Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study.

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study†.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, with median age at diagnosis in the seventh decade. FL in young adults (YAs), defined as diagnosis at ≤40 years, is uncommon. No standard approaches exist guiding the treatment of YA FL, and little is known about their disease characteristics and outcomes. To gain further insights into YA FL, we analyzed the National LymphoCare Study (NLCS) to describe characteristics, initial treatments, and outcomes in this population versus patients aged >40 years. PATIENTS AND METHODS: Using the NLCS database, we stratified FL patients by age: 18-40 (YA), 41-60, 61-70, 71-80, and >80 years. Survival probability was estimated using Kaplan-Meier methodology. We examined associations between age and survival using hazard ratios and 95% confidence intervals (CIs) from multivariable Cox models. RESULTS: Of 2652 eligible FL patients in the NLCS, 164 (6%) were YAs. Of YA patients, 69% had advanced disease, 80% had low-grade histology, and 50% had good-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent underwent observation, 12% received rituximab monotherapy, and 46% received chemoimmunotherapy [in 59% of these: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone)]. With a median follow-up of 8 years, overall survival (OS) at 2, 5, and 8 years was 98% (95% CI 93-99), 94% (95% CI 89-97), and 90% (95% CI 83-94), respectively. Median progression-free survival (PFS) was 7.3 years (95% CI 5.6-not reached). CONCLUSIONS: In one of the largest cohorts of YA FL patients treated in the rituximab era, disease characteristics and outcomes were similar to patients aged 41-60 years, with favorable OS and PFS in YAs. Longer-term outcomes and YA-specific survivorship concerns should be considered when defining management. These data may not support the need for more aggressive therapies in YA FL. CLINICAL TRIAL NUMBER: Roche/Genentech ML01377 (U2963n).

Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT.

BACKGROUND: Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. PATIENTS AND METHODS: In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). RESULTS: One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). CONCLUSIONS: An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent, and medicolegal issues.

The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia (AAGA) yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for <5 min, yet 51% of patients [95% confidence interval (CI) 43-60%] experienced distress and 41% (95% CI 33-50%) suffered longer term adverse effect. Distress and longer term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected AAGA or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39%, and mixed in 31%. Three-quarters of cases of AAGA (75%) were judged preventable. In 12%, AAGA care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of AAGA included medication, patient, and education/training. The findings have implications for national guidance, institutional organization, and individual practice. The incidence of 'accidental awareness' during sedation (~1:15,000) was similar to that during general anaesthesia (~1:19,000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. NAP5 methodology provides a standardized template that might usefully inform the investigation of claims or serious incidents related to AAGA.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.

We present the main findings of the 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia (AAGA). Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19,600 anaesthetics (95% confidence interval 1:16,700-23,450). However, there was considerable variation across subtypes of techniques or subspecialities. The incidence with neuromuscular block (NMB) was ~1:8200 (1:7030-9700), and without, it was ~1:135,900 (1:78,600-299,000). The cases of AAGA reported to NAP5 were overwhelmingly cases of unintended awareness during NMB. The incidence of accidental awareness during Caesarean section was ~1:670 (1:380-1300). Two-thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental, rapid sequence induction, obesity, difficult airway management, NMB, and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One-third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, mostly due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex, age (younger adults, but not children), obesity, anaesthetist seniority (junior trainees), previous awareness, out-of-hours operating, emergencies, type of surgery (obstetric, cardiac, thoracic), and use of NMB. The following factors were not risk factors for accidental awareness: ASA physical status, race, and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from NAP5--the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.

Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset.

BACKGROUND: Carcinoma of unknown primary with a "gastrointestinal profile" is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. PATIENTS AND METHODS: 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. RESULTS: 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1-"consistent with lower GI profile" included 34 patients [CDX-2+, CK20+, CK7-] and Cohort 2-"probable lower GI profile" included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. CONCLUSIONS: Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.

