What to Do, and What Not to Do, When Diagnosing and Treating Breakthrough Cancer Pain (BTcP): Expert Opinion.

Clinical management of breakthrough cancer pain (BTcP) is still not satisfactory despite the availability of effective pharmacological agents. This is in part linked to the lack of clarity regarding certain essential aspects of BTcP, including terminology, definition, epidemiology and assessment. Other barriers to effective management include a widespread prejudice among doctors and patients concerning the use of opioids, and inadequate assessment of pain severity, resulting in the prescription of ineffective drugs or doses. This review presents an overview of the appropriate and inappropriate actions to take in the diagnosis and treatment of BTcP, as determined by a panel of experts in the field. The ultimate aim is to provide a practical contribution to the unresolved issues in the management of BTcP. Five 'things to do' and five 'things not to do' in the diagnosis and treatment of BTcP are proposed, and evidence supporting said recommendations are described. It is the duty of all healthcare workers involved in managing cancer patients to be mindful of the possibility of BTcP occurrence and not to underestimate its severity. It is vital that all the necessary steps are carried out to establish an accurate and timely diagnosis, principally by establishing effective communication with the patient, the main information source. It is crucial that BTcP is treated with an effective pharmacological regimen and drug(s), dose and administration route prescribed are designed to suit the particular type of pain and importantly the individual needs of the patient.

Concomitant high gene copy number and protein overexpression of IGF1R and EGFR negatively affect disease-free survival of surgically resected non-small-cell-lung cancer patients.

BACKGROUND: Insulin-like growth factor 1 receptor (IGF1R) represents a novel molecular target in non-small-cell-lung cancer (NSCLC). IGF1R and epidermal growth factor receptor (EGFR) activation are essential to mediate tumor cell survival, proliferation, and invasion. This study investigates the prognostic role of IGF1R and EGFR in surgically resected NSCLC. MATERIALS AND METHODS: IGF1R and EGFR copy number gain (CNG) were tested by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) in 125 stage I-II-IIIA NSCLC patients. RESULTS: Fourty-six tumors (40.3%) were IGF1R FISH-positive (FISH+), and 76 (67.2%) were EGFR FISH+. Tumors with concomitant IGF1R/EGFR FISH+ were observed in 34 cases (30.1%). IGF1R and EGFR FISH+ were associated with SCC histology (p = 0.01 and p = 0.04, respectively). IGF1R and EGFR protein over-expression (IHC+) were detected in 45 (36.0%) and 69 (55.2%) cases, respectively. Tumors with concomitant IGF1R/EGFR IHC+ were detected in 31 (24.8%) patients. IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were significantly associated (χ(2) = 4.02, p = 0.04). Patients with IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were associated with shorter disease-free survival (DFS) (p = 0.05 and p = 0.05, respectively). Patients with concomitant IGF1R/EGFR FISH+/IHC+ had a worse DFS and overall survival (p = 0.005 and p = 0.01, respectively). The multivariate model confirmed that IGF1R/EGFR FISH+/IHC+ (hazard ratio (HR), 4.08; p = 0.01) and tumor stage (II-III vs I) (HR, 4.77; p = 0.003) were significantly associated with worse DFS. CONCLUSIONS: IGF1R/EGFR FISH+ correlates with IGF1R/EGFR IHC+. IGF1R/EGFR FISH+/IHC+ is an independent negative prognostic factor for DFS in early NSCLC. These features may have important implications for future anti-IGF1R therapeutic approaches.

Carboplatin plus pemetrexed for platinum-pretreated, advanced non-small cell lung cancer: a retrospective study with pharmacogenetic evaluation.

