Gerrit DeBoer

Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.

BACKGROUND & AIMS Early detection of hepatocellular carcinoma (HCC) is critical for successful treatment. However, the differential diagnosis between HCC and benign hepatic lesions is sometimes difficult and new biochemical markers for HCC are required. It has been reported that glypican-3 (GPC3) messenger RNA (mRNA) is significantly increased in most HCCs compared with benign liver lesions or normal liver. The goal of this study is to determine whether GPC3 is also overexpressed at the protein level and whether GPC3 is detectable in the serum of patients with HCC. METHODS GPC3 was assessed in liver tissue sections by immunohistochemistry and in serum by enzyme-linked immunosorbent assay. Serum alpha-fetoprotein (AFP) level was also measured in the same patients. RESULTS Immunohistochemical studies showed that GPC3 is expressed in 72% of HCCs (21 of 29), whereas it is not detectable in hepatocytes from normal liver and benign liver diseases. Consistent with this, GPC3 was undetectable in the serum of healthy donors and patients with hepatitis, but its levels were significantly increased in 18 of 34 patients (53%) with HCC. In addition, only 1 of 20 patients with hepatitis plus liver cirrhosis displayed elevated levels of serum GPC3. Interestingly, in most cases, there was no correlation between GPC3 and AFP values. Thus, at least 1 of the 2 markers was elevated in 82% of the patients with HCC. CONCLUSIONS GPC3 is specifically overexpressed in most HCCs and is elevated in the serum of a large proportion of patients with HCC. The simultaneous determination of GPC3 and AFP may significantly increase the sensitivity for diagnosis of HCC.

P-Glycoprotein Expression as a Predictor of the Outcome of Therapy for Neuroblastoma

BACKGROUND AND METHODS Multidrug resistance in chemotherapy for cancer is characterized by increased genetic expression of P-glycoprotein, which acts as an ATP-dependent drug-efflux pump. To determine whether P-glycoprotein levels are of prognostic value in such cases, we measured these levels immunohistochemically in a retrospective study of sequential tumor samples from 67 children with neuroblastoma. RESULTS P-glycoprotein was not detected in pretreatment samples from either of the 2 patients with Stage I disease, any of the 21 with Stage II disease, or any of the 8 with Stage IVS disease, but it was detected in the samples from 1 of the 17 patients with Stage III disease (6 percent) and 12 of the 19 with Stage IV disease (63 percent). Of the 44 patients with nonlocalized neuroblastoma (Stage III, IVS, or IV), 26 of the 31 who were negative for P-glycoprotein had a complete response to primary treatment, as compared with 6 of the 13 who were positive for P-glycoprotein (84 percent vs. 46 percent, P = 0.0232 by Fishers exact test). Log-rank analysis of outcome, with simultaneous stratification according to tumor stage and age, showed that the group that was negative for P-glycoprotein had significantly longer relapse-free survival (P = 0.0011) and overall survival (P = 0.0373) than the group that was positive. CONCLUSIONS Expression of P-glycoprotein before treatment may predict the success or failure of therapy for nonlocalized neuroblastoma. Neuroblastoma may be a promising tumor to treat with anticancer drug therapy combined with a chemosensitizing agent capable of reversing P-glycoprotein-mediated multidrug resistance.

Feasibility study : watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression

PURPOSE We assessed the feasibility of a watchful waiting protocol with selective delayed intervention using clinical, prostate specific antigen (PSA) or histological progression as treatment indications for clinically localized prostate cancer. MATERIALS AND METHODS In this prospective, single arm cohort study patients with favorable clinical parameters (stage T1b to T2b N0M0, Gleason score 7 or less and PSA 15 ng./ml. or less) are conservatively treated with watchful waiting. When a patient meets disease progression criteria, arbitrarily defined by the 3 parameters of the rate of PSA increase, clinical progression or histological upgrade on repeat prostate biopsy, appropriate treatment is implemented. Patients are followed every 3 months for the first 2 years and every 6 months thereafter. Serum PSA measurement and digital rectal examination are done at each visit and repeat prostate biopsy is performed 18 months after study enrollment. RESULTS Since November 1995, the study has accrued 206 patients with a median followup of 29 months (range 2 to 66). Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons. There was clinical, PSA and histological progression in 16, 15 and 5 cases, respectively. The estimated actuarial probability of remaining on the surveillance protocol was 67% at 2 years and 48% at 4. The probability of remaining progression-free was 81% and 67% at 2 and 4 years, respectively. CONCLUSIONS A policy of watchful waiting with selectively delayed intervention based on predefined criteria of disease progression is feasible. This strategy offers the benefit of an individualized approach based on the demonstrated risk of clinical or biochemical progression with time and, thus, it may decrease the burden of therapy in patients with indolent disease, while providing definitive therapy for those with biologically active disease.