We present the main findings of the 5th National Audit Project on accidental awareness during general anaesthesia. Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19 600 anaesthetics (95% CI 1:16 700-23 450). However, there was considerable variation across subtypes of techniques or subspecialties. The incidence with neuromuscular blockade was ~1:8200 (1:7030-9700), and without it was ~1:135 900 (1:78 600-299 000). The cases of accidental awareness during general anaesthesia reported to 5th National Audit Project were overwhelmingly cases of unintended awareness during neuromuscular blockade. The incidence of accidental awareness during caesarean section was ~1:670 (1:380-1300). Two thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental; rapid sequence induction; obesity; difficult airway management; neuromuscular blockade; and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, most due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex; age (younger adults, but not children); obesity; anaesthetist seniority (junior trainees); previous awareness; out-of-hours operating; emergencies; type of surgery (obstetric, cardiac, thoracic); and use of neuromuscular blockade. The following factors were not risk factors for accidental awareness: ASA physical status; race; and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from 5th National Audit Project - the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home#pt.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent and medicolegal issues.

The 5th National Audit Project of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for < 5 min, yet 51% of patients (95% CI 43-60%) experienced distress and 41% (95% CI 33-50%) suffered longer-term adverse effect. Distress and longer-term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected accidental awareness during general anaesthesia or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39% and mixed in 31%. Three quarters of cases of accidental awareness during general anaesthesia (75%) were judged preventable. In 12% of cases of accidental awareness during general anaesthesia, care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of accidental awareness during general anaesthesia included medication, patient and education/training. The findings have implications for national guidance, institutional organisation and individual practice. The incidence of 'accidental awareness' during sedation (~1:15 000) was similar to that during general anaesthesia (~1:19 000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. The 5th National Audit Project methodology provides a standardised template that might usefully inform the investigation of claims or serious incidents related to accidental awareness during general anaesthesia.

Psychosocial characteristics of adults who experience difficulties with retching.

OBJECTIVES: The current study aimed to reach a greater understanding of psychosocial variables in patients who gag, and is a recognised gap within current literature. Obtaining a profile of patients who gag could provide valuable information in relation to future treatment planning and management of this type of difficulty. METHODS: All new patients aged > or =18 years, identified as having a difficulty with retching, and who attended the Anxiety Management Clinic, Department of Restorative Dentistry, Birmingham Dental Hospital, were invited to complete a brief questionnaire with questions related to general demographic data; difficulties with retching; and an oral health status measurement. This study has reported on 48 patients who attended the dental anxiety management clinic at Birmingham Dental Hospital and who presented with retching difficulties. One patient did not wish to take part in the study, leaving a final sample size of 47. The sample comprised 57% male (n=27) and 43% female (n=20) patients. RESULTS: Retching was more commonly seen in the 40-49-year age group. Onset was frequently related to an earlier dental experience and over half the sample studied had experienced previous psychological difficulties. A fear of choking or suffocation was frequently expressed, supporting a cognitive model in terms of assessment and treatment. CONCLUSION: A number of themes were identified which would be worthy of further exploration. For example, the impact of previous or existing physical health problems such as respiratory complaints, family history of retching, and prevalence of other psychological difficulties. Through participation in this study, patients were able to reach a greater awareness of this commonly encountered difficulty within dentistry.

Kinetics of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641) in humans.

The metabolism and disposition of LY186641, a diarylsulfonylurea with antineoplastic activity identified in preclinical tests, was determined in 21 patients who received 23 courses of orally administered drug. A linear correlation was found between the dose of drug administered and LY186641 peak plasma concentrations and LY186641 area under the curve measurements. Clearance (135 +/- 36 ml/h/m2), terminal half-life (31 +/- 11 h), and volume of distribution (10.2 +/- 2.8 liters) were independent of drug dose. No LY186641 was excreted in urine. Hydroxy and keto metabolites of LY186641 were identified in plasma and urine samples. Urinary excretion of these metabolites during the initial 48 h following drug administration accounted for 20% of LY186641 disposition. Plasma half-life of the hydroxy and keto metabolites was longer than that of parent drug (3.3 and 3.1 days, respectively). Plasma concentrations of parent drug correlated with the presence of methemoglobinemia, the dose-limiting toxicity found with LY186641.

Phase I clinical study of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641).