PURPOSE: In the present study, the combination of carboplatin (CBDCA) plus pemetrexed (PMX) for the treatment of patients with platinum-pretreated, pemetrexed-naïve, advanced non-small cell lung cancer (NSCLC) was investigated. Also, single nucleotide polymorphisms (SNPs) at the XRCC3, XPD, ERCC1, GARFT, DHFR, and TS genes were investigated. METHODS: Eighty patients treated with CBDCA/PMX at two Italian institutions were evaluable. Of these, 73 patients had blood samples collected for pharmacogenetic evaluation. RESULTS: Overall, the median age was 59 years (26-78), 59 patients (73.7%) had a performance status of 0, and 34 patients (42.5%) had stage IIIB disease. Thirty-eight patients (47.5%) had responded to prior first-line platinum-based therapy. Study treatment resulted into one complete and 33 partial responses for an overall response rate of 42.5%. The disease control rate was 77.5%. The median progression-free survival (PFS) and overall survival (OS) were 5.8 and 17.4 months, respectively. Responders achieved a significant longer PFS and OS versus non-responders (P = 0.007 and P = 0.003, respectively). The only grade 3-4 adverse event occurring in more than 5.0% of patients was neutropenia (6 patients, 7.5%). No statistically significant association was noted between polymorphisms of the genes analyzed and clinical outcome. CONCLUSIONS: In patients with platinum-pretreated, advanced NSCLC and favorable clinical prognostic factors, treatment with CBDCA/PMX is associated with a good clinical outcome and toxicity profile. None of the SNPs analyzed was found to be a useful predictor of treatment efficacy.

Domiciliary treatment of febrile episodes in cancer patients: a prospective randomized trial comparing oral versus parenteral empirical antibiotic treatment.

Hospitalization and empirical broad-spectrum, intravenous antibiotics are the standard treatment for febrile cancer patients. Recent evidence supports the suggestion that febrile episodes in a low-risk population can be managed successfully in an outpatient setting, but the optimal drug regimen is unknown. In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o. twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric domiciliary treatment of febrile episodes in low-risk neutropenic and nonneutropenic cancer patients. A total of 173 patients, accounting for 183 febrile episodes, were enrolled in the study. Overall, successful outcomes were recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized to the i.v. regimen: this difference was not statistically significant. The success rate was similar in all subgroups of patients: neutropenic and nonneutropenic, with documented infection and with fever of unknown origin. There were 3 deaths in the group of patients treated with the parenteral regimen, and two of these were related to treatment failure. Both treatments were well tolerated, and the cost of the oral regimen was lower. This prospective study suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection is suspected, and that either an oral or a parenteral regimen can be used. A number of factors may influence the choice between an orally and an i.v.-administered antibiotic, but owing to the easier administration and lower cost, the oral regimen seems to be preferable.

Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer.

Twenty-three patients with brain metastases from non-small cell lung cancer (NSCLC) (median age 62 years, Karnofsky PS 50-100) were treated with cisplatin (100 mg/m2, day 1) and teniposide (80 mg/m2, days 1, 3 and 5) every 3 weeks. Response was evaluated by contrast-enhanced brain CT every two to three cycles of treatment. The objective response rate of brain metastases was 35% (8/23); three patients achieved complete response (CR) and five partial response (PR). The median response duration was 24 weeks for CR patients and 32 weeks for PR patients. The median survival was 21 weeks overall and 45 weeks for responding patients. Grade 3/4 leukocytopenia and thrombocytopenia were seen in 28 and 9%, respectively. Two patients died from infections while in neutropenia. Cisplatin and teniposide seems an active regimen against brain metastases in NSCLC. These data may indicate the need for reconsideration of the role of chemotherapy for brain metastases of NSCLC.

A double-blind study comparing two single-dose regimens of ketorolac with diclofenac in pain due to cancer.

STUDY OBJECTIVE: To compare the analgesic efficacy and safety of two single doses of ketorolac with diclofenac in acute cancer pain. DESIGN: Double-blind, randomized, clinical study. SETTING: Hospital-based clinical research center. SUBJECTS: One hundred eighty patients suffering acute, moderate, or severe cancer pain. INTERVENTIONS: A single intramuscular injection of ketorolac 10 or 30 mg or diclofenac 75 mg. MEASUREMENTS AND MAIN RESULTS: Pain intensity was assessed 30 minutes and 1, 2, 3, 4, 5, and 6 hours after injection or until rescue drug administration. In approximately 70% of patients all treatments provided prompt sustained pain relief throughout the 6-hour observation period. There were no statistically significant differences in any of the analyzed efficacy measures among the three groups. CONCLUSION: Intramuscular ketorolac 10 mg is adequate to relieve cancer pain, and is equivalent to ketorolac 30 mg and to diclofenac 75 mg.

