Early Adjuvant Research Articles

Radical esophagectomy and secondary anastomosis for high-risk patients with intrathoracic esophageal carcinoma.

We have often conducted esophageal reconstruction via a thoracic subcutaneous route in high-risk patients to avoid major complications following anastomotic leakage. This type of reconstruction is nonphysiological, however, and presents a poor cosmetic appearance. In better risk patients, therefore, we usually conduct gastric-tube replacement via a posterior mediastinal route. We have recently begun gastric-tube replacement via the posterior mediastinal route with secondary anastomosis for high-risk patients to avoid anastomotic leakage. From 1996 to 1999, secondary anastomosis was conducted in 25 patients with different degrees of risk--10 with diabetes mellitus, 7 with liver dysfunction, 3 with simultaneous laryngeal and/or pharyngeal cancer, 2 each with induction chemoradiotherapy, cardiac failure, renal dysfunction, respiratory failure, and cardiorespiratory dysfunction, and 1 with cerebral infarction. 6 patients had with multiple combined diseases. Secondary anastomosis was conducted 3-12 weeks (mean: 5.5 weeks) after esophagectomy. Stomach-tube necrosis was not seen in any of the 25 patients undergoing this 2-step procedure. Anastomosis leakage was seen in 5 of the 25 patients (20%), but was slight, in all but 1. Our 2-step procedure has the following advantages: low risk of anastomotic leakage, radical surgery for esophageal cancer, the potential for early adjuvant therapy after esophagectomy, easy and early training in swallowing, and no cosmetic problem. Its disadvantages are prolonged hospitalization, multiple surgery, and esophageal stoma formation. Secondary anastomosis thus appears helpful in treating high-risk patients with advanced esophageal cancer.

Assessment of the biologic markers p53, Ki-67, and apoptotic index as predictive indicators of prostate carcinoma recurrence after surgery.

This study was designed to evaluate the potential of the molecular and cellular markers p53, Ki-67, and apoptotic index (AI) as adjuncts to the commonly available variables of tumor grade, clinical stage, and serum prostate specific antigen to predict prostate carcinoma recurrence after radical prostatectomy. Representative punch biopsy specimens of prostate carcinoma from whole mount paraffin blocks were evaluated from 47 men who underwent radical prostatectomy. Two groups were defined: those without evidence of prostate carcinoma recurrence after 5 years of follow-up (N = 30) and those with carcinoma recurrence (N = 17). Gleason grade, clustered p53 immunostaining, Ki-67 immunostaining, and AI were determined by standard techniques. All variables tested were associated with disease recurrence by univariate analysis: AI (P = 0.005), clustered p53 immunostaining (P = 0.0070), and Ki-67 immunostaining (P = 0.0390). Using multivariate analyses that included each biomarker with routinely available features, only AI (P = 0.0234) and clustered p53 immunostaining (P = 0.0389) added independent prognostic information (Ki-67 immunostaining, P = 0.1285). In the final logistic regression model that included standard variables with AI and p53, only AI reached statistical significance (P = 0.0332). The continued assessment of additional biomarkers for prostate carcinoma recurrence is important to identify better those patients who may be candidates for early adjuvant therapy and also to further our understanding of the neoplastic potential of a particular malignancy.

OUTCOME BASED STAGING FOR CLINICALLY LOCALIZED ADENOCARCINOMA OF THE PROSTATE

Some patients with clinically localized prostate cancer are not cured after radical prostatectomy because of the presence of occult systemic disease. The American Joint Commission on Cancer staging classification for prostate cancer does not reliably distinguish between clinically localized patients who are likely or unlikely to be cured after local therapy. This project was undertaken to develop a staging system capable of predicting long-term outcome after radical prostatectomy on the basis of the clinical parameters obtained routinely during the standard workup for patients with adenocarcinoma of the prostate. A total of 688 clinically localized prostate cancer patients managed with a radical retropubic prostatectomy for adenocarcinoma of the prostate between 1989 and 1996 was evaluated for clinical features predictive of time to prostate specific antigen (PSA) failure using a Cox regression multivariate analysis. A recently defined clinical factor called the calculated prostate cancer volume and its ability to predict time to PSA failure in conjunction with PSA, biopsy Gleason score and clinical stage were evaluated. The calculated prostate cancer volume (p <0.0001) and the pretreatment PSA (p <0.001) provided the optimal staging system for predicting freedom from PSA failure after radical prostatectomy. The calculated prostate cancer volume and PSA may provide clinically useful information regarding outcome after radical prostatectomy, enabling the selection of a therapeutic approach for an individual patient with clinically localized disease. Validation of this staging system is needed.