Between February 1987 and July 1988, 45 patients with advanced refractory cancer were treated with LY186641, a diarylsulfonylurea that has shown a broad spectrum of activity in preclinical testing. Patients received a weekly p.o. dose of LY186641 for 6 consecutive weeks; responding and stable patients continued weekly therapy until progression occurred. Using a standard phase I study design, the first three patients received LY186641 at 30 mg/m2 week; the dose was escalated in subsequent patients until dose-limiting toxicity occurred. Methemoglobinemia was the major toxicity observed and was dose related. Methemoglobin levels peaked approximately 24 h after LY186641 was administered and fell to low levels after 48 h. Six patients developed fatigue, cyanosis, and dyspnea associated with serum methemoglobinemia levels of greater than 20%; four of these patients were subsequently removed from the study. Hemolytic anemia was also observed but was clinically significant in only 10 patients. Other side effects were mild and infrequent. The maximum tolerated dose of LY186641, when given at this schedule, was 2550 mg/m2/week. No objective tumor responses were observed.

Potential utility of serum neuron-specific enolase levels in small cell carcinoma of the lung.

To assess the value of neuron-specific enolase (NSE) as a possible biomarker of small cell lung cancer, serum levels were determined by radioimmunoassay in 93 newly diagnosed untreated patients and were compared to the NSE levels of 20 healthy adult controls [9.6 +/- 0.7 (S.E.) ng/ml]. Serum NSE was elevated (greater than 20 ng/ml) in 73% of all patients including 23 of 39 (59%) with limited-stage disease and 45 of 54 (83%) with extensive-stage disease. The mean serum NSE was significantly higher in extensive-stage disease (94.5 +/- 13.8 ng/ml) compared to the mean value for limited-stage disease (33.7 +/- 4.7 ng/ml) (p less than 0.001). NSE was elevated in all patients with three or more sites of metastatic disease. Serial NSE determinations were obtained on 57 small cell lung cancer patients. NSE levels fell in 40 of 50 (80%) of patients responding to treatment, increased in 5 of 7 (71%) of patients with progressive disease, and increased in 30 of 35 (86%) of patients who relapsed. A persistent rise in serum NSE occurred as many as 12 weeks before the clinical recognition of relapse in 15 of 23 (65%) of patients for whom adequate serial NSE data were available. These findings indicate that serum NSE may be a useful marker for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer.

Combination intraventricular chemotherapy for meningeal neoplasia.

Twenty two patients with meningeal neoplasia were treated with biweekly combination intraventricular chemotherapy using methotrexate, cytosine arabinoside, and thiotepa. Patients with the following malignancies were included: breast cancer, ten patients; lung cancer, seven; non-Hodgkin's lymphoma, two; malignant melanoma, one; transitional cell carcinoma of the bladder, one; and malignant glioma, one. Eight of 22 patients (36%) had a Karnofsky performance status of less than 50%. Eleven of 22 patients received radiotherapy to symptomatic areas, and seven received systemic chemotherapy in addition to combination intraventricular therapy. Patients were evaluated for both toxicity and response to therapy. Myelosuppression was the major toxic condition and occurred in 17 of 22 patients (77%). Ten patients (45%) had a nadir WBC count of less than 1000/microL or a platelet count of less than 25,000/microL. No patient achieved a complete response (CR), although nine patients (41%) had partial responses (PRs) lasting 4 to 24 + weeks. Median survival for the entire group was 10 weeks (range, 6 to 24+ weeks). In this small group of patients, simultaneous triple-drug intraventricular chemotherapy caused unacceptable myelosuppression without increasing the response rate, response duration, or survival when compared with single-agent methotrexate and radiotherapy.

Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer.

Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.

Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy.

We have previously reported complete responses and long-term survival in patients with metastatic poorly differentiated carcinoma (PDC) of unknown primary site who received intensive cisplatin-containing chemotherapy regimens. We reviewed the light microscopic specimens from 113 patients with PDC in an attempt to identify common histopathologic features in the chemotherapy-responsive subgroup, and to rule out the presence of previously unrecognized germ cell tumors. Relatively few diagnoses more specific than PDC could be made. We could identify no histopathologic features by light microscopy that distinguished responsive from unresponsive neoplasms. Only one patient was found to have a previously unrecognized yolk sac carcinoma, and in five other patients the possibility of a germ cell neoplasm was considered in the differential diagnosis by at least one reviewer. The remaining tumors had no histologic features suggestive of germ cell neoplasms. Ninety-six patients had received combination chemotherapy (89 with cisplatin-containing regimens); 27 patients (28%) achieved complete remission, and 16 remain free of disease at a median of 65 months after completion of therapy. Patients with PDC of unknown primary site who are responsive to cisplatin-containing chemotherapy regimens cannot be reliably identified by light microscopy. At present, all such patients should be considered for an empiric trial of chemotherapy with cisplatin-based regimens, since cure is achievable in a minority.