Double-blind evaluation of short-term analgesic efficacy of orally administered diclofenac, diclofenac plus codeine, and diclofenac plus imipramine in chronic cancer pain.

A prospective double-blind randomized trial was conducted on 184 cancer patients with moderate to severe chronic pain to evaluate the analgesic efficacy and tolerability of diclofenac alone (50 mg q.i.d.) or in combination with a weak opioid (codeine 40 mg q.i.d.), or with an anti-depressant (imipramine, 10 or 25 mg t.i.d.). All demographic and clinical characteristics including cancer type, presence of bone metastases, baseline pain severity, neuropathic and nociceptive pain, and depressive state, were well balanced between the three treatment groups. The main analysis of the study was on the VAS scores at visit 2 (day 4). The mean VAS values for both associations imipramine plus diclofenac and codeine plus diclofenac were similar to the association placebo plus diclofenac. Patients on imipramine plus diclofenac and on placebo plus diclofenac were withdrawn mainly for inadequate efficacy, while patients on codeine plus diclofenac discontinued equally for inadequate efficacy or adverse events. In conclusion, in a short-term evaluation the addition of a tricyclic anti-depressant or a weak opioid to diclofenac did not provide further analgesia with respect to diclofenac administration alone.

Attitudes of Italian general practitioners in the treatment of cancer pain. The Committee of the Associazione Italiana di Oncologia Medica (AIOM).

The attitude of Italian general practitioners in prescribing practices for patients with cancer pain was assessed by means of a questionnaire. The results indicated that among most of the doctors who completed the questionnaire the basic principles of pain treatment in cancer patients are largely understood. Oral morphine emerged as the most commonly used opioid (60%) and controlled-release morphine as the preferred preparation. Non-steroidal anti-inflammatory drugs were the most commonly used minor analgesics. Fear of side effects and restrictive prescribing regulations emerged as the most important barrier against adequate pain management. The survey emphasised the need for continued efforts in implementing specific educational programming for improvement in cancer pain management.

A better therapeutic profile for the combination of mitomycin-C, ifosfamide and cisplatin (MIC) in advanced non-small-cell lung cancer: a useful dose-schedule modification.

BACKGROUND: In our previous experience with chemotherapy for non-small-cell lung cancer (NSCLC) the combination of mitomycin, ifosfamide and cisplatin (MIC) showed the highest activity in a three-arm randomized trial; the MIC regimen also yielded the most toxic effects, with 8% WHO grade 2-4 nephrotoxicity, 21% grade 3-4 leukopenia and 10% grade 3-4 thrombocytopenia. In that study cisplatin (120 mg/m2) was delivered on day 1 and ifosfamide and mitomycin on day 2. In an effort to reduce MIC toxicity a modified regimen was tested in a phase II trial: cisplatin 100 mg/m2 was given on day 2 and ifosfamide on day 1 with mitomycin. PATIENTS AND METHODS: From November 1993 to December 1995, 70 advanced NSCLC patients entered the trial. RESULTS: Twenty-nine of 70 patients achieved major response (41%) with 6 complete (9%) and 23 partial remissions (33%). We recorded 4% of WHO grade 3-4 anemia, and 2% of leukopenia and thrombocytopenia. CONCLUSION: We confirmed the activity of the MIC regimen in NSCLC, and the modified schedule seems to substantially improve the safety of the combination.

A phase II trial of combined chemotherapy and surgery in stage IIIA non-small cell lung cancer.

A poor prognosis for patients with Stage IIIA clinical N2 treated by surgery alone has led clinical researchers to find a new treatment modality to improve the curative potential of surgery. Many Phas II trials have been carried out with induction chemo- or chemo-radiotherapy prior to surgery. From June 1988 to July 1991, 46 patients with non-small cell lung cancer (NSCLC) Stage IIIA clinical N2 entered a Phase II induction-chemotherapy trial. Patients received 2-3 cycles of high-dose cisplatin and etoposide. Forty-five were evaluable for response; the response rate was 82% (37/45: 3 CR, 34 PR). Toxicity was primarily hematologic. Surgical resection was performed in 35 patients; radical resection was possible in 28 patients (62%); three patients were incompletely resected and two patients were only explored. Three deaths were surgery-related. Median survival was 24.5 months with a 2-year survival of 53%. Cisplatin with etoposide is an active and safe induction chemotherapy regimen for NSCLC Stage IIIA N2 with a high response rate. The median survival seems to be prolonged and therefore, randomized trials are needed to compare this approach with other treatment modalities.