Early adjuvant therapy beneficial for ER-negative breast cancer

Early adjuvant therapy beneficial for ER-negative breast cancer

Influence of local peritoneal involvement on pelvic recurrence and prognosis in rectal cancer.

To evaluate the influence of involvement of the peritoneal surface by carcinoma of the rectum on local recurrence and prognosis. Prospective analysis of pathological prognostic factors in 209 resections for rectal carcinoma between 1988 and 1993 with meticulous pathological technique particularly to assess the relation of tumour to the peritoneal surface. Comprehensive clinical follow up with cause of death established from all available sources of information (hospital and general practitioner data) with necropsies where necessary. Local recurrence was determined by accepted clinical, radiological and pathological criteria. Local peritoneal involvement was detected in 25.8% (54/209) of cases. It was more common in women and was associated with tumour differentiation, size and site, and lymph node involvement. Local peritoneal involvement showed considerable prognostic disadvantage in all cases and in curative cases alone. Multivariate analysis demonstrated independent prognostic disadvantage for all cases although this was lost in the curative group. With a 30 month median follow up time, comprehensive clinical surveillance detected 25 (12.0%) local recurrences. Thirteen (52%) palliative cases had shown spread to involve the mesorectal (deep, circumferential) resection margin. Of the 12 curative cases, six were upper rectal cancers with local peritoneal involvement suggesting that tumour seeding into the pelvic peritoneal cavity was the cause of local recurrence. Local recurrence of the six other rectal tumours was probably because of intraluminal seeding in two, involvement of the distal margin in one, extensive extramural venous involvement in two, and tumour spread to the bladder in one. Comprehensive pathological analysis of a resection specimen can identify cases with a high probability of local recurrence which may benefit from early adjuvant therapy. Involvement of the peritoneal surface is a common event in rectal cancer, has adverse prognostic influence and may be an important factor in local recurrence of upper rectal carcinoma.

Chromosome 17p allelic loss in colorectal carcinoma. Clinical significance.

To correlate allelic losses on chromosomes 5q, 8p, 17p, and 18q in colorectal adenocarcinomas with histopathologic features of known prognostic significance. DNA was extracted from paired samples of 56 fresh-frozen colorectal adenocarcinomas (one classified as Dukes' stage A, 22 as Dukes' stage B, 27 as Dukes' stage C, and six as Dukes'stage D) and adjacent normal mucosa. Specimens were resected at the University of Chicago (Ill) and the University of Padova (Italy) in 1991. Samples were obtained from consecutive patients. Chromosomes 5q, 8p, 17p, and 18q were studied for loss of heterozygosity by means of Southern hybridization blot analysis of restriction fragment length polymorphisms, and the results were correlated with pathologic tumor stage, degree of differentiation, and lymphatic and/or vascular microinvasion. Chromosomes 17p and 18q exhibited the highest frequency of loss of heterozygosity (40.6% and 48.8%, respectively). Most of the allelic losses were found in advanced tumors (60% in Dukes' stages C and D combined). A statistically significant correlation was found between loss of heterozygosity on chromosome 17p and the presence of lymphatic and/or vascular microinvasion (P < .01, Fisher's Exact Test). There was a significant correlation between loss of heterozygosity on chromosome 17p and the presence of lymphatic and/or vascular microinvasion in colorectal adenocarcinoma, a known stage-independent negative prognostic risk factor. Detection of loss of heterozygosity on chromosome 17p may identify a group of patients who may benefit from more aggressive surgical and/or early adjuvant therapy.