A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer.

This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.

VP-16 and cisplatin as first-line therapy for small-cell lung cancer.

Thirty-one patients with small-cell lung cancer (SCLC) were treated with VP-16 and cisplatin as first-line therapy. In the majority of cases an Adriamycin (Adria Laboratories, Columbus, Ohio) containing regimen was contraindicated because of severe cardiac or hepatic disease. Eight patients who presented with cerebral metastases were also included in the series. Eleven patients had limited disease (LD), and 20 had extensive disease (ED). Of the 28 evaluable patients, 12 (43%) achieved a complete response (CR) and 12 (43%) had a partial response (PR). Four patients (14%) either had no response or progressed on treatment. The median duration of response for patients with LD was 39 weeks and for those with ED, 26 weeks. The median survival time (MST) for the whole group of responding (CR and PR) LD patients was 70 weeks (range, 28 to 181 + weeks), and for responding ED patients, it was 43 weeks (range, 17 to 68 weeks). Gastrointestinal toxicity was mild, but leukopenia and thrombocytopenia were common. There were four febrile episodes during periods of drug-induced neutropenia and this led to one treatment-related death. Nephrotoxicity occurred in 15 patients and required discontinuation of cisplatin in two. These results compare favorably with reports of standard induction chemotherapy regimens and provide further evidence of the activity of the VP-16 and cisplatin regimen in patients with SCLC.

Etoposide (VP-16) and cisplatin: an effective treatment for relapse in small-cell lung cancer.

Seventy-eight patients with evaluable small-cell lung cancer (SCLC) were treated with etoposide (VP-16) and cisplatin after their disease failed to respond to, or relapsed after, induction combination chemotherapy, consisting primarily of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV). Twenty-four patients had limited disease (LD) and 54 had extensive disease (ED). In six (8%) patients, a complete response (CR) was achieved and in 37 (47%), there was a partial response (PR). The median duration of response for responding patients was 22 weeks (range, 4 to 50 weeks) for patients with LD and 18 weeks (range, 4 to 49 weeks) for those with ED. Twelve percent of patients demonstrated stable disease, and 33% of patients had progressive disease on treatment. The median survival times of LD patients achieving a CR or PR were 59 and 34 weeks, respectively, whereas the comparable figures for ED patients were 45 and 23 weeks, respectively. Gastrointestinal toxicity was mild, but myelosuppression, predominantly leukopenia and thrombocytopenia, was common. Mild to moderate nephrotoxicity occurred in 11 patients, but was reversible in all cases. Two febrile episodes occurred during periods of drug-induced neutropenia, but no other significant toxicities were identified. These results provide further evidence that VP-16 and cisplatin is an effective and tolerable combination chemotherapy regimen for SCLC resistant to CAV.

Second primary respiratory tract malignancies in glottic carcinoma

Of 740 cases of glottic cancer, a second respiratory tract tumor developed in 48. Only 14 cases would have been expected in a sample of the same age and sex distribution drawn from the general population of Ontario. Of 25 patients with second tumors in the lung, 23 are dead. Of these 23, 17 had been cured of Stage T1 glottic cancer. An actuarial method for calculating the risk of developing a second respiratory tract tumor amongst the survivors of glottic cancer is described. Of the survivors, 12% will have a second respiratory tract tumor within ten years following initial diagnosis of glottic cancer. Of patients with Stage T1 glottic cancer, 7% will die of a second respiratory tract tumor within ten years. This rate is slightly more than that for those who die of laryngeal cancer in this stage grouping. Late recurrences and/or second primary tumors in the larynx following radiotherapy are rare. Methods for reducing the risk of death from a second respiratory tract tumor are discussed.

PSA doubling time of prostate carcinoma managed with watchful observation alone

PURPOSE To study prostate-specific antigen (PSA) doubling time of untreated, favorable grade, prostate carcinoma. METHODS AND MATERIALS A prospective single-arm cohort study has been in progress to assess the feasibility of a watchful observation protocol with selective delayed intervention using clinical, histologic, or PSA progression as treatment indication in untreated, localized, favorable grade prostate adenocarcinoma (T1b-T2bN0 M0, Gleason Score < or = 7, and PSA < or = 15 ng/mL). Patients are conservatively managed with watchful observation alone, as long as they do not meet the arbitrarily defined disease progression criteria. Patients are followed regularly and undergo blood tests including PSA at each visit. PSA doubling time (Td) is estimated from a linear regression of ln(PSA) on time, assuming a simple exponential growth model. RESULTS As of March 2000, 134 patients have been on the study for a minimum of 12 months (median, 24; range, 12-52) and have a median frequency of PSA measurement of 7 times (range, 3-15). Median age is 70 years. Median PSA at enrollment is 6.3 (range, 0.5-14.6). The distribution of Td is as follows: <2 years, 19 patients; 2-5 years, 46; 5-10 years, 25; 10-20 years, 11; 20-50 years, 6; > 50 years, 27. The median Td is 5.1 years. In 44 patients (33%), Td is greater than 10 years. There was no correlation between Td and patient age, clinical T stage, Gleason score, or initial PSA level. CONCLUSION Td of untreated prostate cancer varies widely. In our cohort, 33% have Td > 10 years. Td may be a useful tool to guide treatment intervention for patients managed conservatively with watchful observation alone.

