in combination with levamisole or leucovorin have shown significant benefit in terms of increased disease-free survival and overall survival. In 1990 adjuvant treatment was recommended as routine therapy in high risk patients in USA. A number of European countries are routinely treating high risk patients with Dukes' C coloncarcinoma. The recommendations are based on results from several cooperative trials reviewed in this article. Treatment related toxicity accelerates with increasing age but was acceptable in the reviewed trials. Adjuvant therapy is widely accepted as an important supplement to surgery in high risk patients. A Conference on the results and experiences now available should take place in the near future in order to establish a national consensus on adjuvant chemotherapy in Denmark. Patients with resected Dukes' C coloncarcinoma should receive adjuvant chemotherapy including 5-fluorouracil and leucovorin. Randomized trials are needed to establish the most effective regimens but "no-treatment" controls are no longer ethically acceptable.     

Normal regional anatomy of the shoulder

Transitional cell carcinoma of the bladder is associated with a high relapse rate, locally and systemically, particularly in patients with nodal or soft-tissue involvement, despite radical cystectomy. The responsiveness of the disease to chemotherapy in the metastatic setting has stimulated the use of systemic therapy in earlier stage disease, either before (neoadjuvant) or after (adjuvant) definitive local therapy. Interpretation of the data is hampered by low patient accrual to randomized trials, lack of standardization of local treatment modalities, and the use of a variety of chemotherapy agents and regimens pointing to the difficulty in reaching a consensus as to what constitutes standard therapy. In this article, we review the use of adjuvant and neoadjuvant chemotherapy, the advantages and disadvantages of both approaches, and the recommendations that can be made based on available data. New approaches to improving survival, potentially with organ preservation, include the development of more effective chemotherapy, and the identification of prognostic features-clinical or biologic-that might be a better guide to patient selection.     

Prognostic factors in resectable gastric cancer: results of EORTC study no. 40813 on FAM adjuvant chemotherapy

BACKGROUND: The high incidence of locoregional recurrences and distant metastases after curative surgery for gastric cancer calls for improved locoregional control and systemic adjuvant treatment. METHODS: In a randomized clinical trial on adjuvant FAM2 chemotherapy, quality of surgery was evaluated by comparing surgical and pathology data. Univariate and multivariate analysis was made to evaluate the effect of prognostic factors on survival and time of recurrence in relation to patients, tumor, and therapy. RESULTS: Of 314 patients randomized from 28 European institutions, 159 comprised the control and 155 the FAM2 group. After a median follow-up of 80 months, no statistically significant difference was found between survivals. However, for recurrence time, treated patients had a significant advantage over controls (p = 0.02). At univariate analysis, statistically significant differences in survival and time to progression emerged for T, N, disease stage and "adequacy" of surgery. The multivariate analysis retained preoperative Hb level, T, N, and "adequacy" of surgery for time of survival; and T, N, "adequacy" of surgery and adjuvant chemotherapy for recurrence time. CONCLUSIONS: Disease stage is the most important prognostic factor. "Adequate" surgery has an important effect. Adjuvant FAM2 delayed time of recurrence, but did not influence overall survival.     

Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials

PURPOSE: An overview is presented of reports published since 1980, in which postoperative adjuvant chemotherapy is compared with surgery alone for patients with gastric cancer. A MEDLINE literature review yielded 123 reports, 14 of which were relevant randomized trials; data from 11 of these trials were (or became) available for analysis of crude mortality odds. These 11 trials included 2,096 patients. METHODS: Odds ratios were calculated by comparing the adjuvant treatment arm with the observation-only arm. Those odds ratios that could be considered homogeneous yielded an estimated common odds ratio of 0.88 (95% confidence interval [CI], 0.78 to 1.08), which was slightly, but far from significantly, in support of adjuvant treatment. RESULTS: The results confirm the common opinion that the adjuvant chemotherapy regimens prescribed in these trials, although effective in phase II studies, do not improve survival. Furthermore they indicate that postoperative chemotherapy in general offers no additional survival benefit for patients with curatively resected gastric cancer. CONCLUSION: In conclusion, at present, postoperative chemotherapy cannot be considered as standard adjuvant treatment. New trials of adjuvant therapy for gastric cancer must include a no-treatment control arm.     

Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial

BACKGROUND: Colon cancer is curable by surgery, but cure rate depends on the extent of disease. We investigated whether adjuvant active specific immunotherapy (ASI) with an autologous tumour cell-BCG vaccine with surgical resection was more beneficial than resection alone in stage II and III colon cancer. METHODS: In a prospective randomised trial, 254 patients with colon cancer were randomly assigned postoperative ASI or no adjuvant treatment. ASI was three weekly vaccinations starting 4 weeks after surgery, with a booster vaccination at 6 months with 10(7) irradiated autologous tumour cells. The first vaccinations contained 10(7) BCG organisms. We followed up patients for time to recurrence, and recurrence-free and overall survival. Analysis was by intention to treat. FINDINGS: The 5.3 year median follow-up (range 8 months to 8 years 11 months) showed 44% (95% CI 7-66) risk reduction for recurrence in the recurrence-free period in all patients receiving ASI (p=0.023). Overall, there were 40 recurrences in the control group and 25 in the ASI group. Analysis by stage showed no significant benefit of ASI in stage III disease. The major impact of ASI was seen in patients with stage II disease, with a significantly longer recurrence-free period (p=0.011) and 61% (18-81) risk reduction for recurrences. Recurrence-free survival was significantly longer with ASI (42% risk reduction for recurrence or death [0-68], p=0.032) and there was a trend towards improved overall survival. INTERPRETATION: ASI gave significant clinical benefit in surgically resected patients with stage II colon cancer. ASI has minimal adverse reactions and should be considered in the management of stage II colon cancer.     