Current Opinion

Breast cancer is the most common malignancy in women in the United Kingdom, and survival of women with a diagnosis of breast cancer is increasing due to early detection and adjuvant treatment. However, this improvement in prognosis is not necessarily associated with a good quality of life since many patients experience debilitating symptoms resulting from estrogen deficiency. The traditional view is that hormone replacement therapy (HRT) is contraindicated because of the fear of precipitating recurrence. Although endogenous risk factors are associated with the development of breast cancer, and ovarian ablation or medical hormone manipulation are effective treatments, there is unconvincing evidence to implicate the oral contraceptive pill and HRT in the pathogenesis of breast cancer. There is also very little evidence that a high endogenous estrogen level is associated with a poor prognosis in patients with breast cancer, and the small non-randomized studies to date have reported no adverse effects of HRT in women after the diagnosis of breast cancer. The time has come for this proscription to be reevaluated.

Radiotherapy for cervical cancer with high-dose rate brachytherapy — correlation between tumor size, dose and failure

This is a retrospective analysis of 659 patients with cervical squamous cell carcinoma with a minimum follow-up of 2 years at Keio University Hospital between May 1974 and March 1990. All patients were treated with external radiation (50 Gy) and high-dose rate (HDR) intracavitary brachytherapy (20–34 Gy). The 5-year survival rates in each stage gradually decreased with the advance of the stage (I, 84%; II, 7I%; III, 47%; and IVa, 12%). When 366 patients with stage III were classified into three groups according to tumor size, i.e. small (S, I02 patients), medium (M, I45) and large (L, 119), a survival gradient of small > medium > large was demonstrated and the differences between them were significant. At follow-up visits conducted between 1 and 2 months after completion of treatment, 135 patients (20%) had physical indications of residual disease. The larger the tumor size, the more likely was residual disease by 2 months. The patients with residual disease had a significantly higher rate of the pelvic failure than those without it. There was no significant correlation between radiation doses by RALS and pelvic failure rates, except in the stage III-L group. In the stage III-L group, intracavitary doses of 24 Gy or less to point A could be correlated with the higher pelvic failure rate and the lower survival rate, in contrast to doses of 27 Gy or more. The incidence of major rectosigmoid complications was 11.8% with doses of 24 Gy or less to point A, 8.1% with 27 Gy and I9.2% with doses of 30 Gy or more. The incidence of major rectosigmoid complications is likely to increase with doses higher than 30 Gy. The incidence of severe urinary complications was less than 1.5% with doses between 20 and 34 Gy. It was concluded that 27 Gy by HDR brachytherapy may be recommended for cervical cancer except for larger tumors or tumor that did not regress promptly. Such poor-prognosis patients should be targeted for the early adjuvant or salvage therapy.

Adjuvant Endocrine Treatment in Early Prostatic Cancer

Adjuvant endocrine treatment of prostatic cancer is not an established method at present. With our knowledge of the mechanisms of endocrine dependence of human prostate cancer and of available clinical data, a beneficial effect on survival seems unlikely. It has been shown by several investigators that endocrine treatment has a more favorable effect on the primary tumor than on distant metastases, and local progression under endocrine management is seen less frequently than progression to distant metastases. Studies in patients with lymph node positive but otherwise locally confined prostate cancer have shown that time to progression can be delayed by a factor of 3 with early adjuvant endocrine treatment. Radical surgery and radiotherapy may be facilitated by preceding endocrine measures. There is, however, no evidence at present that initially inoperable tumors may become accessible to radical surgery or that preceding endocrine treatment improves the results of radical surgery. Such an effect appears to be unlikely unless one assumes that prostate cancer cells growing outside the prostate will disappear completely or retract into that organ, hypotheses that are not supported by clinical or experimental observations. It is unknown at present whether very early adjuvant treatment may prevent the progression and the promotion of focal disease to clinical prostate cancer. This possibility should be made a subject of future research.