POSITIVE RESECTION MARGIN AND/OR PATHOLOGIC T3 ADENOCARCINOMA OF PROSTATE WITH UNDETECTABLE POSTOPERATIVE PROSTATE-SPECIFIC ANTIGEN AFTER RADICAL PROSTATECTOMY: TO IRRADIATE OR NOT?

PURPOSE To evaluate the efficacy of postoperative adjuvant radiotherapy (RT) for positive resection margin and/or pathologic T3 (pT3) adenocarcinoma of the prostate with undetectable postoperative prostate-specific antigen (PSA) levels. METHODS AND MATERIALS We retrospectively analyzed 125 patients with a positive resection margin and/or pT3 adenocarcinoma of the prostate who had undetectable postoperative serum PSA levels after radical prostatectomy. Seventy-three patients received postoperative adjuvant RT and 52 did not. Follow-up ranged from 1.5 to 12.0 years (median 4.2 for the irradiated group and 4.9 for the nonirradiated group). PSA outcome was available for all patients. Freedom from failure was defined as the maintenance of a serum PSA level of < or =0.2 ng/mL, as well as the absence of clinical local recurrence and distant metastasis. RESULTS No difference was found in the 5-year actuarial overall survival between the irradiated and nonirradiated group (94% vs. 95%). However, patients receiving adjuvant RT had a statistically superior 5-year actuarial relapse-free rate, including freedom from PSA failure, compared with those treated with surgery alone (88% vs. 65%, p = 0.0013). In the irradiated group, 8 patients had relapse with PSA failure alone. None had local or distant recurrence. In the nonirradiated group, 15, 1, and 2 had PSA failure, local recurrence, and distant metastasis, respectively. On Cox regression analysis, pre-radical prostatectomy PSA level and adjuvant RT were statistically significant predictive factors for relapse, and Gleason score, extracapsular invasion, and resection margin status were not. There was a suggestion that seminal vesicle invasion was associated with an increased risk of relapse. The morbidity of postoperative adjuvant RT was acceptable, with only 2 patients developing Radiation Therapy Oncology Group Grade 3 genitourinary complications. Adjuvant RT had a minimal adverse effect on urinary continence and did not cause serious gastrointestinal toxicity. CONCLUSION Postoperative adjuvant RT was associated with a lower risk of relapse, including freedom from PSA failure, compared with observation alone for pT3 and/or margin-positive disease with undetectable postoperative PSA levels. This was accomplished with a minimal risk of serious RT morbidity.

Prognostic factors in T2 glottic cancer

During a ten‐year period from 1965 through 1974, 164 patients with T2N0M0 glottic cancer were seen at the Princess Margaret Hospital. These patients were treated by radiotherapy reserving surgery for salvage of recurrent or persistent disease. One hundred and fifty‐four cases have been analyzed in detail with respect to two variables: impairment of mobility and surface extension of disease. Two end‐points of analysis were used: actuarial local recurrence‐free rates and corrected actuarial survival. The five‐year corrected actuarial survival rate was 12% less in the T2N0M0 patients with impaired vocal cord mobility (75.2%) when compared to those cases with normal vocal cord mobility (86.8%) (P = 0.068). No difference in survival was seen with increasing degrees of surface extension of disease when correction for the effects of impairment of mobility was performed. There was a highly significant difference in local control rates with radiotherapy when comparing cases with normal vocal cord mobility (76.7% locally controlled) vs. impaired vocal cord mobility (51.1% locally controlled) (P = 0.015). Again, no significant trend in local control rates could be ascertained with increasing surface extension of disease. The number of patients with nodal disease was insufficient to permit meaningful analysis of the effects of the presence or absence of nodal disease on survival. On the basis of this analysis, we suggest that the Stage T2 grouping in glottic cancer be subdivided into Stage T2a for those tumors with normal vocal cord mobility and T2b for those with impaired vocal cord mobility.