Usefulness of initial chemoendocrine therapy for advanced prostate cancer

The 5 year cancer specific survival rate of advanced prostate cancer, especially in metastatic cancer is less than 40%. Recently, maximum androgen blockade showed some beneficial effects in cases of minor disease but no additional usefulness in major cases. The treatment modality referred to as initial chemoendocrine, used to treat prostate cancer, seems to be a reasonable method because prostate cancer cells contain heterogeneity. This procedure means that the endocrine treatment is best suited to treat hormone sensitive cells, whereas chemotherapy is more appropriately used as a firstline therapy for hormone insensitive cells. We reported that the initial chemoendocrine method showed superiority in the 5 year cancer specific survival category than in the endocrine therapy analyzing non-randomized trials. From that stage on we reviewed the beneficial point of the treatment, and are now trying randomized control studies.     

The lateralizing value of ictal clinical symptoms in uniregional temporal lobe epilepsy

Since 1984, the Cancer and Leukemia Group B (CALGB) has focused its clinical research in stage IV non-small cell lung cancer (NSCLC) on investigations of new agents and combinations. Currently, efforts are aimed at identifying non-cisplatin-based combinations with an increased therapeutic index. In stage III disease multimodality therapies have been pursued. Dillman et al. reported a study comparing standard radiotherapy versus induction chemotherapy followed by radiotherapy in patients with unresectable stage III NSCLC. The chemotherapy-treated patients were found to benefit with a 4-month increase in median survival time compared with patients receiving radiotherapy alone (13.8 vs. 9.7 months) and an increased 3-year survival rate of 23% versus 11%. This was the first randomized cooperative group study demonstrating a survival advantage resulting from the use of induction chemotherapy in locoregionally advanced NSCLC. In a subsequent study, the administration of additional "posterior" chemotherapy was not found to be feasible because of early disease progression and toxicity, while the administration of induction chemotherapy followed by concomitant chemoradiotherapy was feasible; therefore, the latter approach was studied further in a randomized phase III setting. This study compared a standard of two cycles of cisplatin and vinblastine followed by radiotherapy with an experimental arm of cisplatin and vinblastine followed by radiotherapy and concomitant carboplatin. Accrual to this study has been completed and results are expected in the near future. In resectable stage III disease, studies have focused on the optimal sequencing of multimodality therapy. A randomized study comparing standard regional therapy with radiotherapy and surgery versus a previously piloted approach combining chemotherapy, surgery, and radiotherapy was closed prematurely due to poor accrual. The next generation of studies in stage III NSCLC will focus on the integration of new chemotherapy agents into the treatment armamentarium for NSCLC. A randomized phase II study investigating paclitaxel, gemcitabine, and vinorelbine in combination with cisplatin in the induction setting and as concomitant chemoradiotherapy has recently been activated.     

Combined modality therapy in previously untreated patients with advanced Hodgkin's disease: A 24-year follow-up study

PURPOSE: To describe the long-term results of treatment with chemotherapy plus adjuvant low-dose, involved-field radiation therapy (CMT) in patients with advanced Hodgkin's disease. Data on disease-free and failure-free survival, second malignancies, and the results of salvage therapy are presented. PATIENTS AND METHODS: From 1969 to 1989, CMT was administered to 186 patients with previously untreated stage IIB, III, and IV Hodgkin's disease. Chemotherapy included MVVPP (47%), MOPP (25%), MOPP/ABVD (26%) and ABVD (2%). After 6 months of chemotherapy, patients received radiation to all involved sites with the exception of the bone marrow. RESULTS: The failure-free survival for all patients was 63% at 5 years, 56% at 10 years, and 40% at 23.5 years, respectively. Significantly worse results were observed in patients older than 40 years and those with stage IV disease. The overall survival of 45 patients after recurrence was 39% at 10 years, but was only 21% if the initial complete remission lasted less than 1 year. Thus far, 21 of 165 patients (12.7%) who achieved complete remission have developed a second malignancy, and 16 have died. CONCLUSIONS: In comparison with comparable chemotherapy programs, chemotherapy plus radiation therapy may improve disease-free survival; however, the results of treatment in patients older than age 40 or with stage IV disease are still poor. Although patients with initial remissions lasting longer than 1 year can have durable second remissions, the long-term disease-free survival is poor and in the current series the majority of failures were due to recurrent Hodgkin's disease.