Adjuvant systemic therapy for patients with node-negative tumors

Early adjuvant therapy studies, especially adjuvant chemotherapy studies, were performed almost exclusively on patients with histologically involved axillary lymph nodes ("node-positive" patients). These therapies were restricted to this group of patients because the toxicities of adjuvant therapy were believed too great to justify its use in patients with a very good prognosis until its benefits were fully established. However, after it was demonstrated that adjuvant therapy can significantly prolong the disease-free survival of almost all groups of node-positive patients and the overall survival of some patient subsets, adjuvant therapy trials specifically designed for patients without histologically involved lymph nodes ("node-negative" patients) were initiated. Results from some of the largest of these second generation trials were recently published, and the early results from these studies have generated new questions. For example, will the mature results from these studies be nearly identical to the results seen in node-positive patients, or will node-negative patients derive greater benefits from adjuvant therapy? Is it possible that adjuvant therapy will "cure" node-negative patients but not node-positive patients? (Cure is defined here as an effect of therapy that returns a patient to the life expectancy she might have had if she had never been diagnosed with breast cancer). Is it possible that the added years of life from adjuvant therapy or that the number of node-negative patients who benefit are so small that these benefits will be outweighed by delayed toxicities that appear in patients who might have been cured even without adjuvant therapy? At present the available data to answer these questions definitely are either contradictory or nonexistent.

Vimentin—a new prognostic parameter in breast carcinoma?

This report describes a positive relationship between vimentin expression in infiltrating ductal breast carcinoma, and high tumour growth fraction. Vimentin expression is potentially a predictor of aggressive behaviour, and such carcinomas may benefit from early adjuvant therapy. Eighty-four malignant breast neoplasms were stained with monoclonal anti-vimentin and anti-cytokeratin antibodies. The tumour growth fractions were determined by immunostaining cryostat sections with the Ki-67 antibody. Seven (9.2 per cent) of 76 infiltrating ductal carcinomas co-expressed cytokeratin and vimentin intermediate filaments in more than 50 per cent of neoplastic cells. In each case, the corresponding Ki-67 count was much greater than 40 per cent, significantly higher than the mean growth fraction for all tumours examined (P less than 0.0001). Vimentin immunoreactivity was also positively related to the histological grade of the ductal carcinomas (P less than 0.002) and inversely related to tumour ER count (P less than 0.0002) and patient age (P less than 0.01). No relationship was observed between vimentin positivity and either the presence of axillary nodal metastases or primary tumour size.

Recurrent and persistent squamous cell cervical carcinoma in women under age 35

Forty-five patients with invasive cervical squamous cell carcinoma were registered in the Tom Baker Cancer Centre from 1980 to 1985. The natural history of 22 patients (48.9%) who developed persistent or recurrent disease including 11 Stage IB, 8 Stage IIB, and 3 Stage IIIB is reported. Only one patient who had the uncommon papillary variant is alive without evidence of residual disease. The remainder are either dead (16) or alive with residual disease (5). Four patients never achieved a disease-free status and in the remainder recurrences developed on average in 8.7 months. Central or regional disease was not controlled in 20 of 22 patients. Neither radical surgery nor radiotherapy was evidently more effective in preventing persistent or recurrent disease. A reliable predictive marker for persistent or recurrent disease is required: lymph-vascular invasion in the radical hysterectomy specimens was present in 5 of 6 cases but it is subject to interpretive error. Since the disease is frequently systemic at the time of diagnosis, early adjuvant therapy and improved staging techniques are required to improve the survival.

Early doxorubicin treatment of tumor recurrence after liver transplantation for hepatocellular carcinoma: A case report

We report on a patient with primary hepatic carcinoma, most probably developed after a chronic hcpatitis‐B infection, to whom doxorubicin was given when serum alpha‐fetoprotein (AFP) reappeared early after liver transplantation. With this treatment the tumor marker disappeared initially but later clinical metastatis developed. Still, the finding indicates that early adjuvant treatment with anti‐tumor drugs might affect tumor development after liver replacement for malignancy.