Neoadjuvant cisplatin and etoposide for stage IIIA (clinical N2) non-small cell lung cancer.

In an attempt to improve the curative potential of surgery, 46 patients with unresectable Stage IIIA (Clinical N2) non-small cell lung cancer received neoadjuvant chemotherapy with cisplatin and etoposide. After 2 or 3 cycles, 45 patients were evaluable for response; the overall response rate was 82% (37/45) with 3 complete and 34 partial responses. Toxicity was primarily hematologic. Surgical exploration was performed on 35 patients, but resection was possible in only 33 (73%). Of these, 28 resections were complete (62%). Four patients (2CR, 2PR; 9%) had no tumor in biopsy specimen. Three deaths were surgery-related. Median survival of the entire 46 patients was 24.5 months with a 2-year survival of 53%. Cisplatin and etoposide is an effective chemotherapeutic regimen for regionally advanced non-small cell lung cancer; the resection and survival rates justify further trials to compare this approach to other treatment modalities.

Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer.

BACKGROUND: High-dose radiation therapy is generally recommended as standard treatment in regionally advanced unresectable non-small-cell lung cancer (NSCLC), but median- and long-term survival remain poor. Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens. Therefore, we designed a randomized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone. PATIENTS AND METHODS: From March, 1984 to December, 1988, 66 consecutive patients with stage III unresectable NSCLC were randomized to one of two treatment arms; 61 were evaluable for survival and 58 for response and toxicity. Patients randomly assigned to arm A received cisplatin (CDDP 100 mg/m2 on day 1) and etoposide (VP 16 120 mg/m2 on days 1, 2, 3) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes. Patients assigned to arm B received only the same radiotherapy. The 61 eligible patients were comparable in terms of age, performance status, histology and treatment. RESULTS: Response rate was 53% in arm A and 32% in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm. At six years of follow-up all the patients were dead. Toxicity was mild and no treatment-related deaths were recorded. CONCLUSION: Induction chemotherapy produced a better response rate and a trend of improved survival (4 months) but a significant survival advantage was not achieved (p < 0.11), probably because of the small number of patients enrolled in the trial.

[Surgery after neo-adjuvant therapy of non-small cell lung cancer. Preliminary results]. / Chirurgia dopo terapia neo adiuvante del cancro del polmone non a piccole cellule. Risultati preliminari.

The Authors report their personal experience of surgical treatment following neo-adjuvant therapy in NSCLC (III a N2) in order to assess: 1) the feasibility and safety of surgical treatment following major responses to neoadjuvant chemotherapy; 2) the sectile rate; and 3) the survival rate. Preliminary results show that: 1) chemotherapy using cisplatin and VP-16 gives a high rate of major responses in these patients; 2) surgery is feasible; 3) there is high radical sectile rate; 4) further research is needed to obtain statistical significance.

Ceftriaxone versus aztreonam plus cefazolin for infections in cancer patients with adequate neutrophil counts.

In a prospective randomized trial, 154 febrile episodes in cancer patients with adequate neutrophil counts (greater than 1,000 cells/mm3) were treated with either ceftriaxone (72 episodes) or aztreonam plus cefazolin (82 episodes). Documented infections represented almost half of the febrile episodes. The overall response rates among the 144 evaluable episodes were similar for the two regimens: 76% (51/67) with ceftriaxone versus 82% (63/77) with aztreonam plus cefazolin (p = 0.41, not significant). Although not statistically significant, the response rate of the microbiologically documented infections was slightly better in patients treated with the double beta-lactam combination (85% vs. 65%, p = 0.16) and clinically documented infections showed a better response in the group of patients receiving monotherapy (87% vs. 59%, p = 0.12). No serious adverse effects were observed during this study and both regimens were well tolerated. Ceftriaxone or the combination of aztreonam plus cefazolin showed a similar efficacy as empirical therapy for infections in cancer patients with adequate neutrophil counts.