Chronic daily administration of oral etoposide--a phase I trial.

In this phase I study, we administered etoposide (VP-16) orally for 21 consecutive days to patients with advanced refractory cancers. All patients had received previous chemotherapy, and 50% of patients had received more than one combination regimen. When given for 21 consecutive days, the maximum-tolerated dose of oral VP-16 was 50 mg/m2/d. Myelosuppression was the dose-limiting toxicity, and occurred between days 21 and 28. In most patients, blood counts had recovered sufficiently by day 35 to begin another 3-week course. WBC count nadirs of less than 1,000/microL occurred in four of 20 courses at this dose, and three patients required hospitalization for treatment of neutropenia and fever. Alopecia occurred in most patients; gastrointestinal (GI) and other toxicities were uncommon. Five of 16 patients with measurable tumor had partial responses of 3 to 4 months duration. Four of these five patients had malignancies that are usually unresponsive to VP-16 when administered by previously investigated schedules. This method of VP-16 administration is well tolerated, convenient, and may optimize antitumor efficacy by exploiting the schedule dependency of this drug. Phase II studies are necessary to define the level of activity of this schedule of VP-16.

Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience.

PURPOSE: We previously reported excellent responses to cisplatin-based chemotherapy in a minority of patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA) of unknown primary site. We have continued to study and to treat these patients, and now report clinical characteristics, treatment results, and prognostic factors in a large group of patients identified prospectively. PATIENTS AND METHODS: Between February 1978 and December 1989, we treated 220 patients with PDC or PDA of unknown primary site. The median age was 39 years; 48% of patients had predominant tumor location in the mediastinum, retroperitoneum, or peripheral lymph nodes. Specialized pathologic studies resulted in the identification of specific tumor types in only a few cases. All patients received cisplatin-based chemotherapy; between 1978 and 1984, 116 patients received cisplatin, vinblastine, and bleomycin (PVeB) +/- doxorubicin, and 104 patients treated since January 1985 received cisplatin and etoposide +/- bleomycin. RESULTS: One hundred thirty-eight patients (63%) had objective responses to therapy, and 58 (26%) had complete response. Thirty-six patients (16%) are currently disease-free at a median of 61 months following therapy (range, 11 to 142 months). Actuarial 10-year survival is 16%. Favorable prognostic factors identified by Cox regression analysis include: (1) predominant tumor location in the retroperitoneum or peripheral lymph nodes, (2) tumor limited to one or two metastatic sites, (3) no history of cigarette use, and (4) younger age. CONCLUSION: Patients with PDC or PDA of unknown primary site represent another group of patients for whom potentially curative therapy is available. Patients with this syndrome should be distinguished from patients with well-differentiated adenocarcinoma of unknown primary site, and should receive a trial of cisplatin-based chemotherapy.

Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site.

PURPOSE: To determine the frequency of Her-2 overexpression in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. PATIENTS AND METHODS: Tumor specimens from 100 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma were stained for the Her-2 protein using the Dako immunohistochemical method. Clinical and pathologic characteristics of patients with and without Her-2 overexpression were compared. RESULTS: Staining for Her-2 overexpression was successful in 94 of 100 patients. Ten (11%) of 94 tumor specimens overexpressed Her-2. Eight of 10 overexpressors had poorly differentiated adenocarcinoma, and all overexpressors had predominant tumor location above the diaphragm, usually in the mediastinum or lungs. CONCLUSION: Her-2 overexpression occurs in a minority of patients with poorly differentiated carcinoma/adenocarcinoma of unknown primary site. Because most overexpressors had poorly differentiated adenocarcinoma, further evaluation of patients with adenocarcinoma of unknown primary site is necessary to determine the frequency of Her-2 overexpression in this common subgroup. Evaluation of the efficacy of trastuzumab in Her-2 overexpressors with carcinoma of unknown primary site is indicated.