PREDICTIVE VALUE OF LECTIN BINDING ON BREAST-CANCER RECURRENCE AND SURVIVAL

A new approach for predicting long-term survival of breast-cancer patients is the detection of carbohydrate expression in paraffin-embedded sections of the primary tumour. The binding of a lectin (HPA), derived from the albumin gland of the Roman snail, Helix pomatia, to N-acetyl-galactosaminyl oligosaccharides appears valuable in assessing long-term prognosis. The clinical progress of 179 patients, followed-up for 15-20 years, was related to staining of paraffin sections of their primary breast cancers by HPA. All patients had had mastectomy but were not stratified by pathology or treatment. There were significant differences, in premenopausal patients, between groups with and without HPA staining in both time to first recurrence and survival time. HPA binding provides an extra tool for staging to aid decisions in early adjuvant treatment, with the advantage of being applicable to routinely fixed paraffin-embedded material.

Short-term persistence of carcinoma of the uterine cervix after radiation. An indicator of long-term prognosis.

Between 1959 and 1980, 590 evaluable patients received a full course of radiation therapy as primary treatment of invasive epidermoid carcinoma of the cervix. At follow-up visits conducted between 1 and 3 months after the completion of radiation, 72 patients had physical or biopsy findings indicative of persistent disease (PER), whereas an additional 36 had findings suggestive of tumor (SUS). The remaining 482 demonstrated a complete response (CR) by 1 month after the administration of treatment. The lower the stage, the more likely was a CR by 3 months (Stage I, 94.4%; Stage II, 86.2%; Stage III, 62.7%). A higher proportion of CR was obtained in patients with tumor of less than 5 cm in diameter than in those with tumors greater than 5 cm in diameter (82.4% versus 76.3%, respectively; 0.1 greater than P greater than 0.05). CR patients enjoyed a marked survival advantage over those with PER, whereas women with SUS demonstrated intermediate 5-year survival (76.0%, 41.5%, and 7.4%, respectively; P less than 0.0001). The same survival gradient of CR greater than SUS greater than PER was demonstrated when tumors of each stage were analyzed separately. There was no difference in survival between patients with PER or SUS at 1 month and those with PER or SUS at 3 months. The proportion of recurrent tumors diagnosed as exclusively distant metastases decreased from CR to SUS to PER. Analysis of dosimetry data suggests that the likelihood of CR was not a function of treatment variability. It was concluded that tumors that do not regress promptly are likely to recur, most with distant metastases. Such poor-prognosis patients should be targeted for early adjuvant or salvage therapy.

Hormones in breast cancer: Update 1978

The role of cytoplasmic estrogen receptor (ER) assays in determining therapeutic strategies for advanced breast cancer is certainly well established. The use of ER assays in the primary breast tumor specimen to predict for early recurrence and ultimate survival is a new finding, however, and will probably be employed in future trials of adjuvant therapy. The prevalence and significance of nuclear-bound ER still requires additional clarification. Our previous suggestion that progesterone receptor measurements might be a useful marker for hormone dependence in advanced breast cancer is gaining support and may soon have a place in routine therapeutic decision-making. The emphasis on early adjuvant therapy has hastened the search for a safe endocrine therapy that would have good patient compliance and achieve remission rates comparable to previous agents and procedures. Antiestrogens show promise of meeting these requirements. We are now beginning an era in which primary and secondary systemic therapies for breast cancer can be based on sound biologic principles. The empirical approach is out-dated.

Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour.

Radiation survival curves for Lewis lung tumours in the lungs ranging in size from 0-5 to 20 mm3 have been obtained, and a size-dependent variation in hypoxic fraction was found. Cell-survival studies following treatment of various sizes of s.c. tumours indicated that the effects of 60Co gamma-rays and the chemotherapeutic agents 1,3-bas(2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide are all size-dependent. Large pulmonary nodules which had regressed but had not been cured by cyclophosphamide regrew with a radiosensitivity that was characteristic of previously untreated tumours. The results give additional experimental support to the clinical interest in early adjuvant therapy of micrometastases, and sequential combined modality therapy for larger tumours.