Assessment of nausea.

In a standardized way three different methods of measuring nausea have been assessed in 849 patients enrolled in 4 double blind, randomized, clinical trials, and 2 observational studies. Nausea was measured before and 2, 4, 6, 8 and 24 hours after cancer chemotherapy by using a discrete scale (DS), a visual analogue scale (VAS) and a continuous chromatic analogue scale (ACCS), and it was evaluated according to 4 different dimensions: maximal intensity (MI) entity (E) duration (D) and quantity (Q). The distributions of nausea measurements in the population, agreement between the scales and their sensitivity, and agreement between dimensions and their sensitivity were analyzed. A uniform distribution of nausea measurements was found only in patients receiving chemotherapy without any antiemetic treatment. There was substantial equivalence of the different scales, and no advantage was shown an using an analogue (VAS) than a discrete (DS) scale. A trend toward increasing sensitivity in detecting differences as the dimensions of nausea considered became more inclusive of the various aspects of this symptom (Q more sensible than E more sensible than MI) was observed.

Ceftriaxone versus imipenem/cilastatin as empirical monotherapy for infections in cancer patients.

We conducted a prospective randomized clinical trial to compare the efficacy and tolerability of monotherapy with ceftriaxone (active ingredient of Rocephin) (CRO) versus imipenem/cilastatin (I/C) in febrile cancer patients with or without neutropenia. 120 febrile episodes were randomized and 89 (75%) were evaluable for efficacy analysis. The overall response rates to both regimens were good (86 and 79% improved in response to CRO and I/C, respectively). Overall mortality was low and similar in the two groups. Both regimens were well tolerated. Our preliminary data corroborate the efficacy of CRO or I/C as empirical monotherapy for febrile episodes in cancer patients. It will be up to future investigations to show whether one of these regimens is superior to the other.

Analysis of CD4-positive T cell subpopulation in sarcoidosis.

Double-labelling immunofluorescence analysis within the CD4+ cell subset was carried out in 27 bronchoalveolar lavage fluids and 11 peripheral blood samples of sarcoidosis patients with anti-TQ1, anti-2H4 and anti-4B4 monoclonal antibodies. Helper/inducer CD4+TQ1-/4B4+ cells were strongly increased in the lung and slightly, but significantly, decreased in the blood of sarcoidosis patients with respect to normal controls. No differences were found in the number of both lung and blood CD4+2H4+ cells between sarcoidosis patients and controls. The findings are further evidence for a compartmentalization of T cell subsets in sarcoidosis.

Septicaemia due to gram-positive cocci in cancer patients.

Episodes of septicaemia caused by Gram-positive bacteria in five separate investigations of empirical antibiotic treatment for fever in patients with neoplastic disease have been analysed according to the antimicrobial agents administered and the outcome. The results suggest that the addition of an 'anti-staphylococcal agent', such as co-trimoxazole, vancomycin or teicoplanin, to the standard two-drug regimen (a beta-lactam antibiotic and an aminoglycoside) may be advantageous in improving the prognosis, particularly in Staphylococcus aureus septicaemia.

A prospective randomized double-blind crossover study comparing the antiemetic activity of alizapride and metoclopramide in patients receiving cisplatin chemotherapy.

We designed a double-blind randomized crossover study to compare the antiemetic activity and toxicity of high-dose intravenous alizapride (3.5 mg/kg) versus high-dose intravenous metoclopramide (1 mg/kg) both combined with intravenous methylprednisolone in 40 untreated cancer patients submitted to cisplatin chemotherapy alone. The mean number of vomiting episodes (3.6 vs. 1.0), length of vomiting (209.8 vs. 80.9 min), and rate of complete prevention of vomiting (25% vs. 68.4%) at first cycle were in favor of metoclopramide, with a statistically significant difference. This difference was not statistically significant in the second cycle after crossover. Toxicity of both treatments was mild and diarrhea was more frequent in the alizapride-treated patients. Preference expressed by the patients was also in favor of metoclopramide. We conclude that alizapride offers less antiemetic protection than metoclopramide in patients receiving cisplatin chemotherapy. Further use of alizapride in such patients is not recommended.